No meetings
Consensus community valuation
XXXXXX
Average Intrinsic Value
XXXXXX
Undervalued by
The consensus valuation is for members only and has been removed from this chart. Click for membership options.
Contributing Members
Content is delayed by one month. Upgrade your membership to unlock all content. Click for membership options.
#Financials
Added 2 months ago


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: investorrelations@paradigmbiopharma.com




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)


Read More
#Bull Case
Added 2 months ago

@ 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

Read More
#Industry/competitors
Added 2 months ago

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: investorrelations@paradigmbiopharma.com

 

Read More
Valuation of $0.650
Added 5 months ago

As PAR is pre-revenue, you can't tell a lot from the reported numbers (or maybe you can?), so you need to go off the story and expected future numbers.

This is a very risky proposition. Probably the riskiest and smallest in my portfolio.

One way to assess the value of the opportunity is to look at the amounts invested (replacement cost) and how well that capital has been allocated (mgmt quality).

$131m Raised over the last 4 years ($123.7m after costs),and $75m+ before that.

$141.4 m Spent on R&D within the last 4 years.

So the salvage value to big pharma (who will probably own this if / when Phase 3 is successful anyway) is not nothing. They're building an asset here that would not likely get written to zero given the Phase 2 traction they have and mitigating risk of a repurposed drug.

$69.4m in cash @ Dec-23 to last to mid CY25 / FY25 (without additional licensing revenue).

This $69.4m in cash is vs Mkt Cap of $59.9m (@ today's closing SP$ of $0.395) after all underwritten shares issued, but excluding the attaching options (Strike @ $.065, expiring Dec-24). So you have 116% Cash backing! See my straw on #Cap Raise for context tho (burning cash fast).

This is a big bet on the Exec Chair, Founder – Paul Rennie who held > 25% prior to the Cap Raise and will hold > 13% post the raise assuming he doesn't participate.

It's targeting a $14bn Revenue opportunity and should be high margin at maturity. This could take 10 years or more to achieve. See Straw on "Bull Case" for more details.

I don't know what it's worth... but an informal probability weighted 10 bagger within 10 years vs a go to zero and fire sale for scrap due to an inability to raise more capital plus an underwritten $30m cap raise just done @ $0.43 with attaching 1 year options at $0.65 suggests overhang to persist until the next positive trial read out / partnership announcement and until then $0.65 looks like value to me for a small holding.

Disc: Held

Read More
#Bull Case
Added 5 months ago

Founder led - This is a big bet on the Exec Chair, Founder – Paul Rennie.

Could we organise a chat with him @Strawman?

Huge market – 72m Osteoarthritis (OA) sufferers in 2020, expect 120m in 2030 (5% Mkt CAGR). 81% are dissatisfied with current treatment. Targeting 10% of the market (not sure how achievable this might be). Dosage to cost US$2.5k per patient p.a. suggesting a US$14bn market opportunity.

Paradigm’s main product is a repurposed drug being trialed to address a huge unmet need - so the potential is huge but range of outcomes are wide.

As it’s repurposed, there is high confidence that the drug is safe (at a given dosage). This removes a huge potential risk at the Phase 3 trial stage.

As it’s unmet need, the "FDA has granted Fast-track designation to the OA program" – they want this to work and are happy to expedite (as long as it does).

Phase 2 trials have been positive in alleviating pain (key end point) and even improving the condition (improving cartalidge thickness).

Check out the Cap Raise Preso for more info - https://www.marketindex.com.au/asx/par/announcements/investor-presentation-30m-capital-raise-3A629518

Disc: Held (small 'research position')

Read More
#Cap Raise
Added 5 months ago

Further to @GazD's updates and enthusiasm on the progress of Paradigm, I've had a look at their recent cap raise and here's my thoughts.

$35m Mkt Cap (@ $0.43 share price), before new shares issued.

Just raised $30m, fully underwritten (Est $28.5m after costs), but spent $22m in R&D in the Sep-23 Quarter alone!!

Now have $69.4m in cash @ Dec-23 to last to mid CY25 / FY25 (without additional licensing revenue).

Massively dilutive as it almost doubles their share count, and will increase shares on issue by > 1.5x if attaching options from Cap Raise are exercised within the year (expiring Dec-24 w Strike @ $0.65).

So, unless I am missing something they will need another funding injection soon I expect.

There are 3 possible sources for this:

1)   Potential partnering deals to provide material additional non-dilutive cash runway. They expect 1 or more in the next 6 months. I would expect the bargaining power to lie with the partner(s).

2)   Options issued in the Cap Raise, if exercised will raise A$33.8m... but only if $SP > $0.65 (51% above raise price of $0.43) by 30-Nov-24. This will require a very positive outlook – most likely based on Phase 2 & 3 trial progress / read outs between now and then.

3)   Another (thesis busting) capital raise...

If there wasn't such a massive potential here this Cap Raise would have been a thesis breaker for me (i.e. mgmt can't allocate capital well enough).

Disc: Held (just started a small 'research position')

Read More
#Cap Raise
Added 5 months ago

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: investorrelations@paradigmbiopharma.com

  


Read More
#ASX Announcements
Added 5 months ago

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: investorrelations@paradigmbiopharma.com

 

        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: prennie@paradigmbiopharma.com

INVESTOR RELATIONS ENQUIRIES:

Simon White

Director IR

Email: swhite@paradigmbiopharma.com

MEDIA ENQUIRIES:

Rachel Peat

PR and Communication

Email: rpeat@paradigmbiopharma.com

  For more information please visit:

paradigmbiopharma.com

  

Read More
#Bull Case
Added 6 months ago

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

Read More
#ASX Announcements
Added 6 months ago

How exciting! Hoping this is positive news about disease modification


ASX RELEASE

By email: melissa.kostopoulos@asx.com.au

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

Read More
#Quarterly Reports/Updates
stale
Added 8 months ago

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…

Read More
#ASX Announcements
stale
Added 8 months ago

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: investorrelations@paradigmbiopharma.com

 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).

  

Read More
#ASX Announcements
stale
Added 9 months ago

 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: investorrelations@paradigmbiopharma.com

  

Read More
#ASX Announcements
stale
Added 10 months ago

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: investorrelations@paradigmbiopharma.com

  

Read More
#ASX Announcements
stale
Added 10 months ago

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: investorrelations@paradigmbiopharma.com

  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

  

Read More
#Management
stale
Added 10 months ago

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


Read More
#Management
stale
Last edited 11 months ago

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




Read More
#ASX Announcements
stale
Added 11 months ago

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: investorrelations@paradigmbiopharma.com

  

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.


Read More
Valuation of $4.00
stale
Added 12 months ago

Hard to know exact future for this share price. My base case is they will finally win FDA approval and as such the stock will be worth much more than its current price that factors in that uncertainty. That could be $4, it could be $10 or more if a big drug company wants to play in the massive knee arthritis market they address, by way of a takeover. That's basically what mgt are working towards. The likely market in the US, EU and AU is $10 billion + given the drug looks to be much more effective than current standards of care.

Management has significant skin in the game and they are currently in phase 3 trials, so well down the path. Not normally my kind of stock but safety is already proven, their ongoing clinical results for OA looking very promising and there is a lot of upside given the size of the prospective market. It's a small speculative bet with far less risk than is usually the case with drug companies, given safety is already signed off. Will need some patience as the final FDA approval process and likely take-over is probably still a year or two away.

Read More
#Risks
stale
Added one year ago

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


Read More
#R and D Tax Concession
stale
Added one year ago

Just a quick thought on announcements re the R & D tax concession. There is no doubt it is a material Ann, but let's be realistic, it's free kick from the ATO and like all tax rebates, you have to spend a chunk to get a smaller chunk back.

Most larger companies now use this to capitalise tax losses. My view is the only real issue is how much did they get, thereby how much did they spend, how much "bodgy" cross charges went in and how much real R & D got done. If it's a tech or bio company that lives and breaths based on continuing R & D then has to be seen as positive. Quite frankly, some companies R & D, I suspect produce little benefit to revenue or profits going forward.

Read More
#Speeding Ticket?!
stale
Last edited 2 years ago

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?

Read More
#ASX Announcements - Phase 3 Tr
stale
Added 2 years ago

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.”.

Read More
#ASX Announcements - Phase 3 Tr
stale
Added 2 years ago

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.

Read More
#FDA progress
stale
Added 2 years ago

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.

Read More
#FDA progress
stale
Added 3 years ago

Paradigm Biopharmaceuticals Ltd (ASX: PAR) (Paradigm or the Company), wishes to inform the market it has received a written response from the US FDA in relation to its Investigation New Drug (IND) submission for pentosan polysulfate sodium (PPS) to treat pain in subjects with knee Osteoarthritis.

In response to the FDA's one request, Paradigm will make an amendment to Its protocol. Response received from the US FDA. The one outstanding question regarding adrenal gland function related to a preclinical finding in the adrenal gland of rats only and was not seen in the adrenal gland of dogs. Adrenal gland malfunction has not previously been seen by Paradigm or bene pharmaChem in their ongoing pharmacovigilance. This one preclinical finding has been the focus of the ongoing US FDA review.

Paradigm, working with external endocrinologists, presented changes to the clinical trial protocol, which included a comprehensive adrenal screening protocol and clinical monitoring as part of its mitigation plan. In the written communication, the FDA requested modifications to Paradigm’s adrenal screening and mitigation plan. Paradigm plans to amend its clinical trial protocol, including all the FDA’s requests, and respond to the FDA within the next week.

Paradigm assumes the FDA may again take 30 days to respond. Mr Paul Rennie, Paradigm Chief Executive Officer: “Although we understand the agency's obligations for thorough reviews which commenced in March of this year, I am confident that the FDA and Paradigm have now attained a pathway to commence our phase 3 clinical trial in the US”.

***

Another month and another month's delay.  At least the FDA didn't take the full 30 days to respond this time.  Hopefully this is it though and we'll get approval to proceed in October.  [Drums fingers on desk].

[Held]

Read More
#Anecdotal evidence
stale
Last edited 3 years ago

Thanks for bringing this to my attention. I had a patient who was a racehorse owner with terrible arthritis.

He had noticed the amazing effect it had on his animals and had somehow managed to convince the vet that looked after his racehorses to let him have " a couple of extra vials" in case they lost some. 
He swore he was a new man since injecting himself with Cartrofen and was convinced there was some big pharma conspiracy as to why it wasn't available to humans!

id completely forgotten about it til now!

 

EDIT: This is in no way an endorsement of this drug, and absolutely not a suggestion to start injecting yourself with equine products. Furthermore anecdotes are in no way proof.  This was just a funny story I thought I'd share!

Read More
#FDA progress
stale
Last edited 3 years ago

26-Apr-2021:  PARADIGM PROVIDES IND APPLICATION UPDATE

Not sure why CAPITAL LETTERS were required in that announcement title.  Did not think it was worth shouting about.  Perhaps the company secretary just had an extra couple of Weetbix this morning...

INVESTIGATIONAL NEW DRUG (IND) APPLICATION UPDATE

Paradigm Biopharmaceuticals Ltd (ASX: PAR), a clinical stage biopharmaceutical company focussed on repurposing existing molecules for new indications with unmet clinical needs, reports today an update on its IND application to the US Food and Drug Administration (FDA) for the proposed pivotal clinical trial treating subjects with pain associated with Knee Osteoarthritis (OA).

Paradigm previously reported it submitted its over 30,000-page IND application to the US FDA, Friday 26th March 2021, and to date Paradigm has received few questions from the FDA during the current 30-day IND review period. Those few questions were answered by Paradigm within 48 hours of receipt.

On Friday April 23, Paradigm received a verbal indication from the FDA that the FDA would be putting further questions to Paradigm outside the 30-day IND review period. The FDA was unable to provide all questions within the initial IND review period and has advised it will submit them to Paradigm within the next 30 days. Many of the questions which, as we understand from the brief discussion with the FDA, are related to newly submitted non-clinical data (as part of the IND application).

Paradigm is ready to review and answer questions when they are received. Once in receipt of Paradigm’s responses, the FDA will review within 30 days.

Paradigm is committed to keeping investors up to date with our development program and will update the timeline once we receive clarity.

--- ends ---

 

Summary:

FDA:  Coupla questions, some now, some later...

PAR:  Bring it ON!!!

 

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 (PPS) for the treatment of pain associated with musculoskeletal disorders driven by injury, inflammation, aging, degenerative disease, infection or genetic predisposition.

 

[I hold PAR shares.  Warning:  While this is indeed a "late stage" drug development company that is seeking to repurpose a drug that has already got EU approval for use as an antithrombotic medication, the FDA approval remains a binary equation.  Either they will get it, or they won't.  If they do, there is clearly substantial upside.  If they don't there is clearly substantial downside, particularly in terms of their share price.  That is why my PAR position is a very small one.  Never bet more than you can afford to lose on such companies, because if things do not go the way they hope, they can easily go to zero.  The value is all in the potential, and the potential can be easily wiped out with one solid knockback by a regulatory authority as powerful as the FDA.]

View Attachment

Read More
Valuation of $3.77
stale
Added 3 years ago
April 2019: TP: $1.50: Re-purposing a drug - Pentosan Polysulfate Sodium (PPS), an FDA-approved drug that has a long track record of safely treating inflammation over sixty years. Initial focus is on repurposing PPS (under the name ZILOSUL®) to treat Osteoarthritis (OA) – market with over 31m sufferers in the US alone. If trials are successful, should go to well over $3. Otherwise, it could be close to $0. I've chosen the middle of that range - $1.50, but valuing biotechs at this stage is rather like throwing a dart at a dart board from a long way back. You'll usually miss the board (value: $0). However, I think this one has legs, because their starting point is a drug that already has FDA approval for another purpose. . . . . . . . . . October 2019: They blew through my $1.50 price target and promptly doubled from there. They closed today at $3.00. They may pull back a bit before their next leg up, but I think they'll probably get to $3.77 within the next 6 months, so that's my new PT. . . . . . . . . . April 2020: 6 months on, Strawman.com says my valuation for PAR is now stale. I'm still happy with it, but it could take a little while to get back up there - like another 12 to 18 months, but it'll be worth it. They've just raised A$35m at $1.30 and are trading at around $1.60. They were trading at over $4/share for about 3 weeks - from Jan 24 to Feb 17, then fell all the way down to as low as $1.17 on March 19, highlighting what can happen to speccy stocks in a market panic. I topped up my personal holding at $1.56 two weeks ago. Still highly speculative, but should double from here and then some regardless of that - if the current FDA trial goes well (which I think it will). 12-Oct-2020: Time to review this valuation. All good. PAR has hit my $3.77 price target, or exceeded it, on four separate occasions in the past 12 months, and I have every reason to expect they will do so again. Results of their trials in pain relief for knee OA (osteoarthritis) have been very promising - with serious pain reduction experienced by the majority of trial participants. I personally suffer from OA in my hip (the one that hasn't already been replaced) and knees, so I have a personal interest in following this company and their treatment. The big advantage of this company is that they are trialling a drug that has already been approved in many parts of the world as an antithrombotic agent (a drug that reduces the formation of blood clots), so they do NOT have to prove safety (that has already been proven) - they only have to prove efficacy (that it works on OA enough to justify approvals for sale for the treatment of OA), and they are well on their way to achieving that. There is a huge addressable market if they can get the drug approved for OA treatment - How much of that addressable market they can capture will depend on the timing of approvals as well as the effectiveness and cost of the treatment compared to alternative treatment options available at the time. 12-Apr-2021: Review Time: Still good. They've been below my valuation since July 2020, but they'll be back up soon enough. This is a partially de-risked biotech in that the drug they are trying to get permission to market for OA (osteoarthritis, a condition that so far has caused me to have both of my hips replaced) has already been approved for sale in Europe as a antithrombotic drug - helps to reduce the incidence of blood clots. So the safety is already proven - it's just the efficacy (for the treatment of OA) that needs to be established now. Preliminary results are very promising. I still hold PAR shares. They'll be back up soon enough. Am I repeating myself? Must be the 8-yr-old Greenore, it's been a long day...
Read More
#Quarterly Reports
stale
Added 4 years ago

31-July-2020:  Quarterly Activities Report

[I hold PAR shares]

Read More
#FDA progress
stale
Last edited 4 years ago

30-Apr-2020:  EAP treatment completed and Orphan Status achieved for MPS-I

Paradigm reports:  Under the US FDA Expanded Access Program (EAP) treatment is completed for all of the ten planned patients. Paradigm granted Orphan Status by US FDA for MPS-I 
 
KEY HIGHLIGHTS:  

  • Total Patient population (n=10) have completed dosing with Zilosul® (iPPS) in the US under the US IND Expanded Access Program (EAP).
  • The Expanded Access Program remains on-track with patients completing scheduled checkups out to 6 weeks post final injection (Day 83). 
  • Paradigm expects to report results for the entire patient population (n=10) to the market Q3 CY2020. 
  • Patient data reported will be in line with primary and secondary endpoints for the proposed Phase 3 trial.
  • FDA has granted Paradigm orphan designation request for treatment of MPS-I complications - including pain and arthropathy.

Paradigm Biopharmaceuticals Ltd (ASX: PAR) is pleased to announce it has completed treatment of all ten patients with Zilosul® under the FDA IND Expanded Access Program (EAP) in the US. The company has also been advised by the FDA that Paradigm’s orphan designation request for MPSI has been granted, joining the previously granted designation for MPS-VI.

The EAP which commenced on the 18th February with the treatment of the first patient, has now treated all of the ten planned patients. All patients taking part in the study must complete regular evaluations with the treating physician, with the final evaluation taking place 6 weeks post the last injection received (day 83). The EAP program will report on pain outcomes similar to those previously evaluated in the TGA SAS (refer ASX Announcement 6th April) as well as those proposed as endpoints for the Phase 3 Clinical trial. Paradigm expects data for the total population (n=10) of patients to be available to the market during Q3 CY 2020. 

Mr. Paul Rennie, Paradigm’s Chief Executive Officer said: “Paradigm is excited to have achieved this milestone, especially during the current health conditions created by COVID-19 and would like to thank all those involved in the Expanded Access Program for their continued diligence to the treatment program."

--- click on the link above for more, including:

  • What is The FDA Expanded Access Program?
  • Mucopolysaccharidosis type 1 (MPS-I) – Orphan Status
  • What is MPS? 

 

About Injectable PPS (iPPS):  Injectable PPS (iPPS) is not currently registered in Australia, but it is was previously registered in four of the seven major global pharmaceutical markets. In those European markets, iPPS is registered as an antithrombotic agent. In Australia, iPPS for human use is not currently available for sale. 
 
Zilosul® is a registered Trademark of Paradigm Biopharmaceuticals Ltd (ASX: PAR). 

 

[Disclosure:  I hold PAR shares.]

Read More
#ASX Announcements
stale
Last edited 4 years ago

14/02/2020: Half Yearly Report and Accounts

If I'm reading this right, PAR is making a loss but less of a loss than previous QTR.

Interested to see how the market responds on Monday.

Read More
Valuation of $2.00
stale
Added 5 years ago
This is a high risk VERY HIGH reward pick. Nearly impossible to value however with a number of products in various later trial stages this company should, at the very least be on your watch list. For anyone considering I suggest a small initial position and continue to add on positive news.
Read More