We spent a shit tonne of cash despite our focus on conserving capital all the while drawing 900k a year in salary plus incentives (looking at you Paul Rennie and Donna skerret). Increasingly pissed with this business. They are very happy to raise time after time but don’t feel the need to take a more reasonable salary despite dilution of holders.

Drug works but surely there have been options to make a deal with big pharma by now to secure non dilutive funding to see this through phase 3 trials for OA.

I still believe in the drug here but have long lost confidence in the investment case... How will they fund their phase 3 trial???

Here's the carrot being dangled by Paul Rennie at the Biomed conference this month:

The SP has rallied 20% on the news (since yesterday) but that's more a measure of how far the SP has previously fallen...

Positives are that costs have come down. Negative are that despite a 7.3 m R&D refund the business burnt 7mil in a quarter and has just 26 mil in the coffers as of 31st March.

I am stuck holding as I see the potential of the drug and catalysts are likely in the next 12 months but geez where is the money going to come from and is it going to be another epic dilution. I couldn't buy more watching the current rate of cashburn. They need to partner up I guess given they aren't funded to the conclusion of phase 3 (unless the market gets excited with the initiation of phase 3 and they are able to raise at a higher price).

Hold at best...

ASX RELEASE 30 April 2024

March 2024 Quarterly Activities Report & Appendix 4C

Key Highlights

• Type D Meeting with US FDA: Paradigm met with US FDA on the 10th of January

2024 to discuss outstanding requirements for the next stage of the Phase 3 clinical

program in Osteoarthritis. Paradigm has completed the response documents to

this meeting and filed with the US FDA for review and comment.

• Board Addition: Paradigm welcomed Mr Matthew Fry as a Non-Executive

Director.

• OARSI World Congress on OA: An abstract detailing data from the successful

phase 2 PARA_OA_008 clinical trial was selected by the OARSI panel for a

podium presentation during the 2024 conference.

• Primary Endpoint Met: The phase 2 MPS VI study met the primary endpoint of

safety and tolerance and achieved promising clinical improvements in pain and

functional assessments following iPPS administration compared to placebo.

• R&D Tax Incentive: $7.3m refund from the R&D Tax Incentive refund claim for

FY23.

Paradigm Biopharmaceuticals Ltd. (ASX:PAR) (“Paradigm” or “the

Company”) is pleased to provide its quarterly update for the three months ended

31 March 2024 to accompany its Appendix 4C cash flow report for the period.

• Cash balance as of 31 March 2024 was $26.2m (on 31 December 2023 it was

$33.5m).

• Research and development expenditure for the quarter of $13.1m was significantly

reduced compared to the previous quarter of $27.06m. This spend in Q3 FY24 was

related to continued study close-out costs, Clinical Research Organisation costs as

well as FDA meeting fees and consultant costs for the Type D meeting and

subsequent response to the US FDA. Paradigm also incurred spend relating to

clinical trial product manufacturing in preparation of the next stage of the phase 3

OA program.

• The March quarter saw an increase in spend on patent and IP related cost due to

annual renewals and fees for Paradigm’s extensive patent portfolio.

• During the period Paradigm received a $7.3m refund from the R&D Tax Incentive

refund claim for FY23.

• Net cash outflow for the quarter was $6.8m (inclusive of the $7.3m refund) which is

less than the guided $8-11m. Anticipated invoices of $1-1.5m for the March quarter

have been received post 31st March and will be paid during the June quarter.

Revised guidance for the June quarter is expected to be $7-10m cash outflow.

• Encouragingly, corporate and administration costs continued to reduce in the

quarter through Paradigm’s cost containment initiatives that were implemented in

Q3 CY23. Paradigms spend remains focused on clinical and nonclinical activities

that build value in the osteoarthritis clinical program.

• In accordance with Listing Rule 4.7C.3 and as noted in item 6 of the Appendix 4C

Cashflow Statement, payments to related parties and their associates during the

quarter ended 31 March 2023 were fees of $37K for payment of Director fees.

• The quarter also saw payments related to continuing activities described in the

below.

QUARTERLY ACTIVITIES & OUTLOOK

Paradigm is pleased to provide an update on continuing activities.

Phase 3 Clinical Program

Paradigm met with US FDA on the 10th of January 2024 to discuss outstanding

requirements for the next stage of the Phase 3 clinical program in Osteoarthritis. Paradigm’s

clinical and regulatory teams have filed the response to the Type D meeting with the US

FDA containing updated nonclinical and clinical data to the Agency as well as the proposed

clinical trial protocol utilising 2mg/kg twice weekly for the next stage of the phase 3 OA

program. The response package to the US FDA was submitted as directed by the Agency,

through a request for review pathway.

The request for review pathway does not have strict Prescription Drug User Fee Act

(PDUFA) Agency response timelines. Paradigm OA clinical program has FDA granted

Fast-track designation and the feedback through this review pathway is typically received

within three months.

Paradigm Board Changes

During the December quarter Paradigm welcomed Mr Matthew Fry to the Paradigm Board

as a Non-Executive Director. Matthew joins the Paradigm board with more than 25 years

in business creation, strategy, and expansion in healthcare and medical diagnostics

globally. He is currently the CEO, Managing Director and Founder of AM Diagnostics Pty

Ltd, a manufacturer and distributor of world class medical diagnostic products.

Matthew has significant experience with global regulatory agencies, in particular the

Australian TGA and US FDA. Through his role as Founder and CEO of AM Diagnostics,

Matthew drove the company’s expansion into the United States in 2009 and is a leading

biotechnology device supplier with a deep understanding of sales channels in both the US

medical wholesale market and retail market, and how to negotiate with private health

providers.

Paradigm Non-Executive Director, Helen Fisher, notified the Paradigm Board during the

quarter that she would step down from her position to focus on other endeavours.

Mucopolysaccharidosis (MPS) VI

During the quarter, Paradigm reported the top-line data from the PARA_MPSVI_001 phase

2 trial. The multi-centre randomised trial conducted in Brazil successfully met the primary

endpoint and achieved positive results in several of the secondary outcome.

The primary endpoint of the study was safety and tolerability of iPPS compared to placebo.

iPPS was well-tolerated and all adverse events were mild to moderate. The majority of

adverse events were associated with injection site reactions. No adverse events led to

discontinuation of the study treatment, nor were there any serious adverse events or

adverse events of special interest. Analysis of this phase 2 study demonstrates that iPPS

is a safe adjunctive therapy to enzyme replacement therapy for the continual joint pain,

stiffness and functional disability associated with MPS VI.

Multiple clinical endpoints were explored during the phase 2 clinical trial demonstrating

positive responses following iPPS compared to placebo. These included:

• Pain Assessment: An improvement in PROMIS (Patient-Reported Outcomes

Measurement Information System) pain interference is indicated by a lower score.

An improvement in PROMIS pain interference was greater in the iPPS-treated group

compared to placebo at 25 weeks.

• Functional Assessment: Participants receiving iPPS in the phase 2 clinical trial

demonstrated greater improvement than placebo in the 9-hole peg test from baseline

to week 25 on at least one hand.

Dr Roberto Giugliani, MD, PhD, MSc, the Principal Investigator for the phase 2 clinical trial

presented the clinical data at the 17th International Symposium on MPS and Related

Diseases in Würzburg Germany on 4-7th April. The presentation titled “Update on clinical

trials with PPS” was delivered by Dr Giugliani during the “New study approaches” session

of the conference.

Paradigm has now completed clinical studies for MPS I and VI with strong data sets and

meaningful endpoints identified to progress the clinical development of iPPS as an

adjunctive therapy with a commercial partner.

Global Conferences

Managing Director Paul Rennie and Dr Mukesh Ahuja, Paradigm’s Global Head of

Osteoarthritis attended the Annual Osteoarthritis Research Society International World

Congress in Vienna and presented data from the phase 2, randomised, double-blinded

PARA_OA_008 clinical trial exploring the disease modifying potential of iPPS in subjects

with knee OA.

Paradigm submitted a late breaking abstract to the OARSI panel following the release of

the phase 2 data late last year which was reviewed and selected for a podium presentation

during the conference. The podium presentation material delivered by Dr Ahuja to over 300

attendees during the conference is available on the Paradigm website (OARSI Podium

Presentation).

Paradigm management also conducted a sponsored theatre presentation during the

conference detailing Paradigm’s clinical development with iPPS for osteoarthritis and a

comparison between iPPS and currently available therapies for OA. The theatre

presentation can be view here, OARSI Theatre Presentation.

Company Outlook

Phase 3 OA Clinical Program

Subject to FDA clearance, Paradigm intends to promptly move forward with subject

enrolment into the phase 3 clinical trial (PARA_OA_012) in 2H CY2024. Clinical trial sites

in Australia and the US are planned to commence preparation activities during this quarter

(Q2 CY2024) to move the phase 3 program forward as quickly and efficiently as possible.

Once agreement is reached with the US FDA, Paradigm anticipates providing an overview

of the next stage of the phase 3 OA program including an overview of the clinical trial

design, dose justification and proposed participant numbers for the trial.

TGA Provisional Approval Application

Paradigm is finalising the TGA provisional approval determination application for

submission following the response to the US FDA Type D meeting. The determination

application will include information from a manuscript detailing the outcomes from the

PARA_OA_008 phase 2 clinical trial and a manuscript providing a comparison of iPPS

clinical data with other available treatments for osteoarthritis. Should the determination

application decision be positive, Paradigm will prepare a full dossier submission for TGA

provisional approval marketing authorisation.

Provisional approval offers significant benefits to both patients and manufacturers. Patients

gain access to potential life-saving treatments for life-threatening and seriously debilitating

conditions sooner, particularly for those lacking satisfactory alternatives. For

manufacturers, it provides an opportunity to bring innovative therapies to market faster,

while gathering additional clinical data to support full approval. TGA provisional marketing

approval for iPPS in Australia would expedite the pathway to revenues. Paradigm expects

to receive a decision from the TGA on whether the determination application has met the

criteria to move to a full dossier submission during Q2 CY2024.

Other Activities

The PARA_OA_008 phase 2 clinical trial results manuscript has been completed and is

expected to be submitted for peer review and publication. Paradigm has also completed a

comparison manuscript detailing the clinical trial results from the PARA_OA_008 phase 2

trial compared to currently available and pipeline OA therapies. Both manuscripts are

expected to be published during CY2024.

About Paradigm Biopharmaceuticals

Paradigm Biopharmaceuticals Ltd. (ASX:PAR) is a late-stage drug development company

driven by a purpose to improve patients’ health and quality of life by discovering,

developing, and delivering pharmaceutical therapies. Paradigm’s current focus is

developing iPPS for the treatment of diseases where inflammation plays a major

pathogenic role, indicating a need for the anti-inflammatory and tissue regenerative

properties of PPS, such as in osteoarthritis (phase 3) and mucopolysaccharidosis (phase

2).

Forward Looking Statements

This Company announcement contains forward-looking statements, including statements

regarding anticipated commencement dates or completions dates of preclinical or clinical

trials, regulatory developments, and regulatory approval. These forward-looking

statements are not guarantees or predictions of future performance, and involve known

and unknown risks, uncertainties and other factors, many of which are beyond our control,

and which may cause actual results to differ materially from those expressed in the

statements contained in this presentation. Readers are cautioned not to put undue reliance

on forward-looking statements.

Authorised for release by the Paradigm Board of Directors.

FOR FURTHER INFORMATION PLEASE CONTACT:

Simon White

Director of Investor Relations

Tel: +61 404 216 467

Paradigm Biopharmaceuticals Ltd.

ABN: 94 169 346 963

Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA

Email: [email protected]

Rule 4.7B

ASX Listing Rules Appendix 4C (17/07/20) Page 1

+ See chapter 19 of the ASX Listing Rules for defined terms.

Appendix 4C

Quarterly cash flow report for entities

subject to Listing Rule 4.7B

Name of entity

Paradigm Biopharmaceuticals Limited

ABN Quarter ended (“current quarter”)

94 169 346 963 31 March 2024

Consolidated statement of cash flows Current quarter

$A’000

Year to date (9

months)

$A’000

1. Cash flows from operating activities

- 301.1 Receipts from customers

1.2 Payments for

(13,141) (62,145)(a) research and development

(b) product manufacturing and operating

costs

- -

(c) advertising and marketing (147) (284)

(d) leased assets (24) (61)

(e) staff costs (480) (1,684)

(f) administration and corporate costs (507) (1,807)

1.3 Dividends received (see note 3) - -

1.4 Interest received 133 768

1.5 Interest and other costs of finance paid (3) (9)

1.6 Income taxes paid - -

1.7 Government grants and tax incentives 7,327 7,327

1.8 Other (provide details if material) - -

1.9 Net cash from / (used in) operating

activities

(6,842) (57,865)

2. Cash flows from investing activities

- -

2.1 Payments to acquire or for:

(a) entities

(b) businesses - -

(c) property, plant and equipment - -

(d) investments - -

(e) intellectual property - -

(f) other non-current assets - -

Appendix 4C

Quarterly cash flow report for entities subject to Listing Rule 4.7B

ASX Listing Rules Appendix 4C (17/07/20) Page 2

+ See chapter 19 of the ASX Listing Rules for defined terms.

Consolidated statement of cash flows Current quarter

$A’000

Year to date (9

months)

$A’000

2.2 Proceeds from disposal of:

- -(a) entities

(b) businesses - -

(c) property, plant and equipment - -

(d) investments - -

(e) intellectual property - -

(f) other non-current assets - -

2.3 Cash flows from loans to other entities - -

2.4 Dividends received (see note 3) - -

2.5 Other (provide details if material) - -

2.6 Net cash from / (used in) investing

activities

- -

3. Cash flows from financing activities

- 30,117

3.1 Proceeds from issues of equity securities

(excluding convertible debt securities)

3.2 Proceeds from issue of convertible debt

securities - -

3.3 Proceeds from exercise of options - -

3.4 Transaction costs related to issues of

equity securities or convertible debt

securities

-

-

(1,763)

-

3.5 Proceeds from borrowings - -

3.6 Repayment of borrowings (lease liabilities) (27) (78)

3.7 Transaction costs related to loans and

borrowings - -

3.8 Dividends paid - -

3.9 Other (Limited recourse loan repaid under

ESP)

- -

3.10 Net cash from / (used in) financing

activities

(27) 28,276

4. Net increase / (decrease) in cash and

cash equivalents for the period

33,551 56,379

4.1 Cash and cash equivalents at beginning of

period

4.2 Net cash from / (used in) operating

activities (item 1.9 above) (6,842) (57,865)

Appendix 4C

Quarterly cash flow report for entities subject to Listing Rule 4.7B

ASX Listing Rules Appendix 4C (17/07/20) Page 3

+ See chapter 19 of the ASX Listing Rules for defined terms.

Consolidated statement of cash flows Current quarter

$A’000

Year to date (9

months)

$A’000

4.3 Net cash from / (used in) investing activities

(item 2.6 above) - -

4.4 Net cash from / (used in) financing activities

(item 3.10 above)

(27) 28,276

4.5 Effect of movement in exchange rates on

cash held

(461) (569)

4.6 Cash and cash equivalents at end of

period

26,221 26,221

5. Reconciliation of cash and cash

equivalents

at the end of the quarter (as shown in the

consolidated statement of cash flows) to the

related items in the accounts

Current quarter

$A’000

Previous quarter

$A’000

5.1 Bank balances 26,221 33,551

5.2 Call deposits

5.3 Bank overdrafts

5.4 Other (provide details)

5.5 Cash and cash equivalents at end of

quarter (should equal item 4.6 above)

26,221 33,551

6. Payments to related parties of the entity and their

associates

Current quarter

$A'000

6.1 Aggregate amount of payments to related parties and their

associates included in item 1

37

6.2 Aggregate amount of payments to related parties and their

associates included in item 2

Note: if any amounts are shown in items 6.1 or 6.2, your quarterly activity report must include a description of, and an

explanation for, such payments.

Appendix 4C

Quarterly cash flow report for entities subject to Listing Rule 4.7B

ASX Listing Rules Appendix 4C (17/07/20) Page 4

+ See chapter 19 of the ASX Listing Rules for defined terms.

7. Financing facilities

Note: the term “facility’ includes all forms of financing

arrangements available to the entity.

Add notes as necessary for an understanding of the

sources of finance available to the entity.

Total facility

amount at quarter

end

$A’000

Amount drawn at

quarter end

$A’000

7.1 Loan facilities - -

7.2 Credit standby arrangements - -

7.3 Other (please specify) - -

7.4 Total financing facilities - -

7.5 Unused financing facilities available at quarter end -

7.6 Include in the box below a description of each facility above, including the lender, interest

rate, maturity date and whether it is secured or unsecured. If any additional financing

facilities have been entered into or are proposed to be entered into after quarter end,

include a note providing details of those facilities as well.

8. Estimated cash available for future operating activities $A’000

8.1 Net cash from / (used in) operating activities (item 1.9) (6,842)

8.2 Cash and cash equivalents at quarter end (item 4.6) 26,221

8.3 Unused finance facilities available at quarter end (item 7.5) -

8.4 Total available funding (item 8.2 + item 8.3) 26,221

8.5 Estimated quarters of funding available (item 8.4 divided by

item 8.1) 3.83

Note: if the entity has reported positive net operating cash flows in item 1.9, answer item 8.5 as “N/A”. Otherwise, a

figure for the estimated quarters of funding available must be included in item 8.5.

8.6 If item 8.5 is less than 2 quarters, please provide answers to the following questions:

8.6.1 Does the entity expect that it will continue to have the current level of net operating

cash flows for the time being and, if not, why not?

Answer:.

8.6.2 Has the entity taken any steps, or does it propose to take any steps, to raise further

cash to fund its operations and, if so, what are those steps and how likely does it

believe that they will be successful?

Answer:

8.6.3 Does the entity expect to be able to continue its operations and to meet its business

objectives and, if so, on what basis?

Answer:

Note: where item 8.5 is less than 2 quarters, all of questions 8.6.1, 8.6.2 and 8.6.3 above must be answered.

Appendix 4C

Quarterly cash flow report for entities subject to Listing Rule 4.7B

ASX Listing Rules Appendix 4C (17/07/20) Page 5

+ See chapter 19 of the ASX Listing Rules for defined terms.

Compliance statement

1 This statement has been prepared in accordance with accounting standards and policies

which comply with Listing Rule 19.11A.

2 This statement gives a true and fair view of the matters disclosed.

Date: ..30 April 2024.................................................................................

Authorised by: ...By the board................................................................................

(Name of body or officer authorising release – see note 4)

Notes

1. This quarterly cash flow report and the accompanying activity report provide a basis for informing the market about the

entity’s activities for the past quarter, how they have been financed and the effect this has had on its cash position. An

entity that wishes to disclose additional information over and above the minimum required under the Listing Rules is

encouraged to do so.

2. If this quarterly cash flow report has been prepared in accordance with Australian Accounting Standards, the definitions

in, and provisions of, AASB 107: Statement of Cash Flows apply to this report. If this quarterly cash flow report has been

prepared in accordance with other accounting standards agreed by ASX pursuant to Listing Rule 19.11A, the

corresponding equivalent standard applies to this report.

3. Dividends received may be classified either as cash flows from operating activities or cash flows from investing activities,

depending on the accounting policy of the entity.

4. If this report has been authorised for release to the market by your board of directors, you can insert here: “By the board”.

If it has been authorised for release to the market by a committee of your board of directors, you can insert here: “By the

[name of board committee – eg Audit and Risk Committee]”. If it has been authorised for release to the market by a

disclosure committee, you can insert here: “By the Disclosure Committee”.

5. If this report has been authorised for release to the market by your board of directors and you wish to hold yourself out as

complying with recommendation 4.2 of the ASX Corporate Governance Council’s Corporate Governance Principles and

Recommendations, the board should have received a declaration from its CEO and CFO that, in their opinion, the financial

records of the entity have been properly maintained, that this report complies with the appropriate accounting standards

and gives a true and fair view of the cash flows of the entity, and that their opinion has been formed on the basis of a

sound system of risk management and internal control which is operating effectively.

This is progress but also highlights the slow progress the business is making. They would have been disappointed to have had to go back and provide this evidence to the FDA but having got it together is obviously good. Unfortunately it's still a way from phase 3 trial results which is the endgame here. I'm confident from the evidence already released that the drug works but the cashburn is unbelievable and they JUST NEED TO GET THEIR PHASE 3 TRIAL DONE! argh. So frustrated.

ASX RELEASE 19 April 2024

PARADIGM CONFIRMS SUBMISSION TO THE US FDA

TO PROGRESS THE PHASE 3 OA PROGRAM

Paradigm Biopharmaceuticals Ltd (ASX:PAR) (“Paradigm” or “the Company”), a

late-stage drug development company focused on delivering new therapies to address

unmet medical needs, is pleased to announce the submission of key documents to the

US Food and Drug Agency (FDA, the Agency) for review and agreement on the

progression of the phase 3 clinical program in osteoarthritis.

Paradigm has submitted to the US FDA a response to the Type D meeting held on 10

January 2024.

Paradigm’s response sets out the results of five nonclinical studies and data from the

successful phase 2 clinical trial, PARA_OA_008, as well as available clinical data from

600 participants dosed in stage 1 of PARA_OA_002. These additional data were collected

following Paradigm’s Investigational New Drug (IND) submission to the Agency in March

2021 (see ASX release), most of which have not previously been submitted nor reviewed

by the FDA. These data provide a detailed justification for the clinical development for

iPPS with the dosing regimen of 2 mg/kg twice weekly for 6 weeks of initial therapy.

Paradigm also submitted a draft of the phase 3 pivotal clinical trial protocol for agency

review and comment.

The response package to the US FDA has been submitted as directed by the Agency,

through a request for review pathway. The request for review pathway does not have

strict Prescription Drug User Fee Act (PDUFA) Agency response timelines, although

feedback is typically received within three months.

The key items addressed in the Type D response submission to the FDA include:

• The minimal effective dose justification.

• Additional nonclinical studies completed to GLP standards to address previously

noted adrenal findings.

• Draft clinical trial protocol.

• Revised safety monitoring and mitigation plan.

Subject to FDA clearance, Paradigm intends to promptly move forward with subject

enrolment into the phase 3 clinical trial (PARA_OA_012) in 2H CY2024. Clinical trial sites

in Australia and the US are planned to commence preparation activities during this quarter

(Q2 CY2024) to move the phase 3 program forward as quickly and efficiently as possible.

Paradigm Managing Director, Mr Paul Rennie commented: “This is important progress

for Paradigm as we deliver a significant amount of new data to the US FDA for review to

progress to the next stage of the phase 3 OA program. Since Paradigm’s IND submission

in March 2021, we have treated close to 700 participants under a clinical trial setting with

various iPPS doses, which provides strong justification that 2 mg/kg twice weekly is the

lowest effective dose with which to move forward. We look forward to receiving the FDA’s

feedback and remain ready to answer any further questions. We look forward to updating

all our investors in the coming months on the outcome of the agency's review and planned

execution of the phase 3 clinical program. I would like to thank our investors for their

ongoing support as we strive to bring the exciting potential of iPPS to market for those

suffering with osteoarthritis.”

Next Steps

Paradigm will now finalise the TGA provisional approval determination application for

submission. The determination application will include information from a manuscript

detailing the outcomes from the PARA_OA_008 phase 2 clinical trial and a manuscript

providing a comparison of iPPS clinical data with other available treatments for

osteoarthritis. Should the determination application decision be positive, Paradigm will

prepare a full dossier submission for TGA provisional approval marketing authorisation.

Provisional approval offers significant benefits to both patients and manufacturers.

Patients gain access to potential life-saving treatments for life-threatening and seriously

debilitating conditions sooner, particularly for those lacking satisfactory alternatives. For

manufacturers, it provides an opportunity to bring innovative therapies to market faster,

while gathering additional data to support full approval. TGA provisional marketing

approval for iPPS in Australia would expedite the pathway to revenues. The completed

manuscripts are being prepared and will be submitted to separate journals for peer-review

and publication.

-Ends-

About Paradigm Biopharmaceuticals Ltd.

Paradigm Biopharmaceuticals Ltd. (ASX:PAR) is a late-stage drug development

company driven by a purpose to improve patients’ health and quality of life by discovering,

developing, and delivering pharmaceutical therapies. Paradigm’s current focus is

developing injectable (subcutaneous) pentosan polysulfate sodium (iPPS) for the

treatment of diseases where inflammation plays a major pathogenic role, indicating a

need for the anti-inflammatory and tissue regenerative properties of iPPS, such as in

osteoarthritis (phase 3) and mucopolysaccharidosis (phase 2).

Forward Looking Statements

This Company announcement contains forward-looking statements, including statements

regarding anticipated commencement dates or completions dates of nonclinical or clinical

trials, regulatory developments, and regulatory approval. These forward-looking

statements are not guarantees or predictions of future performance, and involve known

and unknown risks, uncertainties, and other factors, many of which are beyond our

control, and which may cause actual results to differ materially from those expressed in

the statements contained in this presentation. Readers are cautioned not to put undue

reliance on forward-looking statements.

To learn more please visit: https://paradigmbiopharma.com

Approved for release by the Paradigm Board of Directors.

FOR FURTHER INFORMATION PLEASE CONTACT:

Simon White

Director of Investor Relations

Tel: +61 404 216 467

Paradigm Biopharmaceuticals Ltd

ABN: 94 169 346 963

Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA

Email: [email protected]

Paradigm's quarterly cash activities report below:

In summary: made good progress on research/evidence base but spent a truckload of money. So much so that the market has shat itself and dumped the stock 20%. Commentary suggests ongoing costs will fall significantly but realistically it seems likely there will be another cap raise prior to commercialisation which I suppose is what the market is selling off.

For me it's more of the same do nothing. I can see the results (even interim results) are likely to be out in the next 12 month period and could be a real catalyst for improved SP which would make raising more funds less of an issue. On the downside if the SP languishes and they have to raise at an even lower SP it's pretty awful dilution even if the drug works incredibly well.

Paradigm Biopharmaceuticals Ltd. (ASX:PAR) (“Paradigm” or “the

Company”) is pleased to provide its quarterly update for the three months ended

31 December 2023 to accompany its Appendix 4C cash flow report for the period.

• Cash balance as of 31 December 2023 was $33.5m (on 30 September 2023 it was

$33.6m).

• During the period Paradigm announced a $30.1 million capital raise (before costs)

comprising a fully underwritten $18m placement and $12m accelerated non

renounceable entitlement offer.

• Paradigm has lodged its R&D Tax Incentive refund claim for FY23 and is awaiting

receipt of the $7.2m refund, expected during Q1 CY24.

• Research and development expenditure for the quarter was $27.06m compared to

the previous quarter of $21.9m. This spend in Q2 FY24 was largely related to costs

incurred during the prior quarter on the Stage 1 dose finding activities of Phase 3

clinical trial, including recruitment, screening, dosing and follow-up of the final

patients enrolled in the study. The cost also includes activities related to the close-

out of stage 1 of the PARA_OA_ 002 phase 3 clinical program. Close-out

procedures for clinical trials require all sites to be monitored by Paradigm’s clinical

research organization and Paradigm staff, to comply with the clinical trial

regulations.

• The costs of the interim analysis performed on initial 300 participants on

PARA_OA_002 are also included in the December quarter. Since completing stage

1 of the phase 3 PARA_OA_002 study in late November 2023, the December

spending for new patient activity costs has significantly reduced. It is forecast that

costs going forward will continue to decline, as study closure completes. All ongoing

and future activities will focus on delivering the next phase of the phase 3 OA trial.

• R&D spend during the December quarter also related to clinical and quantitative

MRI data analysis and completion of the PARA_OA_008 phase 2 clinical trial

activities. The spend also included end of study analysis and shut down cost for the

MPS VI phase 2 study, and an ongoing New Drug Application required nonclinical

studies relating to our OA clinical program.

• The quarter also saw payments related to continuing activities described in the

outlook below.

• In accordance with Listing Rule 4.7C.3 and as noted in item 6 of the Appendix 4C

Cashflow Statement, payments to related parties and their associates during the

quarter ended 31 December 2023 were fees of $57K, which includes $52K for

payment of Director fees, and $5K for legal fees to BioMeltzer (a company related

to Paradigm NED, Amos Meltzer).

QUARTERLY ACTIVITIES & OUTLOOK

Paradigm is pleased to provide an update on continuing activities.

Phase 3 Clinical Program

Paradigm reported in October 2023 findings from an interim analysis conducted once the

first 300 participants from the PARA_OA_002 clinical trial reached day 56 of the study.

The doses (less than 2 mg/kg twice weekly) included in the dose determination part of

phase 3 trial did not meet the prespecified performance threshold, which was based on

prior outcome data produced with the 2mg/kg twice weekly dosing regimen. Following

these findings, Paradigm has prepared a new protocol for the next stage of the phase 3

clinical program using the 2mg/kg twice weekly dose regimen of iPPS which has

demonstrated consistent positive data in the PARA_OA_008, PARA_005 (previous phase

2b) studies and the TGA Special Access Scheme.

Stage 1 activities for the PARA_OA_002 phase 3 clinical trial concluded during the quarter

with the study completing the randomisation of 579 subjects demonstrating Paradigm’s

ability to enrol suitable study participants through the many recruitment initiatives

implemented for the global phase 3 study.

Paradigm remains on track for the protocol review by the US FDA to implement the 2mg/kg

twice weekly dosing regimen into the next stage of the OA phase 3 program, anticipated

in Q1 CY2024. Enrolment activities for next stage of the phase 3 OA clinical program are

expected to commence in Q2 CY 2024.

R&D Expenditure

Paradigm’s expenditure over the last three quarters has been unusually high as Paradigm

has invested heavily in the first stage of the phase 3 clinical program. The activities relating

to the spend include:

• Increased clinical trial site activations and initiatives to support subject recruitment,

• PARA_OA_002 Interim Analysis,

• Close out of stage 1 PARA_OA_002 and PARA_OA_006 studies.

Subject Recruitment

Through the second half of CY2023, Paradigm increased its target clinical trial sites from

80 to 120 clinical trial site activations to support the recruitment increased initiatives

undertaken by the Company. The Phase 3 clinical program has activated sites across

seven countries, comprising Australia, the US and Canada in North America, and the UK,

Belgium, Poland, and Czechia in the EU. The additional trial sites activated aided to

Paradigm to meet the reported 100% enrolment target of June 2023 which was reported

at the beginning of July 2023. The significant one-off upfront investment in the trial setup

costs in the stage 1 of the phase 3 trial ensures trial sites are trained and available to

commence with next stage of the phase 3 clinical program, thus streamlining the

recruitment and enrolment process.

As Paradigm reached the increased target for site activation and these clinical trial sites

became familiar with the study design, it enabled an increase in the number of participants

directed to these sites through the utilisation of several recruitment initiatives. The

implemented initiatives include the introduction of 1nHealth, SubjectWell, and Paradigm’s

partnership with NFL Alumni Health, which together increased the volume of potential

participants to study sites for screening and randomisation. Paradigm also launched a

dedicated clinical trial website www.Hope4OA.com, an ethics-approved easy-to-use public-

facing website for providing trial information and access Paradigm’s OA clinical trials. The

implementation of these recruitment initiatives in stage 1 have enabled identification of

potential participants for stage 2 of the phase 3 study.

Paradigm expects the investment in these activities upfront to enhance the efficiency of

the next stage of the phase 3 clinical trial and mitigate any potential delays.

Interim Analysis

An interim analysis was conducted ahead of schedule to determine the performance of the

three iPPS doses in stage 1 of PARA_OA_002 clinical trial against placebo. This was

conducted following reported data from the phase PARA_OA_008 clinical trial

demonstrating the once weekly iPPS dosing regimen was not providing sufficient clinical

results to that of the 2mg/kg twice weekly Paradigm has reported across multiple programs.

Costs associated with the interim analysis included Clinical Research Organisation (CRO)

and Data Monitoring Committee to analyse data on the first 300 participants who had

reached Day 56. The interim analysis provided Paradigm an earlier indication of the optimal

dose and aided the preparation of the clinical protocol for the next stage of the phase 3 OA

program ahead of schedule.

Phase 3 Stage 1 close out activities

Paradigm completed activities associated with the close out of stage 1 of PARA_OA_002

clinical trial and the PARA_OA_006 extension study. Close-out is a process to ensure all

clinical trial related activities are appropriately reconciled, recorded, and reported at the end

of a trial in accordance with the protocol, standard operating procedures (SOPs) good

clinical practice (GCP), and all other applicable regulatory requirements. Close-out is

integral to the quality control of a clinical trial and is designed to ensure quality of the study

according to Sponsor requirements and to ensure that all necessary documents are in place

should it be necessary for the trial information to be retrieved or inspected, by regulatory

agencies, in the future. Paradigm required the close-out to be conducted in accordance with

the said SOPs and with GCP so that the clinical data could be used in discussion with the

US FDA regarding the minimal effective dose discussions and the revised clinical trial

protocol and at the time of Paradigm’s New Drug Application (NDA) submission.

Cost Containment Measures

As discussed during the capital raise, aggressive cost containment measures have been

implemented to ensure capital is being directed toward completion of the phase 3 OA

clinical trial. Paradigm’s financial commitment to the MPS clinical program has now

completed with a reduced headcount in the MPS clinical team implemented following the

completion of the phase 2 studies in MPS I and VI. Paradigm is actively seeking to partner

this clinical asset to progress iPPS for treatment of MPS toward commercialisation.

Ongoing overheads have been reduced throughout this cost containment phase by over

$1m per quarter which will come into effect from January 2024, with further reductions

planned over the coming months.

Forecast cash outflow for the March 2024 quarter is expected to be $8 - $11m (including

R&D refund) and the June 2024 quarter expected to be in the $6m - $8m range which is

inclusive of phase 3 stage 2 restart costs.

Paradigm has issued short term options (Nov 2024 expiry) as a part of the 2023 capital

raise exercisable at $0.65. Exercise of the outstanding options is expected to add an

additional $33m (approximate).

PARA_OA_008 Phase 2 Clinal Trial

Paradigm’s PARA_OA_008 clinical trial concluded during the December quarter with the

significant data from the 12-month clinical data and 6-month quantitative analysis reported.

The PARA_OA_008 clinical trial phase 2 trial data showing efficacy of iPPS on both

objective (MRI analysis) and subjective measures (patient reported outcomes) compared

to placebo, demonstrates that iPPS both treats the symptoms of OA and has the potential

to preserve and/or regenerate joint tissues.

OBJECTIVE DATA MEASURES Reported (Day)

Improvement in synovial fluid biomarkers associated with OA

disease progression.

56 & 168

Improvement in structural changes in the knee determined by MRI. 168

SUBJECTIVE DATA MEASURES Reported

Significant improvement in mean change from baseline in WOMAC

pain, function, and overall scores.

56, 168 & 365

Significant improvement in Patient Global Impression of Change

(PGIC)

365

During the December quarter Paradigm reported durable and significant responses in

WOMAC scores for pain (p=0.054), function (p=0.048), stiffness and overall (p=0.054)

were observed for iPPS twice weekly compared to placebo control through to Day 365.

The outstanding results for iPPS compared to placebo were strengthened through the

reporting that cumulative rescue pain medication use was over five times higher in the

placebo group compared to iPPS group at Day 365.

This data is a significant outcome for Paradigm as no OA drug has previously shown

durable and meaningful improvements in pain and function at 12 months after a single

course of treatment.

The Company also reported in October quantitative MRI analysis results at the day 168

follow-up from the phase 2 PARA_OA_008 clinical trial, demonstrated that a single 6-week

treatment of iPPS treatment at 2mg/kg twice weekly results in an increase in overall

cartilage thickness (p=0.05) and cartilage volume (p=0.07) compared to a decrease in the

placebo group. Bone marrow lesions (-17%) and synovitis (-1%) were also decreased in

the knee joint following iPPS administration to day 168 compared to small increases in the

placebo group.

The above results of the successful phase 2 clinical trial demonstrate that iPPS both treats

the symptoms of OA and preserves and/or regenerates joint tissues. This is significant from

a commercial perspective because the disease modifying effects of iPPS observed in the

PARA_OA_008 phase 2 clinical trial are expected to support a greater reimbursement

compared to that which would be expected for a therapeutic that only treat the symptoms

of OA.

OA remains the most prevalent form of joint disease, affecting up to 16% of the population in

the developed world, with more than 72 million people in the US, EU5, Canada and

Australia suffering from osteoarthritis.1 The prevalence of OA is increasing in line with the

aging population and increasing rates of obesity. By 2030 the number of people suffering

from OA in the US is predicted to increase by 86% to 67 million.2

OA has a significant impact on day-to-day functioning and, although the levels of pain and

disability may fluctuate, it has no known cure or spontaneous remission and is associated

with irreversible structural damage and progression over time. Presently there are no drugs

approved that can prevent, stop, or even restrain progression of OA. Moreover, the

available medications that claim to mitigate the pain of OA have numerous risk/benefit

considerations and market research indicates that only 19% of knee OA patients are

satisfied with currently available treatments. 2,3

There is an urgent unmet need for a new therapy for OA. This successful phase 2 clinical

trial has provided important data for Paradigm to progress with the TGA Provisional

Approval application, which would expedite the pathway to marketing approval of iPPS in

Australia.

Capital Raising

Paradigm announced on the 30th of October, a fully underwritten $30.1 million (before costs

of $1.76m) capital raising, comprising:

• a placement to institutional investors of approximately 42 million Shares at an issue

price of $0.43 per Share raising approximately $18 million;

• an accelerated non-renounceable Entitlement Offer of 1 Share for every 10 Shares

held by eligible shareholders at an issue price of $0.43 per Share raising

approximately $12.1 million; and

• 3 free-attaching Options for every 4 Shares subscribed for and issued under the

Entitlement Offer and Placement.

The proceeds from the capital raise are being utilised for the Company’s phase 3 OA

clinical program.

Paradigm Board Changes

During the December quarter Non-Executive Director, Mr John Gaffney stepped down from

the Paradigm board following 9-years of service. Non-Executive Director, Helen Fisher also

informed the Paradigm Board during the period that she will be stepping down from the

position as Non-Executive Director on the appointment of a replacement Non-Executive

Director, to focus on other commitments going forward. The Paradigm Board commenced

a search for an Independent Non-Executive Director with commercial experience and

financial expertise and an Independent Chair during the December quarter. Paradigm

expects to make an announcement on additions to the board during H1 CY2024.

Mucopolysaccharidosis VI

The MPS VI study has completed however, the MPS VI data analysis encountered an

unforeseen delay with the service provider conducting the GAG analysis for the phase 2

clinical trial. This is a highly specialised analytical technique with only a small number of

service providers available globally. Paradigm expects to release the top-line data next

week.

Global Conferences

American College of Rheumatology (ACR) Convergence 2023: In November Dr Mukesh

Ahuja, Paradigm Global Head of Osteoarthritis, presented a poster at the ACR

Convergence 2023 held November 10–15 at the San Diego Convention Centre in San

Diego, California. The poster detailing data from the PARA_OA_008 clinical trial on the

therapeutic effects of iPPS on clinical and disease modifying outcomes in subjects with

knee osteoarthritis.

Company Outlook

Phase 3 OA Clinical Program

Paradigm met with US FDA on the 10th of January 2024 to discuss outstanding

requirements for the next stage of the Phase 3 clinical program in Osteoarthritis. Paradigm’s

clinical and regulatory teams are preparing the documentation for submission of updated

nonclinical data to the Agency ahead of the submission of the clinical protocol to the FDA.

The program has FDA granted Fast-track designation and the timeline for the review is

expected in Q1 CY2024. Paradigm plans to proceed with the dose of 2mg/kg twice weekly

for registration studies. Enrolment activities for next stage of the phase 3 OA program are

expected to commence in Q2 CY2024.

TGA Provisional Approval Application

Paradigm is progressing with its TGA Provisional marketing approval in Australia for iPPS,

which is expected to expedite the pathway to revenues. The next stage of the TGA

Provisional Approval pathway, the determination application remains on track with the

determination application planned to be submitted to the TGA toward the end of the current

quarter (Q1 CY2024). Should this prove successful, Paradigm will prepare a full dossier for

submission to the final stage of the TGA provisional approval application process.

Business Development

Paradigm continues to progress business development activities with regional partnering

companies with the aim to have at least one regional partnering by the end of June 2024.

Discussions are ongoing with a number of potential partners. Updates will be provided when

appropriate.

Other Activities

• Paradigm’s PARA_OA_008 phase 2 clinical data has been selected for podium

presentations at two global orthopedic and OA conference. Dr Mukesh Ahuja,

Paradigm’s Global Head of Osteoarthritis will present data from the phase 2 clinical

trial evaluating the clinical and disease modifying outcomes of iPPS in knee OA at

the:

o Orthopedic Research Society (ORS) Annual Meeting 2024, 2–6 February:

Paradigm submitted a late-breaking abstract to the ORS selection committee

following the release of the PARA_OA_008 12-month clinical and 6-month

quantitative MRI data. The abstract titled “The therapeutic effects of pentosan

polysulfate sodium on clinical and disease modifying outcomes in moderate

to severe knee osteoarthritis” was selected for a presentation during the late-

breaking podium session; and

o Osteoarthritis Research Society International (OARSI) 2024, 18–21 April:

Paradigm’s recent clinical and disease modifying outcome data from the

PARA_OA_008 phase 2 clinical trial was reviewed by the OARSI panel and

selected for a podium presentation during the conference.

• Paradigm has lodged the FY23 R&D Tax Incentive Scheme refund claim. The

refund of approximately $7.2m was anticipated to be received during Q4 CY2023,

however it is now expected in Q1 CY2024.

• The overall results produced in the PARA_OA_008 phase 2 clinical trial and MPS-I

study are currently being compiled into a manuscript for peer review and publication.

Both are expected to be published during CY2024.

About Paradigm Biopharmaceuticals

Paradigm Biopharmaceuticals Ltd. (ASX:PAR) is a late-stage drug development company

driven by a purpose to improve patients’ health and quality of life by discovering,

developing, and delivering pharmaceutical therapies. Paradigm’s current focus is

developing iPPS for the treatment of diseases where inflammation plays a major

pathogenic role, indicating a need for the anti-inflammatory and tissue regenerative

properties of PPS, such as in osteoarthritis (phase 3) and mucopolysaccharidosis (phase

2).

Forward Looking Statements

This Company announcement contains forward-looking statements, including statements

regarding anticipated commencement dates or completions dates of preclinical or clinical

trials, regulatory developments, and regulatory approval. These forward-looking

statements are not guarantees or predictions of future performance, and involve known

and unknown risks, uncertainties and other factors, many of which are beyond our control,

and which may cause actual results to differ materially from those expressed in the

statements contained in this presentation. Readers are cautioned not to put undue reliance

on forward-looking statements.

References

1 Global Health Data Exchange, Institute for Health and Metrics Evaluation, University of Washington. Accessed June 2021

http://ghdx.healthdata.org/gbd-results-tool.

2 OARSI. Osteoarthritis: A Serious Disease, Submitted to the U.S. Food and Drug Administration December 1, 2016.

3 Matthews GL, Hunter DJ. Emerging drugs for osteoarthritis. Expert Opin Emerg Drugs. 2011;16(3):479-491.

doi:10.1517/14728214.2011.576670.

Authorised for release by the Paradigm Board of Directors.

FOR FURTHER INFORMATION PLEASE CONTACT:

Simon White

Director of Investor Relations

Tel: +61 404 216 467

Paradigm Biopharmaceuticals Ltd.

ABN: 94 169 346 963

Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA

Email: [email protected]

Rule 4.7B

ASX Listing Rules Appendix 4C (17/07/20) Page 1

+ See chapter 19 of the ASX Listing Rules for defined terms.

Appendix 4C

Quarterly cash flow report for entities

subject to Listing Rule 4.7B

Name of entity

Paradigm Biopharmaceuticals Limited

ABN Quarter ended (“current quarter”)

94 169 346 963 31 December 2023

Consolidated statement of cash flows Current quarter

$A’000

Year to date (6

months)

$A’000

1. Cash flows from operating activities

- 301.1 Receipts from customers

1.2 Payments for

(27,064) (49,004)(a) research and development

(b) product manufacturing and operating

costs

- -

(c) advertising and marketing (137) (137)

(d) leased assets (26) (37)

(e) staff costs (641) (1,204)

(f) administration and corporate costs (772) (1,300)

1.3 Dividends received (see note 3) - -

1.4 Interest received 86 635

1.5 Interest and other costs of finance paid (3) (6)

1.6 Income taxes paid - -

1.7 Government grants and tax incentives - -

1.8 Other (provide details if material) - -

1.9 Net cash from / (used in) operating

activities

(28,557) (51,023)

2. Cash flows from investing activities

- -

2.1 Payments to acquire or for:

(a) entities

(b) businesses - -

(c) property, plant and equipment - -

(d) investments - -

(e) intellectual property - -

(f) other non-current assets - -Appendix 4C

Quarterly cash flow report for entities subject to Listing Rule 4.7B

ASX Listing Rules Appendix 4C (17/07/20) Page 2

+ See chapter 19 of the ASX Listing Rules for defined terms.

Consolidated statement of cash flows Current quarter

$A’000

Year to date (6

months)

$A’000

2.2 Proceeds from disposal of:

- -(a) entities

(b) businesses - -

(c) property, plant and equipment - -

(d) investments - -

(e) intellectual property - -

(f) other non-current assets - -

2.3 Cash flows from loans to other entities - -

2.4 Dividends received (see note 3) - -

2.5 Other (provide details if material) - -

2.6 Net cash from / (used in) investing

activities

- -

3. Cash flows from financing activities

30,117 30,117

3.1 Proceeds from issues of equity securities

(excluding convertible debt securities)

3.2 Proceeds from issue of convertible debt

securities - -

3.3 Proceeds from exercise of options - -

3.4 Transaction costs related to issues of

equity securities or convertible debt

securities

(1,763)

-

(1,763)

-

3.5 Proceeds from borrowings - -

3.6 Repayment of borrowings (lease liabilities) (8) (51)

3.7 Transaction costs related to loans and

borrowings - -

3.8 Dividends paid - -

3.9 Other (Limited recourse loan repaid under

ESP)

- -

3.10 Net cash from / (used in) financing

activities

28,346 28,303

4. Net increase / (decrease) in cash and

cash equivalents for the period

33,559 56,379

4.1 Cash and cash equivalents at beginning of

period

4.2 Net cash from / (used in) operating

activities (item 1.9 above) (28,557) (51,023)

@ slomo

i read your valuation with interest My previous valuation was absurdly high and no doubt I have sunk cost in this stock which clouds my view.

im wondering now whether the greatest risk aside from an unexpected dud result is just that it gets bought out for 2-300% of the current SP. would be absolute chicken feed to big pharma and they would get potentially a blockbuster drug… I would be gutted having ridden this thing for more than 5 years

Paradigm will present at multiple international congresses. Doesn’t hurt to have some peer review and awareness but hardly market sensitive I think.

bring on interim results that might be truly market sensitive!

 ASX RELEASE 30 January 2024

Paradigm’s PARA_OA_008 Clinical Data Selected for Podium Presentations at Major Orthopaedic & OA Conferences

KEY HIGHLIGHTS

• Orthopaedic Research Society (ORS) Annual Meeting 2024, 2–6 February: Abstract accepted for a late-breaking podium presentation during the conference. The abstract details the therapeutic effects of pentosan polysulfate sodium on clinical and disease modifying outcomes in moderate to severe knee osteoarthritis.

• Osteoarthritis Research Society International (OARSI) 2024, 18–21 April: Paradigm’s recent clinical and disease modifying outcome data from the PARA_OA_008 phase 2 clinical trial accepted for podium presentation.

• Acceptance for podium presentations at two leading global medico-scientific conferences in the fields of orthopaedics and osteoarthritis demonstrates the strength and interest of Paradigm’s PARA_OA_008 data amongst our peers.

Paradigm Biopharmaceuticals Ltd (ASX:PAR) (“Paradigm” or “the Company”), a late-stage drug development company focused on delivering new therapies to address unmet medical needs, is pleased to report abstracts of recent data from the successful PARA_OA_008 phase 2 clinical trial have been accepted for oral podium presentations at the 2024 ORS Annual Meeting (California), and the 2024 OARSI World Congress on Osteoarthritis (Vienna, Austria). Conference material presented will be available on the Paradigm website following the conclusion of each conference.

Paradigm Managing Director, Mr Paul Rennie said: “To have our clinical and structural improvement data from the successful PARA_OA_008 phase 2 trial selected for podium presentations at two separate prestigious international scientific conferences, is a testament to the Paradigm clinical program and the impressive effects of iPPS on knee osteoarthritis.

Osteoarthritis impacts an estimated 10 percent of the world’s population over the age of 60 and represents an area of high unmet need for new

therapies which can improve patient outcomes.”

  The phase 2 PARA_OA_008 randomised, double-blind, placebo-controlled, multicentre study evaluating the disease modifying potential of injectable pentosan polysulfate sodium (iPPS) in subjects with knee osteoarthritis (OA) demonstrated not only durable and beneficial effect on pain, function, and the patient’s impression of improvement out to 12 months but also showed improvements in the underlying disease through MRI analysis as early as 6 months following a single 6-week treatment course.

 It provides further validation that the data being produced by iPPS for the

 treatment of knee OA patients is truly world class and is being recognised by a global

 audience of our peers.

 Orthopaedic Research Society 2024 Annual Meeting

Dr Mukesh Ahuja, Paradigm’s Global Head of Osteoarthritis, will be conducting an oral presentation at the ORS 2024 Annual Meeting to be held at the Long Beach Convention Centre in California, USA, from 2–4 February 2024.

Paradigm submitted a late-breaking abstract to the ORS selection committee following the release of the PARA_OA_008 12-month clinical and 6-month quantitative MRI data. The abstract titled “The therapeutic effects of pentosan polysulfate sodium on clinical and disease modifying outcomes in moderate to severe knee osteoarthritis” was selected for a presentation during the late-breaking podium session. Only those abstracts deemed to be of the highest interest and impact to congress attendees are selected for late-breaking presentations.

The ORS Annual Meeting is the largest scientific meeting in the world dedicated solely to the field of research related to the musculoskeletal system and orthopaedics. Meeting attendees include the top basic, translational, and clinical research experts in the world representing academia, industry/private sector, government, and private practice. The meeting provides a platform to share cutting-edge research findings and innovations in the field of musculoskeletal research with a diverse audience of orthopaedic experts.

2024 OARSI World Congress on Osteoarthritis

Dr Mukesh Ahuja, Paradigm’s Global Head of Osteoarthritis, will present data from the phase 2, randomised, double-blinded PARA_OA_008 clinical trial exploring the disease modifying potential of iPPS in subjects with knee OA. The abstract titled “Effects of pentosan polysulfate sodium on clinical outcomes and disease modifying biomarkers in moderate to severe knee osteoarthritis” was reviewed by the OARSI panel and selected for a podium presentation during the conference.

Additionally, Dr Donna Skerrett, Paradigm’s Chief Medical Officer has again

clinical updates from selected companies in clinical development. Dr. Donna Skerrett, Paradigm's Chief Medical Officer has been invited to present the iPPS technology, clinical

translation, and learnings from Paradigm's ongoing OA clinical program.

will facilitate

About Paradigm Biopharmaceuticals

Paradigm Biopharmaceuticals Ltd. (ASX:PAR) is a late-stage drug development company driven by a purpose to improve patients’ health and quality of life by discovering, developing, and delivering pharmaceutical therapies. Paradigm’s current focus is developing injectable (subcutaneous) pentosan polysulfate sodium (iPPS) for the treatment of diseases where inflammation plays a major pathogenic role, indicating a need for the anti-inflammatory and tissue regenerative properties of iPPS, such as in osteoarthritis (phase 3) and mucopolysaccharidosis (phase 2).

  The annual OARSI Congress is the pre-eminent multidisciplinary global forum to showcase and display cutting-edge OA research from academia and industry worldwide.

 The global conference will be held in Vienna, Austria between 18–21 April 2024.

 officially invited to speak at the Clinical Trials Symposium (CTS) scheduled for the day

been

 prior to the commencement of the 2024 OARSI World Congress. The CTS invites

 Furthermore, due to the successful reception last year, Paradigm will also again conduct

 a 15-minute theatre presentation session

which provides

an additional opportunity to

 expand upon Paradigm’s OA clinical development program and

further

 interaction with congress attendees.

 To learn more please visit: www.paradigmbiopharma.com

FOR FURTHER INFORMATION PLEASE CONTACT:

Simon White

Director of Investor Relations

Tel: +61 404 216 467

Paradigm Biopharmaceuticals Ltd ABN: 94 169 346 963

Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA Email: [email protected]

And there it is, they’ve addressed the spectre of cashburn, runway and a falling share price. Shame the raise is at such a low price but I guess that’s what happens when you leave the capital situation up in the air and rates go against you/risk off intervenes.

on the upside they claim to now be funded til completion of the phase 3 trial on pentosan in OA which is the potential blockbuster.

although dilution is always a shame and the SP has taken a 30% hit today to be honest I’m actually happier knowing they have runway in front of them as the drug has such potential.

still think this thing is ridiculously undervalued but that’s probably to be expected in current environment

 ASX RELEASE 31 October 2023

FULLY UNDERWRITTEN $30M CAPITAL RAISE TO FUND COMPANY THROUGH TO TOPLINE READ OUT OF PHASE 3 OSTEOARTHRITIS TRIAL IN MID 2025

KEY HIGHLIGHTS

•

• The placement and the institutional offer raised a total of $21.1m and received strong support from new and existing institutional and sophisticated investors in Australia and internationally (Placement).

• The accelerated offer to eligible institutional shareholders has now completed, raising approximately $3.1 million with a take up of 78%.

•

• The pro-forma cash balance at the completion of the Placement and Entitlement Offer will be $69.4 million, with an additional $33.8 million if all options are exercised before they lapse.

• Funds raised under the offer, and the proceeds from the exercise of options, will be used to fund Paradigm through to mid CY25 (without relying on additional licensing revenue, should that be generated), including the expected top-line readout from the Phase 3 OA clinical trial.

• Key upcoming catalysts for the Company include commencement of next stage of Phase 3 OA program, TGA provisional approval, readout of top-line data for phase 2 program for MPS and potential regional licensing agreements for OA and MPS.

 Paradigm announces fully underwritten $30m capital raise comprising an

 $18m placement and a $12m accelerated non renounceable entitlement offer

 (ANREO or Entitlement Offer)

 The 1 for 10 retail entitlement offer of $9m is fully underwritten and is expected

 to open at 9:00am Monday 6 November.

  Paradigm Biopharmaceuticals Ltd (ASX:PAR) (“Paradigm” or “the Company”), a late-stage drug development company focused on delivering new therapies to address unmet medical needs, is pleased to announce that the $30m capital raise announced 30 October 2023 is fully underwritten by lead manager Bell Potter Securities (Bell Potter or the Underwriter).

The Company has completed the $18m placement that has been strongly supported by new and existing institutional and sophisticated Paradigm shareholders. The Company has now received confirmation that the accelerated entitlement offer to eligible institutional shareholders has received take up by existing institutions totalling $3.1m million with a take up rate of 78% from eligible institutional shareholders.

The record date for the retail entitlement offer is 1 November 2023 (Record Date).

Paradigm Managing Director, Paul Rennie commented: “I would like to thank all the existing shareholders for their continued support of Paradigm and would like to welcome the new institutional investors as we continue to progress iPPS as a potential blockbuster therapy for osteoarthritis. To receive such strong support is a great endorsement of the ongoing strength of our clinical assets and focusses the Company on progressing our phase 3 OA clinical program and commercial licensing discussions to achieve value for all Paradigm shareholders."

Capital Raise Summary

 The fully underwritten capital raise of $30.1 million (before costs) will be comprised of:

• a Placement to institutional investors to subscribe for approximately 42 million shares at an issue price of $0.43 per share to raise approximately $18 million; and

• an accelerated non-renounceable Entitlement Offer of 1 share for every 10 shares held by eligible shareholders on the Record Date at an issue price of $0.43 per share to raise approximately $12.1 million.

• Every 4 shares subscribed for and issued under the Entitlement Offer and Placement will be accompanied by 3 free-attaching options exercisable at $0.65 expiring on 30 November 2024.

Replacement Prospectus

The Company has today lodged a replacement prospectus (Prospectus) with ASIC, updating the original prospectus for the Placement and Entitlement Offer dated 30 October 2023. The key differences between the Prospectus and the original prospectus are to disclose the Company's entry into the Underwriting Agreement pursuant to which the Placement and the Entitlement Offer will be fully underwritten by Bell Potter and to include the offer of up to 10,074,426 options on the same terms as the Options under the Placement and Entitlement Offer (Sub-Underwriter Options) to the Underwriter and/or sub-underwriters of the Entitlement Offer and Placement as previously disclosed in the original prospectus.

The material terms of the Underwriting Agreement, including the fees to be paid to Bell Potter in consideration for its underwriting services are also set out in the Prospectus.

Commencement of the Retail Entitlement Offer

The Entitlement Offer is being conducted through:

• an accelerated offer to eligible institutional shareholders in Australia, New Zealand, Hong Kong, Cayman Islands, Singapore, the United Kingdom and the United States (Institutional Offer) which is now completed; and

• an offer to eligible retail shareholders, being retail shareholders with a registered address in Australia or New Zealand (or that the Company has otherwise determined is eligible to participate without any requirement for a prospectus or any other disclosure document to be lodged or registered and who is not in the United States and not acting for the account or benefit of a person in the United States) (Eligible Retail Shareholders) (Retail Offer).

Eligible Retail Shareholders with a registered address in Australia or New Zealand as at 7:00pm (Sydney time) on the Record Date are invited to participate in the Entitlement offer at the same offer price as the Institutional Offer. The Retail Offer will open at 9:00am (Sydney time) Monday 6 November and close at 5:00pm (Sydney time) on Monday 20 November.

Eligible Retail Shareholders will receive a copy of the Prospectus, including a personalised entitlement and acceptance form, which will provide further details of how to participate in the Retail Offer.

The shortfall, if any, will then be placed in accordance with the terms of the Underwriting Agreement. New Shares issued under the Entitlement Offer shortfall will be subscribed for by the Underwriter or sub-underwriter/s, in accordance with the underwriting agreement between the Company and the Underwriter. The Entitlement Offer is fully sub- underwritten by domestic and international institutional investors.

All new shares to be issued under the Entitlement Offer will rank equally with existing PAR fully paid ordinary shares in all respects. New shares and options under the Retail Offer are expected to be issued on Monday 27 November, and commence normal trading on Tuesday 28 November 2023.

Summary of Use of Funds

Paradigm expects to confirm the 2mg/kg twice weekly optimal dose in Q1 CY 2024 and commence enrolment into the next stage of the phase 3 OA program shortly thereafter.

Paradigm is focussed on partnering its clinical assets and expects any licensing transaction to add further funding sources to bring iPPS through to commercialisation in multiple jurisdictions simultaneously.

The proceeds from the offer will be used to fund the Company’s phase 3 OA clinical program and to pay for the costs of the Placement and Entitlement Offer. The proceeds are expected to fund the Company’s OA phase 3 clinical program to the end of CY2024 with the exercise of options expected to provide further runway to mid CY 2025 and past Paradigm’s expected top-line read out from the phase 3 clinical trial.

 Upcoming Catalysts Event

MPS VI phase 2 clinical trials – top-line data.

Phase 3 OA program – FDA protocol review next stage of Phase 3 program.

TGA Provisional Approval OA - submission for next stage determination application.

Phase 3 OA program – next stage enrollment commencement, subject to regulatory agreement.

Regional licensing agreement(s) in OA and MPS.

Target Date

Q4 CY 2023 Q1 CY 2024

Q1 CY 2024 H1 CY 2024 H1 CY 2024

 TGA Provisional Approval OA - dossier submission, pending determination of application approval.

The MPS I and PARA_OA_008 – Peer Review Publications.

Potential expedited or provisional approval submissions for MPS program (Brazil, Australia).

Entitlement Offer and Placement Timetable

Q3 CY 2024 CY 2024 CY 2024

    An indicative timetable for the Entitlement Offer and Placement is set out below (subject to change):

 Event

Lodgement of original prospectus

Announcement of results of the Placement and the Institutional Offer

Lodgement of replacement prospectus Trading halt lifted

Record Date for the Retail Offer

Prospectus despatched to Eligible Retail Shareholders

Addendum to Notice of AGM despatched to Shareholders

Allotment of Shares under the Placement and the Institutional Offer

Quotation of Shares issued under the Placement and the Institutional Offer

Last day to extend the closing date of the Retail Offer

Closing date of the Retail Offer Announcement of results of Retail Offer

Date

Monday, 30 October 2023 Tuesday, 31 October 2023

Tuesday, 31 October 2023

Wednesday, 1 November 2023

7.00pm (AEDT) Wednesday, 1 November 2023

Monday, 6 November 2023

Monday, 6 November 2023

Wednesday, 8 November 2023 (before noon AEDT)

Thursday, 9 November 2023

Wednesday, 15 November 2023 (before noon AEDT)

Monday, 20 November 2023

Thursday, 23 November 2023 (before noon AEDT)

             Allotment of Shares under the Retail Offer and Options under the Entitlement Offer

  Monday, 27 November 2023 (before noon AEDT)

 Quotation of Shares issued under the Retail Offer and Options under the Entitlement Offer

  Tuesday, 28 November 2023

 Paradigm AGM approval to be sought to issue the Placement Options and (if applicable) Sub-Underwriter Options

  Wednesday, 29 November 2023

 Issue of Placement Options and (if Wednesday, 29 November 2023

applicable) Sub-Underwriter Options

(before noon AEDT)

 Quotation of Placement Options and (if Thursday, 30 November 2023 applicable) Sub-Underwriter Options

* The above timetable is indicative only and is subject to change.

-Ends-

  About Paradigm Biopharmaceuticals Ltd.

 Paradigm Biopharmaceuticals Ltd. (ASX:PAR) is a late-stage drug development company driven by a purpose to improve patients’ health and quality of life by discovering, developing, and delivering pharmaceutical therapies. Paradigm’s current focus is developing injectable (subcutaneous) pentosan polysulfate sodium (iPPS) for the treatment of diseases where inflammation plays a major pathogenic role, indicating a need for the anti-inflammatory and tissue regenerative properties of iPPS, such as in osteoarthritis (phase 3) and mucopolysaccharidosis (phase 2).

 Forward Looking Statements

 This Company announcement contains forward-looking statements, including statements regarding anticipated commencement dates or completions dates of preclinical or clinical trials, regulatory developments and regulatory approval. These forward-looking statements are not guarantees or predictions of future performance, and involve known and unknown risks, uncertainties and other factors, many of which are beyond our control, and which may cause actual results to differ materially from those expressed in the statements contained in this presentation. Readers are cautioned not to put undue reliance on forward-looking statements.

To learn more please visit: https://paradigmbiopharma.com Approved for release by the Paradigm Board of Directors.

FOR FURTHER INFORMATION PLEASE CONTACT: Simon White

Director of Investor Relations

Tel: +61 404 216 467

Paradigm Biopharmaceuticals Ltd

ABN: 94 169 346 963

Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA Email: [email protected]

PAR got a guernsey on the call again yesterday and the summary is quite reasonable (last stock discussed) and the conclusion similar to my current view:

great drug, huge opportunity but need to demonstrate the ability to fund through to completion phase 3 trial whether that’s through partnering up or (argh) a further cap raise. Unfortunately biotech is so beaten up that despite all the great progress and trial results a cap raise would be unreasonably dilutive.

https://podcasts.apple.com/au/podcast/the-call-from-ausbiz/id1506523664?i=1000631812416

more evidence of disease modification released to market on 18th October, it feels like there has been a slew of announcements which really should have led to a market response but rates and the off risk vibe are holding this stock back:

 ASX RELEASE 18 October 2023

iPPS increases cartilage thickness at 6 months in participants with knee osteoarthritis compared to cartilage loss in placebo group

 Webinar

When: Oct 18, 2023 11:00 AM Canberra, Melbourne, Sydney (AEDT) time Topic: Paradigm Biopharma's PARA_OA_008 Day 168 MRI Results Webinar Register for this webinar via: https://us02web.zoom.us/webinar/register/WN_a1INIMLMRz67s_yScRJTIQ

 Paradigm Senior Management will be hosting a webinar at 11:00 AM (AEDT) to discuss new quantitative MRI 6-month data analysis from the PARA_OA_008

 phase 2 clinical trial.

   After registering, you will receive a confirmation email containing information about

 how to join the webinar.

Osteoarthritis (OA) leads to significant structural changes to the entire joint. Bone remodelling, adverse inflammation of the synovium, and cartilage loss are all structural changes in knee OA. In the natural course of the disease, it is expected that a person with moderate to severe knee OA will lose approximately -40 μm (-0.04 mm) of cartilage thickness in the central medial femur per year on MRI (1).

KEY HIGHLIGHTS

• iPPS demonstrates preservation of cartilage in knee OA participants in a phase 2 study.

• A 6-week twice weekly course of subcutaneous iPPS was shown to increase cartilage thickness and volume and reduce bone marrow lesions and synovitis on MRI follow-up at 6 months.

• Participants who received iPPS had an average improvement of cartilage thickness in the central medial femur of the knee of 60 μm (0.06 mm) at 6 months. This is compared to placebo who lost an average -20 μm (-0.02 mm) of cartilage thickness.

 • The twice weekly 2 mg/kg dose for 6 weeks outperformed the once weekly via MRI assessment and is consistent with the optimal clinical dose for knee OA.

• The results indicating a treatment effect on OA beyond the relief of symptoms supports iPPS as a blockbuster opportunity.

 • These data are expected to be key with partnering and regulatory discussions (TGA Provisional Approval and US FDA).

 Paradigm Biopharmaceuticals Ltd (ASX:PAR) (“Paradigm” or “the Company”), a late-stage drug development company focused on delivering new therapies to address unmet medical needs, is pleased to announce very exciting new analysis from the phase 2 PARA_OA_008 clinical trial. demonstrating that a single 6-week treatment of injectable pentosan polysulfate sodium (iPPS) treatment at 2mg/kg twice weekly results in:

 A) An increase in overall cartilage thickness, across all compartments of the knee, of 0.17mm (p=0.05) compared to overall decrease of -0.09mm in placebo;

B) An increase if overall cartilage volume by 1.9% (p=0.07) compared to a decrease of -1.58% in the placebo group;

C) Resolution or decrease in of bone marrow lesions (BML) volume by 17% in the iPPS group, whereas placebo subjects saw a 2% increase in BML and;

D) Reduced area and intensity by 1% of synovitis in the iPPS group compared to an increase 0f 4% in synovitis intensity in placebo.

E) As previously reported (ASX release 10 October 2023) symptomatic improvements of pain and function out to 12 months.

 The above results support that iPPS both treats the symptoms of OA and preserves and/or regenerates joint tissues. This is significant from a commercial perspective because the disease modifying effects of iPPS observed in the PARA_OA_008 phase 2 clinical trial are expected to support a greater reimbursement compared to that which would be expected for a therapeutic that only treat the symptoms of OA.

 In the phase 2 clinical trial, subjects treated with iPPS (2 mg/kg twice weekly) had an average increase of 60 μm of cartilage thickness (0.06 mm) in the central medial femur whereas the placebo group lost an average 20 μm of cartilage (-0.02mm) in the same region. Based on extensive literature research, this phase 2 randomised controlled trial appears to be a world first showing:

• A decline in disease biomarkers compared to placebo at Day 56 and Day 168;

• Durable pain and function improvements over placebo out to Day 365, and now;

• Increased cartilage thickness and increased cartilage volume at Day 168, while placebo showed a reduction in both cartilage thickness and volume.

 Next Steps

 • Paradigm has identified the optimal dose for achieving durable responses in pain, function and patient global impression of change (PGIC). Furthermore, this dose results in structural preservation of cartilage, and reduction in BML and synovitis.

• Paradigm is progressing with the TGA Provisional Approval application which would expedite the pathway to marketing approval in Australia.

• The Company is also moving forward with the 2 mg/kg twice weekly optimal iPPS dose for registration programs for the improvement of pain and function in knee OA.

• These data are expected to further support with partnering discussions.

 Paradigm’s Managing Director, Mr Paul Rennie commented “The treatment of osteoarthritis has not progressed for many years, with available therapies mostly treating the symptoms of the disease for a short period. There is a high unmet need for a new OA therapy to slow OA progression in tandem with symptomatic improvement of pain reduction and functional improvement. In this placebo-controlled clinical trial, Paradigm’s iPPS has now demonstrated that it not only has a durable and beneficial effect on pain, function, and the patient’s impression of improvement out to 12 months, but we are also seeing it is improving the underlying disease as early as 6 months following a single 6- week treatment course. We look forward to presenting the PARA_OA_008 data package to global regulatory agencies including the TGA and FDA.”

“What I find most compelling about these data, is that all participants entered the clinical study with active structural degeneration already occurring and yet iPPS has been able to reverse disease progression. Paradigm aims to reach agreement with the US FDA on what data would be necessary to confirm these results in our larger phase 3 program to include disease modifying data on our label at registration. If this is unachievable within our current timelines and budget, the Company or our partner may undertake subsequent additional studies (post marketing clinical studies) to achieve a disease modifying label once iPPS is registered on the market.”

 Top-line results

Osteoarthritis background

All Compartments/Regions

Overall cartilage thickness (mm)

Overall cartilage volume (mm3)

BML overall (mm2I) Synovitis overall (mm2I)

iPPS-Twice-weekly N=15

Day 168

0.17 (P= 0.05) 191.51 (P= 0.07) -86.26

-5086.13

Placebo N=22 Day 168

-0.09

-86.81

120.65 -2707.38

 Osteoarthritis (OA) is a chronic progressive disease, over time leading to the destruction of all joint tissues. The hallmark of OA is cartilage loss (2). As osteoarthritis progresses, the medial side of the knee tends to lose cartilage more rapidly compared to the lateral side.

Overall Average Change from Baseline

           Table 1: Adjusted Change from Baseline (absolute) least squares mean (LSM) results for overall cartilage thickness, cartilage volume, BML and synovitis size and intensity following twice weekly iPPS compared to placebo in PARA_OA_008 at Day 168.

 In the above table (Table 1) iPPS treatment was shown to increase overall cartilage thickness and volume whilst also reducing overall bone marrow lesions and synovitis on MRI follow up at 6 months from a 6-week treatment course of subcutaneous iPPS. The data presented below will focus on cartilage thickness (mm) and volume (%) in the medial compartment and overall BML and Synovitis percentage changes from baseline. All MRI data including the lateral compartments are shown in the Appendix.

The crucial role of cartilage

 Cartilage loss is generally considered to be the most important structural disease feature of OA (Figure 1). Numerous studies have shown cartilage loss to be predictive of knee replacement surgery for OA.

There has been substantial published research on MRI cartilage measurements showing as osteoarthritis progresses, the medial side of the knee tends to lose cartilage more rapidly than the lateral side (3,4). A reduction of this loss, or an increase in cartilage thickness, may therefore delay time to total knee replacement (TKR) in an osteoarthritic knee. Cartilage serves as a cushion and provides smooth, low-friction movement in the knee joint. When cartilage degenerates, it can lead to bone-on-bone contact, resulting in severe pain. Any improvement in cartilage health can help alleviate pain, improve joint functionality, and improve the quality of life for people with knee osteoarthritis.

In knees with an OA disease severity of 2–4 on the Kellgren and Lawrence (KL) grading scale (such as for the PARA_OA_008 participant cohort and who would already be experiencing cartilage loss), natural OA progression would be expected to result in an estimated continued annual loss in cartilage thickness of around 40 μm (0.04 mm) (1) and an annual loss in cartilage volume of around -4% (6) at the central medial femur.

Figure 1. Composite image showing example front-facing (coronal) knee MRIs with highlighted cartilage layers. Image 1 shows a healthy knee and image 2 shows an osteoarthritic knee with preserved cartilage thickness on the lateral side and severe damage to the medial side, indicated by dAB and tAB labels. Images from Hinterwimmer S. et al. Knee Surg Sports Traumatol Arthrosc. 2014, and Reichenbach S. et al. Ann Rheum Dis. 2010 (7,8).

Increase in cartilage thickness with iPPS

 • The twice weekly iPPS arm consistently demonstrated an improvement in cartilage thickness from baseline to 6 months was reported in all medial knee regions following iPPS treatment (Figures 2 and 3).

• The placebo arm demonstrated a loss in cartilage thickness in all medial regions at 6 months consistent with the natural progression of OA.

• iPPS increased the cartilage thickness in the central medial femur by 60 μm (0.06 mm) compared to a reduction of 20 μm (-0.02 mm) in the placebo group consistent with the naturally occurring cartilage loss rate in knee OA progression (-40 μm or 0.04 mm per year).

 Figure 2. Representative side-on (sagittal) MRI images from PARA_OA_008 of the knee at baseline (left panels) and at Day 168 (right panels) from a participant receiving placebo (top panels) and a participant receiving twice weekly iPPS (bottom panels) demonstrating changes in cartilage thickness in the medial compartments. In the twice weekly iPPS baseline image, there is a small bone marrow lesion in the subchondral bone (bone that is directly under cartilage) of the femur (circled in red), that is resolved at Day 168.

 Figure 3: Cartilage thickness (μm). Absolute adjusted change from baseline (CFB). Least squares mean results by medial region in the knee. iPPS 2xW is iPPS twice weekly.

 140 120 100

80 60 40 20

0 -20 -40 -60

iPPS 2xW Placebo

Central Medial Femur

Medial Femorotibial Compartment

Medial Tibia

Cartilage Thickness (μm)

Adj. CFB (abs) LS Mean Day 168

       Increase in cartilage volume with iPPS

 • At 6 months, subjects receiving twice weekly iPPS showed an average increase in cartilage volume of 3.8% in the central medial femur compared to baseline, whereas the placebo arm showed a loss of cartilage volume of -2.2% (Figure 4).

• This data again demonstrates iPPS is reversing the breakdown of cartilage at 6 months. This is in contrast to placebo which is showing further cartilage volume loss from baseline consistent with the natural progression of the disease (4% reduction in cartilage volume per year).

  7 6 5 4 3 2 1 0

-1 -2 -3

iPPS 2xW Placebo

Central Medial Femur

Medial Femorotibial Compartment

Medial Tibia

Cartilage Volume (% change in mm3)

  %CFB Mean Day 168

     Figure 4: Average percentage (%) change from baseline (CFB) in cartilage volume (mm3) by medial region in the knee. iPPS 2xW is iPPS twice weekly.

Reduced bone marrow lesions (BML) with iPPS treatment

 Subchondral (“below the cartilage”) BMLs are a common finding on MRI, in OA. Loss of the normal weight bearing function of articular cartilage along with shifting contact points

 associated with joint laxity can cause joint overloading and is believed to result in microtrauma which expresses as a BML (Figure 5).

Figure 5. Schematic of a knee joint showing representative locations of bone marrow lesions alongside a representative MRI demonstrating a bone marrow lesion in the medial tibia (circled in red). Figure created with an image from BioRender.com. MRI image, Paradigm PARA_005 clinical trial.

Like cartilage loss, BMLs have been shown to be highly predictive of knee replacement (9–11). This means that the loss of the cushioning cartilage layer in a major weight- bearing joint such as the knee can change how weight is distributed. These incessant gradual forces on a joint where bone is moving on bone can result in cartilage breakdown and bone remodelling to cope with the changing stresses.

 • Overall bone marrow lesion volume in the knee was reduced by 17.6% on average in the iPPS twice weekly group, compared to a 2% increase in the placebo group (Figure 6).

  Figure 6: Average percentage (%) change from baseline (CFB) in overall bone marrow lesions. iPPS 2xW is iPPS twice weekly.

5

0 -5 -10 -15 -20

iPPS 2xW Placebo

BML (% change from baseline)

BML Overall

   %CFB Mean Day 168

Reduced synovitis (joint inflammation) with iPPS

OA-associated synovitis is defined as an inflammation of the synovial membrane, the thin layer of tissue that lines the joints (Figure 7). In OA, the synovial membrane can become inflamed and thickened as the body's immune system responds to joint degeneration. This inflammation can cause increased production of synovial fluid, which is a lubricating fluid that normally helps the joint move smoothly. The excess synovial fluid can lead to joint swelling and can be associated with increased pain and stiffness in the affected joint.

 Figure 7. Schematic of a normal knee joint and an inflamed knee joint with synovitis. Figure created with images from BioRender.com.

• At 6 months in this phase 2 clinical trial, synovitis increased from baseline in the placebo arm (4.6%) compared to a slight decrease (-1%) in the twice weekly iPPS arm (Figure 8).

• The observed reduction in the biomarkers of inflammation reported at Day 56 (ASX release 4 October 2023) such as TNF-alpha and IL-6, are consistent with the reduction in synovitis as demonstrated via quantitative MRI analysis at Day 168.

  5 4 3 2 1 0

-1 -2

iPPS 2xW Placebo

Synovitis (% change from baseline)

Synovitis Overall

    %CFB Mean Day 168

 Figure 8: Percentage change from baseline in overall synovitis as measured by MRI in participants treated with twice weekly iPPS (iPPS 2xW) versus placebo.

 About Paradigm Biopharmaceuticals Ltd.

 Paradigm Biopharmaceuticals Ltd. (ASX: PAR) is a late-stage drug development company driven by a purpose to improve patients’ health and quality of life by discovering, developing, and delivering pharmaceutical therapies. Paradigm’s current focus is developing injectable (subcutaneous) pentosan polysulfate sodium (iPPS) for the treatment of diseases where inflammation plays a major pathogenic role, indicating a need for the anti-inflammatory and tissue regenerative properties of iPPS, such as in osteoarthritis (phase 3) and mucopolysaccharidosis (phase 2).

 Forward looking statements

 This Company announcement contains forward-looking statements, including statements regarding anticipated commencement dates or completions dates of preclinical or clinical trials, regulatory developments and regulatory approval. These forward-looking statements are not guarantees or predictions of future performance, and involve known and unknown risks, uncertainties and other factors, many of which are beyond our control, and which may cause actual results to differ materially from those expressed in the statements contained in this presentation. Readers are cautioned not to put undue reliance on forward-looking statements.

-ENDS-

 APPENDIX

 Summary of studied OA biomarkers

 The PARA_OA_008 trial investigating participants with knee OA who had received a 6- week course of either iPPS treatment versus placebo was unique in both the breadth of biomarkers assessed at 6 months, as well as the duration of clinical effect out to 6 and then 12 months (Figure 9). The results from the broad range of structural and molecular biomarkers studied in combination with the clinical results builds a convincing picture of iPPS effects on OA disease progression.

 Figure 9. Schematic of osteoarthritis biomarkers investigated in PARA_OA_008. These biomarkers are measures of osteoarthritis, a disease of the whole joint, as such, disease pathophysiology locations are indicative. Figure created with images from BioRender.com.

 Semi-quantitative versus quantitative MRI analyses

 Semi-quantitative and quantitative analyses in the context of MRI (Magnetic Resonance Imaging) refer to different approaches for evaluating and measuring various aspects of the images produced by MRI machines. A breakdown of the differences include:

Semi-quantitative analysis:

 • Semi-quantitative analysis involves a subjective assessment of MRI images. Based on visual criteria, a score is assigned to each region.

• This approach relies on broad visual interpretation, comparisons, and subjective judgment by radiologists or researchers.

• It is often used to evaluate features like lesion size, shape, location, and other qualitative aspects of the image.

• Semi-quantitative analysis is useful to establish a preliminary understanding of the MRI changes over time.

 Quantitative analysis:

 • Quantitative analysis, on the other hand, aims to provide precise numerical measurements and data from MRI images.

• It involves the use of specific software tools and algorithms to extract numerical values related to parameters of interest, such as tissue volumes, or signal intensities.

• Quantitative analysis is more objective and less reliant on human interpretation, making it suitable for research, clinical trials, and cases where exact measurements are required.

 Full Quantitative MRI Data Set

 Cartilage thickness

Cartilage Thickness (mm) Adj. CFB (abs.) LSM results.

   Compartments/Regions

Overall Thickness (mm)

Central Medial Femur Thickness (mm)

Medial Femorotibial Compartment Thickness (mm)

Medial Tibia Thickness (mm)

Central Lateral Femur Thickness (mm)

Lateral Femorotibial Compartment Thickness (mm)

Lateral Tibia Thickness (mm)

iPPS-Once N=19 Day 168 0.04

-0.03 -0.01

0.02 -0.02 0.03

0.05

iPPS-Twice N=15 Day 168

0.17 (P= 0.054) 0.06

0.12

0.06 0.03 0.03

0.00

Placebo N=22 Day 168 -0.09

-0.02 -0.04

-0.01 -0.03 -0.06

-0.03

                    200 150 100

50 0 -50 -100 -150

iPPS 1xW iPPS 2xW Placebo

Central

Medial Femur Femorotibial

Medial Tibia

Lateral Tibia

Overall

Medial Compartment

Central

Lateral Femur Femorotibial

Cartilage Thickness (μm)

Lateral Compartment

  Adj. CFB (abs) LS Mean Day 168

   Overall cartilage thickness is calculated as the sum of the medial and lateral compartments, i.e. Medial Femorotibial Compartment + Lateral Femorotibial Compartment.

Cartilage volume

Cartilage Volume (mm3) Adj. CFB (abs.) LSM results.

Compartments/Regions iPPS-Once N=19

Day 168

Overall Volume (mm3) -18.67

iPPS-Twice N=15 Day 168 191.51

Placebo N=22 Day 168 -86.81

    Central Medial Femur Volume (mm3)

Medial Femorotibial Compartment Volume (mm3)

Medial Tibia Volume (mm3)

Central Lateral Femur Volume (mm3)

Lateral Femorotibial Compartment Volume (mm3)

Lateral Tibia Volume (mm3)

-43.56 -33.68

7.78 -15.85 13.24

30.78

(P= 0.073) 61.11 137.32

76.66 32.43 51.45

20.81

-20.01 -42.36

-22.20 -24.86 -47.29

-23.46

            Overall cartilage volume is calculated as the sum of the medial and lateral compartments, i.e. Medial Femorotibial Compartment + Lateral Femorotibial Compartment.

 250

 200

 150

 100

50 0 -50 -100 -150

iPPS 1xW iPPS 2xW Placebo

Adj. CFB (abs) LS Mean Day 168

      Central

Medial Femur Femorotibial

Medial Tibia

Lateral Tibia

Overall

Medial Compartment

Central

Lateral Femur Femorotibial

Cartilage Volume (mm3)

Lateral Compartment

 Bone marrow lesions

BML (mm2I) Adj. CFB (abs.) LSM results.

   Compartments/Regions

BML Overall Region: Femur Region: Tibia Region: Patella

iPPS-Once N=19 Day 168 303.73

316.95 34.12 24.17

iPPS-Twice N=15 Day 168 -86.26

-320.63 149.17 -31.14

Placebo N=22 Day 168 120.65

77.71 -57.47 39.31

  400

 300

 200

 100

0 -100 -200 -300 -400

iPPS 1xW iPPS 2xW Placebo

Overall

Femur

Tibia

Patella

BML (mm2I)

Adj. CFB (abs) LS Mean Day 168

      Synovitis (inflammation)

Synovitis (mm2I) Adj. CFB (abs.) LSM results.

   Compartments/Regions

Synovitis Overall

Region: Suprapatellar recess Region: Medial recess Region: Hoffas fat pad Region: Lateral recess

iPPS-Once N=19 Day 168 4873.47

1115.35 1161.82 387.92 1579.10

iPPS-Twice N=15 Day 168 -5086.13

436.01 -2702.41 -1337.67 -1470.93

Placebo N=22 Day 168 -2707.38

-367.38 -3232.04 -806.95 1450.95

                6000

 4000

 2000

0 -2000 -4000 -6000

iPPS 1xW iPPS 2xW Placebo

Synovitis Overall

Suprapatellar Medial recess Hoffas fat pad Lateral recess recess

Synovitis (mm2I)

    Adj. CFB (abs) LS Mean Day 168

 Previously reported Day 168 molecular biomarker analysis

The structural changes demonstrated via MRI are consistent with data previously reported (4 April 2023). These data showed reductions in molecular biomarkers of cartilage degradation from baseline to Day 168 in iPPS-treated subjects compared to placebo.

  Molecular Biomarker

C2C (Se)

CTX II (U) COMP (SF) COMP (Se) ARGS (SF) ARGS (Se)

Day 168 iPPS v placebo

Reduced (p=0.024)

Reduced Reduced Reduced Reduced (p=0.024) Reduced

        Molecular biomarkers of cartilage degradation reduced following iPPS treatment compared to placebo at Day 168. ARGS = Aggrecan amino acids alanine, arginine, glycine, and serine; C2C = collagen type-II C- terminal cleavage neoepitope; COMP = cartilage oligomeric matrix protein; CTX II = C-terminal crosslinked telopeptide type II collagen; Se = serum; SF = synovial fluid; U = urine.

The biomarkers C2C, CTX II, COMP, and ARGS are known to be associated with cartilage degradation (12,13). PARA_OA_008 results demonstrated reduced biomarker levels in the synovial fluid following iPPS treatment. These changes are consistent with the structural changes of improvement in cartilage thickness and volume seen with MRI.

 PARA_OA_008 clinical trial design

 PARA_OA_008 is a phase 2 exploratory study conducted at two sites in Australia. It explored changes in synovial fluid biomarkers with pentosan polysulfate sodium (iPPS) treatment compared with placebo in participants with knee osteoarthritis pain.

Sixty-one (61) eligible participants were enrolled and randomly assigned to a study intervention. Participants were administered twice weekly subcutaneous (SC) injections of iPPS calculated for ideal body weight (IBW):

• iPPS twice weekly: 2.0 mg/kg IBW PPS twice weekly for 6 weeks, (N = 19).

• iPPS once weekly: 2.0 mg/kg IBW PPS once weekly + placebo once weekly for 6

weeks, (N = 20).

• Placebo: placebo twice weekly for 6 weeks, (N = 22).

 The primary objective of the study is to evaluate the effect of iPPS on synovial fluid biomarkers associated with pain and OA disease progression in participants with knee OA pain.

The Primary Endpoint was change from baseline at Day 56 in one or more synovial fluid biomarkers of inflammation, pain, and joint degradation, including but not limited to cartilage oligomeric matrix protein (COMP), c-terminal telopeptide II (CTX-II), nerve growth factor (NGF), interleukin-1β (IL-1β), tumour necrosis factor alpha (TNFα), IL-6, a disintegrin and metalloproteinase with thrombospondin motif 5 (ADAMTS-5), aggrecan

 ARGS fragment, tissue inhibitor matrix metalloproteinase 1 (TIMP-1), CTX-I, and type II collagen (C2C).

Secondary Objectives included evaluating clinical outcomes, determining the correlation between synovial fluid biomarkers and clinical outcomes, determining the correlation between biomarkers in synovial fluid and biomarkers in serum and urine, and evaluating the effect of iPPS on serum and urine biomarkers associated with inflammation and OA disease progression in participants with knee OA pain.

Participants in the study were asked to provide baseline pain scores using the self- assessed WOMAC Osteoarthritis Index. After patients had initiated treatment, their pain scores were measured at predetermined timepoints from Day 11 out to Day 365 (12 months), with Day 56 the first predetermined timepoint for WOMAC assessment after the completion of treatment (Day 39).

  References

1. Eckstein F, Mc Culloch CE, Lynch JA, Nevitt M, Kwoh CK, Maschek S, et al. How do short-term rates of femorotibial cartilage change compare to long-term changes? Four year follow-up data from the osteoarthritis initiative. Osteoarthritis Cartilage. 2012 Nov;20(11):1250–7.

2. Geng R, Li J, Yu C, Zhang C, Chen F, Chen J, et al. Knee osteoarthritis: Current status and research progress in treatment (Review). Exp Ther Med. 2023 Oct;26(4):481.

3. Cicuttini FM, Jones G, Forbes A, Wluka AE. Rate of cartilage loss at two years predicts subsequent total knee arthroplasty: a prospective study. Ann Rheum Dis. 2004 Sep;63(9):1124–7.

4. Eckstein F, Kwoh CK, Boudreau RM, Wang Z, Hannon MJ, Cotofana S, et al. Quantitative MRI measures of cartilage predict knee replacement: a case-control study from the Osteoarthritis Initiative. Ann Rheum Dis. 2013 May;72(5):707–14.

5. Eckstein F, Wirth W. Quantitative cartilage imaging in knee osteoarthritis. Arthritis. 2011;2011:475684.

6. Wluka AE, Forbes A, Wang Y, Hanna F, Jones G, Cicuttini FM. Knee cartilage loss in symptomatic knee osteoarthritis over 4.5 years. Arthritis Res Ther. 2006;8(4):R90.

7. Hinterwimmer S, Feucht MJ, Steinbrech C, Graichen H, von Eisenhart-Rothe R. The effect of a six- month training program followed by a marathon run on knee joint cartilage volume and thickness in marathon beginners. Knee Surg Sports Traumatol Arthrosc Off J ESSKA. 2014 Jun;22(6):1353–9.

8. Reichenbach S, Yang M, Eckstein F, Niu J, Hunter DJ, McLennan CE, et al. Does cartilage volume or thickness distinguish knees with and without mild radiographic osteoarthritis? The Framingham Study. Ann Rheum Dis. 2010 Jan;69(1):143–9.

9. Dore D, Quinn S, Ding C, Winzenberg T, Zhai G, Cicuttini F, et al. Natural history and clinical significance of MRI-detected bone marrow lesions at the knee: a prospective study in community dwelling older adults. Arthritis Res Ther. 2010;12(6):R223.

10. Tanamas SK, Wluka AE, Pelletier JP, Martel-Pelletier J, Abram F, Wang Y, et al. The association between subchondral bone cysts and tibial cartilage volume and risk of joint replacement in people with knee osteoarthritis: a longitudinal study. Arthritis Res Ther. 2010;12(2):R58.

11. Walsh DA, Sofat N, Guermazi A, Hunter DJ. Osteoarthritis Bone Marrow Lesions. Osteoarthritis Cartilage. 2023 Jan;31(1):11–7.

12. Hunter D, Li J, LaValley M, Bauer D, Nevitt M, DeGroot J, et al. Cartilage markers and their association with cartilage loss on magnetic resonance imaging in knee osteoarthritis: the Boston Osteoarthritis Knee Study. Arthritis Res Ther. 2007;9(5):R108.

13. Huang K, Wu L. Aggrecanase and Aggrecan Degradation in Osteoarthritis: A Review. J Int Med Res. 2008 Dec;36(6):1149–60.

  To learn more please visit: https://paradigmbiopharma.com Approved for release by the Paradigm Board of Directors.

FOR FURTHER INFORMATION PLEASE CONTACT: Simon White

Director of Investor Relations

Tel: +61 404 216 467

Paradigm Biopharmaceuticals Ltd

ABN: 94 169 346 963

Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA Email: [email protected]

        PARA_OA_008 PHASE 2 TRIAL TOP-LINE RESULTS DAY 168 QUANTITATIVE MRI DATA ANALYSIS

  Disclaimer

This document, together with any information communicated by Paradigm Biopharmaceuticals Ltd ASX:PAR (known as “Paradigm”, “Paradigm Biopharma” or “the Company”), in any presentation or discussion relating to this document (collectively, “Information”) is confidential, and has been prepared by the Company on the condition that it is for the exclusive information and use of the recipient. The Information is proprietary to Paradigm and may not be disclosed to any third party or used for any other purpose without the prior written consent of the Company.

The Information is based upon management forecasts and reflects prevailing conditions, which are accordingly subject to change. In preparing the Information, the Company has relied upon and assumed, without independent verification, the accuracy and completeness of all information available from public sources, or which was otherwise reviewed by it. In addition, the analyses are not and do not purport to be appraisals of the assets, stock or business of the Company. Even when the Information contains a kind of appraisal, it should be considered preliminary, suitable only for the purpose described herein and should not be disclosed or otherwise used without the prior written consent of Paradigm. The Information is provided on the understanding that unanticipated events and circumstances may occur which may have significant valuation and other effects.

This Company presentation contains forward-looking statements, including statements regarding anticipated commencement dates or completions dates of preclinical or clinical trials, regulatory developments and regulatory approval.

These forward-looking statements are not guarantees or predictions of future performance, and involve known and unknown risks, uncertainties and other factors, many of which are beyond our control, and which may cause actual results to differ materially from those expressed in the statements contained in this presentation. Readers are cautioned not to put undue reliance on forward-looking statements. The rate and timing of enrolment of our clinical trials and the timing of top-line results of our clinical trials should be regarded as forward-looking statements and the actual dates could differ materially from the expectations and projections set forth in Company presentations or statements especially during a pandemic.

Paradigm Biopharma April 2023 2

  Paradigm Biopharma OCT 2023 3

  Executive Summary

PARA_OA_008

Key Highlights – Structural improvements at Day 168

• iPPS shows improvement in joint structures at Day 168 vs placebo in a randomised, double-blind, placebo-controlled phase 2 clinical study (PARA_OA_008):

o Improved cartilage volume and thickness.

o Reduced bone marrow lesion size and volume. o Reduced Synovitis intensity.

• MRI data consistent with WOMAC pain and function improvements at Day 168.

• Consistent with the durability and significant pain and function improvements reported at Day 365.

• High unmet need for new OA therapies to slow OA progression in tandem with symptomatic improvement (pain reduction and functional improvement).

• Enhances data package for discussions with key regulatory agencies and attractiveness of iPPS to potential partners.

   Near-term News flow

Upcoming Catalysts

Near-term news flow

ü PARA_OA_008 clinical trial – 12-month clinical outcome data.

ü PARA_OA_008 clinical trial – 6-month quantitative MRI data.

• DMOAD pathway – discussion with regulatory agencies (FDA, EMA) Q1 CY2024.

• TGA Provisional Approval – Update on application timeline Q4 CY2023

• MPS VI phase 2 clinical trials – top-line data Q4 CY2023.

• PARA_OA_002 Dose Selection followed by phase 3 progression – Q1 CY2024.

• The MPS I and PARA_OA_008 – clinical data sets are currently being prepared for peer review. Publication likely in CY2024.

• Paradigm is currently in active discussion with potential regional partners for its phase 2 asset in mucopolysaccharidosis (MPS) and phase 3 asset in OA.

Paradigm Biopharma OCT 2023 4

  Knee anatomy

Cross-sectional images from a side-on view

Paradigm Biopharma

OCT 2023 5

     Patella (kneecap)

Femur

Cartilage

Tibia Fibula

Femur Cartilage

Tibia

    Knee side-on view schematic

Knee side-on view MRI

Figure created with images from BioRender.com

  Knee compartments

As seen via MRI with a front-on view

Paradigm Biopharma OCT 2023 6

    Lateral compartments

Lateral compartments

  Right knee

Left knee

Medial compartments

Figure created with images from BioRender.com

  Biomarkers of osteoarthritis

A disease of the whole joint

  Subchondral bone degeneration (bone thickening)

 Cartilage thickness & volume

Progressive loss & destruction of articular cartilage

Adverse bone remodelling

 Cartilage breakdown products (C2C, COMP, CTX-I, CTX-II)

Bone marrow lesions

   Extracellular matrix breakdown products (ARGS)

Osteophyte (bone spur) formation

  Enzymes degrading aggrecan that is linked to cartilage repair (ADAMTS-4 & -5)

 Figure created with images from BioRender.com

Synovial inflammation & joint capsule swelling

MRI biomarker

Molecular biomarker

Joint synovitis, effusion volume

 Inhibitors of cartilage breakdown (TIMP-1)

 Mediators of cartilage breakdown (MMP-3)

Pain mediators (NGF)

 Inflammatory cytokines (IL-1β, IL- 6, TNF-α)

 PARA_OA_008

OA

  Paradigm Biopharma OCT 2023 9

  Top-Line Results

PARA_OA_008

Top-Line Results – Day 168 Quantitative MRI

• MRI quantitative analysis data demonstrates that a six-

week iPPS treatment course can alter osteoarthritis (OA) disease progression compared to placebo in a study of 61 participants with knee OA by:

o Increase in cartilage volume and thickness most notably in the medial compartment where the highest proportion (72%) of knee OA occurs.

o Reduction in bone marrow lesions.

o Reduction in inflammation (synovitis).

• As osteoarthritis progresses, the medial side of the knee tends to lose cartilage more rapidly than the lateral side.

  Paradigm Biopharma OCT 2023 10

  Cartilage Thickness & Volume

PARA_OA_008

Day 168 Top-Line Results – Cartilage Thickness and Volume

• Considered the most important feature of OA disease.

• Predictive of knee replacement surgery in OA sufferers.

• As knee osteoarthritis progresses, the medial side of the knee tends to lose cartilage more rapidly than the lateral side.

• The reduction of cartilage loss (cartilage preservation), may therefore delay time to total knee replacement (TKR) in an osteoarthritic knee.

• In the natural progression of OA, knees with Kellgren Lawrence (KL) grades of 2-4 (PARA_OA_008 subject cohort) would be expected to have an annual loss in cartilage thickness of around 50μm and loss in cartilage volume of around -4% at the central medial femur.

  PARA_OA_008

Top-Line Day 168 Quantitative MRI Results

Paradigm Biopharma OCT 2023 11

  Cartilage Thickness (μm) Adj. CFB (abs.) LSM results by medial region in the knee

Changes in Cartilage Thickness from baseline

• Twice weekly iPPS arm, demonstrated a consistent pattern across regions of cartilage thickening over 6 months

• Placebo showed a loss in cartilage thickness in all medial compartments at 6 months.

• iPPS increased the cartilage thickness in the central medial femur by 60μm (0.06mm) compared to a reduction of -20μm (-0.02mm) in the placebo group at 6 months.

• Placebo consistent with the naturally occurring cartilage loss rate in knee OA progression (- 40μm or 0.04mm per year).

  PARA_OA_008

Top-Line Day 168 Quantitative MRI Results

Paradigm Biopharma OCT 2023 12

  Average percentage (%) change from baseline (CFB) in cartilage thickness (mm) by medial region in the knee.

Changes in Cartilage Volume from baseline

• iPPS showed an average increase in cartilage volume of 4.6%, in the medial femorotibial compartment compared to baseline, whereas the placebo arm showed a loss of cartilage volume of -1.7%.

• iPPS is reversing the breakdown of cartilage at 6 months, compared to placebo which is showing further cartilage volume loss from baseline consistent with the natural progression of the disease (4% reduction in cartilage volume per year).

  Cartilage thickness

PARA_OA_008 representative images

Cartilage thickness improvement in medial compartment

Baseline

Day 168

Paradigm Biopharma OCT 2023 13

Cartilage thinning

in medial compartment

 Twice-weekly iPPS Placebo

    Bone Marrow Lesion

PARA_OA_008

01/04/21 14 Paradigm Biopharma April 2023 14

Day 168 Top-Line Results – Bone Marrow Lesion (BML) Volume

• BML's appear as increased signal intensity within the bone marrow.

• Subchondral BML’s are a common in knee OA and believed to be related to microtrauma resulting from overloading caused by loss of the normal weight bearing function of articular cartilage

• Increasing presence of BML are predictive of increased cartilage loss and like cartilage loss, BML’s have been shown to be predictive of knee replacement.

  PARA_OA_008

Top-Line Day 168 Quantitative MRI Results

Changes in bone marrow lesions from baseline

• Overall BML volume in the knee was reduced on average by 17.6% in the iPPS twice weekly, compared to a 2% increase in the placebo group.

• The reduction in BMLs is consistent with reduced inflammation and cartilage preservation.

Paradigm Biopharma OCT 2023 15

  Average percentage (%) change from baseline (CFB) in overall bone marrow lesions

  Bone marrow lesions

PARA_OA_008 representative images

Resolution of BML at Day 168.

Baseline

Day 168

Paradigm Biopharma OCT 2023 16

BML increase in size at Day 168

  Twice-weekly iPPS Placebo

  Paradigm Biopharma OCT 2023 17

  Synovitis

Synovial joint inflammation

• In OA, the synovial membrane can become inflamed and thickened in response to joint degeneration.

• Inflammation causes increased synovial fluid production.

• Excess synovial fluid can lead to joint swelling and can be

associated with increased pain and stiffness.

Figure created with images from BioRender.com

Synovial membran

Synovial flueid

Bone erosion

Swollen inflamed synovial membrane

 Normal knee joint

Synovitis of the knee joint

  PARA_OA_008

Top-Line Day 168 Quantitative MRI Results

Paradigm Biopharma

OCT 2023 18

  Changes in synovitis from baseline

• At Day 168 in this phase 2 clinical trial synovitis increased from baseline in the placebo arm (4.6%) compared to a slight decrease (-1%) in the twice weekly iPPS arm.

• MRI images analysed from baseline and at 6 months following iPPS twice

weekly versus placebo demonstrate an overall reduction in the intensity of synovitis.

 Average (SD) percentage (%) change from baseline (CFB) in overall knee joint synovitis.

  Synovitis

PARA_OA_008 representative images

Reduced intensity

of synovitis at Day 168

Baseline

Day 168

Paradigm Biopharma OCT 2023 19

Increased intensity of

synovitis at Day 168

  Twice-weekly iPPS Placebo

  Paradigm Biopharma

OCT 2023 20

  Optimal Dose

OA Program

iPPS optimal dose 2 mg/kg twice-weekly

• A lot of clinical experience with 2 mg/kg twice-weekly:

o PARA_005, 121 participants total.

o PARA_OA_008, 61 participants total.

o TGA Special Access Scheme (SAS), >600 patients.

• Regulatory authorities requested identifying the minimal effective dose.

• Included a dose finding arm in the two-stage global placebo- controlled, randomised, adaptive PARA_OA_002 phase 3 trial.

• Program to proceed with dose of 2 mg/kg iPPS twice weekly

for further development based on the above clinical experience and dose finding results.

  PARA_OA_008

Summary of phase 2 randomised controlled clinical trial

Paradigm Biopharma OCT 2023 21

  iPPS demonstrated efficacy on both objective and subjective measures compared to placebo

 OBJECTIVE DATA MEASURES

Improvement in synovial fluid biomarkers associated with OA disease progression Improvement in structural changes in the knee determined by MRI

SUBJECTIVE DATA MEASURES

Significant improvement in mean change from baseline in WOMAC pain, function, and overall scores.

Significant improvement in Patient Global Impression of Change (PGIC)

Reported

Day 56 & 168 Day 168

Reported

Day 56, 168 & 365

Day 365

  Paradigm Biopharma

OCT 2023 22

  Contacts

CORPORATE ENQUIRIES:

Paul Rennie

Managing Director

Email: [email protected]

INVESTOR RELATIONS ENQUIRIES:

Simon White

Director IR

Email: [email protected]

MEDIA ENQUIRIES:

Rachel Peat

PR and Communication

Email: [email protected]

  For more information please visit:

paradigmbiopharma.com

long term this announcement is important as further confirmation that the drug works and will be approved (sooner or later)

short term I think this will be a catalyst for the SP to recover having been pummeled as part of the pre-revenue blow up and risk off environment.

still need to watch cashburn but hopefully the scariest times are behind

How exciting! Hoping this is positive news about disease modification

ASX RELEASE

By email: [email protected]

Melissa Kostopoulos

Adviser, Listings Compliance (Melbourne) ASX Limited

Dear Melissa

Request for a trading halt

6 October 2023

Paradigm Biopharmaceuticals Limited ACN 169 346 963 (ASX: PAR) (the Company), requests that the Company's securities be placed into trading halt with immediate effect.

The Company is requesting a trading halt pending the release of new clinical data from the PARA_OA_008 Phase 2 clinical trial investigating iPPS in knee OA to the market on Tuesday 10 October 2023. Accordingly pursuant to ASX Listing Rule 17.1, the Company requests the trading halt in order to finalise its review and update to the market.

The Company requests that the trading halt remains in place until the earlier of the Company making an announcement in relation to the new clinical data or commencement of trading on Tuesday 10 October 2023.

The Company is not aware of any reason why the trading halt should not be granted. Authorised for release on behalf of the Board of Paradigm Biopharmaceuticals Limited.

Yours faithfully,

Abby Macnish Niven Company Secretary

This is a little scary. The cashburn is so significant that even with nearly 60 mil in the bank they’re looking at less than 4 quarters of cash…

unfortunately I can see this leading to sag in SP which then makes the cash raise more dilutive… the question as an investor then is do you sell down some knowing there’s a raise coming? I still believe in the product and think this will be profitable long term…

The below announcement confirms previously espoused guidance that the molecule studied by paradigm is a distinct molecule covered by approvals with the FDA and other bodies.

The potential upside is significant as even after patents expire for particular conditions the regulators may force generic producers to conduct studies of their particular molecule prior to releasing to market effectively eliminating competition

of course none of this is relevant until paradigm’s pentosan is actually approved for OA etc

ASX RELEASE 27 July 2023

Collaborative research article from bene pharmaChem, Kiel University, and Paradigm is accepted for publication.

Paradigm Biopharmaceuticals Ltd (ASX:PAR) (“Paradigm” or “the Company”), a late-stage drug development company focused on delivering new therapies to address unmet medical needs, is pleased to announce that a scientific article arising from a collaboration between bene pharmaChem, Kiel University, and Paradigm Biopharma scientists, has been accepted for publication in the scientific journal Carbohydrate Polymers. The article entitled “Chemical and biological differences between original and mimetic pentosan polysulfates” (1) is currently available as an open-access pre-print on the journal website.

Carbohydrate Polymers, published by Elsevier, is a major journal within the field of glycoscience and is devoted to scientific and technological aspects of medically and industrially relevant polysaccharides.

The collaborative study has demonstrated that Paradigm's pentosan polysulfate sodium (PPS) drug substance is different from other available PPS drug substances, both with respect to their respective structure and biological characteristics. This finding is commercially impactful in that it validates that Paradigm can expect to command a regulatory moat around PPS which is in addition to its extensive patent portfolio. Having a regulatory moat means that would be generic PPS manufacturer must perform their own clinical efficacy and safety studies in order to attain approval to market their PPS products.

PPS was originally manufactured by bene pharmaChem and is a semisynthetic sulfated polysaccharide derived from European beech tree wood. The manufacturing undergoes a complex process to produce a final mixture comprising of a spectrum of sulfated glucuronoxylans which are very challenging to be characterised by structural analysis. Although attempts have been made by other competitive PPS manufacturers , the bene pharmaChem PPS is the only product that has been approved by FDA and EMA for clinical use. PPS is currently approved for oral treatment of interstitial cystitis in Australia, Canada, the European Union, and the USA.

Dr Christian Reiter, Paradigm’s Senior Principal Researcher, commented: “This collaborative study involving University of Kiel, bene pharmaChem and Paradigm for the first time has described multiple structural differences in the chemical composition of bene PPS compared to the other commercially available PPS products. Our study gives evidence that PPS is a complex drug and that products from different manufacturers are chemically and functionally not identical.”

Paradigm’s Chair and Managing Director, Mr Paul Rennie said, “I am pleased that this peer-reviewed publication in this highly regarded journal emphasis that the bene PPS

is unique structurally and functionally and furthermore, Paradigm has demonstrated the safety and clinically efficacy in its osteoarthritic and rare disease indications. It would appear to be a significant challenge by competitors to develop a convincingly similar or generic PPS by further investigations to meet the regulatory requirement for clinical use. Furthermore, Paradigm’s patents cover the use of bene’s PPS in a range of medical indications in musculoskeletal diseases”.

About Paradigm Biopharmaceuticals

To learn more please visit: www.paradigmbiopharma.com

FOR FURTHER INFORMATION PLEASE CONTACT:

Simon White

Director of Investor Relations

Tel: +61 404 216 467

Paradigm Biopharmaceuticals Ltd ABN: 94 169 346 963

Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA Email: [email protected]

 Paradigm Biopharmaceuticals Ltd. (ASX:PAR) is a late-stage drug development company driven by a purpose to improve patients’ health and quality of life by discovering, developing, and delivering pharmaceutical therapies. Paradigm’s current focus is developing injectable (subcutaneous) pentosan polysulfate sodium (iPPS) for the treatment of diseases where inflammation plays a major pathogenic role, indicating a need for the anti-inflammatory and tissue regenerative properties of iPPS, such as in osteoarthritis (phase 3) and mucopolysaccharidosis (phase 2).

 Not sure this really required an announcement but nice to know they’re recruiting solidly… look forward to results of stage 1 of the trial, nice to at least know what dose is being studied… results still so far away although interim results could be a decent catalyst for a re-rate… as would interest from big pharma which I think is plausible

ASX RELEASE 4 July 2023

PARA_OA_002 Phase 3 Clinical Trial Update

KEY HIGHLIGHTS

• Stage 1 (dose selection) of the PARA_OA_002 phase 3 clinical trial completes recruitment. The final stage 1 participants are currently completing the protocol- mandated screening and randomization which is expected to be complete early in Q3 CY2023.

• Paradigm is on track to conclude dose selection once all stage 1 participants reach 84 days post initial treatment. Post dose selection, newly recruited participants will proceed to stage 2 of PARA_OA_002 with the most effective dose. Additionally, PARA_OA_003 the confirmatory study will proceed with the selected dose.

• Paradigm has achieved its target by (i) activating 120 clinical trial sites across 7 countries and (ii) initiating a number of innovative recruitment initatives.

• The timeline for Paradigm’s New Drug Application (NDA) with the US FDA remains on track.

• The independent Data Monitoring Committee recommends, based on two formal safety reviews, to proceed, with the pivotal Phase 3 clinical trial, without modification. The most recent DMC review occurred on June 20, 2023.

Paradigm Biopharmaceuticals Ltd (ASX:PAR) (“Paradigm” or “the Company”), a late-stage drug development company focused on delivering new therapies to address unmet medical needs, is pleased to provide an update on the recruitment progress for the PARA_OA_002 phase 3 clinical trial evaluating the change from baseline in pain and joint function following injectable pentosan polysulfate sodium (iPPS) compared to placebo in participants with knee osteoarthritis (OA).

Paradigm can confirm that participants have been identified for completion of stage 1 of the PARA_OA_002 clinical trial. Paradigm expects the final participants in screening to be randomised during Q3 this calendar year. Once all participants in stage 1 are randomised and reach the pre-specified timepoint, the data monitoring committee (DMC) will select the optimal dose for proceeding to stage 2. Following dose selection, the PARA_OA_003 confirmatory trial can commence.

The DMC has to date conducted two formal safety reviews of the PARA_OA_002 clinical trial. The DMC is responsible for assessing safety and efficacy during the conduct of Paradigm’s PARA_OA_002 study, as well as ensuring the validity and scientific merit of the trial. The recommendation from the reviews by the DMC were that the clinical trial proceed without modification.

The completion of stage 1 and dose selection remains within previously reported timelines, with dose selection and stage 2 activities of the PARA_OA_002 clinical trial to occur in 2H CY2023. The timeline for Paradigm’s NDA with the US FDA remains on track.

Paradigm has been able to progress its recruitment with the assistance of several recruitment initiatives. The PARA_OA_002 clinical trial has activated 120 sites across 7 countries comprising Australia, the US and Canada in North America, the UK, Belgium, Poland and Czechia in the EU. As Paradigm has reached its target for site activation and these clinical trial sites have become familiar with the study design, Paradigm has been able to increase the number of participants directed to these sites through the utilisation of the recruitment initiatives. The implemented initiatives include the introduction of 1nHealth, SubjectWell, and Paradigm’s partnership with NFL Alumni Health, which together have driven potential participants to study sites for screening and randomisation. Paradigm has recently launched a dedicated clinical trial website www.Hope4OA.com, an ethics-approved easy-to-use public-facing website for providing trial information and access to an eligibility questionnaire for Paradigm’s OA clinical trials.

Paradigm’s Managing Director, Mr Paul Rennie commented: “Our progress has been achieved by a team of dedicated professionals, which is very encouraging, since it augurs well for our upcoming clinical milestones. Over the last 6 months, we have achieved a rapid increase in pre-screening and patient enrolment numbers. Due to the multiple effective recruitment initiatives, we expect this recruitment rate to be maintained throughout stage 2 as well as the confirmatory PARA_OA_003 study.”

 The PARA_OA_002 trial

 The purpose of PARA_OA_002, a

 phase 3 clinical trial, is to measure the change from

 baseline in WOMAC pain and function with subcutaneous injections of

compared

 with subcutaneous injections of placebo in participants with knee OA pain.

placebo-controlled, multicentre

two-stage, adaptive, randomised, double-blind, iPPS

Stage 1 comprises approximately 468 participants randomised to receive one of three iPPS dose regimens or placebo for 6 weeks. The primary objective of stage 1 is to identify the optimal dose for stage 2 and for Paradigm’s confirmatory trial. Selection of the selected dose is based on considerations of optimal efficacy and optimal safety.

Participants in stage 1 are randomly allocated to receive one of the following:

• 1.5 mg/kg calculated for ideal body weight (IBW) iPPS twice weekly,

• 2 mg/kg IBW iPPS once weekly + placebo once weekly,

• Fixed doses

o 100 mg iPPS for ≤65 kg IBW once weekly + placebo once weekly, or

o 150 mg iPPS for >65 to ≤90 kg IBW once weekly + placebo once weekly,

or

o 180 mg iPPS for >90 kg IBW once weekly + placebo once weekly 

• Placebo twice weekly

In stage 2, approximately 470 participants will be randomised 1:1 to receive the selected

iPPS dose regimen or placebo for 6 weeks.

Participants in stage 2 will be randomly allocated to receive:

• iPPS dose regimen selected by the DMC, or

• Placebo twice weekly.

The primary endpoint in the PARA_OA_002 study will be change from baseline at day 56 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain. Secondary outcomes include change from baseline at multiple timepoints out to day 168 in WOMAC pain and function, Patient Global Impression of Change (PGIC), and Quality of Life (QoL).

Phase 3 Clinical Program Recruitment Initiatives

Hope4OA

To facilitate current and potential trial participants, Paradigm launched a new clinical trials website called Hope4OA.com. The website is designed for ease of use where potential participants can discover trial details and find answers to commonly asked questions. If interested, they are invited to complete an online questionnaire to determine their eligibility as a potential trial participant. The website hosts helpful explanations and instructional videos about clinical trials in general, as well as providing links to patient support and further information.

1nHealth

1nHealth is a global patient recruitment company that has established a strong reputation in the supporting full enrolment for pharma sponsors across a wide range of therapeutic areas. 1nHealth excels in engaging and enrolling participants through its patient-centric content and technology-enabled approach, making the process seamless for patients and for the study’s research sites alike. Through the partnership with Paradigm, 1nHealth employs a thorough pre-screening process to ensure participants are more likely to meet eligibility criteria for the PARA_OA_002 clinical trial, enabling a more seamless enrolment process.

SubjectWell

SubjectWell is a leading recruitment platform that excels in connecting sponsors and researchers with eligible trial participants. Leveraging advanced technology and a vast network of potential participants SubjectWell streamlines the recruitment process making it faster and more efficient. Through their user-friendly interface, they match individuals to relevant clinical trials based on specific criteria, medical history demographics, and location. SubjectWell’s capabilities extend beyond traditional recruitment methods, as they employ digital marketing strategies, social media outreach, and targeted advertising to reach a diverse pool of potential participants. Their data driven approach ensures high quality referrals optimising the enrolment process and enhancing the speed of trial completion.

NFL Alumni Health Research Partnership

Following the successful Expanded Access Program (EAP) where 10 ex-NFL players were treated with iPPS, Paradigm entered a research partnership with NFL Alumni Health (see ASX announcement 13 July 2022). NFL Alumni Health is a wholly owned subsidiary of NFL Alumni, offering informational resources, programs, services, and other benefits to both NFL Alumni members (former NFL players, coaches, executives, spouses, cheerleaders, and associate members). Since the formation of this partnership, Paradigm has conducted several presentations to NFL Alumni Chapter Presidents to provide information about osteoarthritis disease onset and progression, current treatment options, and clinical trials throughout the US. Through this partnership, Paradigm has seen strong interest from NFL Alumni members in accessing further information on the PARA_OA_002 clinical trial which has boosted enrolment numbers. This partnership with NFL Alumni Health is expected to continue throughout the phase 3 clinical program.

 About Paradigm Biopharmaceuticals

 Paradigm Biopharmaceuticals Ltd. (ASX:PAR) is a late-stage drug development company driven by a purpose to improve patients’ health and quality of life by discovering, developing, and delivering pharmaceutical therapies. Paradigm’s current focus is developing injectable (subcutaneous) pentosan polysulfate sodium (iPPS) for the treatment of diseases where inflammation plays a major pathogenic role, indicating a need for the anti-inflammatory and tissue regenerative properties of iPPS, such as in osteoarthritis (phase 3) and mucopolysaccharidosis (phase 2).

 Forward Looking Statements

This Company announcement contains forward-looking statements, including statements regarding anticipated commencement dates or completions dates of preclinical or clinical trials, regulatory developments and regulatory approval. These forward-looking statements are not guarantees or predictions of future performance, and involve known and unknown risks, uncertainties and other factors, many of which are beyond our control, and which may cause actual results to differ materially from those expressed in the statements contained in this presentation. Readers are cautioned not to put undue reliance on forward-looking statements.

To learn more please visit: www.paradigmbiopharma.com

FOR FURTHER INFORMATION PLEASE CONTACT:

Simon White

Director of Investor Relations

Tel: +61 404 216 467

Paradigm Biopharmaceuticals Ltd ABN: 94 169 346 963

Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA Email: [email protected]

If I’m honest, I don’t actually consider indications other than OA in my thesis for PAR but they could turn out as nice bonuses for PAR and for the patients.

MPS 1 is a comparatively rare disease and may end up being sorted out by gene therapy etc (I’m a massive optimist about these therapies) but in the meantime anything that improves symptoms in this cohort would be very welcome (and reasonably remunerated I think)

the other nice point here is more evidence of safety

of course this is only a phase 2 trial and part of me hopes there not burning too much cash with this kind of thing when OA is clearly the main game

 ASX RELEASE 6 June 2023

MPS I phase 2 clinical trial shows promising results of primary, secondary, and exploratory endpoints.

KEY HIGHLIGHTS

• Primary Endpoint attained: iPPS was well tolerated with no serious adverse events reported out to 73 weeks.

• Secondary Endpoints also attained; meaningful improvements in pain, function, and activities of daily living and an overall improvement in quality of life were observed in all patients.

• Changes in biomarker profiles at 49 and 73 weeks of iPPS treatment suggest that iPPS has the potential to modulate the biomarkers that are associated with joint degeneration and arthralgia in MPS I patients.

• The predominant MPS I GAG fragment decreased from baseline at Week 73.

• Aggregate (paediatric and adult) PROMIS T scores for pain behaviour, pain interference, and fatigue improved in all subjects evaluated at all timepoints (Weeks 49 and 73).

Paradigm Biopharmaceuticals Ltd (ASX:PAR) (“Paradigm” or “the Company”),

report a top-line summary of outcomes from the phase 2 open-label, single centre pilot study to evaluate injectable pentosan polysulfate sodium (iPPS) treatment in subjects with mucopolysaccharidosis type I (MPS I). Four subjects (n=4) were sequentially allocated to Cohort 1 (0.75 mg/kg) or Cohort 2 (1.5 mg/kg) and administered iPPS subcutaneous injections once weekly through to Week 12, then fortnightly to Week 48. Eligible subjects were invited to continue in a study extension for an additional 6 months of treatment (Week 72). The MPS I clinical trial has shown positive outcomes in primary, secondary, and exploratory endpoints, supporting iPPS as an adjunct therapy to treat the residual joint pain and reduced function observed in MPS I sufferers.

The results from this study in MPS I are a significant development in the treatment of this rare disease. This release details the summary of outcomes from the Phase 2 trial only, as Paradigm intends to release the complete data set in a peer reviewed publication.

MPS I is a rare disease caused by reduced levels, or the complete lack of an enzyme responsible for the catabolism (break down) of  s

GAGs The disorder causes problems with neurological, skeletal, and cardiovascular development. There is no cure and children born with the most severe form of MPS I do not typically survive beyond 10 years of age without treatment. Current standard treatments include bone marrow transplant and enzyme replacement therapy to address the underlying cause of the disease.

The primary objective of the study was to evaluate safety and tolerability of iPPS over an initial 48-week treatment period, with a 6-month treatment extension available, in patients treated with the current standard of care. Secondary and exploratory

  disruption of normal cellular processes results in the progressive accumulation of

glycosaminoglycans (GAG

). This

in bodily tissues.

objectives included examining the effects of iPPS on pain, function, and quality of life, pharmacokinetics, biomarkers of inflammatory processes. The study was conducted at the Adelaide Women’s and Children’s Hospital with Dr David Ketteridge, the Principal Investigator and Dr Drago Bratkovic (Head of the Metabolic Clinic) leading the clinical trial.

Paradigm Managing Director, Mr Paul Rennie commented: “The top-line summary of results from this phase 2 trial are a significant outcome not only for Paradigm but also for those with MPS who suffer ongoing pain and joint disfunction. The Company is in the process of developing a manuscript for peer review publication and look forward to sharing the full data and outstanding results with investors and the MPS community. I congratulate the Paradigm MPS team for the completion of this study and the data produced prior to our reported timelines”.

Top-Line Data Summary

The primary endpoint, safety, and tolerability of iPPS in subjects with MPS I, showed positive outcomes in the phase 2 study. Subcutaneous iPPS was well tolerated at doses of 0.75 and 1.5 mg/kg out to 72 weeks of dosing with no serious adverse events reported.

Secondary and exploratory endpoints assessed the efficacy of iPPS in MPS I subjects. A summary of secondary and exploratory outcomes include:

• Improved outcomes in physical tests (e.g., 2-minute and 6-minute walk tests, gait/stairs/Gower's/chair test, 9-hole peg test) demonstrating improved mobility and dexterity.

• Improvements in patient reported outcomes (PRO) of pain, function, fatigue, and quality of life.

• Changes in the profile of biomarkers after 48 and 72 weeks of iPPS treatment suggest that PPS has the potential to modulate bone and cartilage degradation biomarkers that are associated with cartilage loss and arthralgia in MPS I patients.

• Reduction from baseline (standard of care) in urinary MPS I GAG fragments.

Paradigm Global Head of Safety and MPS, Dr Michael Imperiale commented: “I am very pleased that iPPS has demonstrated a favourable safety profile, along with significant improvements in both biomarkers and clinical outcomes in MPS I patients. Paradigm is encouraged that iPPS may be an important addition to the armamentarium for treating this devastating disease.”

About Paradigm Biopharmaceuticals

Forward Looking Statements

This Company announcement contains forward-looking statements, including statements regarding anticipated commencement dates or completions dates of preclinical or clinical trials, regulatory developments and regulatory approval. These

 Paradigm Biopharmaceuticals Ltd. (ASX:PAR) is a late-stage drug development company driven by a purpose to improve patients’ health and quality of life by discovering, developing, and delivering pharmaceutical therapies. Paradigm’s current focus is developing injectable (subcutaneous) pentosan polysulfate sodium (iPPS) for the treatment of diseases where inflammation plays a major pathogenic role, indicating a need for the anti-inflammatory and tissue regenerative properties of iPPS, such as in osteoarthritis (Phase 3) and mucopolysaccharidosis (Phase 2).

forward-looking statements are not guarantees or predictions of future performance, and involve known and unknown risks, uncertainties and other factors, many of which are beyond our control, and which may cause actual results to differ materially from those expressed in the statements contained in this presentation. Readers are cautioned not to put undue reliance on forward-looking statements.

Authorised for release by the Paradigm Board of Directors. To learn more please visit: www.paradigmbiopharma.com

FOR FURTHER INFORMATION PLEASE CONTACT: Simon White

Director of Investor Relations

Tel: +61 404 216 467

Paradigm Biopharmaceuticals Ltd

ABN: 94 169 346 963

Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA Email: [email protected]

Animal evidence, it’s consistent with human trials in suggesting the drug works for pain for a reasonable duration. Whether it’s accepted as evidence of disease modification I’m not too sure…

 ASX RELEASE 1 June 2023

iPPS demonstrates durable effects on pain, function and cartilage volume in canine osteoarthritis model at 3-year human equivalent time point.

KEY HIGHLIGHTS

• Injectable pentosan polysulfate sodium (iPPS) provided durable improvements in pain, joint function, and cartilage volume compared to placebo at both 8 and 26 weeks from baseline.

• The 26-week timepoint in the canine model is equivalent to approximately 3 years in humans, highlighting the durability of positive iPPS treatment effects on osteoarthritis pain, joint structure and function.

• iPPS was shown to stabilise disease progression at week 8 and week 26 in osteoarthritic dogs.

• iPPS favourably regulates serum levels of molecular biomarkers CTX-1, HA, and TIMP-1 at week 8 and week 26 in osteoarthritic dogs. The observed biomarker data changes support the proposed PPS mechanisms of action.

• The canine study provides consistent supporting evidence which mirror the improvements in clinical outcomes previously reported from the phase 2 PARA_OA_008 Day 168 results. It supports the clinical development of Paradigm’s phase 3 trials PARA_OA_002/003 (treatment of pain and improvement in function) and observational follow-up studies PARA_OA_006/007 (duration of treatment effect).

Paradigm Biopharmaceuticals Ltd (ASX:PAR) (Paradigm or the Company) is pleased to present positive data from the double-blinded study of 20 companion dogs with naturally occurring osteoarthritis (OA), randomised to either subcutaneous iPPS (1.7 mg/kg human equivalent dose) or placebo in a 2:1 ratio, respectively. Data analysed from the canine study at 26 weeks demonstrates positive trends with meaningful effect size on subjective measurements of pain, objective functional clinical outcomes, and objective measurements of cartilage volume and biomarkers, following iPPS administration.

The canine model of naturally occurring OA was designed to gather further preclinical proof-of-concept and translational data to determine the long-term effects of iPPS out to an equivalent of 3 years in humans. These durable effects of iPPS out to at least 26 weeks in dogs support the findings from the recently reported phase 2 PARA_OA_008 Day 168 clinical data (1).

The positive data produced from this canine model will be packaged with the MRI, molecular biomarker, and clinical results from the phase 2 PARA_OA_008 and will be presented to the US and EU regulatory authorities (FDA and EMA). We aim to determine the necessary requirements to achieve a disease modifying OA drug (DMOAD) label for iPPS through the Company’s current phase 3 program. The canine model data will also be prepared for a peer-reviewed publication and conference presentation.

Paradigm CEO, Paul Rennie commented: “iPPS has again shown consistent clinical and functional improvements, this time in a double-blinded, placebo-controlled study of osteoarthritis in dogs. Pleasingly, this canine study provides consistent and supporting evidence which mirror the improvements in clinical outcomes previously reported from

the phase 2 PARA_OA_008 study at Day 168. In addition, and similarly to the PARA_OA_008 study, the canine study was performed concurrently with the PARA_OA_002 phase 3 study and therefore, did not interfere with nor impede the progress of our pivotal Phase 3 clinical trial. The market for OA is seeking safe and effective treatments for patients which provide clinically significant improvements in pain and function, and for those effects to be durable. Additionally, the canine data demonstrated that iPPS reduced cartilage degradation at the 3-year human equivalent time-point (canine 26 weeks) and improved the disease biomarker profile by reducing CTX-1 and hyaluronic acid and increasing TIMP-1 compared to placebo. Paradigm will use these canine data in our ongoing discussions with the Regulators”.

Top-Line Results on the Effects of iPPS at 26 Weeks in the Canine Model of Naturally Occurring OA

To assess differences between iPPS and placebo, effect size calculations were performed as this exploratory pilot study had low numbers between the groups. The effect size isthe magnitude of difference between groups and provides a meaningful relationship between variables or the differences between groups. Effect sizes are independent of the sample size and are categorised as small (0.20–0.49), medium (0.50– 0.79) or large (>0.80). The Hedges’ g calculation (https://www.statology.org/hedges-g/) was imputed in all the assessments reported in this study. The Hedges’ g effect size determines the iPPS effect size compared to placebo and considers sample bias, difference in the means, and standard deviations between treatment groups.

iPPS reduces pain at week 8 and week 26 in osteoarthritic dogs with meaningful effect size (Figure 1).

iPPS demonstrated pain reductions compared to placebo at week 8 and week 26 in osteoarthritic dogs with meaningful effect sizes based on the mean scores of the Helsinki Chronic Pain Index (HCPI). The HCPI is an owner-based subjective questionnaire developed to assess chronic pain in the dog (2). The data demonstrate a large meaningful effect size of 1.79 in pain reduction at week 26 compared to the percentage change from the previous follow-up (%CFPF) at week 8. This suggests that iPPS treatment results in a durable reduction in pain compared to placebo for up to 26 weeks.

   Figure 1

Pain Index

iPPS improves joint function at week 8 and week 26 in osteoarthritic dogs with meaningful effect size (Figure 2).

iPPS improves joint function at week 8 and week 26 in osteoarthritic dogs with a meaningful effect size on gait assessment by Total Pressure Index (TPI%). The dogs enrolled in the study were assessed with GAITRite®, a system successfully used in different clinical lameness studies in dogs. The effect size in improvement of function due to iPPS was a medium effect of 0.5 at both week 8 and week 26 based on the mean percentage change from baseline (%CFB) in TPI%. Furthermore, the responses to iPPS compared to placebo were considered to be clinically meaningful improvements in function, passing a benchmark of 5% change from baseline (3).

Figure 2

iPPS inhibits OA disease progression by stabilising cartilage volume changes at week 8 and week 26 in the stifle joints of osteoarthritic dogs (Figure 3).

iPPS stabilises OA disease progression as seen by effect size on cartilage volume changes from baseline at week 8 and week 26 in the affected stifle joint (knee equivalent) of osteoarthritic dogs. Analysis of the mean %CFB in cartilage volume at week 8 and week 26 indicated that iPPS demonstrated a large effect size (1.06) at week 8 and a medium effect size (0.73) at week 26 relative to placebo in reducing cartilage loss in the stifle joint of the affected limb. Results at both time points suggest stabilisation of OA disease progression in the stifle joints of osteoarthritic dogs.

   Total Pressure Index (Function)

 Figure 3

iPPS favourably regulates serum levels of the biomarkers CTX-1, HA and TIMP-1 with meaningful effect size at week 8 and week 26 in osteoarthritic dogs (Figure 4).

iPPS favourably regulates serum levels of molecular biomarkers determined by effect size on CTX-1 (4) a degradation fragment of type 1 collagen, hyaluronic acid (5) (HA) a marker of cartilage degradation, and TIMP-1 (6,7) an endogenous inhibitor of the cartilage degradation enzyme ADAMTS-5, at week 8 and week 26 in osteoarthritic dogs. The observed biomarker changes support PPS mechanisms of action targeting structural biomarkers of cartilage degradation as detailed in prior clinical results. The large favourable treatment effect sizes at week 26 observed for these biomarkers support the durability of iPPS effects inhibiting cartilage degradation and promoting structural stabilisation of the cartilage.

  Biomarkers

 Figure 4

Paradigm Chief Scientific Officer, Dr Ravi Krishnan, commented on the study: “Naturally occurring osteoarthritis in this translational model in dogs mirror the characteristics of osteoarthritis progression in humans. We are pleased that we have good preclinical translational supportive evidence for iPPS as a potential treatment to modify the progression of OA and provide long term durability of effect corresponding to 3 years in humans. Furthermore, these data provide confidence in our ongoing phase 3 clinical program evaluating pain, function, and durability of response in humans.”

Study Design

This study consisted of 14 iPPS treated dogs and 6 placebo treated dogs of varying breeds that presented at the U-Vet Werribee Animal Hospital, Victoria, Australia, for lameness assessment. A broad range of breeds comprising 12 males and 8 females were recruited and randomised in the study. Dogs of both genders with either radiologically and/or clinically defined OA of the knee/stifle (hind limb) or elbow (front limb) were randomised to receive subcutaneous iPPS at a dose of 3 mg/kg (human equivalent dose of 1.7 mg/kg) weekly for 6 weeks.

Clinical outcome measures of pain, function, joint structure imaging by MRI and biomarkers were determined at baseline, 8 weeks and at the final follow-up at 26 weeks from the initiation of treatment.

Pain Assessment: Helsinki Chronic Pain Index is an owner-based subjective questionnaire developed to assess chronic pain in the dog.

Functional Gait Analysis: Dogs enrolled in the study were assessed on a GAITRite® Portable Walkway System (http://www.gaitrite.com) for gait analysis. GAITRite is a portable walkway validated for use in dogs.

Cartilage Volume Analysis: Total cartilage volume was assessed by measurements of Magnetic Resonance Imaging (MRI) image sequencing of regions of the patella, tibial plateau, and femoral condyle that were acquired at baseline, week 8 and week 26.

Serum Biomarker Analysis: Serum levels of the molecular biomarkers CTX-1 (degradation fragment of type 1 collagen); Hyaluronic Acid (HA) (marker of cartilage degradation in serum); and TIMP-1 (endogenous inhibitor of cartilage degradation enzyme ADAMTS-5) were determined at baseline, week 8 and week 26 in osteoarthritic dogs. The studies of other biomarkers such as the inflammatory biomarkers (IL-1 beta, TNF-alpha, IL-6 and NGF) were unsuccessful since the assays were not verified to detect canine antigens. Furthermore, since synovial joint aspirates from these dogs were not subject to lavages (ethics requirement) the volumes were limited and did not allow the processing for further biomarker analysis.

Naturally Occurring Canine OA and Translational Relevance of the Canine OA Model

The phenotypic characteristics and heterogeneity of OA are similar in both humans and dogs. Therefore, it is expected that the canine model of OA would provide relevant translational data that parallel the human clinical scenario (1).

Both human and canine OA are progressive degenerative disorders and are influenced by similar risk factors. OA in humans primarily affects the knee, hip, and shoulder joints, and pathological changes closely resemble those observed in the canine stifle (knee), hip, and shoulder joints (1). Because the dog's lifespan is shorter relative to that of humans, all stages of development from birth to adulthood and ageing are represented over a shorter time frame, including disease onset and manifestation. This aspect of the

canine model is potentially advantageous in rapidly evaluating DMOAD status of iPPS that otherwise would require a longer assessment period in humans to analyse OA joint structural changes.

About Paradigm Biopharmaceuticals

Paradigm Biopharmaceuticals Ltd. (ASX:PAR) is a late-stage drug development company driven by a purpose to improve patients’ health and quality of life by discovering, developing, and delivering pharmaceutical therapies. Paradigm’s current

 developing injectable (subcutaneous) pentosan polysulfate sodium (iPPS) for the treatment of diseases where inflammation plays a major pathogenic role, indicating a

need for the anti-inflammatory and tissue regenerative properties of PPS,

osteoarthritis (phase 3) and mucopolysaccharidosis (phase 2).

Forward Looking Statements

such as in

This Company announcement contains forward-looking statements, including statements regarding anticipated commencement dates or completions dates of preclinical or clinical trials, regulatory developments and regulatory approval. These forward-looking statements are not guarantees or predictions of future performance, and involve known and unknown risks, uncertainties and other factors, many of which are beyond our control, and which may cause actual results to differ materially from those expressed in the statements contained in this presentation. Readers are cautioned not to put undue reliance on forward-looking statements.

References

1) Meeson RL, Todhunter RJ, Blunn G, Nuki G, Pitsillides AA. Spontaneous dog osteoarthritis — a One Medicine vision. Nat Rev Rheumatol. 2019 May;15(5):273–87.

2) Hielm-Bjorkman AK, Kapatkin AS, Rita HJ Reliability and validity of a visual analogue scale used by owners to measure chronic pain attributable to osteoarthritis in their dogs. Am J Vet Res 2011;72:601–607.

3) Carr BJ, Canapp SO, Meilleur S, Christopher SA, Collins J, Cox C. The Use of Canine Stifle Orthotics for Cranial Cruciate Ligament Insufficiency. Vet Evid [Internet]. 2016 Jan 22 [cited 2022 Sep 20];1(1). Available from: http://www.veterinaryevidence.org/index.php/ve/article/view/10

4) Bihlet AR, Byrjalsen I, Bay-Jensen AC, Andersen JR, Christiansen C, Riis BJ, Karsdal MA. Associations between biomarkers of bone and cartilage turnover, gender, pain categories and radiographic severity in knee osteoarthritis. Arthritis Res Ther. 2019 Sep 3;21(1):203. doi: 10.1186/s13075-019-1987-7. PMID: 31481084; PMCID: PMC6724319.

5) Kaneko, H., Ishijima, M., Doi, T. et al. Reference intervals of serum hyaluronic acid corresponding to the radiographic severity of knee osteoarthritis in women. BMC Musculoskelet Disord 14, 34 (2013).

6) Hegemann N, Kohn B, Brunnberg L, Schmidt MF. Biomarkers of joint tissue metabolism in canine osteoarthritic and arthritic joint disorders. Osteoarthritis Cartilage. 2002;10(9):714-721.

doi:10.1053/joca.2002.0820

7)

Authorised for release by the Paradigm Board of Directors. To learn more please visit: www.paradigmbiopharma.com FOR FURTHER INFORMATION PLEASE CONTACT:

Simon White

Director of Investor Relations

Tel: +61 404 216 467

Paradigm Biopharmaceuticals Ltd ABN: 94 169 346 963

Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA Email: [email protected]

  Onitsuka K, Murata K, Kokubun T, Fujiwara S, Nakajima A, Morishita Y, Kanemura N. Effects of Controlling Abnormal Joint Movement on Expression of MMP13 and TIMP-1 in Osteoarthritis. Cartilage. 2020 Jan;11(1):98-107. doi: 10.1177/1947603518783449. Epub 2018 Jun 25. PMID: 29938527; PMCID:

focus is

  PMC6921957

only 10k but I guess it’s better than nothing

Appendix 3Y Change of Director’s Interest Notice

Rule 3.19A.2

Information or documents not available now must be given to ASX as soon as available. Information and documents given to ASX become ASX’s property and may be made public.

Introduced 30/09/01 Amended 01/01/11

Name of entity Paradigm Biopharmaceuticals Limited ABN 94 169 346 963

We (the entity) give ASX the following information under listing rule 3.19A.2 and as agent for the director for the purposes of section 205G of the Corporations Act.

Name of Director  Helen Fisher Date of last notice  26 February 2021

Part 1 - Change of director’s relevant interests in securities

In the case of a trust, this includes interests in the trust made available by the responsible entity of the trust

Note: In the case of a company, interests which come within paragraph (i) of the definition of “notifiable interest of a director” should be disclosed in this part.

Appendix 3Y Change of Director’s Interest Notice

   Direct or indirect interest

Date of change

No. of securities held prior to change

Class

Number acquired Number disposed

Value/Consideration

Note: If consideration is non-cash, provide details and estimated valuation

No. of securities held after change

+ See chapter 19 for defined terms. 01/01/2011 Appendix 3Y Page 1

Direct

18 May 2023 Nil

Ordinary Shares 10,204

Not applicable $10,020

10,204 Fully Paid Ordinary Shares

 Nature of indirect interest

(including registered holder)

Note: Provide details of the circumstances giving rise to the relevant interest.

  Not applicable

Appendix 3Y

Change of Director’s Interest Notice

Part 2 – Change of director’s interests in contracts

Note: In the case of a company, interests which come within paragraph (ii) of the definition of “notifiable interest of a director” should be disclosed in this part.

 Nature of change

Example: on-market trade, off-market trade, exercise of options, issue of securities under dividend reinvestment plan, participation in buy-back

  On-market trade

 Detail of contract Nature of interest

Name of registered holder (if issued securities)

Date of change

Interest acquired

Interest disposed

Value/Consideration

Note: If consideration is non-cash, provide details and an estimated valuation

Interest after change Part 3 – +Closed period

Not applicable Not applicable

Not applicable Not applicable

Not applicable Not applicable Not applicable

Not applicable

    No. and class of securities to which

interest related prior to change

Note: Details are only required for a contract in relation to which the interest has changed

  Not applicable

      Were the interests in the securities or contracts detailed No above traded during a +closed period where prior written

 clearance was required?

If so, was prior written clearance provided to allow the trade to proceed during this period?

If prior written clearance was provided, on what date was this provided?

+ See chapter 19 for defined terms. Appendix 3Y Page 2

Not applicable Not applicable

    01/01/2011

Paul Rennie who knows the business better than anybody just bought 70k shares in market.

#stillbullish

Appendix 3Y Change of Director’s Interest Notice

Rule 3.19A.2

Information or documents not available now must be given to ASX as soon as available. Information and documents given to ASX become ASX’s property and may be made public.

Introduced 30/09/01 Amended 01/01/11

Name of entity Paradigm Biopharmaceuticals Limited ABN 94 169 346 963

We (the entity) give ASX the following information under listing rule 3.19A.2 and as agent for the director for the purposes of section 205G of the Corporations Act.

Name of Director  Paul Rennie

Date of last notice  22 December 2022

Part 1 - Change of director’s relevant interests in securities

In the case of a trust, this includes interests in the trust made available by the responsible entity of the trust

Note: In the case of a company, interests which come within paragraph (i) of the definition of “notifiable interest of a director” should be disclosed in this part.

Direct or indirect interest Direct and indirect interest

Date of change 12 May 2023

Appendix 3Y Change of Director’s Interest Notice

    Nature of indirect interest

(including registered holder)

Note: Provide details of the circumstances giving rise to the relevant interest.

  Mr Paul Rennie is the legal and beneficial owner of 100% of the securities in KZEE Pty Ltd.

Mr Paul Rennie is the legal and beneficial owner of 100% of the securities in EAR Investments Pty Ltd.

   + See chapter 19 for defined terms. 01/01/2011 Appendix 3Y Page 1

Appendix 3Y

Change of Director’s Interest Notice

 No. of securities held prior to change

  Paul Rennie

– 8,426,697 Fully Paid Ordinary Shares

KZEE Pty Ltd ATF KZEE Superannuation Fund

– 10,914,902 Fully Paid Ordinary Shares registered in the name of KZEE Pty Ltd. Mr Paul Rennie is the legal and beneficial owner of 100% of the securities in KZEE Pty Ltd.

EAR Investments Pty Ltd ATF EAR Investments Trust

– 1,097,355 Fully Paid Ordinary Shares registered in the name of EAR Investments Pty Ltd. Mr Paul Rennie is the legal and beneficial owner of 100% of the securities in EAR Investments Pty Ltd.

Total No. of shares held after change

– 20,438,954 Fully Paid Ordinary Shares

  Class

Number disposed

Ordinary Shares

Not applicable

Number acquired

  Paul Rennie

– 73,851 Fully Paid Ordinary Shares

  Value/Consideration

Note: If consideration is non-cash, provide details and estimated valuation

  Paul Rennie

– $76,001

  + See chapter 19 for defined terms. Appendix 3Y Page 2

01/01/2011

Detail of contract Nature of interest

Name of registered holder (if issued securities)

Date of change

Interest acquired Interest disposed

+ See chapter 19 for defined terms. 01/01/2011 Appendix 3Y Page 3

Not applicable Not applicable

Not applicable Not applicable

Not applicable Not applicable

Appendix 3Y Change of Director’s Interest Notice

 No. of securities held after change

  Paul Rennie

– 8,500,548 Fully Paid Ordinary Shares

KZEE Pty Ltd ATF KZEE Superannuation Fund

– 10,914,902 Fully Paid Ordinary Shares registered in the name of KZEE Pty Ltd. Mr Paul Rennie is the legal and beneficial owner of 100% of the securities in KZEE Pty Ltd.

EAR Investments Pty Ltd ATF EAR Investments Trust

– 1,097,355 Fully Paid Ordinary Shares registered in the name of EAR Investments Pty Ltd. Mr Paul Rennie is the legal and beneficial owner of 100% of the securities in EAR Investments Pty Ltd.

Total No. of shares held after change

– 20,512,805 Fully Paid Ordinary Shares

 Nature of change

Example: on-market trade, off-market trade, exercise of options, issue of securities under dividend reinvestment plan, participation in buy-back

  On-market trade

  Part 2 – Change of director’s interests in contracts

Note: In the case of a company, interests which come within paragraph (ii) of the definition of “notifiable interest of a director” should be disclosed in this part.

    No. and class of securities to which interest

related prior to change

Note: Details are only required for a contract in relation to which the interest has changed

  Not applicable

Appendix 3Y

Change of Director’s Interest Notice

Value/Consideration

Note: If consideration is non-cash, provide details and an estimated valuation

Interest after change Part 3 – +Closed period

Not applicable Not applicable

    Were the interests in the securities or contracts detailed No above traded during a +closed period where prior written

 clearance was required?

If so, was prior written clearance provided to allow the trade to proceed during this period?

If prior written clearance was provided, on what date was this provided?

Not applicable Not applicable

    + See chapter 19 for defined terms. Appendix 3Y Page 4

01/01/2011

Key points:

~ cashburn in latest quarter ~ 10 mil giving 7 quarters in the bank at current burn

~ clinical progress excellent with evidence of disease modification and clinical response in trials thus far

~ stage 1 recruitment pivotal trial should be complete this quarter!

exciting times

 ASX RELEASE 28 April 2023

MARCH 2023 QUARTERLY ACTIVITIES REPORT

Key Highlights

• Top-line PARA_OA_008 Six-month Data Release: Paradigm reported exciting novel 6- months data from the phase 2 study, that is complementary to the ongoing phase 3 clinical trial. The phase 2 study is exploring the disease modifying and clinical effects of injectable pentosan polysulfate sodium (iPPS) compared to placebo in 61 subjects with knee osteoarthritis (OA). Disease modifying therapies are expected to attract a significantly higher price. Six-month data reported participants receiving iPPS treatment demonstrated improvement in cartilage loss, reductions in bone marrow lesions, and reductions in marginal osteophytes as measured by MRI compared to placebo. The disease modifying OA drug (DMOAD) potential for iPPS in knee OA treatment was also supported by changes and trends in four key biomarkers (ARGS, COMP, C2C, and CTX-II) at six months. The PARA_OA_008 trial successfully achieved its primary endpoint of a change from baseline at Day 56 in one or more synovial fluid biomarkers, with Paradigm reporting a positive change in six biomarkers associated with OA disease progression following iPPS treatment compared to placebo. Additionally, iPPS-treated subjects demonstrated statistically significant improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function scores at Day 56 for the twice-weekly group compared to placebo. This measurement is also the primary endpoint for the ongoing phase 3 clinical trial.

• Global Phase 3 Progress: In March, Paradigm reported that regulatory and ethics approvals were received via Europe’s Clinical Trial Information System for Paradigm’s pivotal PARA_OA_002 clinical trial. These approvals enabled Paradigm to commence PARA_OA_002 clinical trial site start-up activities in Belgium, Poland, and the Czech Republic.

• OARSI 2023 World Congress on Osteoarthritis: During March, Paradigm’s management and clinical team conducted three presentations at the Osteoarthritis Research Society International (OARSI) 2023 World Congress held in Denver, Colorado. Dr. Donna Skerrett, Paradigm's Chief Medical Officer, was invited to present iPPS technology, its mechanism of action, and clinical translation potential for Paradigm's ongoing global OA program at the Clinical Trial Symposium, held the evening prior to the congress commencement. Dr. Mukesh Ahuja, Paradigm’s Global Clinical Head of OA, presented a poster detailing the clinical trial design and Day 56 top-line data from the PARA_OA_008 clinical trial exploring the disease modifying potential of iPPS. Paradigm’s Chief Scientific Officer Dr. Ravi Krishnan and Dr. Mukesh Ahuja gave an oral presentation covering Paradigm’s global OA program, including the Day 56 top-line data from the PARA_OA_008 clinical trial.

Paradigm Biopharmaceuticals Ltd. (ASX:PAR) (“Paradigm” or “the Company”) is pleased to provide its quarterly update for the three months ended 31 March 2023 to accompany its Appendix 4C cash flow report for the period.

• Cash balance as of 31 March 2023 was $73.20m (on 31 December 2022 it was $83.92m).

• Research & development expenditure for the quarter was $8.95m compared to the previous quarter of $13.2m. The spend in Q3 FY23 is related to ongoing subject recruitment and new site identification and activation for the PARA_OA_002 study, as well as subject monitoring and analytical activity regarding biomarker and MRI analysis for the PARA_OA_008 phase 2 clinical trial. The spend also included site operations for MPS I and MPS VI phase 2 studies, and an ongoing New Drug Application (NDA) enabling nonclinical studies related to our MPS and OA clinical programs. The quarter also saw payments related to continuing activities described in the outlook below.

• In accordance with Listing Rule 4.7C.3 and as noted in item 6 of the Appendix 4C Cashflow Statement, payments to related parties and their associates during the quarter ended 31 March 2022 were fees of $77K, which includes $66K for payment of Director fees, and $10K for legal fees to BioMeltzer (a company related to Amos Meltzer).

OUTLOOK

Paradigm is pleased to provide an update on continuing activities.

PARA_OA_002 Phase 3 Clinical Trial

• Recruitment remains ongoing for stage 1 of the pivotal PARA_OA_002 2-stage adaptive clinical trial. Site activation continues to increase with a total of 102 sites activated across 6 countries out of a planned 120 sites.

• Paradigm is scheduled to complete enrolment of stage 1 of the PARA_OA_002 clinical trial by the end of the current quarter.

• Paradigm continues to progress its partnership with NFL Alumni Health to inform interested alumni and affiliates regarding developments in OA drug development. Paradigm is scheduled to conduct multiple webinars with NFL Alumni chapter presidents during the quarter, with evidence of strong interest in the phase 3 program through ethics-approved pre-screening activities.

PARA_OA_008 Synovial Fluid Biomarker Study

Paradigm’s PARA_OA_008 clinical trial has now met the primary endpoint and delivered positive clinical data at both Day 56 and Day 168. The trial demonstrated both symptomatic relief through reduction in pain and improvement in function and additionally showed structural improvement as measured by molecular and structural biomarkers associated with OA disease progression. Highlights from both the Day 56 and Day 168 top-line data releases include:

Day 56

• Successfully met the study's primary endpoint with a change from baseline in one or more molecular biomarkers associated with OA disease progression following iPPS treatment compared to placebo. Paradigm reported positive changes in 6 key biomarkers (NGF, TNF-α, IL-6, COMP, ARGS, and TIMP-1).

• iPPS treatment showed statistically significant improvements at Day 56 in pain, function and overall WOMAC scores for twice-weekly iPPS compared to the placebo arm. The primary endpoint for Paradigm’s Phase 3 program is a change from baseline in WOMAC pain and function at Day 56.

Day 168 (6 months)

• Structural changes in several disease features as measured by MRI were consistent with potential DMOAD activity in iPPS-treated participants compared to placebo. Most notably, iPPS demonstrated:

o 21%improvementinmeancartilagelossscorecomparedto4%worsening in the placebo group,

o Statistically significant reductions in bone marrow lesions compared to placebo, and

o Reduction of marginal osteophytes compared to an increase in the placebo group.

• Reductions in molecular biomarkers of cartilage degradation (C2C, CTX II, COMP, ARGS) were observed in iPPS-treated subjects compared to placebo control. Following discussions with a leading expert in the research of predictive biomarkers and their role in OA progression, it was suggested that these four biomarkers be highlighted during discussions with the key regulatory agencies.

• Durable clinical responses were reported out to Day 168 in WOMAC index scores for pain, function, stiffness, and overall for twice-weekly iPPS compared to placebo control. The placebo group reported using rescue medication on an average of 23 days compared to an average of only 5 days in the twice-weekly iPPS group. This comparison is highly relevant as rescue medication was not permitted prior to Day 56, as per the clinical protocol.

Discussions will be undertaken with key regulatory agencies (FDA and EMA) in order to reach agreement on disease modification labelling pathways for iPPS. Paradigm’s current Phase 3 clinical trials have been designed to collect molecular (serum and urine) and structural (MRI) biomarker data. Paradigm expects to conduct these meetings prior to the commencement of the PARA_OA_003 confirmatory trial.

The PARA_OA_008 clinical trial continues to monitor participants out to 12 months, with this follow-up data expected to be reported in the 2H CY2023.

Canine OA Model

The complete study report examining both week 8 and week 26 responses in the final cohort of dogs is expected to be reported during the current quarter. This study data aims to provide informative data in conjunction with the data released from the PARA_OA_008 phase 2 clinical

 trial in humans to assess the potential of iPPS as a DMOAD.

 The key data being analysed from this study are changes from baseline at week 8 and week 26, in:

• Joint function as measured by percentage body weight distribution (BWD%) in the affected limb as measured by the total pressure index percentage (TPI%).

• Biomarkers of joint degeneration; and

• Structural changes determined by OA clinical scores as assessed by X-ray and MRI.

Mucopolysaccharidosis (MPS I and VI)

The open-label MPS I trial has been completed and data analysis is currently underway. iPPS is well tolerated in this population with no serious adverse events reported to date. Additionally, to date, there appears to be an overall trend toward meaningful improvements in pain, function, activities of daily living (ADL) , and overall improvement in quality of life. Further data will be reported on this study once the analysis and clinical study report has been completed.

Paradigm’s MPS VI phase 2 trial based in Brazil has completed enrolment of participants. This placebo-controlled, double-blind, and randomised 24-week study compares iPPS to placebo in participants with the ultra-rare disease MPS VI. The primary objective of the study is to evaluate the safety and tolerability of iPPS in subjects with MPS VI at 6, 12, and 24 weeks. Throughout the study, multiple safety reviews have been completed by the safety monitoring physician allowing enrolment of participants aged 5 and over into the study.

Upcoming Conferences

• NFL Alumni Health Symposium: Paradigm has been invited to present at the NFL Alumni Health Symposium being held at the NFL Draft on April 28 in Kansas City, MO. Paradigm’s Global Head of OA, Dr Mukesh Ahuja, will participate in a live panel discussion to discuss conditions relevant to the NFL Alumni, of which OA being a major concern. The

• Bio 2023 International Conference: Paradigm has been accepted to present at the upcoming Bio International Conference that will be conducted in Boston on June 5–8. Paradigm’s Managing Director, Mr. Paul Rennie and Chief Medical Officer Dr. Donna Skerrett, will be in attendance to present Paradigm’s clinical development program and conduct 1x1 meetings in conjunction with Plexus Ventures, Paradigm’s Business Development Consultant.

The longer follow-up period at week 26 (roughly equivalent to 3 human years) aims to provide data on the long-term durability of effect of iPPS compared to placebo on structural and

 molecular biomarkers.

 symposium is free to the public and will provide a platform for medical experts to discuss the latest advancements in osteoarthritis research and development, as well as the challenges and opportunities for developing new therapies. NFL Alumni Health hopes to raise awareness about the importance of addressing osteoarthritis in NFL players and the

 wider community.

About Paradigm Biopharmaceuticals

Paradigm Biopharmaceuticals Ltd. (ASX:PAR) is a late-stage drug development company driven by a purpose to improve patients’ health and quality of life by discovering, developing, and delivering pharmaceutical therapies. Paradigm’s current focus is developing iPPS for the treatment of diseases where inflammation plays a major pathogenic role, indicating a need for the anti-inflammatory and tissue regenerative properties of PPS, such as in osteoarthritis (phase 3) and mucopolysaccharidosis (phase 2).

Forward Looking Statements

This Company announcement contains forward-looking statements, including statements regarding anticipated commencement dates or completions dates of preclinical or clinical trials, regulatory developments, and regulatory approval. These forward-looking statements are not guarantees or predictions of future performance, and involve known and unknown risks, uncertainties and other factors, many of which are beyond our control, and which may cause actual results to differ materially from those expressed in the statements contained in this presentation. Readers are cautioned not to put undue reliance on forward-looking statements.

Authorised for release by the Paradigm Board of Directors. FOR FURTHER INFORMATION PLEASE CONTACT:

Simon White

Director of Investor Relations

Tel: +61 404 216 467

Paradigm Biopharmaceuticals Ltd. ABN: 94 169 346 963

Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA Email: [email protected]

Appendix 4C

Quarterly cash flow report for entities subject to Listing Rule 4.7B

Name of entity

Paradigm Biopharmaceuticals Limited

ABN

94 169 346 963

1. Cash flows from operating activities

1.1 Receipts from customers

1.2 Payments for

(a) research and development

(b) product manufacturing and operating costs

(c) advertising and marketing

(d) leased assets

(e) staff costs

(f) administration and corporate costs

1.3 Dividends received (see note 3)

1.4 Interest received

1.5 Interest and other costs of finance paid

1.6 Income taxes paid

1.7 Government grants and tax incentives

1.8 Other (provide details if material)

1.9 Net cash from / (used in) operating activities

2. Cash flows from investing activities

2.1 Payments to acquire or for:

(a) entities

(b) businesses

(c) property, plant and equipment

(d) investments

(e) intellectual property

(f) other non-current assets

ASX Listing Rules Appendix 4C (17/07/20)

+ See chapter 19 of the ASX Listing Rules for defined terms.

Quarter ended (“current quarter”)

31 March 2023

-

(8,953) -

(79)

(16) (1,195) (736) - 649 (4) - - -

- - - - - -

23

(30,805) -

(387) (70) (2,317) (2,729) - 805 (13) - 7,405 -

- - - - - -

Page 1

Rule 4.7B

     Consolidated statement of cash flows

  Current quarter $A’000

  Year to date (9 months) $A’000

    (10,334)

  (28,088)

2.2 Proceeds from disposal of:

(a) entities

(b) businesses

(c) property, plant and equipment

(d) investments

(e) intellectual property

(f) other non-current assets

2.3 Cash flows from loans to other entities

2.4 Dividends received (see note 3)

2.5 Other (provide details if material)

2.6 Net cash from / (used in) investing activities

3. Cash flows from financing activities

3.1 Proceeds from issues of equity securities (excluding convertible debt securities)

3.2 Proceeds from issue of convertible debt securities

3.3 Proceeds from exercise of options

3.4 Transaction costs related to issues of equity securities or convertible debt securities

3.5 Proceeds from borrowings

3.6 Repayment of borrowings (lease liabilities)

3.7 Transaction costs related to loans and borrowings

3.8 Dividends paid

3.9 Other (Limited recourse loan repaid under ESP)

3.10 Net cash from / (used in) financing activities

4. Net increase / (decrease) in cash and cash equivalents for the period

4.1 Cash and cash equivalents at beginning of period

4.2 Net cash from / (used in) operating activities (item 1.9 above)

ASX Listing Rules Appendix 4C (17/07/20)

+ See chapter 19 of the ASX Listing Rules for defined terms.

- - - - - - - - - - - - - - - - - -

- 65,988

-- -- - (3,765)

--

-- (23) (80)

--

Appendix 4C Quarterly cash flow report for entities subject to Listing Rule 4.7B

  Consolidated statement of cash flows

   Current quarter $A’000

  Year to date (9 months) $A’000

  -

  -

            - 56

83,926 (10,334)

- 188

39,721 (28,088)

Page 2

    33

  62,331

Appendix 4C Quarterly cash flow report for entities subject to Listing Rule 4.7B

  Consolidated statement of cash flows

  Current quarter $A’000

  Year to date (9 months) $A’000

  4.3

4.4

4.5

4.6

   Net cash from / (used in) investing activities (item 2.6 above)

Net cash from / (used in) financing activities (item 3.10 above)

Effect of movement in exchange rates on cash held

Cash and cash equivalents at end of period

  - 33

(422)

   - 62,331

(761)

  73,203

 73,203

  5. Reconciliation of cash and cash equivalents

at the end of the quarter (as shown in the consolidated statement of cash flows) to the related items in the accounts

  Current quarter $A’000

  Previous quarter $A’000

 5.1 Bank balances

5.2 Call deposits

5.3 Bank overdrafts

5.4 Other (provide details)

5.5 Cash and cash equivalents at end of quarter (should equal item 4.6 above)

6.1 Aggregate amount of payments to related parties and their associates included in item 1

6.2 Aggregate amount of payments to related parties and their associates included in item 2

Note: if any amounts are shown in items 6.1 or 6.2, your quarterly activity report must include a description of, and an explanation for, such payments.

73,203 83,926

 73,203

 83,926

    6. Payments to related parties of the entity and their associates

Current quarter $A'000

   77

    ASX Listing Rules Appendix 4C (17/07/20)

+ See chapter 19 of the ASX Listing Rules for defined terms.

Page 3

Appendix 4C Quarterly cash flow report for entities subject to Listing Rule 4.7B

   Total facility amount at quarter end $A’000

  Amount drawn at quarter end $A’000

 7. Financing facilities

Note: the term “facility’ includes all forms of financing arrangements available to the entity.

Add notes as necessary for an understanding of the sources of finance available to the entity.

7.1 Loan facilities

7.2 Credit standby arrangements

7.3 Other (please specify)

7.4 Total financing facilities

7.5 Unused financing facilities available at quarter end

- -

- -

- -

- -

-

      7.6 Include in the box below a description of each facility above, including the lender, interest rate, maturity date and whether it is secured or unsecured. If any additional financing facilities have been entered into or are proposed to be entered into after quarter end, include a note providing details of those facilities as well.

    8. Estimated cash available for future operating activities

8.1 Net cash from / (used in) operating activities (item 1.9)

8.2 Cash and cash equivalents at quarter end (item 4.6)

8.3 Unused finance facilities available at quarter end (item 7.5)

8.4 Total available funding (item 8.2 + item 8.3)

8.5 Estimated quarters of funding available (item 8.4 divided by item 8.1)

$A’000

 (10,334) 73,203 - 73,203

    Note: if the entity has reported positive net operating cash flows in item 1.9, answer item 8.5 as “N/A”. Otherwise, a figure for the estimated quarters of funding available must be included in item 8.5.

8.6 If item 8.5 is less than 2 quarters, please provide answers to the following questions:

8.6.1 Does the entity expect that it will continue to have the current level of net operating cash flows for the time being and, if not, why not?

8.6.2 Has the entity taken any steps, or does it propose to take any steps, to raise further cash to fund its operations and, if so, what are those steps and how likely does it believe that they will be successful?

8.6.3 Does the entity expect to be able to continue its operations and to meet its business objectives and, if so, on what basis?

Note: where item 8.5 is less than 2 quarters, all of questions 8.6.1, 8.6.2 and 8.6.3 above must be answered.

ASX Listing Rules Appendix 4C (17/07/20) Page 4 + See chapter 19 of the ASX Listing Rules for defined terms.

7.08

   Answer:

   Answer:

   Answer:

1

2

Date:

Appendix 4C Quarterly cash flow report for entities subject to Listing Rule 4.7B

This statement has been prepared in accordance with accounting standards and policies which comply with Listing Rule 19.11A.

This statement gives a true and fair view of the matters disclosed.

..28 April 2023.................................................................................

 Compliance statement

Authorised by: ...By the board................................................................................

(Name of body or officer authorising release – see note 4)

Notes

1. This quarterly cash flow report and the accompanying activity report provide a basis for informing the market about the entity’s activities for the past quarter, how they have been financed and the effect this has had on its cash position. An entity that wishes to disclose additional information over and above the minimum required under the Listing Rules is encouraged to do so.

2. If this quarterly cash flow report has been prepared in accordance with Australian Accounting Standards, the definitions in, and provisions of, AASB 107: Statement of Cash Flows apply to this report. If this quarterly cash flow report has been prepared in accordance with other accounting standards agreed by ASX pursuant to Listing Rule 19.11A, the corresponding equivalent standard applies to this report.

3. Dividends received may be classified either as cash flows from operating activities or cash flows from investing activities, depending on the accounting policy of the entity.

4. If this report has been authorised for release to the market by your board of directors, you can insert here: “By the board”. If it has been authorised for release to the market by a committee of your board of directors, you can insert here: “By the [name of board committee – eg Audit and Risk Committee]”. If it has been authorised for release to the market by a disclosure committee, you can insert here: “By the Disclosure Committee”.

5. If this report has been authorised for release to the market by your board of directors and you wish to hold yourself out as complying with recommendation 4.2 of the ASX Corporate Governance Council’s Corporate Governance Principles and Recommendations, the board should have received a declaration from its CEO and CFO that, in their opinion, the financial records of the entity have been properly maintained, that this report complies with the appropriate accounting standards and gives a true and fair view of the cash flows of the entity, and that their opinion has been formed on the basis of a sound system of risk management and internal control which is operating effectively.

 ASX Listing Rules Appendix 4C (17/07/20) Page 5 + See chapter 19 of the ASX Listing Rules for defined terms.

this announcement is hugely positive for PAR although it was already pretty clear the drug worked for pain relief in knee osteoarthritis it is now highly probable that it also modifies progress if the disease.

what cost to delay/prevent a joint replacement?

massive difference between analgesia and disease modification and will drive interest from big pharmacy IMO.

caveats are you still need to be patient as pivotal trial results still years away but wow!

 ASX RELEASE 4 April 2023

Injectable PPS Demonstrates Multiple Signals of a DMOAD in PARA_OA_008 Phase 2 Clinical Study

KEY HIGHLIGHTS

• Day 168 data from Paradigm’s phase 2 PARA_OA_008 clinical trial demonstrates multiple signals that injectable pentosan polysulfate sodium (iPPS) may slow disease progression in knee osteoarthritis (OA).

• Structural changes in several disease features as measured by magnetic resonance imaging (MRI) were consistent with potential DMOAD activity. Most notably, iPPS demonstrated:

o 21% improvement in mean cartilage loss score compared to 4% worsening in the placebo group,

o Statistically significant reductions in bone marrow edema lesions compared to placebo, and

o Reductionofmarginalosteophytescomparedtoincreasesintheplacebogroup.

• The disease modifying OA drug (DMOAD) potential for iPPS in knee OA treatment is also supported by changes and trends in four key biomarkers (ARGS, COMP, C2C, and CTX-II) evaluated in this phase 2 study.

• Persistent positive clinical responses in WOMAC pain, function, stiffness and overall WOMAC scores have been observed in the twice-weekly iPPS compared to placebo to Day 168.

o In addition to durable pain responses, the average number of days participants used rescue medication was four times higher in the placebo group (23 days) compared to the twice-weekly iPPS group (5 days) to Day 168.

• The results of these new MRI, molecular biomarker and clinical outcomes will be presented to the Regulatory Authorities (FDA and EMA). Paradigm will seek their input as to what additional data, from a larger controlled study (PARA_OA_003), may be required to obtain a DMOAD label.

• Paradigm will be hosting an investor webinar today, 4 April 2023 at 9:30am (AEST), to present and discuss the novel Day 168 data from the PARA_OA_008 clinical trial.

Paradigm Biopharmaceuticals Ltd (ASX:PAR) (Paradigm or the Company), a late- stage drug development company focused on delivering new therapies to address unmet medical needs, is pleased to announce top-line data from the Day 168 (6-month) time point in the PARA_OA_008 study exploring the disease modifying potential of iPPS. Data received at Day 168 analysed by independent clinical research organisations and key opinion leaders in osteo and rheumatoid arthritis, demonstrates iPPS is not only having a durable response on Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, function and stiffness scores, but also showing multiple signals of slowing or halting the OA disease progression through structural biomarkers identified by

MRI and improvements of key molecular biomarkers associated with cartilage degradation.

Data from PARA_OA_008 confirms a continuation of positive clinical outcomes from Day 56 through to Day 168 in WOMAC pain, function, and stiffness. Despite the study not initially being powered to demonstrate significance, several time points reached statistical significance for the twice-weekly iPPS-treated group compared to placebo. Trends or statistically significant differences in several serum, urine, and synovial fluid biomarkers of osteoarthritis progression were observed through Day 168 in iPPS-treated groups, reinforcing the disease-modifying potential of iPPS. New data includes the semi- quantitative analysis of structural markers of OA progression with the comparison of MRI at Day 168 compared to baseline scores established from the screening MRI images. Positive signals for iPPS-treated subjects compared to placebo were observed (including for cartilage loss and bone marrow edema lesions) indicating a potential slowing of the disease process.

All trends, results and signals in all tests and biomarkers indicated that iPPS is beneficial for treating both the symptoms and diseases progression of knee OA.

Paradigm Chief Medical Officer, Dr Donna Skerrett commented: “We are seeing clinical and biomarker responses in both iPPS treatment groups over the 168-day study period. Although many of the clinical responses are stronger in the twice-weekly group, biomarker and MRI responses are present in both iPPS groups. Given the small sample sizes in this study, variability is expected however the signals we have identified are consistent and concordant and support DMOAD mechanisms. Moving forward we will work to establish the clinical and regulatory characterisation of these findings for defining the DMOAD pathway for iPPS in order to confirm these findings in our larger clinical trial program.”

Paradigm Managing Director and Chairman, Paul Rennie also commented: “A non- opioid drug for treating the symptoms of osteoarthritis (pain and joint stiffness) with durability of effect out to 168 days (6 months) plus signals of disease modifying potential, is well poised to address a major unmet medical need. These data are expected to assist our partnering discussions.”

The Urgent Need for a Disease Modifying OA Drug (DMOAD)

Osteoarthritis is the most prevalent form of arthritis, with the risk of developing OA rising with age. This degenerative disorder can significantly reduce quality of life as it primarily affects the hands, lower back, neck, and weight-bearing joints such as knees, hips, and feet. A recent 2022 analysis of results from the 2019 Global Burden of Disease Study found that approximately 397.6 million cases of hip and knee OA existed worldwide, and that global trends showed a 114.5% increase in years lived with disability due to OA from 1990 to 2019 (1). Further underlining the economic burden, a comprehensive 2013 study estimated that total US arthritis-attributable medical expenditures reached almost $US140 billion, which when combined with wage losses, totalled losses of over $US303 billion (2).

A disease modifying OA drug (DMOAD) is defined as a drug that will “alter the natural history of disease progression by arresting joint structural change and ameliorate symptoms, either by reducing pain or improving physical function” (3). However, t

 here are

 no established DMOADs, as current treatments such as paracetamol, opioids, and nonsteroidal anti-inflammatory drugs (NSAIDs), as well as intra-articular medications, such as corticosteroids and hyaluronic acid, are solely focused on symptom management

 (3)  (4)

. Due to patient dissatisfaction with current OA treatments

medical need for new therapies that can effectively reduce pain, improve joint function,

 and impede OA progression in tandem with symptomatic improvement.

Market research conducted through a global market intelligence and research organisation (ASX release 8 November 2021) found that payers in the United States would likely accept a price of US$2,000 to US$3,000 per year for iPPS as a therapy to reduce pain and improve function in knee OA. If approved by the FDA with a disease modifying label, the price per year of therapy in the US could increase to US$6,000 and potentially higher. The first registration of a drug proven to prevent progression of the disease of OA, rather than merely alleviate symptoms, is likely to encourage a review of the treatment recommendations and prescribing behaviour. Such an agent would likely be recommended as a first-line treatment.

PARA_OA_008 Day 168 Top-Line Results

The Australian clinical trial operating at two sites in Victoria and NSW aims to gather data on the medium-term structure-modifying and symptom-modifying effects of iPPS on knee OA. Participants have been randomised into three treatment groups according to a 1:1:1 ratio (19 randomised to iPPS twice weekly, 20 randomised to iPPS once weekly plus a placebo injection once weekly, 22 randomised to placebo twice weekly). Of the 61 patients, 48 (78%) had Kellgren Lawrence (KL) grades 3-4 (where 4 is the most severe), and the average median baseline self-reported WOMAC scores were 6.6 for pain and 6.9 for function. This phase 2 clinical study was designed to identify trends in clinical outcomes, and to explore the potential of iPPS as a DMOAD through changes in chemical and structural biomarkers. It is therefore exploratory in nature and is not powered for significance.

MRI Outcomes (semi-quantitative analysis)

During the screening process for this phase 2 study, potential participants underwent examination by MRI to determine their baseline level of OA disease. Participants then received follow-up MRIs at Day 168 which aimed to identify any differences in disease progression between the iPPS groups versus placebo. Semi-quantitative MRI analysis was performed, which involves systematically interpreting MRI images using a rating scale or scoring system. This approach is often used in research studies to objectively evaluate changes in disease severity or treatment response over time. The rating system typically assigns scores to specific imaging features, such as the presence of lesions, the size and location of lesions, and the degree of contrast enhancement. The scores are then used to calculate a total score or index, which provides a quantitative measure of disease activity or severity. Whole-ORgan MRI Scoring (WORMS) was used to assess changes in joint structures considered to be important to the functional integrity of the knee and associated with OA.

Despite the relatively small number of subjects in each arm and the short follow-up interval compared to the generally slow structural progression in OA, changes consistent with DMOAD efficacy were observed in a number of disease features. These changes were most notably related to cartilage loss, bone marrow lesions, and osteophyte formation, as early as 6 months after initiating treatment with iPPS. Collectively, the majority of the statistically significant changes observed were consistent with a positive disease modifying effect of treatment with iPPS on OA.

Cartilage loss is generally considered to be the most important disease feature of OA. Numerous studies have shown cartilage loss to be predictive of knee replacement surgery

, there is a high unmet

for OA (8,9). In this study, subjects receiving once-weekly iPPS demonstrated an average 21% improvement in mean cartilage loss score in the medial femur, whereas the placebo arm showed a slight (4%) worsening of cartilage loss (p=0.065). The twice-weekly iPPS group, showed trends of improvement (though not statistical) or stabilisation of cartilage preservation compared to the placebo group.

A build-up of fluid in the bone marrow (subchondral bone marrow edema lesions) is a common finding in OA and is believed to be related to microtrauma resulting from overloading. Like cartilage loss, bone marrow edema lesions have been shown to be predictive of knee replacement (10–12). In this study, bone marrow lesions in the lateral femur decreased by an average 38% in the once-weekly iPPS arm, whereas in the placebo arm it increased by 47% (p=0.056). Bone marrow edema lesions in the entire lateral tibiofemoral compartment decreased by an average 17% in the once-weekly iPPS arm, but increased by 56% in the placebo arm (p=0.028).

Marginal osteophytes—also known as bone spurs—form between the cartilage and bone and are an early finding in OA. They are associated with bone remodelling, as osteophytes typically increase in number and size as the disease progresses. In this study, osteophytes decreased slightly or remained stable in all three compartments of the knee among patients treated with iPPS, compared to an increase (numerically, though not statistically significantly) in the placebo arm.

Paradigm intends to complete additional quantitative analysis on the full MRI dataset to further characterise the structural changes identified to date.

Clinical Outcomes

Participants in the study were asked to provide baseline pain scores using the self- assessed WOMAC osteoarthritis index. After patients had initiated treatment, their pain scores are measured at predetermined timepoints from Day 11 out to Day 365 (12 months), with Day 56 the first predetermined timepoint for WOMAC assessment after the completion of treatment (Day 39). Paradigm’s primary endpoints in the current PARA_OA_002 phase 3 trial are improvements in pain and function from baseline at Day 56 using the WOMAC osteoarthritis index.

Paradigm previously reported that participants receiving twice-weekly iPPS demonstrated a statistically significant improvement at Day 56 in pain, function, stiffness, and overall WOMAC scores compared to the placebo arm. The proportions achieving ≥30% and ≥50% improvement in pain were 73% and 60%, respectively.

Persistent responses out to Day 168 in WOMAC index scores for pain, function, stiffness, and overall are observed for twice-weekly iPPS compared to placebo control. Positive trends or statistical significance are demonstrated at days 112 for stiffness (p=0.029), function (p=0.059), and overall (p=0.067). At Day 168, a 50% improvement in function was reported in 53.3% of twice-weekly iPPS compared to 22.1% of placebo (p=0.067).

WOMAC pain demonstrated a durable response and separation from the placebo group at Day 168. At Day 168, statistically significant changes in pain and function were not demonstrated in the once-weekly iPPS group compared to placebo, however this group demonstrated variability in responses with improvement noted in some subjects. The patient global impression of change (PGIC) remained favourable showing a positive trend for iPPS compared to placebo at Day 168 (p=0.061).

The twice-weekly iPPS treatment group used rescue medication the least during the first six months of the study (Day 168). Rescue medications could include paracetamol or NSAIDs used by participants to manage pain symptoms. The placebo group reported using rescue medication on an average of 23 days compared to an average of only 5 days in the twice-weekly iPPS group.

Biomarkers

A broad panel of potential biomarkers in the blood (serum), urine, and the knee joint space (synovial fluid) were assessed. Specifically, markers of OA progression such as serum and synovial fluid ARGs (an articular cartilage breakdown product), serum and synovial fluid COMP (a marker of cartilage turnover), serum C2C and urinary CTX II (markers of cartilage breakdown) were informative. DMOAD potential for iPPS in knee OA treatment has been identified by the patterns of change of four biomarkers evaluated in this study. Namely, serum and synovial fluid ARGs, serum and synovial fluid COMP, serum C2C and urinary CTX II show persistent beneficial effects of PPS compared to placebo. These biomarkers of cartilage matrix degradation (5–7) and risk of osteoarthritis progression (COMP, C2C and urinary CTXII) indicate cartilage sparing changes in iPPS subjects when measured by serum, urine, or synovial fluid at Days 56 and 168. Molecular biomarkers of cartilage degradation in iPPS-treated subjects were favourable compared to placebo control (Table 1).

Table 1: Molecular biomarkers of cartilage degradation

  Molecular Biomarker C2C (Se)

CTX II (U)

COMP (SF)

COMP (Se) ARGS (SF) ARGS (Se)

Day 168 iPPS v placebo Reduced (p=0.024) Reduced

Reduced

Reduced

Reduced (p=0.024) Reduced

  ARGS = Aggrecan amino acids alanine, arginine, glycine, and serine; C2C = collagen type-II C-terminal cleavage neoepitope; COMP = cartilage oligomeric matrix protein; CTX II = C-terminal crosslinked telopeptide type II collagen; Se = serum; SF = synovial fluid; U = urine.

Safety

Safety data through to Day 168 has been assessed with no new safety signals identified in the study. A summary of the safety profile during the PARA_OA_008 phase 2 study determined iPPS was well tolerated. The majority of the treatment-emergent adverse events (TEAEs) reported were injection site reactions, which were mild in severity and mostly self-limiting, which is consistent with the known safety profile of PPS.

Next Steps

During the second half of CY2023, Paradigm intends to initiate discussion with key regulatory agencies (FDA and EMA) in order to reach agreement on disease modification label pathways for iPPS. The Fast Track designation granted by the FDA for Paradigm’s OA program allows for easier access to the FDA and opportunities for more frequent dialogue on the development program for iPPS in OA. Through meetings with the FDA and EMA, Paradigm aims to agree with the agencies on the required regulatory pathway for DMOAD indication labelling. By obtaining feedback from key regulators, Paradigm hopes to continue to harmonise global regulatory requirements for further indication labelling. Additional Disease modifying outcomes will be assessed for confirmation in the phase 3 clinical program.

Feedback from the EMA may be further useful for assessing the next steps towards TGA provisional approval as Australia follows the EMA’s guidelines on “Clinical investigation of medicinal products used in the treatment of osteoarthritis” which details expectations for structure modification studies.

The complete data set from the Day 56 and Day 168 timepoints in the PARA_OA_008 phase 2 clinical study will be prepared for peer review and publication.

Investor Webinar

Paradigm Biopharmaceuticals will hold an investor webinar today, 4 April 2023 at 9:30am (AEST), to present and discuss the novel Day 168 data from the PARA_OA_008 clinical trial. The webinar will feature Managing Director, Mr Paul Rennie; Chief Medical Officer, Dr Donna Skerrett; and Global Head of OA, Dr Mukesh Ahuja.

Please register for the webinar via the following link:

https://us02web.zoom.us/webinar/register/WN_HL24yen3SKuWLoZxuTJG1A

After registering, you will receive a confirmation email. A copy of the presentation is available via the ASX or on the Paradigm website. Following the webinar, a recording will become available on the Paradigm website.

PARA_OA_008 Clinical Trial Design

The PARA_OA_008 phase 2 clinical trial is designed to evaluate the treatment effects of iPPS on synovial fluid biomarkers associated with OA-related pain, inflammation, and disease progression in humans. The study also evaluates the effect of iPPS on these biomarkers in serum and urine and investigates any correlation with synovial fluid biomarkers. In a prior phase 2b clinical trial, Paradigm observed serum and urine changes in COMP, ADAMTS-5, and CTX-II biomarkers, providing promising signals of iPPS mechanisms of action on joint preservation.

Patients had moderate to severe arthritis with Kellgren Lawrence (KL) grade 2-4 (where 4 is the maximum indicating severe

OA), and baseline WOMAC pain scores of 4.6 to 10.

 In the PARA_OA_008 clinical trial, subjects (n=61) were randomised and received either a subcutaneous injection of 2 mg/kg iPPS twice weekly, iPPS once weekly plus one

 placebo injection, or two placebo injections for 6 weeks.

 This phase 2 clinical trial is an

 exploratory study and was not intended to be powered to obtain statistical significance. The aim is to provide novel scientific evidence to test the hypothesis that iPPS acts locally in the knee joint of OA subjects as well as provide data on whether biomarker changes correlate with clinical outcome (WOMAC pain and function assessments). Further

 evaluation on serum, synovial fluid and urine biomarker correlations, and further longer-

 term clinical outcomes are in progress.

 Biomarkers that alter in relation to clinical outcomes could help further clarify the multiple proposed mechanisms of action for iPPS in OA. This contrasts with currently available pharmacological agents which have thus far failed to deliver durable satisfactory patient

 outcomes of improved pain and/or function and disease modification.

About WOMAC Scores

•

• •

About Paradigm Biopharmaceuticals

(13):

 The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is a widely used, proprietary set of standardised questionnaires used by health professionals to evaluate the condition of patients with OA of the knee and hip, and includes pain, stiffness, and physical functioning of the joints. The WOMAC has also been used to assess back pain, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus

 erythematosus, and fibromyalgia. It consists of 24 items divided into 3 sub-scales

 Pain (5 items): during walking, using stairs, in bed, sitting or lying, and standing

 upright;

 Stiffness (2 items): after first waking and later in the day;

 Physical function (17 items): using stairs, rising from sitting, standing, bending, walking, getting in / out of a car, shopping, putting on / taking off socks, rising from bed, lying in bed, getting in / out of bath, sitting, getting on / off toilet, heavy

 domestic duties, light domestic duties.

Paradigm Biopharmaceuticals Ltd. (ASX:PAR) is a late-stage drug development company driven by a purpose to improve patients’ health and quality of life by discovering, developing, and delivering pharmaceutical therapies. Paradigm’s current

 developing injectable (subcutaneous) pentosan polysulfate sodium (iPPS) for the treatment of diseases where inflammation plays a major pathogenic role, indicating a

osteoarthritis (phase 3) and mucopolysaccharidosis (phase 2).

Forward Looking Statements

This Company announcement contains forward-looking statements, including statements regarding anticipated commencement dates or completions dates of preclinical or clinical trials, regulatory developments and regulatory approval. These forward-looking statements are not guarantees or predictions of future performance, and involve known and unknown risks, uncertainties and other factors, many of which are beyond our control, and which may cause actual results to differ materially from those expressed in the statements contained in this presentation. Readers are cautioned not to put undue reliance on forward-looking statements.

References

1. Long H, Liu Q, Yin H, Wang K, Diao N, Zhang Y, et al. Prevalence trends of site-specific osteoarthritis from 1990 to 2019: findings from the Global Burden of Disease Study 2019. Arthritis Rheumatol [Internet]. 2022 [cited 2022 Mar 4];74(7). Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/art.42089

2. Murphy LB, Cisternas MG, Pasta DJ, Helmick CG, Yelin EH. Medical Expenditures and Earnings Losses Among US Adults With Arthritis in 2013. Arthritis Care Res. 2018 Jun;70(6):869–76.

3. Oo WM, Yu SPC, Daniel MS, Hunter DJ. Disease-modifying drugs in osteoarthritis: current understanding and future therapeutics. Expert Opin Emerg Drugs. 2018 Oct 2;23(4):331–47.

4. Matthews GI, Hunter DJ. Emerging drugs for osteoarthritis. Expert Opin Emerg Drugs. 2011 Sep;16(3):479–91.

focus is

 need for the anti-inflammatory and tissue regenerative properties of PPS,

such as in

5. Vilím V, Olejárová M, Machácek S, Gatterová J, Kraus VB, Pavelka K. Serum levels of cartilage oligomeric matrix protein (COMP) correlate with radiographic progression of knee osteoarthritis. Osteoarthritis Cartilage. 2002 Sep;10(9):707–13.

6. Kraus VB, Collins JE, Hargrove D, Losina E, Nevitt M, Katz JN, et al. Predictive validity of biochemical biomarkers in knee osteoarthritis: data from the FNIH OA Biomarkers Consortium. Ann Rheum Dis. 2017 Jan;76(1):186–95.

7. Larsson S, Lohmander LS, Struglics A. Biological variation of human aggrecan ARGS neoepitope in synovial fluid and serum in early-stage knee osteoarthritis and after knee injury. Osteoarthr Cartil Open. 2022 Dec;4(4):100307.

8. Cicuttini FM, Jones G, Forbes A, Wluka AE. Rate of cartilage loss at two years predicts subsequent total knee arthroplasty: a prospective study. Ann Rheum Dis. 2004 Sep;63(9):1124–7.

9. Eckstein F, Kwoh CK, Boudreau RM, Wang Z, Hannon MJ, Cotofana S, et al. Quantitative MRI measures of cartilage predict knee replacement: a case-control study from the Osteoarthritis Initiative. Ann Rheum Dis. 2013 May;72(5):707–14.

10. Scher C, Craig J, Nelson F. Bone marrow edema in the knee in osteoarthrosis and association with total knee arthroplasty within a three-year follow-up. Skeletal Radiol. 2008 Jul;37(7):609–17.

11. Dore D, Quinn S, Ding C, Winzenberg T, Zhai G, Cicuttini F, et al. Natural history and clinical significance of MRI- detected bone marrow lesions at the knee: a prospective study in community dwelling older adults. Arthritis Res Ther. 2010;12(6):R223.

12. Tanamas SK, Wluka AE, Pelletier JP, Martel-Pelletier J, Abram F, Wang Y, et al. The association between subchondral bone cysts and tibial cartilage volume and risk of joint replacement in people with knee osteoarthritis: a longitudinal study. Arthritis Res Ther. 2010;12(2):R58.

13. WOMAC Osteoarthritis Index [Internet]. Physiopedia. [cited 2022 Sep 28]. Available from: https://www.physio- pedia.com/WOMAC_Osteoarthritis_Index

Authorised for release by the Paradigm Board of Directors.

Zilosul® is the registered trademark of Paradigm Biopharmaceuticals Ltd. for injectable pentosan polysulfate sodium in the treatment of osteoarthritis.

To learn more please visit: www.paradigmbiopharma.com

FOR FURTHER INFORMATION PLEASE CONTACT:

Simon White

Director of Investor Relations

Tel: +61 404 216 467

Paradigm Biopharmaceuticals Ltd ABN: 94 169 346 963

Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA Email: [email protected]

        PHASE 2 PARA_OA_008 CLINICAL TRIAL DAY 168 TOP-LINE RESULTS PRESENTATION

  Disclaimer

This document, together with any information communicated by Paradigm Biopharmaceuticals Ltd ASX:PAR (known as “Paradigm”, “Paradigm Biopharma” or “the Company”), in any presentation or discussion relating to this document (collectively, “Information”) is confidential, and has been prepared by the Company on the condition that it is for the exclusive information and use of the recipient. The Information is proprietary to Paradigm and may not be disclosed to any third party or used for any other purpose without the prior written consent of the Company.

The Information is based upon management forecasts and reflects prevailing conditions, which are accordingly subject to change. In preparing the Information, the Company has relied upon and assumed, without independent verification, the accuracy and completeness of all information available from public sources, or which was otherwise reviewed by it. In addition, the analyses are not and do not purport to be appraisals of the assets, stock or business of the Company. Even when the Information contains a kind of appraisal, it should be considered preliminary, suitable only for the purpose described herein and should not be disclosed or otherwise used without the prior written consent of Paradigm. The Information is provided on the understanding that unanticipated events and circumstances may occur which may have significant valuation and other effects.

This Company presentation contains forward-looking statements, including statements regarding anticipated commencement dates or completions dates of preclinical or clinical trials, regulatory developments and regulatory approval.

These forward-looking statements are not guarantees or predictions of future performance, and involve known and unknown risks, uncertainties and other factors, many of which are beyond our control, and which may cause actual results to differ materially from those expressed in the statements contained in this presentation. Readers are cautioned not to put undue reliance on forward-looking statements. The rate and timing of enrolment of our clinical trials and the timing of top-line results of our clinical trials should be regarded as forward-looking statements and the actual dates could differ materially from the expectations and projections set forth in Company presentations or statements especially during a pandemic.

Paradigm Biopharma April 2023 2

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April 2023

  Executive Summary

PARA_OA_008

Key Highlights – Day 168 Results

• Multiple signals at Day 168 of DMOAD efficacy with iPPS.

• MRI at Day 168 demonstrated changes in several structural

disease features, consistent with DMOAD efficacy.

o Most notably improvements in cartilage loss, bone marrow lesions and marginal osteophytes.

• Four key biomarkers ARGS, C2C, COMP, and CTX II demonstrated favourable changes in iPPS-treated subjects compared to placebo.

• Durable positive clinical responses in WOMAC pain, function, stiffness, and overall WOMAC score.

o Rescue medication use over 4 times more frequent in the placebo group compared to twice-weekly iPPS.

• New MRI, molecular biomarker, and clinical outcomes will be presented to the Regulatory Authorities (FDA & EMA).

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  Exploratory Rationale

DMOAD Program

Why Paradigm is exploring iPPS DMOAD potential in parallel to pain and function

• High unmet need for new OA therapies to slow OA progression in tandem with symptomatic improvement (Pain reduction and Functional improvement).

• Currently there are no approved DMOAD therapies for OA.

• 81% of OA patients are dissatisfied with current OA therapies

(Matthews GI et al, Expert Opin Emerg Drugs. 2011;16)

• Independent global market research conducted in 2021 stated that a DMOAD label for iPPS would:

• Significantly increase price per treatment course.

• Physicians would be more likely to use iPPS as a first-line therapy.

  Potential DMOAD

Programs investigating iPPS as a potential DMOAD

Paradigm Biopharma

April 2023 5

  PARA_005 – Australia (completed)

• 126 participants randomized to iPPS or placebo. • 2mg/kg PPS twice weekly for 6 weeks vs

placebo.

• Day 53 Molecular Biomarker Results:

o Reduction in serum levels of COMP

(p=0.0024) and ADAMTS-5.

o Reduction in urinary levels of CTX II (p=0.0116)

• MRI Outcomes:

o Bone Marrow Edema Lesion (BML) Grade by MRI demonstrated clinically meaningful reduction in the iPPS group compared to placebo (P=0.03)

PARA_008 – Australia (ongoing)

• 61 participants randomized to iPPS or placebo.

• 2mg/kg ideal body weight (IBW) twice weekly, 2mg/kg IBW once weekly plus placebo once weekly or placebo twice weekly for 6 weeks

• Day 56 Synovial Fluid Biomarker Results:

o Reduction in inflammatory cytokines (TNF-α

and IL-6),

o Reduction in pain mediator NGF,

o Reduction in by products of cartilage degradation COMP and ARGS

o Increase in inhibitor of cartilage degrading enzymes TIMP-1

  Mechanism of action

• Multiple modes of action • Previous phase 2B, SAS,

and EAP experience • New phase 2 data

OA

MPS

ARDS

HF

Viral Arthralgia

Pentosan Polysulfate Sodium (PPS)

Paradigm Biopharma

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     NF-κB

   Inflammation Pain

TNF-α, IL-1β, IL-6 NGF

Immune Sensory Cells Nerve

Cells

Tissue Preservation

ADAMTS-4 & -5, MMPs

Improved Blood Flow

Cell-adhesion molecules Anti-thrombotic effects

Capillary Endothelial Cells

         Tissue/ Cartilage Cells

  Current hypothesis for PPS mechanism of action

  PARA_OA_008

OA

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April 2023

 Exploring the potential of iPPS as a disease modifying OA drug (DMOAD)

• Biomarker study assessing change from baseline in multiple objective measures associated with disease progression of OA.

 DMOAD Program

PARA_OA_008

•

• 61 participants received iPPS 2 mg/kg once or twice weekly, or placebo.

• Follow-up period out to 12 months. Outstanding top-line results reported at Day 56:

• iPPS improved multiple biomarkers measured in the synovial fluid.

• iPPS treatment showed statistically significant improvements at Day 56 in pain, function, stiffness, and overall WOMAC scores for twice-weekly iPPS compared to the placebo arm.

• Significant changes in pain and function were not apparent in the once-weekly iPPS group compared to placebo

  Paradigm Biopharma

April 2023 9

 Structural imaging biomarkers being evaluated for PPS as a potential disease modifying treatment for OA

  Imaging Biomarkers

DMOAD Investigation

Biomarker

Subchondral BML area and volume

Joint synovitis / effusion volume

Cartilage thickness

Bone shape / osteophytes

Joint space width

Evaluated

MRI MRI MRI MRI

MRI & X- Ray

Biomarker Pathology

Pain and cartilage degeneration Inflammation and pain Cartilage degeneration Adverse bone remodelling Adverse bone remodelling

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01/04/21 10 April 2023 10

 MRI Outcomes

PARA_OA_008

• Despite the relatively small number of subjects in each arm and the short follow-up interval compared to the generally slow structural progression in OA, changes consistent with DMOAD efficacy were observed in a number of disease features.

• Structural changes were most noticeably observed in: o Cartilage loss

o Bone marrow lesions o Osteophyte formation

Day 168 Top-Line Results – Structural changes in the bone and knee joint via MRI

 • Baseline levels of OA disease were established by MRI prior to treatment.

• Follow-up MRIs were obtained at Day 168 to identify any differences in disease progression between the iPPS groups versus placebo.

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01/04/21 11 April 2023 11

 Day 168 Top-Line Results – Structural changes in the bone and knee joint via MRI

Cartilage Loss

• Considered the most important feature of OA disease.

• Predictive of knee replacement surgery in OA sufferers.

 MRI Outcomes

PARA_OA_008

• Once-weekly iPPS showed an average 21% improvement in mean cartilage loss score in the medial femur, whereas the placebo arm showed a 4% worsening of cartilage loss (p=0.065).

• Twice-weekly iPPS group, showed trends of improvement (though not statistical) or stabilisation of cartilage preservation compared to the placebo group.

Bone Marrow Lesions

• Predictive of knee replacement.

• Bone marrow lesions in the lateral femur decreased by an average 38% in the once-weekly iPPS arm, whereas in the placebo arm it increased by 47% (p=0.056).

• Bone marrow lesions in the entire lateral tibiofemoral compartment decreased by an average 17% in the once-weekly iPPS arm, whereas increased by 56% in the placebo arm (p=0.028).

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 MRI Outcomes

PARA_OA_008

Day 168 Top-Line Results – Structural changes in the bone and knee joint via MRI

Marginal Osteophytes

  • "Bone spurs" that form between the cartilage and bone and are an early finding in OA.

• Osteophytes increase in number and size as the disease progresses.

• Osteophytes in PARA_OA_008 decreased slightly or remained stable in all three compartments of the knee among patients treated with iPPS, compared to an increase (numerically, though not statistically significantly) in the placebo arm.

 Representative image of osteophytes from Prezja F et al. Sci Reports 2022;12.

    Clinical Outcomes

PARA_OA_008

• Twice-weekly iPPS demonstrated durable responses in WOMAC scores for pain, function, stiffness and overall WOMAC scores compared to placebo.

• Twice-weekly iPPS compared to placebo showed:

o Durable WOMAC pain reduction

o WOMAC function: 50% improvement for 53.3% of twice- weekly iPPS compared to 22.1% of placebo (p=0.067).

Day 168 Top-Line Results – Changes in WOMAC Pain, Function, Stiffness and PGIC

o PGIC favourable at Day 168 (p=0.061)

o Day 112 iPPS showed WOMAC stiffness (p=0.029), function

(p=0.059), and overall (p=0.067)

• Placebo group used rescue medications four times as often as the twice-weekly iPPS group, on 23 days versus 5 days.

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 Paradigm Biopharma

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 Molecular biomarkers being evaluated for PPS as a potential disease modifying treatment for OA

  Molecular Biomarkers

DMOAD Investigation

Biomarker

Pro-inflammatory Cytokines

IL-1b IL-6 TNF-α

Pain Mediator

NGF

Joint Degradation Biomarkers

ARGS TIMP-1 CTX-I CTX-II C2C COMP ADAMTS-4 ADAMTS-5 MMP-3

Biological Fluids

Synovial Fluid Synovial Fluid Synovial Fluid

Synovial Fluid, Serum

Synovial Fluid, Serum

Synovial Fluid, Serum Synovial Fluid, Serum, Urine Synovial Fluid, Urine, Plasma Synovial Fluid, Serum Synovial Fluid, Serum Serum

Synovial Fluid, Serum Serum

   Molecular Bio markers

PARA_OA_008

• Synovial fluid and serum samples of ARGs and COMP showed favourable changes in the iPPS group compared to placebo.

• Data analysed from Serum C2C and urinary CTX II also demonstrated persistent beneficial effects of iPPS compared to placebo.

• The four biomarkers of focus have are extensively researched in literature in their role of cartilage breakdown in OA subjects.

Paradigm Biopharma

Day 168 Top-Line Results – Changes in Synovial Fluid, Serum, and Urinary Biomarkers

• iPPS disease modifying potential in knee OA treatment as demonstrated by alterations in four of the biomarkers.

01/04/21 15 April 2023 15

   Paradigm Biopharma

Day 168 Top-Line Results – Changes in Synovial Fluid, Serum, and Urinary Biomarkers

01/04/21 16 April 2023 16

  •

Molecular biomarkers of cartilage degradation in iPPS-treated subjects were favourable compared to placebo control.

 Molecular Biomarkers

PARA_OA_008

Molecular Biomarker

C2C (Se) CTX II (U) COMP (SF) COMP (Se) ARGS (SF) ARGS (Se)

Day 168 iPPS v placebo

Reduced (p= 0.024) Reduced

Reduced Reduced

Reduced (p=0.024) Reduced

  ARGS = Aggrecan amino acids alanine, arginine, glycine, and serine; C2C = collagen type-II C-terminal cleavage neoepitope; COMP = cartilage oligomeric matrix protein; CTX II = C-terminal crosslinked telopeptide type II collagen; Se = serum; SF = synovial fluid; U = urine.

   NEXT STEPS

DMOAD

   01/04/21 18 Paradigm Biopharma April 2023 18

 Expected regulatory discussions following data release

 Next Steps

DMOAD Program

• New MRI, molecular biomarker, and clinical outcomes will be presented to the Regulatory Authorities (FDA and EMA).

• Paradigm intends to initiate discussions with FDA during the second half of 2023.

• Fast Track designation facilitates easier access to FDA and opportunity for more frequent dialogue on the development program for iPPS in OA.

• Paradigm aims to agree with the FDA and EMA on the required regulatory pathway for a DMOAD indication.

• Feedback from EMA will be particularly useful to assess next steps with TGA provisional approval.

• Data set from the Day 56 and Day 168 timepoints in the PARA_OA_008 phase 2 clinical study will be prepared for peer review and publication.

   Near-term News flow

Upcoming Catalysts

Near-term news flow

• MPS VI phase 2 clinical trial – 100% recruitment Q2 CY2023.

• Canine OA Model – 26-week (3-year human equivalent) data

Q2 CY2023.

• PARA_OA_002 clinical trial – update Q2 CY2023.

• PARA_OA_008 clinical trial – 12-month clinical outcome data 2HCY2023.

• MPS I & VI phase 2 clinical trials – top-line data Q4CY2023

• Paradigm is currently in active discussion with multiple potential partners for its phase 2 asset in mucopolysaccharidosis (MPS).

Paradigm Biopharma

April 2023 19

  For more information please visit:

paradigmbiopharma.com

or email any questions to [email protected]

Paradigm Biopharma April 2023 20

I have little doubt that zilosul (pentosan polysulphate) has a meaningful effect on OA within the e knee…

if the business is able to transform this pharmacology into any meaningful slice of the OA analgesia market at all it will be worth many multiples of its current market cap…

the cashburn in the most recent year, however, was ~30 mil with about 70 mil sitting in the bank…

whilst I’m hoping it was a costly half because of the roll out of the pivotal trial km realistic enough to expect ongoing costs of a similar magnitude…

the way out? A big pharma buy out or partnership triggered by the release of promising results this year… or ANOTHER cap at a pretty sub optimal time with respect to macro conditions…

watch this space …

disclosure held IRL and clearly in SM

This is business as usual but positive news in progressing the pivotal trial of zilosul in knee OA. Access to Poland, Czech Republic and Belgium!

another tick

my only real concern right now is timing of cash burn vs positive trial announcements…

 ASX RELEASE 14 March 2023

Paradigm receives parallel European regulatory and ethics approvals for the pivotal PARA_OA_002 global clinical trial.

Key Highlights

• Regulatory and ethics approvals have been received via Europe’s Clinical Trial Information System (CTIS) for Paradigm’s pivotal PARA_OA_002 clinical trial.

• Paradigm now has all required approvals in place to commence clinical trial site start-up activities in Belgium, Poland, and the Czech Republic for the PARA_OA_002 clinical trial.

• The CTIS is a recently implemented system for the evaluation of clinical trial applications and harmonises regulatory and ethics committee reviews by European countries.

• Paradigm is in the process of activating up to seven sites across the three countries to enrol participants with knee osteoarthritis (OA) into the PARA_OA_002 study.

is pleased to announce it has received parallel regulatory and ethics approvals for the pivotal PARA_OA_002 clinical trial in Belgium, Poland, and the

Czech Republic.

The phase 3 pivotal PARA_OA_002 clinical trial is a randomised, double-blind, placebo- controlled, multicentre (US/AU/UK/EU/CA) study that will evaluate the dose and treatment effect of injectable pentosan polysulphate sodium (iPPS) in participants with knee osteoarthritis pain.

Paradigm’s PARA_OA_002 application was submitted via Europe’s recently implemented the CTIS for evaluation in these three European countries. As such, Paradigm’s iPPS dossier underwent harmonised review by the three countries’ regulatory and ethics committees, resulting in a single decision to authorise the trial to proceed. Paradigm now has all the required approvals in place to commence clinical trial site start-up activities in these countries for the pivotal PARA_OA_002 global clinical trial. Paradigm has identified sites and is in the process of activating up to seven sites across the three countries to enrol participants with knee OA into the PARA_OA_002 study.

  Paradigm Biopharmaceuticals Ltd (ASX:PAR) (“Paradigm” or “the Company”), a

 late-stage drug development company focused on delivering new therapies to address

 unmet medical needs,

The CTIS has been established in Europe to support the Implementation of Clinical Trial Regulation No 536/2014. The CTIS portal facilitates communication between clinical trial sponsors, European Union (EU) Member States, European Economic Area (EEA) countries, and the European Commission throughout the lifecycle of a clinical trial. The CTIS portal went live on 31 January 2022 and became mandatory for all clinical trial submissions from 31 January 2023.

Paradigm’s Managing Director, Paul Rennie, commented: “Paradigm’s pivotal PARA_OA_002 global clinical protocol continues to gain acceptance and approval by key regulatory bodies. The Company has focused on gaining approval in Poland, Belgium, and the Czech Republic due to the large pool of OA sufferers and number of experienced clinical trial sites with proven recruitment capabilities. This harmonised approval paves the way for further regulatory and ethics applications in additional European countries for the upcoming confirmatory phase 3 clinical trial, PARA_OA_003.”

-Ends-

Paradigm Biopharmaceuticals Ltd. (ASX:PAR) is a late-stage drug development company driven by a purpose to improve patients’ health and quality of life by discovering, developing, and delivering pharmaceutical therapies. Paradigm’s current focus is developing iPPS for the treatment of diseases where inflammation plays a major pathogenic role, indicating a need for the anti-inflammatory and tissue regenerative properties of PPS, such as in osteoarthritis (phase 3 clinical trial) and mucopolysaccharidosis (phase 2 clinical trial).

Forward Looking Statements

This Company announcement contains forward-looking statements, including statements regarding anticipated commencement dates or completions dates of preclinical or clinical trials, regulatory developments and regulatory approval. These forward-looking statements are not guarantees or predictions of future performance, and involve known and unknown risks, uncertainties and other factors, many of which are beyond our control, and which may cause actual results to differ materially from those expressed in the statements contained in this presentation. Readers are cautioned not to put undue reliance on forward-looking statements.

Authorised for release by the Paradigm Board of Directors. To learn more please visit: www.paradigmbiopharma.com FOR FURTHER INFORMATION PLEASE CONTACT:

Simon White

Director of Investor Relations

Tel: +61 404 216 467

Paradigm Biopharmaceuticals Ltd. ABN: 94 169 346 963

 About Paradigm Biopharmaceuticals

Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA Email: [email protected]

Presentation given at JP Morgan conference 11/1/23:

https://paradigmbiopharma.com/performance-progress/#presentations.

nothing too much new but reaffirms timelines etc…

this is one for the patient (been holding for years) but 2023/2024 will see some big catalysts when data starts coming out of the pivotal phase 3 trial I think

28th Dec: good news (if expected), no bumps in the road with pivotal trial for now:

 ASX RELEASE 28 December 2022

Paradigm’s

advise that the first safety review meeting of the Data Monitoring Committee (DMC) for the pivotal PARA_OA_002 clinical trial was conducted on 20 December 2022. The DMC review of trial progress and safety data concluded that the PARA_OA_002 clinical trial should proceed without modification.

The DMC is responsible for assessing safety and efficacy during the conduct of Paradigm’s PARA_OA_002 study, as well as ensuring the validity and scientific merit of the trial.

The Phase 3 Pivotal PARA_OA_002 clinical trial is a randomised, double-blind, placebo-controlled, multicentre (US/AU/UK/EU/CA) study that will evaluate the dose and treatment effect of injectable pentosan polysulphate sodium (iPPS) in participants with knee osteoarthritis (kOA) pain.

Paradigm Managing Director, Mr Paul Rennie commented: “The DMC is a formal review process, and a written response has been received by the Company. This is a positive outcome for Paradigm that the early safety data from the pivotal PARA_OA_002 clinical trial has been reviewed by the DMC and it was recommended to continue without modification. Injectable PPS has been well tolerated throughout all of Paradigm’s clinical programs, including real-world evidence with treatment of over 600 participants via the TGA Special Access Scheme. I look forward to updating our shareholders in calendar year 2023 on the progress of Paradigm’s exciting OA clinical program with further PARA_OA_002 updates, as well as 6-month data from our PARA_OA_008 clinical trial exploring the disease modifying potential of iPPS”.

About PARA_OA_002

PPS

(kOA This is a 2-stage, adaptive study that will evaluate the dose and

treatment effect of iPPS in participants with kOA pain.

Stage 1 comprises phase 2b dose selection, with approximately 468 participants randomised to receive 1 of 3 iPPS dose regimens or placebo for 6 weeks. The primary objective of stage 1 is to identify the minimal effective dose that will be used in stage 2 and in Paradigm’s confirmatory trial. The selected dose is based on an optimal balance of efficacy and safety.

PARA_OA_002 Pivotal Phase 3 Clinical Trial to Proceed Without

 Modification Following Formal Safety Review

 Paradigm Biopharmaceuticals Ltd (ASX:PAR) (“Paradigm” or “the Company”), a late-stage drug

 development company focused on delivering new therapies to address unmet medical needs, is

 pleased to

 The purpose of this study is to measure the change in pain and function with subcutaneous

 injections of i

 osteoarthritis

compared with subcutaneous injections of placebo in participants with knee

 ) pain.

Participants in stage 1 will be randomly allocated to receive one of the following:

• 1.5 mg/kg calculated for ideal body weight (IBW) iPPS twice weekly

• 2 mg/kg IBW iPPS once weekly + placebo once weekly

• Fixed doses

o 100 mg iPPS for ≤65 kg IBW once weekly + placebo once weekly, or

o 150 mg iPPS for >65 to ≤90 kg IBW once weekly + placebo once weekly, or o 180 mg iPPS for >90 kg IBW once weekly + placebo once weekly

• Placebo twice weekly

In stage 2 (phase 3), approximately 470 participants will be randomised 1:1 to receive the

selected iPPS dose regimen or placebo for 6 weeks. Participants in stage 2 will be randomly allocated to receive:

• One of the 3 stage 1 iPPS dose regimens selected by the DMC, or

• Placebo twice weekly

The primary endpoint in the pivotal study is a change from baseline at day 56 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain. Secondary outcomes include change from baseline at multiple time points out to day 168 in WOMAC pain and function, Patient Global Impression of Change (PGIC), and Quality of Life (QoL).

About Paradigm Biopharmaceuticals

Authorised for release by the Paradigm Board of Directors. To learn more please visit: www.paradigmbiopharma.com FOR FURTHER INFORMATION PLEASE CONTACT:

Simon White

Director of Investor Relations

Tel: +61 404 216 467

Paradigm Biopharmaceuticals Ltd.

ABN: 94 169 346 963

Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA Email: [email protected]

Paradigm Biopharmaceuticals Ltd. (ASX:PAR) is a late-stage drug development company driven

 by a purpose to improve patients’ health and quality of life by discovering, developing, and

 delivering pharmaceutical therapies. Paradigm’s current focus is developing injectable

 (subcutaneous) pentosan polysulfate sodium (iPPS) for the treatment of diseases where

 inflammation plays a major pathogenic role, indicating a need for the anti-inflammatory and

 tissue regenerative properties of PPS, such as in osteoarthritis (phase 3) and

 mucopolysaccharidosis (phase 2).

nice to see some on market buying from the head honcho - Paul Rennie (60k) particularly in the setting of the recent unexpected departure of a recently appointed CEO…

Appendix 3Y Change of Director’s Interest Notice

Rule 3.19A.2

Information or documents not available now must be given to ASX as soon as available. Information and documents given to ASX become ASX’s property and may be made public.

Introduced 30/09/01 Amended 01/01/11

Name of entity Paradigm Biopharmaceuticals Limited ABN 94 169 346 963

We (the entity) give ASX the following information under listing rule 3.19A.2 and as agent for the director for the purposes of section 205G of the Corporations Act.

Name of Director  Paul Rennie

Date of last notice  19 September 2022

Part 1 - Change of director’s relevant interests in securities

In the case of a trust, this includes interests in the trust made available by the responsible entity of the trust

Note: In the case of a company, interests which come within paragraph (i) of the definition of “notifiable interest of a director” should be disclosed in this part.

Direct or indirect interest Direct and indirect interest

Date of change 16-19 December 2022

Appendix 3Y Change of Director’s Interest Notice

    Nature of indirect interest

(including registered holder)

Note: Provide details of the circumstances giving rise to the relevant interest.

  Mr Paul Rennie is the legal and beneficial owner of 100% of the securities in KZEE Pty Ltd.

Mr Paul Rennie is the legal and beneficial owner of 100% of the securities in EAR Investments Pty Ltd.

   + See chapter 19 for defined terms. 01/01/2011 Appendix 3Y Page 1

Appendix 3Y

Change of Director’s Interest Notice

 No. of securities held prior to change

  Paul Rennie

– 8,378,977 Fully Paid Ordinary Shares

KZEE Pty Ltd ATF KZEE Superannuation Fund

– 10,914,902 Fully Paid Ordinary Shares registered in the name of KZEE Pty Ltd. Mr Paul Rennie is the legal and beneficial owner of 100% of the securities in KZEE Pty Ltd.

EAR Investments Pty Ltd ATF EAR Investments Trust

– 1,097,355 Fully Paid Ordinary Shares registered in the name of EAR Investments Pty Ltd. Mr Paul Rennie is the legal and beneficial owner of 100% of the securities in EAR Investments Pty Ltd.

Total No. of shares held after change

– 20,391,234 Fully Paid Ordinary Shares

  Class

Number disposed

Ordinary Shares

Not applicable

Number acquired

  Paul Rennie

– 47,720 Fully Paid Ordinary Shares

  Value/Consideration

Note: If consideration is non-cash, provide details and estimated valuation

  Paul Rennie

– $61,521

  + See chapter 19 for defined terms. Appendix 3Y Page 2

01/01/2011

Detail of contract Nature of interest

Name of registered holder (if issued securities)

Date of change

Interest acquired Interest disposed

+ See chapter 19 for defined terms. 01/01/2011 Appendix 3Y Page 3

Not applicable Not applicable

Not applicable Not applicable

Not applicable Not applicable

Appendix 3Y Change of Director’s Interest Notice

 No. of securities held after change

  Paul Rennie

– 8,426,697 Fully Paid Ordinary Shares

KZEE Pty Ltd ATF KZEE Superannuation Fund

– 10,914,902 Fully Paid Ordinary Shares registered in the name of KZEE Pty Ltd. Mr Paul Rennie is the legal and beneficial owner of 100% of the securities in KZEE Pty Ltd.

EAR Investments Pty Ltd ATF EAR Investments Trust

– 1,097,355 Fully Paid Ordinary Shares registered in the name of EAR Investments Pty Ltd. Mr Paul Rennie is the legal and beneficial owner of 100% of the securities in EAR Investments Pty Ltd.

Total No. of shares held after change

– 20,438,954 Fully Paid Ordinary Shares

 Nature of change

Example: on-market trade, off-market trade, exercise of options, issue of securities under dividend reinvestment plan, participation in buy-back

  On-market trade

  Part 2 – Change of director’s interests in contracts

Note: In the case of a company, interests which come within paragraph (ii) of the definition of “notifiable interest of a director” should be disclosed in this part.

    No. and class of securities to which interest

related prior to change

Note: Details are only required for a contract in relation to which the interest has changed

  Not applicable

Appendix 3Y

Change of Director’s Interest Notice

Value/Consideration

Note: If consideration is non-cash, provide details and an estimated valuation

Interest after change Part 3 – +Closed period

Not applicable Not applicable

    Were the interests in the securities or contracts detailed No above traded during a +closed period where prior written

 clearance was required?

If so, was prior written clearance provided to allow the trade to proceed during this period?

If prior written clearance was provided, on what date was this provided?

Not applicable Not applicable

    + See chapter 19 for defined terms. Appendix 3Y Page 4

01/01/2011

absolutely no mention of why the CEO is standing down…

concerning.

I don’t mind Paul Rennie having an increased role as I see him as a founder type BUT this unexpected change makes me worry… toxic culture? CEO concerns about the likelihood of success/trial progression? Who knows…

Not selling out but not enjoying this completely unexplained instability

 ASX RELEASE 22 November 2022

Paradigm CEO stepping down & Appointment of MD

Paradigm Biopharmaceuticals Ltd (ASX:PAR, “Paradigm” or “the Company”), a late-stage drug development company focused on delivering new therapies to address unmet medical needs, today announces that its CEO, Mr Marco Polizzi, has stepped down from his role and will cease employment with the Company on 20 February 2023. The Paradigm Board said “The Paradigm Board would like to thank Mr Polizzi for his service to Paradigm."

The Paradigm Board has appointed Paradigm’s founder and Non-executive Chairman Mr Paul Rennie as Paradigm’s Managing Director during this transition period to 20 February 2023 and thereafter. Mr Rennie said: “I am pleased to advise that the personal circumstances that originally required my stepping down from the Managing Director role in 2021, have now been successfully resolved. I look forward to working closely again with the Paradigm executive team and the Board in continuing our journey together."

Mr Rennie will continue to serve on the Paradigm Board, now as an Executive Chairman. The Board has appointed Mr Rennie as Managing Director, having considered his in-depth knowledge of all aspects of the Company’s technology and business which will support a seamless transition and will place the Company in the best position to achieve its objectives.

Mr Rennie first founded Paradigm in 2014, took the Company public in 2015 and negotiated the bene pharmaChem exclusive supply agreement. He has generated and in-licensed patents, such as the MPS and lysosomal storage disease patent to grow Paradigm’s intellectual property portfolio. These accomplishments along with a myriad of financial and investor relationships in the Paradigm Board's view make Mr Rennie the optimal Managing Director appointment to continue to cultivate and drive the business forward.

A summary of Mr Rennie’s material terms of employment agreement (which reflects the same salary as the existing CEO position) is included as an annexure to this announcement.

-Ends-

About Paradigm Biopharmaceuticals

Paradigm Biopharmaceuticals Ltd. (ASX:PAR) is a late-stage drug development company driven by a purpose to improve patients’ health and quality of life by discovering, developing, and delivering pharmaceutical therapies. Paradigm’s current

(subcutaneous) pentosan polysulfate sodium (iPPS) for the treatment of diseases where

inflammation plays a major pathogenic role, indicating a need for the anti-inflammatory and

focus is developing injectable

  tissue regenerative properties of PPS,

 mucopolysaccharidosis (phase 2).

Forward Looking Statements

such as in osteoarthritis (phase 3) and

This Company announcement contains forward-looking statements, including statements regarding anticipated commencement dates or completions dates of preclinical or clinical trials, regulatory developments and regulatory approval. These forward-looking statements are not guarantees or predictions of future performance, and involve known and unknown risks, uncertainties and other factors, many of which are beyond our control, and which may cause actual results to differ materially from those expressed in the statements contained in this presentation. Readers are cautioned not to put undue reliance on forward-looking statements.

Authorised for release by the Paradigm Board of Directors. To learn more please visit: www.paradigmbiopharma.com

FOR FURTHER INFORMATION PLEASE CONTACT:

Simon White

Director of Investor Relations

Tel: +61 404 216 467

Paradigm Biopharmaceuticals Ltd.

ABN: 94 169 346 963

Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA Email: [email protected]

Paul Rennie Employment Contract - summary of material terms of employment agreement

1. Position

Mr Rennie is appointed Managing Director and Executive Chairman.

2. Term

The appointment will commence on 22 November 2022 and is ongoing with no fixed term.

3. Remuneration

The remuneration Involves a combination of fixed pay and Incentives (Short and Long term). It has been benchmarked against salary packages for comparable conditions and comprised three primary components as follows:

 4.

• Fixed Annual Remuneration (FAR) – Fixed Pay of AUD$1,060,000 inclusive of compulsory superannuation

• Short Term Incentive (STI) – Annual Short Term Incentive to a maximum of 30% of FAR

• Long Term Incentive (LTI) – Long Term Incentive is intended to be in the form of Performance

Rights which will be determined as per the Company’s LTI Employee plan.

Termination provisions

 The employment may be terminated in the circumstances and on the terms described below:

• Termination on notice: the Company at any time by giving 6 months notice in writing, and the Company may make a payment in lieu of notice.

• Resignation: The CEO may resign by giving six months' written notice.

• Immediate termination for serious misconduct.

The employment agreement also contains usual terms in respect of duties and responsibilities, conflicts of interest, hours of work, leave, confidential information, intellectual property, return of property, resignation from offices, monitoring and surveillance, privacy.

As expected

 ASX RELEASE 18th November 2022

Paradigm Receives $7.4m R&D Tax Incentive Refund

advise as part of the Australian Government’s R&D Tax Incentive Scheme, Paradigm has received a R&D incentive refund of $7,409,117. This incentive recognises the significant research activities undertaken by Paradigm in multiple potential indications for Pentosan Polysulfate Sodium during the financial year ended 30 June 2022.

The Australian Government R&D Tax Incentive encourages companies to engage in R&D benefiting Australia, by providing a tax offset of up to 43.5% (refundable) for eligible R&D activities. 

The $7.4m in additional funding received via the incentive refund will continue to support Paradigm’s Phase 3 clinical program in OA and Phase 2 clinical program in MPS, as well as multiple pre-clinical programs being undertaken by the Company.

About Paradigm Biopharmaceuticals

Authorised for release by the Paradigm Board of Directors. To learn more please visit: www.paradigmbiopharma.com

FOR FURTHER INFORMATION PLEASE CONTACT: Simon White

Director of Investor Relations

Tel: +61 404 216 467

Paradigm Biopharmaceuticals Ltd

ABN: 94 169 346 963

Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA Email: [email protected]

 Paradigm Biopharmaceuticals Ltd (ASX: PAR) (“Paradigm” or “the Company”), a late-stage drug development company focused on delivering new therapies to address unmet medical needs, is

 pleased to

 Paradigm Biopharmaceuticals Ltd. (ASX:PAR) is a late-stage drug development company driven by a purpose to improve patients’ health and quality of life by discovering, developing, and delivering pharmaceutical therapies. Paradigm’s current focus is developing injectable (subcutaneous) pentosan polysulfate sodium (iPPS) for the treatment of diseases where inflammation plays a major pathogenic role, indicating a need for the anti-inflammatory and tissue regenerative properties of PPS, such as in osteoarthritis (phase 3) and

 mucopolysaccharidosis (phase 2).

Solid progress

 ASX RELEASE 26th October 2022

First UK Subject Randomised and Dosed for the Pivotal Phase 3 Trial for the Treatment of Pain Associated with Knee OA

KEY HIGHLIGHTS

• The first UK subject has now been randomised and has commenced dosing in the global PARA_OA_002 phase 3 study.

• This pivotal two-stage, adaptive, randomised, double-blinded, placebo-controlled, multicentre (US/CAN/AUS/UK/EU) trial will evaluate the dose and treatment effect of injectable pentosan polysulfate sodium (iPPS) in participants with knee osteoarthritis (OA) pain.

• To date, over 50 sites across three jurisdictions are actively screening and recruiting candidates.

Paradigm Biopharmaceuticals Ltd (ASX:PAR, “Paradigm” or “the Company”), a late-stage drug development company focused on delivering new therapies to address unmet medical needs, is pleased to announce that the first subject in the United Kingdom (UK) has been randomised and dosed in the pivotal PARA_OA_002 clinical trial, evaluating injectable pentosan polysulfate sodium (iPPS/Zilosul®) for the treatment of pain associated with knee osteoarthritis (OA). The first subject was randomised at Leeds University, by lead investigator, Professor Hemant Pandit. Paradigm aims to activate a total of seven sites across the UK for this phase 3 study.

This PARA_OA_002 global phase 3 trial has activated 8 sites across Australia, and 58 sites in the US. From the start of the calendar year, clinical trial site activation has been a key focus for Paradigm, to enable the largest pool of potential candidates to be identified and processed for participation. Site selection, initiation, and activation for Europe and Canadian is in progress with Paradigm to update investors as milestones are reached.

Dr. Donna Skerrett, Paradigm’s Chief Medical Officer said: “To have our first participant randomised outside of the US and Australia is another important milestone in our global phase 3 program. Dr Pandit and his team at Leeds University have demonstrated strong interest the Paradigm OA clinical program and we look forward to many more participants joining the study throughout the UK”.

About PARA_OA_002

 The purpose of this pivotal phase 3 study is to establish the efficacy of subcutaneous

 PPS This is a two-stage, adaptive, randomised, double-blinded, placebo-controlled, multicentre (US/CAN/AUS/UK/EU) study that will evaluate both the dose and treatment effect of iPPS in participants with knee OA pain.

Stage 1 will comprise a phase 2b dose selection component, with randomised participants receiving 1 of 3 iPPS dose regimens or placebo for 6 weeks. The primary objective of stage 1 will be to select the dose for use in stage 2 and in Paradigm’s confirmatory trial (PARA_OA_003). The selected dose will be based on an optimal balance of efficacy and safety.

In stage 2, participants will be randomised 1:1 to receive the selected PPS dose regimen or placebo for 6 weeks.

The primary endpoints in this pivotal study are changes from baseline at day 56 (two weeks after the final dose) in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain. Secondary outcomes include change from baseline at multiple time points out to day 168 (24 weeks from the start of the study, and 18 weeks after the last treatment) in WOMAC pain and function, Patient Global Impression of Change (PGIC), and Quality of Life (QoL) assessments.

Additional information on Paradigm’s clinical trials can be found at ClinicalTrials.gov (002 -

UK Lead Investigator

The UK lead investigator for the PARA_OA_002 phase 3 clinical study is Professor Hemant Pandit. Prof. Pandit has pursued a career in translational research in orthopaedics, having previously worked in Oxford for 16 years, and is particularly interested in hip and knee arthroplasty. He completed his DPhil (PhD) in knee kinematics and was first to describe the problems associated with metal-on-metal hips (pseudotumours). Prof. Pandit’s contributions in the fields of arthroplasty, enhanced peri- operative recovery, teaching and training medics and paramedics are well recognised. He has also made a significant contribution towards teaching and capacity building in the low/middle-income countries of Asia and Africa. He has published more than 250 scientific articles and book chapters.

Professor Pandit also holds the title of Professor of Orthopaedic Surgery with the University of Oxford. He collaborates with various colleagues both nationally as well as internationally and is a member of various National Joint Registry (NJR) subcommittees.

injections of

(iPPS) participants with knee OA pain.

  NCT04809376, 006 - NCT04814719) or via the Paradigm website under the

 Investor tab www.paradigmbiopharma.com.

 In April this year, Paradigm’s OA program investigating PPS received Fast Track

 Designation from the US FDA.

Market Potential in Osteoarthritis

Osteoarthritis is the most prevalent form of joint disease, affecting up to 16% of the population in the developed world, with more than 72 million people in the US, EU5, Canada, and Australia suffering from OA.1

OA has a significant impact on day-to-day functioning and, although the levels of pain and disability may fluctuate, it has no known cure or spontaneous remission and is associated with irreversible structural damage and progression over time. Presently there are no drugs approved that can prevent, stop, or even restrain progression of OA. Moreover, the available medications that claim to mitigate the pain of OA have numerous risk/benefit considerations and market

.2,3

The prevalence of OA is increasing in line with the aging population and increasing rates of obesity. By 2030 the number of people suffering from OA in the US is predicted to increase by 86% to 67 million.2 If we assume a similar increase across the other markets defined above, even allowing for lower rates of obesity in non-US markets, it is plausible that more than 120 million people will be suffering from osteoarthritis by 2030.

About Paradigm Biopharmaceuticals

Paradigm Biopharmaceuticals Ltd. (ASX:PAR) is a late-stage drug development company driven by a purpose to improve patients’ health and quality of life by discovering, developing, and delivering pharmaceutical therapies. Paradigm’s current

 research indicates that only 19% of knee OA

 patients are satisfied with currently available treatments

 focus is

 developing injectable (subcutaneous) pentosan polysulfate sodium (iPPS) for the

 treatment of diseases where inflammation plays a major pathogenic role, indicating a

 need for the anti-inflammatory and tissue regenerative properties of PPS,

osteoarthritis (phase 3) and mucopolysaccharidosis (phase 2).

Forward Looking Statements

This Company announcement contains forward-looking statements, including statements regarding anticipated commencement dates or completions dates of preclinical or clinical trials, regulatory developments and regulatory approval. These forward-looking statements are not guarantees or predictions of future performance, and involve known and unknown risks, uncertainties and other factors, many of which are beyond our control, and which may cause actual results to differ materially from those expressed in the statements contained in this presentation. Readers are cautioned not to put undue reliance on forward-looking statements.

References

1 Global Health Data Exchange, Institute for Health and Metrics Evaluation, University of Washington. Accessed June 2021 http://ghdx.healthdata.org/gbd-results-tool.

2 OARSI. Osteoarthritis: A Serious Disease, Submitted to the U.S. Food and Drug Administration December 1, 2016.

such as in

3 Matthews GL, Hunter DJ. Emerging drugs for osteoarthritis. Expert Opin Emerg Drugs. 2011;16(3):479- 491. doi:10.1517/14728214.2011.576670.

Authorised for release by the Paradigm Board of Directors.

Zilosul® is the registered trademark of Paradigm Biopharmaceuticals Ltd. for injectable pentosan polysulfate sodium in the treatment of osteoarthritis.

To learn more please visit: www.paradigmbiopharma.com FOR FURTHER INFORMATION PLEASE CONTACT:

Simon White

Director of Investor Relations

Tel: +61 404 216 467

Paradigm Biopharmaceuticals Ltd.

ABN: 94 169 346 963

Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA Email: [email protected]

Re Announcement 4/10/22 - 002 Trial in OA.

Essentially the results of this trial read very positively.

They found not only biochemical evidence of disease modification (or potential for it at minimum) but also demonstrated again a statistically significant improvement in WOMAC pain and function scores when compared with placebo (Placebo itself demonstrated an improvement in scores also but there was a large reassuring gap between these effects).

It seems to me that every time pentosan is trialled in OA the results confirm the beneficial effects on pain and function which gives me confidence that the pivotal trial currently underway will demonstrate a clinical benefit and this should lead to FDA/TGA etc approval.

I feel this is a massively derisked business which has an effective drug for an incredibly common condition with poor treatment options. If it is approved for disease modification it will be more profitable but I think it could be used for treatment and remain very profitable.

I haven't posted my valuation because I found it pretty challenging but I might do so shortly for what it's worth.

Suffice to say I think PAR is still good value at this price.

haven’t read this thoroughly yet but biochemical evidence of disease modification is a big plus hence this asx announcement goes straight to the bull case tag

ASX RELEASE 4th October 2022

Paradigm Achieves Primary Endpoint in PARA_OA_008 Synovial Fluid Biomarker Phase 2 Clinical Trial

KEY HIGHLIGHTS

• Primary endpoint relating to synovial fluid biomarkers achieved and positive top-line results reported for the PARA_OA_008 phase 2 clinical trial (n=61).

• Several osteoarthritis (OA) biomarkers analysed were observed to favourably change over time in patients treated with injectable PPS (iPPS) compared to placebo. These biomarker changes provide insight into iPPS mechanisms of action as well as signals of disease modifying potential.

• iPPS was associated with positive changes for several chondroprotective biomarkers.

• Additionally, iPPS-treated subjects demonstrated statistically significant improvement in WOMAC pain, function, and stiffness scores at day 56 for the twice-weekly group compared to placebo.

• Of the 61 patients, 48 (78%) had KL grades 3-4, indicating moderate to severe OA.

• In a separate canine study, positive interim observations on the effects of iPPS treatment on dogs with naturally occurring OA are also reported.

• Seven of nine dogs treated with iPPS had a clinically meaningful functional improvement in the affected limb as measured by the total pressure index percentage (TPI%) at week 8 compared to baseline. This provides supporting evidence on the improvements in clinical outcomes in PARA_OA_008 following iPPS.

• Paradigm will be hosting a webinar to discuss the positive top-line results at 9:30am (AEDT) today, Tuesday 4th October.

Paradigm Biopharmaceuticals Ltd (ASX:PAR) (Paradigm or the Company), a late- stage drug development company focused on delivering new therapies to address unmet medical needs, is pleased to announce that the primary endpoint has been met and additionally significant improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function scores were demonstrated for injectable iPPS in the PARA_OA_008 phase 2 clinical trial.

The day 56 data analysed by an independent clinical research organisation, demonstrates synovial fluid biomarker change from baseline for the iPPS treatment group. iPPS impacted multiple biomarkers measured in the synovial fluid. Reductions in nerve growth factor (NGF) indicate iPPS mechanisms related to pain reduction. Reductions in TNF-α and IL-6 indicate mechanistic effects on inflammatory pathways. Reductions in COMP and ARGS and an increase in TIMP-1 provide important insights into iPPS mechanisms of action impacting cartilage preservation and potential disease modification. In all cases, the synovial biomarker changes in iPPS-treated subjects at day 56 were favourable compared to placebo controls.

WOMAC data has also been collected from baseline. iPPS treatment showed statistically significant improvements at day 56 in pain, function, stiffness, and overall WOMAC scores for twice-weekly iPPS compared to the placebo arm. The proportions achieving ≥30% and ≥50% improvement in pain were 73% and 60%, respectively.

iPPS was well tolerated in this randomised, placebo-controlled study. There were no serious adverse events and no adverse events of special interest in any patient receiving iPPS or placebo. The most common adverse reactions were injection site reactions, all of which were mild in intensity and self-limiting.

Paradigm is also pleased to present preliminary data from nine dogs treated with iPPS in the ongoing canine model of naturally occurring OA. Initial data in this study demonstrates a trend towards functional improvement in osteoarthritic dogs following iPPS treatment as well as a trend towards reductions in cartilage degrading biomarkers locally within the joint (synovial fluid) and systemically (serum).

The Urgent Need for a Disease Modifying OA Drug (DMOAD)

Osteoarthritis is the most prevalent form of arthritis and the risk of developing degenerate OA rises with increasing age. This debilitating disorder severely impacts upon quality of life due to primarily affecting the hands, lower back, neck, and weight-bearing joints such as knees, hips, and feet. A recent 2021 analysis of results from the 2017 Global Burden of Disease Study found that approximately 303.1 million cases of hip and knee OA existed worldwide, accounting for a global cumulative 9.6 million years lived with disability(1). Further underlining the economic burden, an additional comprehensive study estimated that in 2013, total US arthritis-attributable medical expenditures reached almost $US140 billion, which when combined with wage losses, totalled losses of over $US303 billion (2).

A DMOAD is defined as a drug that will “alter the natural history of disease progression by arresting joint structural change and ameliorate

symptoms, either by reducing pain or improving physical function”(3).

Market research conducted through a global market intelligence and research organisation (ASX release 8th November 2021) found that payers in the United States would likely accept a price of US$2,000 to US$3,000 per year for iPPS as a therapy to reduce pain and improve function in knee OA.

If approved by the FDA with a disease modifying label, the price per year of therapy in the US could increase to US$6,000 and potentially higher.

PARA_OA_008 Clinical Trial Design

The PARA_OA_008 phase 2 clinical trial is designed to evaluate the treatment effects of iPPS on synovial fluid biomarkers associated with OA-related pain, inflammation, and disease progression in humans. The study also evaluates the effect of iPPS on these

 Current OA therapies, such as paracetamol, opioids, and nonsteroidal anti-inflammatory drugs (NSAIDs), as well as intra-articular medications, such as corticosteroids and hyaluronic acid, are solely focused on symptom management, as there are no established

 disease modifying therapies

(3)

. Due to patient dissatisfaction with current OA

 treatments

(4)

, there is a high unmet medical need for new therapies that can effectively

 reduce pain, improve joint function, and impede OA progression in tandem with

 symptomatic improvement.

biomarkers in serum and urine and investigates any correlation with synovial fluid biomarkers. In a prior phase 2b clinical trial, Paradigm observed serum and urine changes in biomarkers COMP, ADAMTS-5, and CTX-II, providing promising signals of iPPS mechanisms of action on joint preservation.

Patients had moderate to severe arthritis with Kellgren Lawrence (KL) grade 2-4 (where 4 is the maximum indicating severe

OA), and baseline WOMAC pain scores of 4.6 to 10.

 In the PARA_OA_008 clinical trial, subjects (n=61) were randomised and received either a subcutaneous injection of 2 mg/kg iPPS twice weekly, iPPS once weekly plus one

 placebo injection, or two placebo injections for 6 weeks.

 exploratory study and was not intended to be powered to obtain statistical significance. The aim is to provide novel scientific evidence to test the hypothesis that iPPS acts locally in the knee joint of OA subjects as well as provide data on whether biomarker changes correlate with clinical outcome (WOMAC pain and function assessments). Further evaluation on serum and urine biomarker correlations, and further longer-term clinical

This phase 2 clinical trial is an

 outcomes are in progress.

 Biomarkers that alter in relation to clinical outcomes could help further clarify the multiple proposed mechanisms of action for iPPS in OA. This contrasts with currently available pharmacological agents which have thus far failed to deliver durable satisfactory patient

 outcomes of improved pain and/or function and disease modification.

PARA_OA_008 Top-Line Results

The Australian clinical trial operating at two sites in Victoria and NSW aims to gather data on the medium-term structure-modifying and symptom-modifying effects of iPPS on knee OA. Participants have been randomised into three treatment groups according to a 1:1:1 ratio (19 randomised to iPPS twice-weekly, 20 randomised to iPPS once-weekly plus a placebo injection once-weekly, 22 randomised to placebo twice-weekly). Of the 61 patients, 48 (78%) had KL grades 3-4, and the average median baseline WOMAC scores were 6.6 for pain and 6.9 for function.

Synovial Fluid Biomarkers

The primary endpoint for PARA_OA_008 is change from baseline at day 56 (two weeks post final injection) in one or more synovial fluid biomarkers. The analysed biomarkers include inflammatory cytokines (TNF-α, IL-1β, and IL-6); pain mediator NGF, and cartilage degrading markers such as COMP, ARGS and other disease modifying molecular biomarkers.

in a cellular model of canine OA(5); differentiated human osteocytes derived from samples obtained during arthroplasty for knee OA(6); and

(8,9).

 iPPS has been shown to exert anti-inflammatory activity by blocking the effects of

 proinflammatory cytokines, such as TNFα and IL-1β,

 inhibit

the expression of NGF, a pain mediator, in

subchondral bone

 inhibit

cartilage degrading enzymes known to play a key role in OA disease

 progression(

7)

. In small clinical studies

of 114 and 20 participants respectively,

PPS has

 been shown to reduce pain and improve joint function in patients with knee OA

 ing

by  ing

 Synovial Biomarker

  iPPS compared to Placebo

  Biomarker Function

 NGF

  Reduced

 Nerve growth factor (NGF) is an important mediator of chronic pain and has been demonstrated to be increased in the synovial fluid of patients with OA. NGF production is also increased via upregulation of pro-inflammatory cytokines, such as TNF-α(6,10).

 TNF-α

 Reduced

 Tumour necrosis factor alpha (TNF-α) is a pro- inflammatory cytokine that is upregulated in the synovial membrane in OA and contributes to cartilage degradation and hyperalgesia. TNF-α has been reported to activate sensory neurons directly via its receptors and initiates inflammatory reactions via production of interleukins. Serum levels of this cytokine have also been demonstrated to negatively correlate with WOMAC scores in OA patients(11).

 IL-6

  Reduced

 Interleukin-6 (IL-6) is a pro-inflammatory cytokine implicated in the inflammation that contributes to the development and progression of OA. Increased concentrations of IL-6 have been detected in both the synovial fluid and serum of OA patients(12).

 COMP

  Reduced

  COMP is a structural protein integral to proper articular cartilage function and increasing levels of COMP in serum have been correlated to subsequent radiographic degradation of articular surfaces in the knee(13).

 ARGS

 Reduced

 Alanine–Arginine–Glycine–Serine (ARGS) is a biomarker used to assess the degradation of aggrecan, a major extracellular matrix (ECM) component. Increased ARGS concentrations in the synovial fluid, reflecting cartilage degradation, have been observed in OA patients in several studies(14).

 TIMP-1

  Increased

  Tissue inhibitor of MMPs (TIMP-1) is a major endogenous inhibitor of cartilage degrading enzymes. TIMP-1 has been demonstrated to be reduced in OA(15).

 Table 1: Biomarkers analysed with favourable results

WOMAC Pain and Function

• correlation between synovial fluid biomarker changes and clinical outcomes;

• changes in one or more synovial fluid biomarkers from baseline to 6 months;

 Paradigm is assessing a number of key secondary and exploratory endpoints in the

 PARA_OA_008 phase 2 clinical trial, including:

•

• MRI changes in the bone and joint.

 changes in WOMAC pain, function, stiffness, and patient global impression of

 change (PGIC) from baseline at designated timepoints; and

 Participants in the study were asked to provide baseline pain scores using the WOMAC osteoarthritis index. After patients had initiated treatment, their pain scores are measured at predetermined timepoints from day 11 out to 12 months, with day 56 the predetermined

 endpoint for WOMAC assessment.

In Para_OA_008, the mean percentage change from

 baseline in WOMAC pain is 50% compared to 30%, p=0.05 for twice weekly iPPS and placebo, respectively. The mean percentage change from baseline in WOMAC function is 50% compared to 25%, p=0.017 for twice weekly iPPS compared to placebo,

 respectively.

 Paradigm’s primary endpoints in the current PARA_OA_002 phase 3 trial are improvements in pain and function from baseline at day 56 using the WOMAC

 osteoarthritis index.

Dr Donna Skerrett, Paradigm’s Chief Medical Officer, said: "We are very encouraged by the synovial fluid biomarker signals we see in this study. The observed changes indicate mechanistic effects through pain, inflammation, and chondroprotective pathways. These changes are consistent with the clinical effects observed in this and prior studies of iPPS in osteoarthritis. Evidence of multimodal effects supports our understanding of the actions of iPPS. These biomarker changes in the joint, following subcutaneous administration of iPPS, demonstrate local effects in the synovial fluid. These are meaningful signals that we will evaluate together with clinical and imaging outcomes in order to demonstrate disease modifying effects and to pursue regulatory authority guidance on a disease modifying pathway."

Preliminary Analysis of the Ongoing Canine Model of Naturally Occurring OA

Interim analysis of the effects of iPPS treatment on dogs with naturally occurring OA has identified positive trends. This ongoing study consists of 21 client-owned dogs of varying breeds that presented at the U-Vet Werribee Animal Hospital, Victoria, Australia, for lameness assessment. Dogs of both genders with either radiologically and/or clinically defined OA of the knee/stifle (hind limb) or elbow (front limb) are progressively screened and randomised in a 2:1 ratio to either treatment with iPPS or saline (placebo) groups to attain a total of 14 iPPS treated and 7 control dogs.

The canine OA study aims to confirm the in vivo mechanism of action of iPPS and to define potential disease modification outcomes. The key data sought from this study are changes from baseline at week 8 and week 26, in:

i) Joint function as measured by percentage body weight distribution (BWD%) in the affected limb as measured by the TPI%.

ii) Biomarkers of joint degeneration within the synovial fluid and in serum; and

iii) Structural changes determined by OA clinical scores as assessed by X-ray and MRI.

Early interim observations in nine osteoarthritic dogs who had received subcutaneous iPPS at a dose of 3 mg/kg (human equivalent dose of 1.7 mg/kg) weekly for 6 weeks demonstrated the following:

i) ii)

Seven of nine dogs treated with iPPS had a clinically meaningful improvement in the affected limb as measured by TPI% at week 8 compared to baseline.

A mean percentage change (improvement) from baseline in TPI% of 10.08% was observed for the affected hind limb (n=5) and 5.6% for the affected front limb (n=4). A mean increase of 5% in TPI% is considered to be a clinically meaningful improvement (16,17).

Dogs demonstrated a response to iPPS treatment with changes in cartilage degradation biomarkers in the synovial fluid. Aggrecan degradation neoepitope (ARG) the canine equivalent of human ARGS, levels were reduced in the synovial joint of 3/4 iPPS-treated dogs. These results support the in vivo MoA since iPPS inhibits ADAMTS-5 enzyme, which degrades aggrecan in cartilage to produce ARG (18). Furthermore, it is known that degrading cartilage matrix releases hyaluronic acid (HA) into the synovial fluid in OA (19). In this study, 4/4 dogs had reduced levels of HA following iPPS treatment.

Analysis of serum biomarkers demonstrated that 3/6 dogs showed a reduction in serum ARG, and 5/9 dogs had reduced serum HA, supporting the effect of iPPS on these biomarkers observed in the synovial fluid. Additionally, in the serum, it was demonstrated that 7/9 iPPS-treated dogs responded to treatment with reduced levels of C3M (a degradation fragment of type III collagen), 6/9 dogs had lower levels of CTX-I (a degradation fragment of type I collagen), and 4/9 dogs had reduced levels of CTX-II (a degradation product of type II collagen) (20).

iv)

iii)

Paradigm Chief Scientific Officer, Dr Ravi Krishnan, commented on the study: “We are encouraged by these preliminary data on the potential of iPPS to improve joint function and reduce the levels of biomarkers of cartilage degeneration in this translationally relevant model of naturally occurring OA. We are continuing with the recruitment of dogs to obtain the complete set of data points to allow comparisons with iPPS treated and placebo-treated dogs to provide supportive evidence for iPPS as a potential treatment to modify the progression of OA and provide long term durability of effect”.

Naturally Occurring Canine OA and Translational Relevance of the Canine OA Model for Evaluating DMOADs

The phenotypic characteristics and heterogeneity of OA are similar in both humans and dogs. Therefore, it is expected that the canine model of OA would provide relevant translational data that parallel the human clinical scenario (21).

Both human and canine OA are progressive degenerative disorders and are influenced by similar risk factors. OA in humans primarily affects the knee, hip, and shoulder joints, and pathological changes closely resemble those observed in the canine stifle (knee), hip, and shoulder joints (21). Because the dog's lifespan is shorter relative to that of humans, all stages of development from birth to adulthood and ageing are represented over a shorter time frame, including disease onset and manifestation. This aspect of the canine model is potentially advantageous in rapidly evaluating DMOAD status of iPPS that otherwise would require a longer assessment period in humans to analyse OA joint structural changes.

Early top-line results indicate that iPPS treatment in osteoarthritic dogs likely demonstrates a functional improvement in BWD% as measured by the TPI%. TPI% is functionally equivalent to BWD%, and since TPI% is not influenced by stride frequency, it was identified to be the most accurate and valuable measurement for veterinarians when evaluating a heterogeneous group of dogs. Improvement in the TPI% scores is defined as a numerical increase in the TPI% value of the affected limb.

In four iPPS-treated dogs, the front limb demonstrated an initial trend towards improved TPI%. A similar positive trend was also observed in the hind limb in five iPPS-treated dogs.

iPPS treatment in osteoarthritic dogs may also demonstrate a reduction in cartilage degradation biomarkers locally within the synovial joint and systemically via serum analysis. Responders are defined as dogs that demonstrated a reduction in the level of a specific biomarker at week 8 when compared to the biomarker level at baseline. At the time of analysis, synovial fluid biomarker data was only available for four out of the nine dogs.

Six-month Follow-up (day 168) Data

The PARA_OA_008 phase 2 clinical trial will continue to monitor trial participants following treatment through the 6-month and out to 12-month timepoints. The 6-month time point for PARA_OA_008 will provide further data on the duration of effect of iPPS on WOMAC pain and function compared to placebo combined with observations on changes to the joint structure by MRI of iPPS treated subjects compared to placebo. The secondary and exploratory endpoints at 6-month timepoint, include:

• changes in one or more synovial fluid biomarkers;

• changes and correlation between synovial fluid, serum, and urine biomarkers and

correlation with changes in clinical outcomes;

• changes in WOMAC pain, function, stiffness and quality of life scores;

• MRI changes in the bone and joint; and

• Incidence of treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs).

Paradigm expects to report on the 6-month data in Q1 CY2023. Data from this study will be prepared for peer-review and publication with the Company providing an update once timing can be confirmed.

Recruitment for the canine OA model remains ongoing in order to complete treatment groups to enable meaningful comparisons to be made. The longer follow-up period at week 26 (equivalent to 3 years in human terms) will allow for collective analyses of pain, function, joint structure, and biomarker levels following iPPS therapy, and will provide informative data to assess the potential of iPPS as a DMOAD. The complete study report examining both week 8 and week 26 responses in the final cohort of dogs will be reported in 1H CY2023.

Paradigm CEO, Marco Polizzi commented: “Achieving the primary endpoint with consistent significant reductions in pain in iPPS-treated patients compared to placebo is an outstanding milestone for the Company. The top-line results are encouraging at day 56 and we look forward to further data at 6 and 12 months.

 The biomarker changes following iPPS, the statistically significant signals that we are observing in the WOMAC scores along with the safety and tolerability of iPPS in this

 , will be valuable in discussions with regulatory bodies (FDA and TGA) and commercial partners”.

Investor Webinar

Paradigm Biopharmaceuticals will hold an investor webinar on Tuesday 4th October 2022 at 9:30am (AEDT) with CEO, Marco Polizzi; Chief Medical Officer, Dr Donna Skerrett; and Chief Scientific Officer, Dr Ravi Krishnan.

The webinar will discuss the positive top-line results from the PARA_OA_008 phase 2 trial and early observations from the canine OA model released to the market.

Please register for the webinar at the following link:

https://us02web.zoom.us/webinar/register/WN_Yf-BLoMjTKODHnnfduX1uA

After registering, you will receive a confirmation email about joining the webinar. Following the webinar, a recording will become available on the Paradigm website.

exploratory study

 A copy of the presentation can be viewed on the Paradigm website

https://paradigmbiopharma.com/performance-progress/#presentations

About WOMAC Scores

•

• •

About Paradigm Biopharmaceuticals

(22):

 The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is a widely used, proprietary set of standardised questionnaires used by health professionals to evaluate the condition of patients with OA of the knee and hip, and includes pain, stiffness, and physical functioning of the joints. The WOMAC has also been used to assess back pain, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus

 erythematosus, and fibromyalgia. It consists of 24 items divided into 3 sub-scales

 Pain (5 items): during walking, using stairs, in bed, sitting or lying, and standing

 upright;

 Stiffness (2 items): after first waking and later in the day;

 Physical function (17 items): using stairs, rising from sitting, standing, bending, walking, getting in / out of a car, shopping, putting on / taking off socks, rising from bed, lying in bed, getting in / out of bath, sitting, getting on / off toilet, heavy

 domestic duties, light domestic duties.

Paradigm Biopharmaceuticals Ltd. (ASX:PAR) is a late-stage drug development company driven by a purpose to improve patients’ health and quality of life by discovering, developing, and delivering pharmaceutical therapies. Paradigm’s current

 developing injectable (subcutaneous) pentosan polysulfate sodium (iPPS) for the treatment of diseases where inflammation plays a major pathogenic role, indicating a

osteoarthritis (phase 3) and mucopolysaccharidosis (phase 2).

Forward Looking Statements

such as in

This Company announcement contains forward-looking statements, including statements regarding anticipated commencement dates or completions dates of preclinical or clinical

focus is

 need for the anti-inflammatory and tissue regenerative properties of PPS,

trials, regulatory developments and regulatory approval. These forward-looking statements are not guarantees or predictions of future performance, and involve known and unknown risks, uncertainties and other factors, many of which are beyond our control, and which may cause actual results to differ materially from those expressed in the statements contained in this presentation. Readers are cautioned not to put undue reliance on forward-looking statements.

References

1. Safiri S, Kolahi AA, Smith E, Hill C, Bettampadi D, Mansournia MA, et al. Global, regional and national burden of osteoarthritis 1990-2017: a systematic analysis of the Global Burden of Disease Study 2017. Ann Rheum Dis. 2020 Jun 1;79(6):819–28.

2. Murphy LB, Cisternas MG, Pasta DJ, Helmick CG, Yelin EH. Medical Expenditures and Earnings Losses Among US Adults With Arthritis in 2013. Arthritis Care Res. 2018 Jun;70(6):869–76.

3. Oo WM, Little C, Duong V, Hunter DJ. The Development of Disease-Modifying Therapies for Osteoarthritis (DMOADs): The Evidence to Date. Drug Des Devel Ther. 2021;15:2921–45.

4. Matthews GL, Hunter DJ. Emerging drugs for osteoarthritis. Expert Opin Emerg Drugs. 2011 Sep;16(3):479–91.

5. Sunaga T, Oh N, Hosoya K, Takagi S, Okumura M. Inhibitory Effects of Pentosan Polysulfate Sodium on MAP-Kinase Pathway and NF-κB Nuclear Translocation in Canine Chondrocytes In Vitro. J Vet Med Sci. 2012;74(6):707–11.

6. Stapledon CJM, Tsangari H, Solomon LB, Campbell DG, Hurtado P, Krishnan R, et al. Human osteocyte expression of Nerve Growth Factor: The effect of Pentosan Polysulphate Sodium (PPS) and implications for pain associated with knee osteoarthritis. Heymann D, editor. PLOS ONE. 2019 Sep 26;14(9):e0222602.

7. Troeberg L, Mulloy B, Ghosh P, Lee MH, Murphy G, Nagase H. Pentosan polysulfate increases affinity between ADAMTS-5 and TIMP-3 through formation of an electrostatically driven trimolecular complex. Biochem J. 2012 Apr 1;443(1):307–15.

8. Ghosh P, Edelman J, March L, Smith M. Effects of pentosan polysulfate in osteoarthritis of the knee: A randomized, double-blind, placebo-controlled pilot study. Curr Ther Res Clin Exp. 2005 Nov;66(6):552– 71.

9. Kumagai K, Shirabe S, Miyata N, Murata M, Yamauchi A, Kataoka Y, et al. Sodium pentosan polysulfate resulted in cartilage improvement in knee osteoarthritis - An open clinical trial. BMC Clin Pharmacol. 2010 Dec;10(1):7.

10. Aloe L, Tuveri MA, Carcassi U, Levi-Montalcini R. Nerve growth factor in the synovial fluid of patients with chronic arthritis. Arthritis Rheum. 1992 Mar;35(3):351–5.

11. PenninxBWJH,AbbasH,AmbrosiusW,NicklasBJ,DavisC,MessierSP,etal.Inflammatorymarkers and physical function among older adults with knee osteoarthritis. J Rheumatol. 2004 Oct;31(10):2027– 31.

12. WiegertjesR,vandeLooFAJ,BlaneyDavidsonEN.Aroadmaptotargetinterleukin-6inosteoarthritis. Rheumatol Oxf Engl. 2020 Oct 1;59(10):2681–94.

13. Verma P, Dalal K. Serum cartilage oligomeric matrix protein (COMP) in knee osteoarthritis: a novel diagnostic and prognostic biomarker. J Orthop Res Off Publ Orthop Res Soc. 2013 Jul;31(7):999–1006.

14. Bay-Jensen AC, Mobasheri A, Thudium CS, Kraus VB, Karsdal MA. Blood and urine biomarkers in osteoarthritis – an update on cartilage associated type II collagen and aggrecan markers. Curr Opin

Rheumatol. 2022 Jan;34(1):54–60.

15. Plsikova Matejova J, Spakova T, Harvanova D, Lacko M, Filip V, Sepitka R, et al. A Preliminary Study

of Combined Detection of COMP, TIMP-1, and MMP-3 in Synovial Fluid: Potential Indicators of

Osteoarthritis Progression. Cartilage. 2021 Dec;13(2_suppl):1421S-1430S.

16. Carr BJ, Canapp SO, Meilleur S, Christopher SA, Collins J, Cox C. The Use of Canine Stifle Orthotics

for Cranial Cruciate Ligament Insufficiency. Vet Evid [Internet]. 2016 Jan 22 [cited 2022 Sep 20];1(1).

Available from: http://www.veterinaryevidence.org/index.php/ve/article/view/10

17. Canapp SO, Canapp DA, Ibrahim V, Carr BJ, Cox C, Barrett JG. The Use of Adipose-Derived Progenitor Cells and Platelet-Rich Plasma Combination for the Treatment of Supraspinatus Tendinopathy in 55 Dogs: A Retrospective Study. Front Vet Sci [Internet]. 2016 Sep 9 [cited 2022 Sep

20];3. Available from: http://journal.frontiersin.org/Article/10.3389/fvets.2016.00061/abstract

18. Germaschewski FM, Matheny CJ, Larkin J, Liu F, Thomas LR, Saunders JS, et al. Quantitation OF ARGS aggrecan fragments in synovial fluid, serum and urine from osteoarthritis patients. Osteoarthritis

Cartilage. 2014 May;22(5):690–7.

19. Elliott AL, Kraus VB, Luta G, Stabler T, Renner JB, Woodard J, et al. Serum hyaluronan levels and

radiographic knee and hip osteoarthritis in African Americans and Caucasians in the Johnston County

Osteoarthritis Project. Arthritis Rheum. 2005;52(1):105–11.

20. Duclos ME, Roualdes O, Cararo R, Rousseau JC, Roger T, Hartmann DJ. Significance of the serum

CTX-II level in an osteoarthritis animal model: a 5-month longitudinal study. Osteoarthritis Cartilage.

2010 Nov 1;18(11):1467–76.

21. Meeson RL, Todhunter RJ, Blunn G, Nuki G, Pitsillides AA. Spontaneous dog osteoarthritis — a One

Medicine vision. Nat Rev Rheumatol. 2019 May;15(5):273–87.

22. WOMACOsteoarthritisIndex[Internet].Physiopedia.[cited2022Sep28].Availablefrom:www.physio-

 pedia.com/WOMAC_Osteoarthritis_Index

Authorised for release by the Paradigm Board of Directors.

Zilosul® is the registered trademark of Paradigm Biopharmaceuticals Ltd. for injectable pentosan polysulfate sodium in the treatment of osteoarthritis.

To learn more please visit: www.paradigmbiopharma.com

FOR FURTHER INFORMATION PLEASE CONTACT:

Simon White

Director of Investor Relations

Tel: +61 404 216 467

Paradigm Biopharmaceuticals Ltd ABN: 94 169 346 963

Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA Email: [email protected]

The results from this PARA008 trial could be super important to paradigm… at the very least a result suggesting disease modification would attract interest from big pharma but as a clinician this could be the first drug to modify the disease process in one of the most ubiquitous conditions in the world (OA).

and of course addressing a real problem is going to be valuable for investors…

a result which demonstrates not evidence of doease modification would be a bit sad but not a dealbreaker for the company in my view as long as the pivotal trial demonstrates improved pain and function

 Market Announcement 30 September 2022

Paradigm Biopharmaceuticals Limited (ASX: PAR) – Trading

Halt

Description

The securities of Paradigm Biopharmaceuticals Limited (‘PAR’) will be placed in trading halt at the request of PAR, pending it releasing an announcement. Unless ASX decides otherwise, the securities will remain in trading halt until the earlier of the commencement of normal trading on Tuesday, 4 October 2022 or when the announcement is released to the market.

 Issued by

Melissa Kostopoulos

Compliance Adviser, Listings Compliance (Melbourne)

30 September 2022

ASX Limited

Market Announcement 1/1

ASX Customer Service Centre 131 279 | asx.com.au

 ASX RELEASE

By email: [email protected]

Melissa Kostopoulos

Adviser, Listings Compliance (Melbourne) ASX Limited

Dear Melissa

30 September 2022

 Request for a trading halt

Paradigm Biopharmaceuticals Limited ACN 169 346 963 (ASX: PAR) (the Company), requests that

the Company's securities be placed into trading halt with immediate effect.

The Company has received biomarker and clinical data from an independent contract research organisation (CRO) relating to its phase II PARA_008 clinical trial. The Company is requesting a trading halt so it has time to analyse the data and prepare an ASX Announcement and webinar presentation on the data, to be released to the market on Tuesday 4 October 2022. Accordingly pursuant to ASX Listing Rule 17.1, the Company requests the trading halt in order to finalise its review and update to the market.

The Company requests that the trading halt remains in place until the earlier of the Company making an announcement in relation to the received PARA_008 data or commencement of trading on Tuesday 4 October 2022.

The Company is not aware of any reason why the trading halt should not be granted. Authorised for release on behalf of the Board of Paradigm Biopharmaceuticals Limited

Yours faithfully,

Abby Macnish Niven Company Secretary

Paradigm Biopharmaceuticals Ltd | ABN: 94 169 346 963 Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA

The Cap Raise in Summary:

66 million dollar raise

45.7 mil institutional placement

20.3 mil entitlement offer pro rata 1:15 (non renouncable)

Price for both is $1.30/share (30% discount to recent price but 80% premium to almost as recent price) So as @Strawman says it's really all about what value 'you' place on the shares.

Cash to be used for:

Finishing Phase 3 trial in OA and some murkier things 'business related activities & working capital'

But also some more practical things ie production (autoinjector for example).

It feels as though perhaps they're moving away from a reliance on partnering up and more towards carrying this through to completion and even production (to me this would be the best outcome from this cap raise if it's simply getting the cash required from shareholders/institutional placement instead of partnering up and sharing the spoils.

Love to hear other views.

Of course the other question as a holder is, do you buy in? I'm already overweight so probably not even though I feel that the business is progressing well towards a profitable future.

https://research.onlineinvesting.westpac.com.au/LoadPDF?docKey=B64ENCeyJkayI6IjE0MTAtMDI1NTMwNzctM01RRTk2SFI1QTFWRUFUNDExTDRBREpNR1QifQ==

Trading Halt announced for a cap raise today... Anybody else bemused by a 200% increase in share price on new real news rolling into a cap raise? I mean... I guess I should be happy it's less dilutive (I presume, offer price not named yet)

https://app.sharelinktechnologies.com/announcement/asx/30eabe8e6fcf3180d10749e32c1274cf

I don't understand why this announcement would lead to the surge in share price seen. I guess this is just the volatility you see in a pre-clinical pharmaceutical company's SP.

MPS is very rare and as such the target population would be small for this indication. I'm excited by the potential for helping kids/young adults with a really distressing condition but not sure about the share price response to be honest...

ASX RELEASE 8th August 2022

MPS Clinical Program Update and Paradigm to Present at the

International Conference on Lysosomal Diseases

KEY HIGHLIGHTS

• Paradigm has been invited to present results from the mucopolysaccharidosis

(MPS) program, with an oral presentation at the XVII International Conference

on Lysosomal Diseases (ICLD 2023), to be held in Sydney, Australia, February

20-21, 2023.

• Dr Drago Bratkovic, Head of the Metabolic Clinic at the Adelaide Women’s and

Children’s Hospital, will present the research entitled: Pentosan Polysulfate

Sodium: A Potential Treatment to Improve Bone and Joint Manifestations of

Mucopolysaccharidosis I.

• Three of the four subjects included in Paradigm’s open-label Phase 2 trial of

pentosan polysulfate sodium (PPS) in MPS-I have completed the 48-week

study, with a 6-month treatment extension available.

• Preliminary data from the MPS-I study were previously presented at 14th

International Congress of Inborn Errors of Metabolism in Sydney in 2022 and

indicated favourable clinical responses and overall tolerance to PPS.

• In Paradigm’s MPS-VI phase 2 trial based in Brazil, 50% of planned number of

subjects have been recruited to the 24-week study comparing PPS to placebo

in a blinded, randomised and controlled trial.

• The Safety Monitoring Physician for the MPS-VI study confirmed successful

evaluation of subjects aged 16 and above and the study is now scheduled to

assess PPS in two younger cohorts (9 to 16 years, then following another safety

review, 5 to 9 years).

• During the Bio International Partnering conference in June 2022, Paradigm saw

significant interest in its rare disease clinical development program. Paradigm

is currently exploring strategic partnerships to progress current and future

clinical studies to further evaluate PPS as a treatment to address the critical

unmet need in MPS patients.

Paradigm Biopharmaceuticals Ltd (ASX: PAR) (“Paradigm” or “the Company”), a

late-stage drug development company, is pleased to announce that it is scheduled to

present data from the open-label phase 2 study of pentosan polysulfate sodium (PPS) for

mucopolysaccharidosis type I (MPS-I), and an update on the ongoing multi-centre double-

blind randomised phase 2 study comparing PPS to placebo in mucopolysaccharidosis

type VI (MPS-VI) patients as an oral presentation at the 2023 ICLD meeting.

The mucopolysaccharidoses and related disorders belong to a group of more than 40

inherited lysosomal storage diseases. Lysosomes are the recycling centres of all cells

that break down excess or worn-out cell parts with their digestive enzymes.Mucopolysaccharidoses disorders are due to errors with one of the enzymes that break

down and recycle glycosaminoglycans (GAGs), previously known as

mucopolysaccharides. As these waste products cannot be eliminated, they accumulate

within the lysosomes of virtually every type of cell in the body, causing cells, tissues, and

organs to function abnormally, leading to progressive damage. The heart, bones, joints,

respiratory system, and central nervous system, including cognitive function, may

eventually be affected. In most cases, symptoms are not apparent at birth, but emerge

gradually as a result of defective lysosomal storage and resulting cell damage over time

(1,2) . Eleven different types of mucopolysaccharidosis have been described, where each

is the result of a deficiency in one of the enzymes in the glycosaminoglycan degradation

pathway.

Mucopolysaccharidosis type I

Mucopolysaccharidosis type I is a relentlessly progressive and potentially fatal rare

genetic disorder with a spectrum of disease. It is caused by reduction or absence in the

amount of enzyme responsible for the catabolism (break down) of glycosaminoglycans,

resulting in the progressive GAG accumulation in tissues. The disorder causes problems

with neurological, skeletal, and cardiovascular development.

There is no cure and children born with the most severe form of MPS-I do not typically

survive beyond 10 years of age, without treatment. Current standard treatments include

bone marrow transplant and enzyme replacement therapy to address the underlying

cause of the disease.

MPS-I open-label trial

Paradigm is partnering with the Adelaide Women and Children’s Hospital, South Australia

for a study evaluating PPS as an adjunctive therapy to enzyme replacement therapy

and/or haematopoietic stem cell transplantation in an open-label, single-centre, phase 2

trial. The primary aim of the study is to evaluate safety and tolerability of PPS over an

initial 48-week period, with a 6-month treatment extension available, in patients treated

with the current standard of care. Secondary and exploratory objectives include

examining the effects of PPS on pain, function, and quality of life, pharmacokinetics,

biomarkers, and inflammatory processes.

Four patients with this rare disease have been enrolled, and three have completed the

48-week treatment regimen with no serious adverse events reported to date. Interim

results presented at the 14th International Congress of Inborn Errors of Metabolism in

Sydney (2022) indicated an overall trend toward providing meaningful improvements in

pain, function, activities of daily living, and overall improvement in quality of life (3) . PPS

was well tolerated at weekly doses of 0.75 and 1.5 mg/kg for 47 weeks.

The data from the clinical trial participants treated to date is due to be presented at ICLD

2023 to be held in Sydney, Australia, February 20-21, 2023, by Dr Drago Bratkovic, Head

of the Metabolic Clinic at the Adelaide Women and Children’s hospital. The presentation

of the research is titled: Pentosan Polysulfate Sodium: A Potential Treatment to Improve

Bone and Joint Manifestations of Mucopolysaccharidosis I. The presentation will report

on the safety and effect of pentosan polysulfate sodium in MPS-1 subjects along with

clinical data including the clinical endpoints of pain, joint function, activities of daily living

and biomarkers of disease.Paradigm’s Global Head of Safety and Head of the MPS program, Dr. Michael

Imperiale, said “Current MPS therapies are essential for MPS patients, however, they

don’t provide relief from the daily pain and discomfort caused by their disorders. We are

very excited by the global recognition of Paradigm’s clinical development in this rare

disease and the opportunity to present the exciting work we are undertaking at the

International Conference on Lysosomal Diseases early next year”.

Mucopolysaccharidosis type VI

Mucopolysaccharidosis type VI, also known as Maroteaux-Lamy syndrome, is a rare

autosomal recessive lysosomal storage disorder that affects between 0.36 and 1.30 of

every 100,000 live births(4) . It results in the development of multisystem clinical

manifestations. Mucopolysaccharidosis type VI ranges from very slowly to rapidly

progressing disease, depending on the specific disease-causing mutation.

Current treatments for MPS VI patients include enzyme replacement therapy, however

MPS-VI patients undergoing this therapy continue to report ongoing stiffness, pain, and

inflammation. The current standards of care are not adequate in treating the pain

associated with joint inflammation and musculoskeletal issues.

MPS-VI multi-centre double-blinded phase 2 trial

Brazil has one of the highest rates of MPS-VI and researchers there are evaluating the

use of Paradigm’s PPS to treat patients with MPS-VI in a Phase 2 study. The study is a

randomized, double blind, placebo-controlled study to evaluate the safety and tolerability

of PPS in patients with MPS-VI. According to the study protocol, approximately 12

patients will be randomised 2:1 to receive PPS or placebo. Participants are dosed weekly

for 24-weeks with the primary endpoint being safety. The secondary endpoints are

improvements in pain and function. The study is the largest of its kind in the world and

has attracted the interest of medical researchers and MPS patient advocacy groups

globally.

To date, three adult subjects have been enrolled in the study and fifty-two weeks of

cumulative data across the subjects have been assessed. Under the clinical protocol, a

mandated safety review has been completed with no serious adverse events reported.

This is a key milestone for the phase 2 study, which now allows the inclusion of subjects

aged between ages of 9 to 16 years to assess the safety and tolerability of PPS among

paediatric populations. An additional safety review will be completed once 3 patients in

this age group have been enrolled and reach the specified timepoint.

A positive additional safety review will support the inclusion of subjects in the 5- to 9-year-

old age group. These additional age groups are highly relevant to future potential

therapeutic registration as the disease is detected and can manifest early in children and

adolescents. Additionally, a 5-year extension program is being offered to subjects who,

after completion of the trial, are deemed by their physician to benefit from ongoing

treatment per local regulatory requirements.

Paradigm’s CEO, Marco Polizzi, said “Alongside our robust osteoarthritis clinical

program, Paradigm is proud to work with specialists in the field of lysosomal storage

diseases to potentially enable MPS sufferers to function more easily in their day-to-day

activities. We are continuing discussions to progress the development of PPS for patients

with MPS and believe that this data will contribute to planning and design for theregistration of injectable PPS as an adjunctive therapeutic option for patients with MPS-I

and MPS-VI.”

Dr Donna Skerrett (Chief Medical Officer) and Dr Michael Imperiale (Global Head of

Safety and Head of MPS) attended the BIO International partnering conference that was

held in June in San Diego. Dr Skerrett delivered a presentation on Paradigm’s clinical

development program and with Dr Imperiale undertook many 1 on 1 meetings with

potential partner companies. During the conference Paradigm saw significant interest in

its rare disease clinical development program. Paradigm is currently exploring strategic

partnerships to progress current and future clinical studies to further evaluate PPS as a

treatment to address the critical unmet need of ongoing musculoskeletal symptoms in this

rare patient population.

About Paradigm Biopharmaceuticals

Paradigm Biopharmaceuticals LTD (ASX: PAR) is a late-stage drug development

company whose mission is to develop and commercialise Pentosan Polysulfate Sodium

for the treatment of pain associated with musculoskeletal disorders driven by injury,

inflammation, aging, degenerative disease, infection, or genetic predisposition.

Paradigm is also exploring proof-of-concept studies for the use of PPS in respiratory and

heart failure indications.

Forward Looking Statements

This Company announcement contains forward-looking statements, including statements

regarding anticipated commencement dates or completions dates of preclinical or clinical

trials, regulatory developments and regulatory approval. These forward-looking

statements are not guarantees or predictions of future performance, and involve known

and unknown risks, uncertainties and other factors, many of which are beyond our control,

and which may cause actual results to differ materially from those expressed in the

statements contained in this presentation. Readers are cautioned not to put undue

reliance on forward-looking statements.

References:

1. Kobayashi H. Recent trends in mucopolysaccharidosis research. J Hum Genet. 2019 Feb;64(2):127–37.

2. Peters H, Ellaway C, Nicholls K, Reardon K, Szer J. Treatable lysosomal storage diseases in the advent of

disease-specific therapy. Intern Med J. 2020 Nov;50 Suppl 4:5–27.

3. ASX Release 23rd November 2021: Positive interim data from phase 2 rare disease trial presented at international

medical congress.

4. Muenzer J. Overview of the mucopolysaccharidoses. Rheumatology. 2011 Dec 1;50(suppl 5):v4–12.

Authorised for release by the Paradigm Board of Directors.

To learn more please visit: www.paradigmbiopharma.com

FOR FURTHER INFORMATION PLEASE CONTACT:

Simon White

Director of Investor Relations

Tel: +61 404 216 467

Paradigm Biopharmaceuticals Ltd

ABN: 94 169 346 963

Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA

Email: [email protected]

Has anyone else noted the share price run from a low of 85.5 cents at end of June to a current SP of 1.52 on essentially no news!

What a great example of the market being there to serve and not to inform!

Or am I missing something?

Ok I'm a doctor not a finance guy but here's my understanding of what was announced today (was the 10% uptick related or just the general sentiment on the market today?):

2,000,000 shares were issued to Marc Polizzi the recently appointed CEO. They are staggered to come out of escrow in one year, two years and three years?

If the outstanding shares are 230 million as listed on yahoo finance this equates to just under 1% of the market cap of the company... If this is in lieu of income then I'm in favour, after all they need to conserve cash until they get the phase 3 trial done and are able to partner up, get bought out or actually go into production/profitability...

Given most of you are better qualified to understand financials and remuneration than me does anyone have other thoughts on all of this?

Add: I guess the other nice thing about a couple of million shares is the instant alignment with shareholders (although I confess I haven’t looked at the CEO’s salary separately)

   haven’t got time to decode this right now so if anyone smarter wants to explain feel free!!!

Notification of Issue, Conversion or Payment up of Unquoted Equity Securities

 Announcement Summary

Entity name

PARADIGM BIOPHARMACEUTICALS LIMITED..

Date of this announcement

Thursday July 07, 2022

The +securities the subject of this notification are:

+Securities issued under an +employee incentive scheme that are subject to a restriction on transfer and are not being quoted on ASX until the restriction ends

 Total number of +securities to be issued/transferred

ASX +security code

New class - code to be confirmed

New class - code to be confirmed

New class - code to be confirmed

Security description

666,667 Loan Funded Ordinary Shares issued at $0.96 per share restricted & in escrow until 01 Jul 23

666,667 Loan Funded Ordinary Shares issued at $0.96 per share restricted & in escrow until 01 Jul 24

666,666 Loan Funded Ordinary Shares issued at $0.96 per share restricted & in escrow until 01 Jul 25

Total number of +securities to be

issued/transferred Issue date

666,667 01/07/2022

666,667 01/07/2022

666,666 01/07/2022

Refer to next page for full details of the announcement

 Notification of Issue, Conversion or Payment up of Unquoted 1 / 12 Equity Securities

  Notification of Issue, Conversion or Payment up of Unquoted Equity Securities

 Part 1 - Entity and announcement details

1.1 Name of entity

PARADIGM BIOPHARMACEUTICALS LIMITED..

We (the entity named above) give notice of the issue, conversion or payment up of the following unquoted +securities.

 1.2 Registered number type

ABN

1.3 ASX issuer code

PAR

1.4 The announcement is

New announcement

1.5 Date of this announcement

7/7/2022

Registration number

94169346963

  Notification of Issue, Conversion or Payment up of Unquoted Equity Securities

2 / 12

 Notification of Issue, Conversion or Payment up of Unquoted Equity Securities

 Part 2 - Issue details

2.1 The +securities the subject of this notification are:

+Securities issued under an +employee incentive scheme that are subject to a restriction on transfer and are not being quoted on ASX until the restriction ends

2.2a This notification is given in relation to an issue of +securities in a class which is not quoted on ASX and which:

does not have an existing ASX security code ("new class")

   Notification of Issue, Conversion or Payment up of Unquoted 3 / 12 Equity Securities

       Notification of Issue, Conversion or Payment up of Unquoted Equity Securities

 Part 3C - number and type of +securities the subject of this notification (new class) where issue has not previously been notified to ASX in an Appendix 3B

New +securities issued under an +employee incentive scheme

 ASX +security code

New class - code to be confirmed

+Security type

Ordinary fully or partly paid shares/units

+Security description

666,667 Loan Funded Ordinary Shares issued at $0.96 per share restricted & in escrow until 01 Jul 23

ISIN code

Date the +securities the subject of this notification were issued

1/7/2022

Will all the +securities issued in this class rank equally in all respects from their issue date?

Yes

Were any of the +securities issued to +key management personnel (KMP) or an +associate?

Yes

Provide details of the KMP or +associates being issued +securities.

Name of KMP Name of registered holder Number of +securities

Marco Polizzi Marco Polizzi 666,667

Have you received confirmation from ASX that the terms of the +securities are appropriate and equitable under listing rule 6.1?

Yes

Please provide a URL link for a document lodged with ASX setting out the material terms of the +securities being issued.

  Ordinary fully or partly paid shares/units Details

+Security currency

AUD - Australian Dollar

Are there CDIs issued over the +securities?

No

Is it a Partly Paid class of +security?

No

Is it a stapled class of +security?

Notification of Issue, Conversion or Payment up of Unquoted Equity Securities

4 / 12

        Notification of Issue, Conversion or Payment up of Unquoted Equity Securities

 Is it a stapled class of +security?

No

Please provide a URL link for a document lodged with ASX detailing the terms of the +employee incentive scheme or a summary of the terms

https://www.asx.com.au/asxpdf/20201125/pdf/44q865364w4lhs.pdf

Any other information the entity wishes to provide about the +securities the subject of this notification

Issue details

Number of +securities

666,667

New +securities issued under an +employee incentive scheme

 ASX +security code

New class - code to be confirmed

+Security type

Ordinary fully or partly paid shares/units

+Security description

666,667 Loan Funded Ordinary Shares issued at $0.96 per share restricted & in escrow until 01 Jul 24

ISIN code

Date the +securities the subject of this notification were issued

1/7/2022

Will all the +securities issued in this class rank equally in all respects from their issue date?

Yes

Were any of the +securities issued to +key management personnel (KMP) or an +associate?

Yes

Provide details of the KMP or +associates being issued +securities.

Name of KMP Name of registered holder Number of +securities

Marco Polizzi Marco Polizzi 666,667

Have you received confirmation from ASX that the terms of the +securities are appropriate and equitable under listing rule 6.1?

Yes

Notification of Issue, Conversion or Payment up of Unquoted 5 / 12 Equity Securities

        Notification of Issue, Conversion or Payment up of Unquoted Equity Securities

 Please provide a URL link for a document lodged with ASX setting out the material terms of the +securities being issued.

Ordinary fully or partly paid shares/units Details

+Security currency

AUD - Australian Dollar

Are there CDIs issued over the +securities?

No

Is it a Partly Paid class of +security?

No

Is it a stapled class of +security?

No

Please provide a URL link for a document lodged with ASX detailing the terms of the +employee incentive scheme or a summary of the terms

https://www.asx.com.au/asxpdf/20201125/pdf/44q865364w4lhs.pdf

Any other information the entity wishes to provide about the +securities the subject of this notification

Issue details

Number of +securities

666,667

New +securities issued under an +employee incentive scheme

  ASX +security code

New class - code to be confirmed

+Security type

Ordinary fully or partly paid shares/units

Notification of Issue, Conversion or Payment up of Unquoted Equity Securities

+Security description

666,666 Loan Funded Ordinary Shares issued at $0.96 per share restricted & in escrow until 01 Jul 25

ISIN code

6 / 12

       Notification of Issue, Conversion or Payment up of Unquoted Equity Securities

 Date the +securities the subject of this notification were issued

1/7/2022

Will all the +securities issued in this class rank equally in all respects from their issue date?

Yes

Were any of the +securities issued to +key management personnel (KMP) or an +associate?

Yes

Provide details of the KMP or +associates being issued +securities.

Name of KMP Name of registered holder Number of +securities

Marco Polizzi Marco Polizzi 666,666

Have you received confirmation from ASX that the terms of the +securities are appropriate and equitable under listing rule 6.1?

Yes

Please provide a URL link for a document lodged with ASX setting out the material terms of the +securities being issued.

Ordinary fully or partly paid shares/units Details

+Security currency

AUD - Australian Dollar

Are there CDIs issued over the +securities?

No

Is it a Partly Paid class of +security?

No

Is it a stapled class of +security?

No

Please provide a URL link for a document lodged with ASX detailing the terms of the +employee incentive scheme or a summary of the terms

https://www.asx.com.au/asxpdf/20201125/pdf/44q865364w4lhs.pdf

Any other information the entity wishes to provide about the +securities the subject of this notification

    Notification of Issue, Conversion or Payment up of Unquoted 7 / 12 Equity Securities

  Notification of Issue, Conversion or Payment up of Unquoted Equity Securities Issue details

Number of +securities

666,666

  Notification of Issue, Conversion or Payment up of Unquoted 8 / 12 Equity Securities

 Notification of Issue, Conversion or Payment up of Unquoted Equity Securities

  Notification of Issue, Conversion or Payment up of Unquoted 9 / 12 Equity Securities

 Notification of Issue, Conversion or Payment up of Unquoted Equity Securities

 Part 4 - +Securities on issue

4.1 Quoted +Securities (Total number of each +class of +securities quoted)

ASX +security code and description

PAR : ORDINARY FULLY PAID

4.2 Unquoted +Securities (Total number of each +class of +securities issued but not quoted on ASX)

 Following the issue, conversion or payment up of the +securities the subject of this application, the +securities of the entity will comprise:

(A discrepancy in these figures compared to your own may be due to a matter of timing if there is more than one application for quotation/issuance currently with ASX for processing.)

ASX +security code and description

PARAB : OPTION EXPIRING 28-FEB-2023 EX $1.75

PARAL : ORDINARY FULLY PAID RESTRICTED

PARAM : ORDINARY FULLY PAID RESTRICTED

PARAP : ORDINARY FULLY PAID RESTRICTED

PARAN : ORDINARY FULLY PAID RESTRICTED

PARAO : ORDINARY FULLY PAID RESTRICTED

PARAH : ORDINARY FULLY PAID RESTRICTED

PARAJ : ORDINARY FULLY PAID RESTRICTED

PARAC : OPTION EXPIRING 24-MAR-2023 EX $1.75

PARAQ : ORDINARY FULLY PAID RESTRICTED

PARAS : ORDINARY FULLY PAID RESTRICTED

PARAT : ORDINARY FULLY PAID RESTRICTED

New class - code to be confirmed : 666,667 Loan Funded Ordinary Shares issued at $0.96 per share restricted & in escrow until 01 Jul 23

Notification of Issue, Conversion or Payment up of Unquoted 10 / 12 Equity Securities

Total number of +securities on issue

275,000

366,667

366,667

900,000

900,000

900,000

638,332

638,337

550,000

125,000

125,000

125,000

666,667

Total number of +securities on issue

227,595,795

 Notification of Issue, Conversion or Payment up of Unquoted Equity Securities

 New class - code to be confirmed : 666,667 Loan Funded Ordinary Shares issued at $0.96 666,667 per share restricted & in escrow until 01 Jul 24

New class - code to be confirmed : 666,666 Loan Funded Ordinary Shares issued at $0.96 666,666 per share restricted & in escrow until 01 Jul 25

 Notification of Issue, Conversion or Payment up of Unquoted 11 / 12 Equity Securities

 Notification of Issue, Conversion or Payment up of Unquoted Equity Securities

 Part 5 - Other Listing Rule requirements

Yes

5.1a Select the number of the applicable exception in Listing Rule 7.2

13

 5.1 Were the +securities issued under an exception in Listing Rule 7.2 and therefore the issue did not need any security holder approval under Listing Rule 7.1?

  Notification of Issue, Conversion or Payment up of Unquoted 12 / 12 Equity Securities

approval for UK and Canada recruitment to pivotal phase 3 trial given.

just expected progress but better than the alternative

ASX RELEASE 6th July 2022

Paradigm reports important global progress for the PARA_OA_002 phase 3 clinical trial evaluating Zilosul® for osteoarthritis.

KEY HIGHLIGHTS

• Regulatory and ethics approval are in place for the UK. The first UK screening site for the phase 3 study is now active, enabling Paradigm to commence screening and enrolling participants.

• Regulatory approval for the Para_OA_002 phase 3 trial has been granted by Health Canada

is pleased to announce it has activated the first trial site in the UK. The Company has received UK regulatory and ethics approvals to proceed with the Para_OA_002 phase 3 clinical trial evaluating knee osteoarthritis (OA). Now that the first site is activated in the UK participant screening and enrolment will begin imminently. This first site is located at the University of Leeds under lead investigator Prof. Hemant Pandit. Paradigm aims to activate a total of seven sites across the UK for the phase 3 study. The remaining sites will be activated in the coming months.

Paradigm is also pleased to announce that the global PARA_OA_002 phase 3 osteoarthritis clinical trial has regulatory approval from Health Canada. An ethics submission has been made to the research ethics board in Canada, with approval pending. Once ethics approval has been granted, Paradigm will activate clinical sites to begin participant screening and enrolment for the phase 3 study. Paradigm plans to activate up to 10 sites across Canada.

Paradigm’s phase 3 trial now has regulatory approvals to proceed from the US FDA, the UK Medicines and Healthcare products Regulatory Agency (MHRA), Health Canada, and the Australian TGA. Recruitment milestones will be announced as they are achieved.

Dr Donna Skerrett, Paradigm CMO commented: “I am pleased we are moving forward with regulatory approval within another planned jurisdiction for the global phase 3 program. The interaction with Health Canada was positive throughout the regulatory process and the Company looks forward to announcing anticipated ethics approval and subsequent participant recruitment in Canada. Equally, the achievement by the Paradigm team to activate participant recruitment in the UK highlights Paradigm's ongoing execution of activities for this global phase 3 trial in knee OA.”.

I look forward to these results Q3 2022… if they suggest disease modification it will be very positive for the price of the drug when approved… my belief is there is currently no drug demonstrated to modify disease progression in OA

ASX RELEASE 1st July 2022

PARA_OA_008 Study Evaluating Zilosul® Mechanism and Disease Modifying Effects Completes Recruitment

KEY HIGHLIGHTS

• The phase 2 clinical trial evaluating clinical and biomarker endpoints has reached 100% recruitment.

• The study will evaluate changes in synovial fluid biomarkers associated with osteoarthritis pain, inflammation, and disease progression.

• 60 subjects have been randomised into either PPS twice weekly, once weekly, or placebo groups.

• Top-line data from day 56 endpoints remain on track for release during Q3 CY22.

• Paradigm expects to also provide data updates as the study population reaches 6-

month and 12-month timepoints.

• The canine OA study, also evaluating biomarkers and clinical endpoints is nearing completion of recruitment with initial data expected to be available in Q3 2022.

Paradigm Biopharmaceuticals Ltd (ASX: PAR) (Paradigm or the Company), a clinical-stage biopharmaceutical company focussed on repurposing existing molecules for new indications with unmet clinical needs, is pleased to announce complete recruitment of PARA_OA_008. The phase 2 clinical trial evaluating the treatment effects of pentosan polysulphate sodium (PPS/Zilosul®) against placebo on synovial fluid biomarkers in participants with knee osteoarthritis (OA) pain, has reached 100% recruitment (n=60).

PARA_OA_008 Study evaluating synovial fluid biomarkers

The clinical trial is being run at two sites in Vic and NSW and aims to gather data on the medium- to long-term structure-modifying and symptom-modifying effects of PPS on Knee OA. Sixty subjects have been randomised to receive either PPS twice weekly, once weekly, or placebo. Participants have been randomised into each treatment group according to a 1:1:1 ratio (i.e. 20 randomised to PPS twice-weekly, 20 randomised to PPS once-weekly, 20 randomised to placebo over a 6 week treatment course).

This phase 2, PARA_OA_008, clinical trial aims to provide evidence that disease specific biomarkers in the synovial fluid of symptomatic OA patients are a potential marker of Zilosul® effects on the joint. The data collected from this phase 2 study will be the first OA clinical trial data reported by Paradigm since the release of the Phase 2B (PARA_OA_005) clinical trial data in 2018. Paradigm expects to release data as the various timepoints are reached, such as day 56 biomarker and clinical endpoints, 6-month MRI and clinical endpoints, and 1 year follow-up clinical effect duration endpoint data.

The Company remains on track for the interim (day 56) data to be released to the market in Q3 2022.

Canine OA Model Evaluating Disease Modification markers

To generate further data establishing the in vivo mechanism of action of PPS in disease modification and provide complimentary data in parallel with the PARA_OA_008 human clinical trial, Paradigm is concurrently conducting a trial in dogs with naturally occurring OA at the U-Vet Werribee Animal Hospital.

In the proposed investigation, up to 21 dogs with osteoarthritis of the stifle joint are treated with 3mg/kg PPS (1.7mg/kg human equivalent) or placebo (2:1 randomisation) via a subcutaneous weekly injection for 6-weeks. Clinical outcomes of pain and function will be assessed, together with structural changes from baseline as determined by the global OA score measured by X-ray, and bone marrow lesions and cartilage volume by MRI. In addition, molecular biomarkers associated with inflammation, cartilage degradation, and pain will be assessed in the synovial fluid and serum to ascertain correlations with clinical outcome measures of pain and function as well as structural changes. The longer 20- week follow-up period (equates to approximately 3 years in a human lifespan) from the cessation of treatment in the study will assess the durability of response and structural changes following therapy. The collective analyses of pain, function, joint structure, and biomarker levels following PPS therapy will provide informative data to assess the potential of PPS as a disease-modifying osteoarthritis drug (DMOAD).

Paradigm intends to have data from the canine OA model available for release to the market In Q3 2022.

Dr Donna Skerrett, Paradigm’s Chief Medical Officer said:

“We have reached an important milestone with 100% completed recruitment in our PARA_OA_008 clinical trial. We thank all our volunteer trial participants, research physicians and their staff, and our dedicated and enthusiastic clinical staff for their time and commitment to this important study. Paradigm looks forward to sharing early data outcomes in Q3 2022 from this exciting exploratory study as well as our continued progress in the ongoing global Phase 3 clinical trial.”

About Para_OA_008

Osteoarthritis (OA) is a heterogenous and chronic progressive disease of the whole joint, where patients experience persistent pain and progressively reduced joint function. The disease pathogenesis in OA is mediated by inflammation, cartilage degradation, and adverse remodelling of the subchondral bone. Pre-clinical and clinical evidence has demonstrated that PPS is active through multiple modes of action including decreasing inflammation by down-regulating inflammatory cytokines, reducing pain by reducing the production of NGF, protecting cartilage as evidenced by the downregulation of cartilage degrading enzymes, and supporting bone repair through improved blood flow. Until now, these effects have been evaluated by measuring serum biomarkers which may not fully describe the changes in the local OA joint environment. Therefore, the PARA_OA_008 study will evaluate molecular biomarkers in the synovial fluid to more directly evaluate the disease modifying potential of PPS on the diseased joint.

About Paradigm Biopharmaceuticals

Paradigm Biopharmaceuticals LTD (ASX: PAR) is a late-stage drug development company with the mission to develop and commercialise pentosan polysulfate sodium for the treatment of pain associated with musculoskeletal disorders driven by injury, inflammation, ageing, degenerative disease, infection or genetic predisposition.

Forward Looking Statements

This Company announcement contains forward-looking statements, including statements regarding anticipated commencement dates or completions dates of preclinical or clinical trials, regulatory developments and regulatory approval. These forward-looking statements are not guarantees or predictions of future performance, and involve known and unknown risks, uncertainties and other factors, many of which are beyond our control, and which may cause actual results to differ materially from those expressed in the statements contained in this presentation. Readers are cautioned not to put undue reliance on forward-looking statements.

Authorised for release by the Paradigm Board of Directors.

Zilosul® is a registered Trademark of Paradigm Biopharmaceuticals Ltd (ASX: PAR).

PAR has been seriously beaten down in the recent sell off. Yes it’s pre revenue but in phase 3 trials with what I believe are excellent prospects of a good outcome.

they have cash in the bank. If they did have to dilute further they would still be worth a huge amount when the drug is commercialised.

aside from the phase 3 trial failing can anyone see a threat to this stock? I am overweight on both straw and IRL and maybe I’m missing the forest for the trees here…

hopefully this bodes well for patent approval in USA also.

Australian Patent Application Acceptance by IP Australia

is pleased to provide an update to the market that it has received official acceptance of the Australian patent application “Treatment of bone marrow pathologies with polysulfated polysaccharides (Australian application number (2021201198). The expiry date of the Australian patent (2021201198)

is 6th August 2038.

The first claim of the accepted patent (2021201198) refers to “a method of improving knee function where the subject has a bone marrow lesion and osteoarthritis in a knee by administering pentosan polysulfate sodium”.

Paradigm clarified in an ASX Announcement 9th March 2022, that a pending patent application with the US Patent and Trademark Office (the USPTO), had received a final rejection notice for the patent application titled “Treatment of bone marrow pathologies with polysulfated polysaccharides” (US application number 16/636,545). This is the same patent as the recently issued Australian patent (above). Paradigm clarified that a final rejection is not final, and the prosecution of this patent continues with Paradigm expected to file its response, to the US patent and trademark office (USPTO), by the end of July 2022.

Paradigm Chairman, Mr Paul Rennie commented, “It is very exciting for the Company’s strategic plans to have a patent which claims the treatment of people with osteoarthritis and bone marrow lesions with pentosan polysulphate sodium (PPS) and we expect further acceptance and grants in other territories in the coming months. We continue to work in partnership with our patent attorneys to proactively prosecute new patents to extend our protection on the use of PPS in disease indications with unmet medical needs.”

Summary of IP

Paradigm’s PPS has a multi-faceted protection consistent with composition of matter encompassing manufacturing, patents, and exclusive in-licensing and supply for new indications with unmet clinical needs.

There is only one FDA approved manufacturer of Pentosan Polysulfate Sodium (PPS), bene pharmaChem GmbH (bene), with whom Paradigm has an exclusive, sublicensable, global supply agreement for the manufacture and commercial use of PPS for multiple indications extending for 25 years post first marketing approval. In addition, Paradigm has an ongoing collaboration agreement with bene for product related development support for meeting regulatory milestones and development of PPS for new indications and second-generation molecules.

PPS is a highly complex molecular platform technology; a highly sulphated semisynthetic

 Paradigm Biopharmaceuticals Ltd (ASX: PAR) (“Paradigm” or “the Company”), a clinical stage biopharmaceutical company focussed on repurposing existing molecules

 for new indications with unmet clinical needs,

xylan-based polysaccharide that structurally resembles glycosaminoglycans, which is derived from beechwood hemicellulose. The manufacture and composition of PPS is a trade secret tightly held by bene for over 60 years.

A generic manufacturer would be required to develop an identical molecular fingerprint of the bene PPS. The complex molecular structure of PPS means generic manufacturers face a task of similar difficulty to that of developing a copy of a biosimilar. Potential generic entrants must provide GPC (gas permeable chromatography) data demonstrating identical structure and purity for each of the multiple moieties.

A generic copy is highly unlikely to be identical as described above. Therefore, a full clinical development program to demonstrate equivalent pharmacokinetic, pharmacodynamic, clinical safety and efficacy profiles will be required. Paradigm has a broad patent portfolio covering multiple indications in all key jurisdictions. Paradigm’s primary and foundational patents (US10,610,542, US9,861,657 and US9,101,650) which have been granted in the US and several other jurisdictions are for the use of PPS to treat bone marrow edema (BME). Since BME is associated with painful knee OA our patent protection blocks any generic use to treat knee OA in the absence of BME.

Paradigm is proactively prosecuting new patents to extend its protection on the use of PPS in disease indications with unmet medical needs where the actions of PPS have been scientifically (in preclinical proof-of concept models) and/or clinically (population of patients) been ascertained to be therapeutically effective. For example, a patent related to the action of PPS in pain mediated by NGF is currently being prosecuted in key jurisdictions.

Currently registered oral formulations of PPS are not suitable for conditions requiring systemic distribution for treatment effect. The bioavailability of oral formulations of PPS is 3.3 -3.5%.1

In summary, Paradigm’s injectable PPS is well protected with

• a 25-year post-marketing exclusive supply agreement with the only FDA

approved manufacturer of the API,

• trade-secret and complex manufacturing processes of the API from the extracted

biological starting material and,

• method of use patents covering multiple disease indications in key jurisdictions

globally.

With no FDA approved generics of injectable PPS, the barrier to entry for potential competitors is high.2

About Paradigm Biopharmaceuticals

Paradigm Biopharmaceuticals LTD (ASX: PAR) is a late-stage drug development company with the mission to develop and commercialise Pentosan Polysulfate Sodium for the treatment of pain associated with musculoskeletal disorders driven by injury, inflammation, aging, degenerative disease, infection, or genetic predisposition. Paradigm is also exploring proof-of-concept studies for the use of PPS in respiratory and heart failure indications.

Forward Looking Statements

This Company announcement contains forward-looking statements, including statements regarding anticipated commencement dates or completions dates of preclinical or clinical trials, regulatory developments, and regulatory approval. These forward-looking

statements are not guarantees or predictions of future performance, and involve known and unknown risks, uncertainties, and other factors, many of which are beyond our control, and which may cause actual results to differ materially from those expressed in the statements contained in this presentation. Readers are cautioned not to put undue reliance on forward-looking statements.

References

1. Greenslade D, Vickers J, Hopkins R. (3H)-Sodium Pentosan Polysulfate: A Pharmacokinetic Study in Man after Oral Administration. Hazleton Laboratories; 1983.

2. Smith RB. Repositioned drugs: integrating intellectual property and regulatory strategies. Drug Discov Today Ther Strateg. 2011;8(3-4):131-137. doi:10.1016/j.ddstr.2011.06.008

Authorised for release by the Paradigm Board of Directors. To learn more please visit: www.paradigmbiopharma.com

FOR FURTHER INFORMATION PLEASE CONTACT:

Simon White

Director of Investor Relations

Tel: +61 404 216 467

Paradigm Biopharmaceuticals Ltd ABN: 94 169 346 963

Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA Email: [email protected]

8.2 million dollar R&D Rebate. Helps a bit with the cash burn associated with the pivotal phase 3 trial! (Seems like about 20% of their annual cash burn at current level)

read below about the new CEO:

• another piece in the puzzle
• although Donna skerret the CMO has done her best as acting CEO I believe she’s best suited as a CMO and glad she is able to return to that role
• to my inexperienced eyes Marco Polizzi appears to have the right kind of experience to commercialise zilosul
• US based as appropriate to the huge market for zilosul there
• Another step forward!!!

ASX RELEASE 30th May 2022

Paradigm Appoints Marco Polizzi as Chief Executive Officer

has appointed experienced pharmaceutical industry executive Mr. Marco Polizzi as its full-time Chief Executive Officer (CEO), effective 1 July 2022.

Mr. Polizzi has a proven track record that is highlighted by several successful business and product launches in the USA. These include a new Institutional (Hospital & Specialty Markets) business unit at Sandoz, driving the growth of a $900M P&L, as well as directing commercial functions for a product launch (Bivalirudin) that achieved $100M+ sales in its first year.

Paradigm Chairman, Paul Rennie said “We expect that Marco’s, broad expertise will lead Paradigm in attaining its strategic program objectives and increase shareholder value. Paradigm has been seeking a CEO with the skills to fully unlock the commercial value of the company. Marco brings to Paradigm extensive US pharmaceutical experience, a pharmaceutical industry network, operational excellence, transactional expertise, product launch and product pricing and reimbursement experience. We are confident that this experience will provide significant development and commercial value to Paradigm. Marco will commence his tenure with Paradigm on 1 July 2022. He will be based in the United States and travel to Australia, Europe and Asia as required”.

Paradigm’s incoming CEO, Marco Polizzi commented, “With my pharmaceutical experience, I believe I will be able to make a significant contribution to the Paradigm business in the short and long term. I have had the opportunity to meet the Paradigm Board and key management personnel and I can say the Paradigm’s business excites me. Primarily on account of ZilosulTM, a blockbuster potential product, that may bring relief to the millions of people globally suffering from the pain and other debilitating effects of osteoarthritis and significantly increase shareholder returns. I look forward to meeting our shareholders in the coming months”.

The Paradigm Board thanks Dr Donna Skerrett for her unwavering dedication and invaluable contribution to the Company’s progress while she served as interim CEO. Moving forward, Dr. Donna Skerrett with continue as CMO with a keen focus to successfully complete the global phase 3 clinical programs for ZilosulTM following the FDA’s fast track designation protocol.

 Paradigm Biopharmaceuticals Ltd (ASX: PAR) (“Paradigm” or “the Company”), a clinical stage biopharmaceutical company focussed on repurposing existing molecules for new indications with

 unmet clinical needs,

 Mr. Polizzi brings to Paradigm over 30 years of experience in the pharmaceutical industry in various commercially focused roles, including the creation of new divisions within branded and generic pharmaceutical businesses. In these roles, Mr. Polizzi achieved outstanding sales results, forged a multitude of license, asset purchase, and other agreements with multiple top 10 global pharmaceutical companies and numerous other business partners and generated significant

returns for investors.

About Marco Polizzi

During his career Mr Polizzi established Mallinckrodt’s Brand Pharmaceutical business unit from scratch, growing it from 0 products and 0 to 148 employees, and building it to~$200M Net Sales & ~$100M in Operating Income. This business is now a multi- billion-dollar revenue division of Mallinckrodt.

Before starting Mallinckrodt’s branded business unit, Marco was a lead executive in driving and executing the phenomenal growth of Mallinckrodt’s Generic Pharmaceutical business from $8M to $800M to become the 5th largest Generic company in the U.S. for pain management products.

 He developed a new Institutional (Hospital & Specialty Markets) business unit at Sandoz, leading growth from 2 to 40 team members, and driving growth of a $900M P&L, while directing all commercial functions for a product launch that achieved $100M+ sales in its first year (Bivalirudin).

Mr Polizzi successfully led the process for several dozen U.S. and International Pharma strategic license and acquisitions, from identification of target companies, negotiations, and due diligence through execution. Evaluated hundreds of prospective M&A, licensing, or acquisition transactions throughout his career.

He was also able to achieve a CAGR of 35% during his first two years at JHP Pharmaceutical’s (from $62M to $115M) following the previous 2-year period of single digit growth. Created a new generic commercial division. JHP Pharma was eventually purchased by Par/Endo.

About Paradigm Biopharmaceuticals

Paradigm Biopharmaceuticals LTD (ASX: PAR) is a late-stage drug development company with the mission to develop and commercialise Pentosan Polysulfate Sodium for the treatment of pain associated with musculoskeletal disorders driven by injury, inflammation, aging, degenerative disease, infection or genetic predisposition. Paradigm is also exploring proof-of-concept studies for the use of PPS in respiratory and heart failure indications.

Authorised for release by Paradigm Chairman, Mr Paul Rennie. To learn more please visit: www.paradigmbiopharma.com

More progress

First Subjects Randomised and Dosed in the US under Phase 3 Pivotal Trial for the treatment of pain associated with Knee OA

KEY HIGHLIGHTS

• The first subjects have now commenced dosing in the PARA_OA_002 phase 3 study in activated sites in the US.

• To date, 21 sites have begun screening and recruiting potential candidates.

• With the initiation of 56 selected sites in the US Paradigm now has a large potential

pool of candidates from which to screen.

Paradigm Biopharmaceuticals Ltd (ASX: PAR) (“Paradigm” or “the Company”), a clinical stage biopharmaceutical company focussed on repurposing existing molecules for new indications with unmet clinical needs, is pleased to report that the first subjects have been randomised and dosed in the United States (US) in the PARA_OA_002 pivotal clinical trial, evaluating injectable pentosan polysulfate sodium (PPS/Zilosul®) for the treatment of pain associated with knee osteoarthritis (kOA). The first subject randomisation was confirmed at Northwestern University, Chicago, by Lead Investigator, Dr Thomas Schnitzer.

The global pivotal phase 3, PARA_OA_002, study is currently screening and enrolling subjects in 8 sites across Australia, and in 21 of the 56 selected sites in the US. Clinical trial site activation has been a key focus for Paradigm from the start of the calendar year to enable a large pool of potential candidates to be identified across the activated sites and to begin the screening process. Site activations in the US will continue and UK and EU sites are also being initiated throughout CY22.

Dr. Donna Skerrett, Paradigm’s Chief Medical Officer and interim CEO said: “To have our first subjects randomised in the US is an important milestone in the OA clinical program. The Paradigm clinical team has been working tirelessly to initiate and activate sites throughout the US and we are seeing a large number of subjects entering the screening phase throughout the US. We look forward to continuing the strong momentum in the phase 3 program and reporting important recruitment milestones to our shareholders”.

About Para_OA_002

PPS

This is a 2-stage, adaptive, randomised, double-blinded,

placebo-controlled, multicentre (US/CAN/AUS/UK/EU) study that will evaluate the dose and treatment effect of iPPS in participants with kOA pain.

Stage 1 will comprise a phase 2b dose selection, with participants randomised receiving 1 of 3 iPPS dose regimens or placebo for 6 weeks. The primary objective of stage 1 will

  The purpose of this study is to measure the change in pain and function with

 subcutaneous injections of participants with kOA pain.

compared with subcutaneous injections of placebo in

be to select the dose for use in stage 2 and Paradigm’s confirmatory trial (PARA_OA_003), the selected dose will be based on an optimal balance of efficacy and safety.

In stage 2, participants will be randomised 1:1 to receive the selected PPS dose regimen or placebo for 6 weeks.

The primary endpoints in the pivotal study are change from baseline at Day 56 in WOMAC® pain with secondary outcomes to include change from baseline at multiple time points out to day 168 in WOMAC® pain and function, Patient Global Impression of Change (PGIC) and Quality of Life (QoL).

Additional information on a Paradigm’s clinical trials can be found at ClinicalTrials.gov (002 -

US Lead Investigator

The US lead Investigator for the phase 3 clinical study Para_OA_002 is Dr. Thomas Schnitzer MD, PHD. Thomas J. Schnitzer, MD, PhD, is Professor in the Departments of Physical Medicine and Rehabilitation, Internal Medicine/Rheumatology and Anaesthesiology at Northwestern University Feinberg School of Medicine. He is a graduate of Harvard Medical School and has trained at Johns Hopkins Hospital, the National Institutes of Health, the MRC Rheumatism Unit in Taplow, England, and at the Imperial Cancer Research Institute in London, England. Professor Schnitzer has a long- standing interest in chronic musculoskeletal pain and the development of new therapeutic approaches to its management. At Northwestern University, he founded and directed the Office of Clinical Research and was assistant dean for clinical research at the medical school. He is a Master of the American College of Rheumatology, served on the editorial board of numerous journals, and has published over 200 peer-reviewed publications.

Market Potential in Osteoarthritis

Osteoarthritis (OA) is the most prevalent form of joint disease, affecting up to 16% of the population in the developed world, with more than 72 million people in the US, EU5, Canada and Australia suffering from OA.1

OA has a significant impact on day-to-day functioning and, although the levels of pain and disability may fluctuate, it has no known cure or spontaneous remission and is associated with irreversible structural damage and progression over time. Presently there are no drugs approved that can prevent, stop, or even restrain progression of OA. Moreover, the available medications that claim to mitigate the pain of OA have numerous risk/benefit considerations and market

. 2,3

The prevalence of OA is increasing in line with the aging population and increasing rates of obesity. By 2030 the number of people suffering from OA in the US is predicted to increase by 86% to 67 million.2 If we assume a similar increase across the other markets defined above, even allowing for lower rates of obesity in non-US markets, it is plausible that more than 120 million people will be suffering from osteoarthritis by 2030.

 NCT04809376, 006 - NCT04814719) or via the Paradigm website

 www.paradigmbiopharma.com.

 Paradigm’s OA program investigating PPS has recently received Fast Track Designation

 from the US FDA.

 research indicates that only 19% of kOA patients

 are satisfied with currently available treatments

About Paradigm Biopharmaceuticals

 Paradigm Biopharmaceuticals LTD (ASX: PAR) is a late-stage drug development company with the mission to develop and commercialise pentosan polysulfate sodium for the treatment of pain associated with musculoskeletal disorders driven by injury, inflammation, ageing, degenerative disease, infection or genetic predisposition. Paradigm is also investigating proof-of-concept for the use of PPS

 in respiratory and heart failure indications.

Forward Looking Statements

This Company announcement contains forward-looking statements, including statements regarding anticipated commencement dates or completions dates of preclinical or clinical trials, regulatory developments and regulatory approval. These forward-looking statements are not guarantees or predictions of future performance, and involve known and unknown risks, uncertainties and other factors, many of which are beyond our control, and which may cause actual results to differ materially from those expressed in the statements contained in this presentation. Readers are cautioned not to put undue reliance on forward-looking statements.

References

1 Global Health Data Exchange, Institute for Health and Metrics Evaluation, University of Washington. Accessed June 2021 http://ghdx.healthdata.org/gbd-results-tool.

2 OARSI. Osteoarthritis: A Serious Disease, Submitted to the U.S. Food and Drug Administration December 1, 2016.

3 Matthews GL, Hunter DJ. Emerging drugs for osteoarthritis. Expert Opin Emerg Drugs. 2011;16(3):479-

The announcement made today in favour of fast track designation is a massive boost for PAR.

America is the big market for this drug. Huge addressable market. Quicker approval (very likely as there is a lot of evidence supporting the drug's safety and efficacy) means less spend on trials/approvals process.

Also the increased rate of progress this may bring about is an incentive for big pharma to make their offers if they're considering... Time to buy. (Disc held on Straw and IRL)

ASX RELEASE 12th April 2022

US FDA Grants Fast Track Designation

for Paradigm’s Phase 3 Osteoarthritis Program

KEY HIGHLIGHTS

• FDA Fast Track Designation for Pentosan Polysulfate Sodium (Zilosul™/PPS)

offers pathways to expedite development of Paradigm’s osteoarthritis clinical

program.

• FDA Fast Track acknowledges osteoarthritis as a serious disease with unmet

need and the potential for PPS to offer a treatment for OA.

• Fast Track designation allows Paradigm the opportunity to interact and

collaborate with FDA more frequently during program development. This

enables a stronger overall program in line with the FDA’s expectations and

provides opportunity for shorter review timelines.

• In February, Paradigm submitted a request for Fast Track Designation, which

has now been approved, following the 60-day FDA review process.

ASX RELEASE 17th March 2022

Paradigm has received regulatory and ethics approvals for the

PARA_OA_002 clinical trial in the UK.

KEY HIGHLIGHTS

• Regulatory and ethics approval has been received from the Medicines and

Healthcare products Regulatory Agency (MHRA) in the United Kingdom

(UK).

• Paradigm now has all the required approvals in place to commence clinical

trial site activation in the UK for PARA_OA_002.

• Paradigm was granted permission to become part of the pilot test phase

rollout of the combined regulatory and ethics applications, thereby reducing

both time and costs.

• 5 sites in the UK are planned for initiation and activation to enrol participants

with knee OA into the PARA_OA_002 study.

Paradigm Biopharmaceuticals Ltd (ASX: PAR) (“Paradigm” or “the Company”), a

clinical stage biopharmaceutical company focussed on repurposing existing molecules

for new indications with unmet clinical needs, is pleased to announce it has received

regulatory and ethics approval from the MHRA in the UK. Paradigm now has all the

required approvals in place to commence clinical trial activities in the UK for its global

Phase 3 PARA_OA_002 clinical trial and expects to imminently commence enrolling

participants with knee OA into the PARA_OA_002 study in 5 sites in the UK.

The current sell down I believe relates to impatience with the progress/read out dates of the pivotal trial and maybe to the general market sentiment around future profits in the setting of inflation and rising interest rates. All reasons to continue buying it you believe as I do that the drug will be shown to work and the trial will get done (there is an important assumption there)

The recent approval of phase 3 trials by the FDA for a pivotal trial for pentosan polysulphate in OA could be the catalyst for an uptick in stock price. More importantly, I believe the trial will confirm that this is a safe and effective drug for OA. This alone would justify a massive valuation given the TAM, however the 008 trial looking at disease modification may boost the value further. The variant perception here I believe is the likelihood of success in the recently approved phase 3 trial. There is a lot of data to suggest the drug works and also basic science evidence as to the mechanism. I think the stock is more de-risked than the market gives it credit for.