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.]

03-Feb-2021:  Consistent pain reduction and improvement in function data

Patients under the TGA SAS program with OA knee pain continue to experience consistent pain reduction and improvement in function.

KEY HIGHLIGHTS

• Pain reduction in 89 SAS patients (13 new patient data) being treated using the Phase 3 product (Zilosul®) are consistent with prior reports under TGA SAS.
• The chronic pain response as measured by the WOMAC pain score demonstrated a mean reduction of 49.6%.
• After 89 SAS treated patients, the pain reducing effects of Zilosul®, in subjects with knee OA as measured using the WOMAC pain score, shows a very consistent reduction in pain of nearly 50%.
• The cumulative patient data collected includes new data on 13 patients and previously reported data on 76 patients.
• The upcoming Phase 3 clinical trial (PARA-002) primary endpoint will assess change in WOMAC pain and WOMAC function from baseline.
• Paradigm previously reported data on the first 76 patients of this cohort, with the mean reduction being 47.3% (Refer announcement 1st October 2020).
• The WOMAC pain score which is a composite of 5 pain subgroups demonstrated pain reductions across patients in; night-time pain (64.6%); sitting (57.6%), standing (52%), walking on flat surface (48%) and pain on stairs (41.5%).
• WOMAC reduction from baseline scores were observed at day 84 or week 12 after the first Zilosul® injection.
• PPS remains well tolerated across SAS and Paradigm’s other development programs.
• SAS program is expected to commence in Q3 CY2021 under pay-for-use program, once the first pivotal study has completed recruitment in Australia.

Paradigm Biopharmaceuticals Ltd (ASX: PAR) is pleased to report this ongoing data update on patients who received Zilosul® under the Therapeutic Goods Administration (TGA) Special Access Scheme (SAS). Paradigm released its first set of data using the WOMAC pain scoring index on April 6th (refer ASX announcement) after receiving feedback from the US FDA (Food and Drug Administration) during its pre-IND meeting that reduced WOMAC pain from baseline would be an acceptable endpoint for the company’s upcoming Phase 3 trials. Paradigm reported data on the first 34 patients of this cohort, with the mean reduction in WOMAC pain being 44.9%. Data from a further 42 patients was released on 1st of October (refer ASX announcement), updating the mean reduction in WOMAC pain across 76 patients to 47.3%.

Paradigm has received additional data on 13 patients bringing the cumulative average WOMAC reduction in pain from baseline for the 89-patient cohort to 49.6% (Table 2). In the 89 patients treated with Zilosul®, 75.3% reported at least a 25% reduction in WOMAC pain with 56.2% of patients reporting a greater than 50% reduction in WOMAC Pain.

Patients under the SAS program treated across multiple sites have either failed standard of care and /or alternative therapies. Baseline WOMAC pain scores are recorded prior to commencing the 6-week treatment program where each patient receives 2mg/kg of Zilosul® twice weekly.

SAS data has provided consistent evidence of clinically meaningful improvements in chronic pain. Clinically meaningful reduction of chronic pain has been defined to be between 25-30% pain reduction.

--- click on the link at the top for the rest of this announcement ---

[I hold PAR shares.  I have just had my second hip replacement - 2 weeks ago - and now only have OA in my knees, with my left knee currently giving me the majority of my pain.  This trial by PAR is therefore of particular interest to me.  Even more so because their drug (Zilosul® - injectable PPS - Pentosan Polysulfate Sodium) has already been proven safe for use, as it is already widely used in European countries as an antithrombotic - which reduces the formation of blood clots (thrombi).  PAR therefore only need to prove that it is also effective at treating OA (Osteoarthritis) and then get it approved for treatment of OA, which is much easier than getting a drug approved from scratch.  This is why they describe themselves as a "late-stage drug development company" - all of the early stages have already been completed.  The results of this trial continue to be very promising.]

21-Dec-2020:  R&D Investor Presentation

[I hold PAR shares.]

14-Dec-2020:  Paradigm Provides Phase 3 Clinical Trial Update

[I hold PAR shares.]

30-Oct-2020:  Quarterly Update and Appendix 4C - Quarterly Report

QUARTERLY ACTIVITIES REPORT

KEY HIGHLIGHTS (INCLUDING SIGNIFICANT EVENTS POST END OF QUARTER)

• Clear Path to Registration in Europe: Feedback from an EMA scientific advice meeting has provided Paradigm with a clear path forward to registration for Zilosul® in Europe. The regulatory engagement conducted with the EMA covered key elements of the Phase 3 clinical trial protocol and associated pre-clinical and manufacturing processes for Zilosul® that will support the submission of a Marketing Authorisation Application (MAA) in Europe after completion of the Phase 3 clinicals.
• Extension of Exclusive Agreement with Bene pharmaChem: Paradigm now has an exclusive supply term of 25 years from the date of marketing approval, expansion of territories to include all major Pharmaceutical markets and additional indications. As Paradigm moves towards commercialization, the exclusive supply of PPS for 25 years following marketing approval provides an elevated level of commercial protection with the only FDA approved manufacturer of PPS.
• Successful FDA Expanded Access Program: 65% mean reduction in WOMAC pain from baseline across total patient population (n=10) using WOMAC Pain Subscale in the FDA Expanded Access Program in the USA.
• Consistent Real-World Evidence: Paradigm received additional data on 42 patients bringing the cumulative average WOMAC reduction in pain from baseline for the 76-patient cohort to 47.3%. In the 76 patients treated, 73.7% reported at least a 25% reduction in WOMAC pain with 52.6% of patients reporting a greater than 50% reduction in WOMAC Pain. In addition, 76% (58 out of 76) of SAS patients had reported Patient global impression of Change (PGIC) of moderately to definite and considerable improvement in their OA condition with iPPS (Zilosul®) treatment.
• New staff appointments: Further strengthening of the Paradigm team with significant additions to the senior management team in Beverley Huttmann (Commercial Head), Justin Cahill (Chief Financial Officer) and Catherine Stapledon (R&D Translational Scientist). Both Beverley and Justin bring big pharma expertise to Paradigm assisting with commercailisation of Zilosul® post registration approval.
• New Board Appointment: Dr Donna Skerrett joined the Paradigm board as Executive Director. Dr Skerrett is Paradigm’s current Chief Medical Officer based in New York and brings to the board significant medical and strategic experience from her more than 30 years in the medical practice and Pharmaceutical Industry.

Paradigm Biopharmaceuticals Ltd (ASX:PAR) is pleased to provide its quarterly update for the three months ended 30th September 2020 to accompany its Appendix 4C cash flow report for the period.

• Cash balance as at 30th September 2020 was $98.8m (at 31 March 2020: $104m) with a net operating cash outflow during the quarter of $6.32m.
• Research & development expenditure for the quarter was $5.5m compared to the previous quarter of $4.2m. Details of the research and development activities are summarised in the continuing activities under Outlook below.

OUTLOOK

• Paradigm has submitted the briefing pack to the US FDA on the 23rd October for a Type C meeting. The company expects a written response from the FDA to questions in relation to the clinical trial design and associated supporting clinical data later this quarter. Once agreed and finalised with the US FDA, Paradigm will inform the market of the Phase 3 clinical trial design.
• Paradigm’s goal has been to gather and consolidate feedback from the FDA, EMA and TGA to have a pivotal protocol acceptable to all major jurisdictions and streamline the approval process globally. Paradigm’s IND submission requires the feedback from the FDA’s written response from the Type C meeting. Due to the current COVID-19 pandemic causing slight delays in the US, the feedback from the FDA is indicated to be received toward the end of Q4 CY2020. The Company believes it is very important that a clear path to registration is established, with the US FDA’s input, prior to opening the IND and commencement of the Phase 3 clinical trials. Under this scenario this avoids the situation of completing the Phase 3 clinical trial only to find it is not a registration enabling design and is insufficient for filing.
• The Company continues to prepare information that was requested by the TGA for the next stage of submission for the Provisional Approval determination. The company will further update the market on the progress of this process once it has received feedback from the FDA from the Type C meeting.
• MPS-I open label Phase 2 clinical trial has been initiated with patient enrollment having commenced after receiving 1st patient consent. The open-label trial will evaluate the safety and tolerability of injectable pentosan polysulfate sodium in subjects with Mucopolysaccharidosis type I (MPS-I). Paradigm will provide further detail to the market once 1st patient is dosed.
• The MPS-VI program continues to progress with Paradigm expecting to provide an update on the protocol development for the proposed clinical program during the current quarter.
• Paradigm previously reported the commencement of a research program investigating safety and efficacy of iPPS in a viral induced respiratory disease model. Work is progressing to plan with top-line results of this pilot study to be announced in Q2CY2021.
• The Phase 2b osteoarthritis clinical trial and the Phase 2A Viral Arthritis clinical trial manuscripts are currently undergoing peer review. Paradigm will communicate a timeline for release once this process has been complete.

About Paradigm Biopharmaceuticals

Paradigm Biopharmaceuticals LTD (ASX: PAR) is a late stage drug development company with the mission to develop and commercialise pentosan polysulphate sodium for the treatment of pain associated with musculoskeletal disorders driven by injury, inflammation, aging, degenerative disease, infection or genetic predisposition.

Disclaimer and 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 Paul Rennie, Managing Director & CEO.

Zilosul® is a registered Trademark of Paradigm Biopharmaceuticals Ltd (ASX: PAR).

--- click on the link at the top for the remainder of the report, including the Appendix 4C ---

[I own PAR shares.]

13-Oct-2020:  PARADIGM ADDS MORE TALENTED SENIOR EXECUTIVES TO ITS TEAM

Paradigm Biopharmaceuticals Ltd (ASX: PAR) is pleased to announce three recent senior executive appointments. Beverley Huttmann, Justin Cahill and Catherine Stapledon have all joined the Paradigm team, bringing with them skills and experience that further strengthen the capabilities of Paradigm’s management, as the company continues to move toward commercialisation.

Commercial Head, Beverley Huttmann, is a highly experienced pharmaceutical commercial leader, with more than 25 years’ experience with global pharmaceutical companies including CSL and GSK (GlaxoSmithKline).  Her past responsibilities have encompassed all facets of pharmaceutical commercial management including market and product analysis, strategic planning and budgeting, licensing, pricing and reimbursement, government liaison, in-market promotion, demand forecasting and team leadership.  She has held senior commercial roles in many therapeutic areas including pain, rheumatology, respiratory disease, allergy, immunology, and dermatology.

Beverley will be responsible for developing and implementing commercial strategy including partnerships, licensing, pricing and reimbursement, product differentiation, patient and physician acceptance and life cycle management.

Chief Financial Officer, Justin Cahill, has over 20 years’ experience in strategic finance roles across a broad spectrum of industries and global organisations. In one of his more prominent roles, Justin spent 9 years at CSL, including 5 years in the US as Divisional CFO of CSL Plasma. Justin is a CPA and holds a master’s in accounting.

As Paradigm’s operations expand and become more global, Justin will oversee the financial management of and control over Paradigm’s increasingly complex activities.

R&D Translational Scientist, Catherine Stapledon, PhD, will be working alongside Chief Science Officer, Ravi Krishnan. Catherine had undertaken her PhD studies at the Centre for Orthopaedic & Trauma Research, Faculty of Health and Medical Sciences, University of Adelaide. Catherine’s research involved a multidisciplinary approach to investigate the roles of neurotrophic factors on osteocyte function in osteoarthritis. Of significance were Catherine’s studies which elucidated the mode of action of PPS related to the regulation of Nerve Growth Factor as a mediator of pain in bone osteocytes derived from osteoarthritis patients.

Catherine has extensive experience in the development and design of a number of studies ranging from basic cell culture to animal and human studies. Her expertise will be a valuable asset to Paradigm’s R&D programs, involving GLP and GLP-like preclinical proof-of concept studies, and in translational disease models.

Paradigm CEO, Paul Rennie, commented: “We are extremely excited to welcome three highly talented and experienced individuals in Beverley, Justin and Catherine to the team. Like Paradigm’s recently appointed COO, Dr Jeannie Joughin, Justin also worked for CSL in the USA and was part of CSL’s executive leadership and development program. Each brings with them specific expertise and deep knowledge that will greatly assist and enhance the efforts of the current Paradigm staff in their drive to achieving our mission: to develop and commercialise PPS for the treatment of arthralgia driven by injury, inflammation, aging, degenerative disease, infection or genetic predisposition.”

--- ends ---

[I hold PAR shares.]

01-Oct-2020:  ZILOSUL REDUCES PAIN IN PATIENTS WITH KNEE OA

ZILOSUL® REDUCES PAIN IN PATIENTS WITH KNEE OSTEOARTHRITIS (OA)

KEY HIGHLIGHTS

• Pain reduction in 76 SAS patients (42 new patient data) being treated using the Phase 3 product (Zilosul®) are consistent with prior reports under TGA SAS. The chronic pain response as measured by the WOMAC pain score demonstrated a mean reduction of 47.3%.
• The cumulative patient data collected includes new data on 42 patients and previously reported data on 34 patients.
• Phase 3 clinical trial primary endpoint will assess change in WOMAC pain and WOMAC function from baseline.
• Paradigm previously reported data on the first 34 patients of this cohort, with the mean reduction being 44.9% (Refer ASX Announcement 6th April 2020)
• The WOMAC pain score which is a composite of 5 pain subgroups demonstrated pain reductions across patientsin; night-time pain (63.7%); sitting (56.1%), standing (49.8%), walking on flat surface (45.6%) and pain on stairs (39.1%).
• PPS remains well tolerated across SAS and Paradigm’s other development programs
• WOMAC reduction from baseline scores were observed at day 84 or week 12.
• Paradigm expects to report on further patients receiving Zilosul® treatment under the SAS program in Q4, 2020

Paradigm Biopharmaceuticals Ltd (ASX: PAR) is pleased to report additional data on patients who received Zilosul® under the Therapeutic Goods Administration (TGA) Special Access Scheme (SAS). Paradigm has received additional data on 42 patients bringing the cumulative average WOMAC reduction in pain from baseline for the 76-patient cohort to 47.3%. In the 76 patients treated, 73.7% reported at least a 25% reduction in WOMAC pain with 52.6% of patients reporting a greater than 50% reduction in WOMAC Pain.

Paradigm released its first set of data using the WOMAC pain scoring index on April 6th (refer ASX announcement) after receiving feedback from the FDA during its pre-IND meeting that reduced WOMAC pain from baseline would be an acceptable endpoint for the company’s upcoming Phase 3 trials. Paradigm reported data on the first 34 patients of this cohort, with the mean reduction being 44.9%.

Patients under the SAS program treated across multiple sites have failed alternative therapies. Baseline WOMAC pain scores are recorded prior to commencing the 6-week treatment program where each patient receives 2mg/kg of Zilosul® twice weekly.

SAS data has provided consistent evidence of clinically meaningful improvements in chronic pain. “Clinically meaningful reduction of chronic pain has been defined to be between 25-30% pain reduction”.

--- click on link above for more ---

[I hold PAR shares and I also have severe OA which has so far resulted in one total hip replacement and multiple knee operations.  I will need my other hip replaced soon also.]

29-Sep-2020:  EXTENSION OF EXCLUSIVE AGREEMENT WITH BENE PHARMACHEM

PARADIGM EXTENDS TERM, INDICATIONS AND TERRITORIES UNDER EXCLUSIVE SUPPLY AGREEMENT WITH BENE PHARMACHEM

Paradigm Biopharmaceuticals Ltd (ASX: PAR) is pleased to announce that its exclusive license and supply agreement with bene pharmaChem of 11 November 2014 has been amended with positive and material commercial outcomes for Paradigm. This is an important development for Paradigm as bene pharmaChem remains the only FDA approved manufacturer/supplier of Pentosan Polysulphate Sodium (PPS). This major upgrade in arrangements for the long-term supply of bene PPS is very important to Paradigm’s commercial plans and represents a further significant de-risking for Paradigm’s investors.

--- click on the link above for the full announcement ---

[I hold PAR shares.]

17-Sep-2020:  Paradigm Presentation to Emerging Leaders Conference

[I hold PAR shares.]

11-August-2020:  MPS RECEIVES CRITICAL APPROVALS AND FEEDBACK FROM AGENCIES

PARADIGM RECEIVES CRITICAL APPROVALS AND FEEDBACK FROM AGENCIES TO PROGRESS MPS CLINICAL AND COMMERCIAL DEVELOPMENT

KEY HIGHLIGHTS

• MPS-VI receives Orphan Status from the European Medical Agency.
• Paradigm now has approved Orphan Designations for MPS-I and MPS-VI in the US and the EU.
• Paradigm receives positive feedback from its Parallel Scientific Advice meeting with the FDA and the EMA. Both Agencies agreed on the ultra-rare nature of MPS VI and provided clarification on both the clinical trial design and regulatory path forward.
• MPS-I Phase 2 clinical trial approved by the Human Research Ethics Committee.
• Paradigm’s proposed clinical trial for MPS-I to be conducted at Adelaide’s Women’s & Children’s hospital with Dr David Ketteridge as the Principal Investigator.
• Paradigm’s investigation of PPS for MPS seeks to establish whether PPS may be an effective adjunct/combination therapy with current Enzyme Replacement Therapy treatments.

--- click on the link for the full 5-page report ---

[I hold PAR shares.  This announcement details a number of critical developments required to progress investigation into the use of PAR's core drug Pentosan Polysulfate Sodium (PPS) in the treatment of the rare disease mucopolysaccharidosis (MPS).]

31-July-2020:  Quarterly Activities Report

[I hold PAR shares]

30-7-2020:  EAP - 65% PAIN REDUCTION IN 10 OA PATIENTS IN USA

Also:  29-7-2020:  Appendix 4C - quarterly

Highlights from today's announcement:

• 65% mean reduction in WOMAC pain from baseline across total patient population (n=10) using WOMAC Pain Subscale.
• WOMAC pain results were reported at week 12 (day 81-83).
• All patients in the program reported meaningful improvements in WOMAC Pain, Function and NRS pain (77.79% reduction).
• The WOMAC pain score which is a composite of 5 pain subgroups demonstrated pain reductions across patients in; pain walking on flat surface (61.6%), pain on stairs (57.6%), night pain (69.7%), pain sitting (61.6%) and pain standing (68.3%).
• Patients in the EAP treated with Paradigm’s Phase 3 product was well tolerated with no serious Adverse Events (AE’s) reported.
• Expanded Access Program Results Presentation released.
• Paradigm has also released a Results Video which include testimonialsfrom patients who participated in this program.

Paradigm Biopharmaceuticals Ltd (ASX: PAR) is pleased to announce a mean pain reduction of 65% at week 12 (Day 81-83), across the ten patients treated with Zilosul® under the FDA approved Expanded Access Program (EAP) in the US.

65% Reduction (from baseline) in WOMAC Pain

“Oral NSAID treatment and potent oral opioids (such as oxycodone) reduced pain with similar effect ie of around a 30% reduction in the patients’ pain. In short, each of these medications helped reduce pain, with similar reported effects. The finding on average of 30% reduction in pain is very consistent with studies of many treatments for chronic pain”.

A review of many clinical studies (meta-analysis) using the WOMAC pain scale conclude “NSAIDs and opioids offer similar pain relief in OA patients of roughly 30% reduction from baseline”.

Paradigm’s Zilosul® in the FDA EAP demonstrated a 65% reduction in pain (from baseline) 12 weeks following initiation of treatment. We believe these FDA EAP results, if replicated in a confirmatory Phase 3 clinical study, would provide a compelling product alternative to the use of current treatments of moderate to severe OA pain (NSAIDs and Opioids) as Zilosul® has demonstrated a significant improvement in pain reducing effects over current therapies (65% vs 30%), plus both NSAID and Opioids have undesirable side-effects.

So, what does a 65% reduction in pain (from baseline) 12 weeks from the initiation of the treatment mean for further development and commercialization?  Paradigm believes the combined pain reducing effects and tolerance of Zilosul® would allow it to become front-line OA (OsteoArthritis) therapy for patients with moderate to severe OA pain that have not responded to initial oral pain therapy.

Paradigm submitted an Expanded Access Investigational new drug application (IND) for pentosan polysulfate sodium (PPS) for the treatment of approximately 10 patients with pain associated with knee osteoarthritis (KOA) with concurrent bone marrow lesions where patients have failed to respond to current standard of care. The US FDA provided clearance for this program to proceed in September 2019.

The US FDA Expanded Access Program

Each Patient enrolled in the program was screened to measure their baseline pain scores under the WOMAC osteoarthritis index and evaluated with MRI scans to determine the presence of Bone Marrow Edema Lesions (BMEL) within the Knee joint.

The EAP commenced on the 18th February with the treatment of the first patient and the last patient completing treatment on the 30th April (refer ASX Announcement).  All patients taking part in the study completed regular evaluations with the treating physician (Dr East).  Follow up scan and pain measurements were then recorded at 6 weeks post treatment completion (day 81/83).

--- click on link above for the full announcement ---

[I hold PAR shares.  There's plenty of hype, but that is mostly due to the fact that the drug has already been approved for use throughout Europe (in 4 of the 7 major global pharmaceutical markets) as an antithrombotic agent.  Paradigm is simply attempting to succesfully repurpose this drug for the treatment of OA (OsteoArthritis) and associated pain relief.  And their results to date have been nothing but encouraging.  There is always less risk with a drug that already has widespread approval for another use.  That doesn't mean PAR are NOT without risk.  They are risky.  Because they are a speculative biotech.  However, they have less risk than companies who are still trying to prove the safety of their drug in addition to its efficacy.  We already know that iPPS is safe.  They just need to establish how effective it is in treating OA.]

Zilosul® is a registered Trademark of Paradigm Biopharmaceuticals Ltd (ASX: PAR).

12-May-2020:  BLOCK TRADE TO INSTITUTIONAL INVESTORS

This announcement starts off with details of a block trade by current PAR directors to offshore institutional investors, mostly to fund loan repayments that those directors are due to pay to the company by the end of this month.  In addition to the Employee Share Loan sell down, Founder and Managing Director Paul Rennie has sold an additional 4,039,460 shares as part of the block trade.   The purpose of the sale is to fund a residential property, ESP loan, tax liabilities and balance his investment portfolio. In regard to the sale, PAR provided the following additional context:

• This is the first share sale by Mr Rennie since he founded the company in 2014.
• Mr Rennie largely funded the entire Company with his personal cash prior to IPO.  
• Since IPO Mr Rennie has put a combined $400,000 of equity capital into the Company.
• In addition, Mr Rennie has made multiple on-market purchases of shares since IPO.
• This total sale represents only 17.48% of Mr Rennie’s holding. Mr Rennie still owns 19,509,222 shares and owns 8.68% of the company and is the single largest shareholder in the company.  
• Mr Rennie has voluntarily agreed to escrow the balance of his holding until 31 December 2022. 

Mr Graeme Kaufman, Paradigm Chairman: “We appreciate the support of these offshore institutions for helping facilitate this transaction as our share register continues to globalize. We are pleased that after 6 years and founding the Company with the idea to treat to OA with PPS, Paul has been able to realise a small portion of liquidity to secure the financial future of his family. He has created tremendous shareholder wealth for a large number of our shareholders and we look forward to that continuing as we move towards some very large catalysts for the company over the next 2-3 years“. 

Paradigm’s proposed news flow for the remainder of CY 2020:

• Potential to be included into the ASX 300 index during the rebalance scheduled to occur 19th June.
• Initial feedback from the Joint Parallel Scientific Advice submission to both the FDA and EMA during Q2. The submission put forward by Paradigm staff detailed the proposed trial design for a pivotal/registrational trial for MPS.
• Expanded Access Program results to be released for entire patient population (n=10) treated under the EAP will be released to the market in Q3.
• New data on 100 patients under the TGA SAS using the primary and secondary endpoints for Paradigm’s proposed phase 3 trials, (i) reduced WOMAC pain from baseline and (ii) improved Patient Global Impression of Change (PGIC) at week 8 (Day 53). The company expects the data to be released to the market in Q3.
• Commencement of Paradigm’s MPS I Phase 2 clinical trial in Adelaide, Q3.
• Multi-Centered Phase 2/3 US and EU clinical trial for MPS VI on track to begin late CY2020.  
• Phase 2b Osteoarthritis clinical trial and Phase 2A Viral Arthritis clinical trial Peer Reviewed Articles to be released to the market Q4.  
• FDA Investigational New Drug (IND) submission for Osteoarthritis expected in Q4.  
• TGA Provisional Approval submission likely Q4.  
• New Patent Filings Q4.  
• Partnership and Commercial discussion remain ongoing. 

Addressable Market:  Osteoarthritis (OA) is the most common joint disorder in the United States. Symptomatic knee OA occurs in 10% men and 13% in women aged 60 years or older. The number of people affected with symptomatic OA is likely to increase due to the aging of the population and the obesity epidemic.  ABOUT 54.4 MILLION ADULTS IN THE U.S. HAVE DOCTOR-DIAGNOSED ARTHRITIS.  (Barbour – MMWR [66] 2017).  There are over 100 million OA sufferers in the USA, Europe and Japan. 

About injectable PPS (Zilosul®):  Injectable PPS is not currently registered in Australia, but it is registered in four of the seven major global pharmaceutical markets.  In those European markets, injectable PPS is registered as an antithrombotic agent. In Australia, injectable PPS for human use is not currently available for sale.  Injectable PPS for human use is only available by inclusion into a Paradigm Sponsored clinical trial or via a treating physician applying for its use in patients via the TGA’s SAS - Category B.

Zilosul® is a registered Trademark of Paradigm Biopharmaceuticals Ltd (ASX: PAR). 

[Disclosure:  I hold PAR shares.  I am not concerned with the director sell-down.  I think it is well-explained and the fact that PR has agreed to voluntarily escrow his remaining shares - which represent 8.68% of the company - even after the sell-down - until the end of December 2022 is a real positive.]

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.]

28-Apr-2020:  Quarterly Update and Appendix 4C - quarterly

Thought I'd done a bull case straw for PAR.  Seems I haven't.  Anyway, see my PAR valuation commentary for my bull case.

Morgans have released three reports/updates on PAR recently, one in Feb, one in March, and one in April (10 days ago).  Here they are:

17-Feb-2020:  Morgans: PAR: Update 1 (Reduce, TP: $2.16)

17-Mar-2020:  Morgans: PAR: Update 2 (Hold, TP: $2.16)

07-Apr-2020:  Morgans: PAR: Update 3 (Hold, TP: $1.74)

PAR closed at $1.675 today, suggesting there is limited upside according to Morgans.  Disclosure:  I hold PAR shares.  I have given my reasons in my bull case straw.

06-Apr-2020:  PAR were in a trading halt, and have today turned that into a voluntary trading suspension, pending the finalisation of a capital raising, and associated announcements.  In the meantime, they've given us this to be going on with:

06-Apr-2020:  Paradigm Latest Corporate Presentation, plus Paradigm receives clarity on US regulatory pathway and Paradigm Reports Very Encouraging Real World Data

That's how it's done!

24-Mar-2020:  All 10 participants in US FDA EAP have commenced treatment

That's the "price sensitive" announcement today - another positive one, and they also released this:

Paradigm to present at Virtual Conference, Friday 27th March

Virtual conferences.  Webinars.  Conference Calls.  Where would be without technology eh?!

10-Sep-2019:  PAR Expanded Access IND Cleared by US FDA

Also:

30-Aug-2019:  Appendix 4E and 2019 Annual Report

29-Aug-2019:  PARs drug reduces cartilage degradation in subjects with OA

21-Feb-2020:  Paradigm reports Positive Pre-IND meeting with US FDA

KEY HIGHLIGHTS

• Paradigm reports it had a positive and informative Pre-IND meeting to discuss the development and market authorisation plans for injectable Pentosan Polysulfate Sodium (iPPS) (Zilosul) for the treatment of symptomatic osteoarthritis.
• Paradigm will provide further information to the market by receipt of final minutes from the US FDA.
• Development plans are proceeding toward an IND filing by Q4 CY2020.
• The company is fully funded for the proposed Phase 3 Clinical Trial. 

21 February 2020: ASX listed biotechnology company Paradigm Pharmaceuticals Limited (ASX: PAR, “Paradigm” or the “Company”) is pleased to announce a positive and informative pre-IND meeting with the US FDA. The meeting took place at the FDA offices in Washington and was attended by several of the Paradigm team and consultants.

In the Pre-IND meeting Paradigm discussed its clinical, pre-clinical and CMC (Manufacturing) data with the US FDA.

Paradigm will provide further information from the Pre-IND meeting to the market by receipt of final minutes from the US FDA.

Mr. Paul Rennie, Paradigm’s Chief Executive Officer said: “The team and I are pleased with the positive feedback from the FDA at the Pre-IND meeting that took place yesterday. Paradigm looks forward to providing a more detailed update to the market once the final minutes of the meeting have been received.”

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).

18-Feb-2020:  Paradigm - first patient dosed in USA under FDA approved EAP

Paradigm reports: first patient dosed in USA under  FDA approved Expanded Access Program  
 
KEY HIGHLIGHTS

• First Participant dosed with Zilosul® (iPPS) in the US under the FDA approved Expanded Access Program (EAP).
• The Participants in the program will receive two Zilosul® injections per week over a 6-week period in line with the proposed protocol for the forthcoming Phase 3 Pivotal Study to be discussed with FDA in upcoming Pre-IND meeting on 19th February.
• Paradigm will treat 10 patients (comprised of Ex-NFL Players) under the EAP.  In males under the age of 60, osteoarthritis is over 3 times more prevalent in retired NFL players than in the general U.S. population.
• The remaining nine patients to be treated under the EAP will be staggered to commence over the next 4 weeks, with Paradigm expecting last patient final dosing to occur mid – May. Paradigm expects to report results to the market early CY Q3.

Summary:  Paradigm Biopharmaceuticals Ltd (ASX: PAR) is pleased to announce the first patient has been dosed under the US FDA approved EAP.  This milestone marks the first patient treated with Zilosul® in the United States.  Patients under the EAP will receive treatment in line with the proposed treatment protocol for Paradigms proposed Phase 3 Pivotal study.  Each patient will receive two Zilosul® injections subcutaneously per week for a period of 6 weeks.  Paradigm will stagger the commencement of the remaining patient’s treatment over the next 4 weeks, with the final patient likely to receive their last injection towards the middle of May.  Paradigm Expects to report data on patient outcomes around the beginning of Q3.

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Disclosure:  I hold PAR shares.  On the one hand they can be classed as an early-stage biotech company (which I usually avoid these days), but on the other hand, they are actually repurposing a drug that already has approval for use in seven major global pharmaceutical markets.  Injectable PPS (iPPS) is not currently registered in Australia, but in those European markets, iPPS is registered as an antithrombotic agent.  The fact that it is proven safe for use in humans, and has already been approved for use - and used by people - throughout Europe - without adverse side-effects - is a significant factor in derisking this company in terms of an investment proposition.  However, their ultimate success still depends on positive trial results, so there is still risk there of course, as there is with all such companies - just less risk with this particular one - in my opinion.  That said, I jumped on board at much lower levels.  I don't think I'd be buying PAR up here.
 
Zilosul® is a registered Trademark of Paradigm Biopharmaceuticals Ltd (ASX: PAR). 

13-Feb-2020:  Paradigm presents MPS VI poster at WORLD Symposium

Disclosure:  I hold PAR shares, bought at $1.10 (average price paid) - accumulated in December 2018 and January 2019.  I've trimmed the holding on the way up, but still hold some.  They are trading at $4.40 today - 300% above my average buy price, so one of my better speccy "investments".

Plenty of promise, but certainly not without risk.

07 August 2019:  PARADIGM FILES FIRST IND WITH US FDA

KEY HIGHLIGHTS

• Paradigm has filed its first IND submission to the US FDA for an Expanded Access Program under which ten people from the USA may be treated with Zilosul (iPPS).
• The ten Americans are anticipated to include some retired NFL players who have early-onset Osteoarthritis and have also failed standard of care.
• In males under the age of 60, osteoarthritis is over 3 times more prevalent in retired NFL players than in the general U.S. population. This excess of early-onset arthritis may be due to the high incidence of injury in football.
• Paradigm’s Clinical and Regulatory Teams continue to work on submissions to the US FDA for the Phase 2/3 Clinical Trial in the very rare lysosomal storage disease (MPS), the Phase 3 Clinical Trial in Osteoarthritis and the Australian Therapeutic Goods Administration (TGA) for the Provisional Approval of Zilosul (iPPS) to treat Osteoarthritis.
• Commercial discussions are ongoing regarding potential partnership deals or commercial transactions.

Moving towards commercialisation

Paradigm Biopharmaceuticals Ltd (ASX: PAR) continues its drive towards commercialisation of Zilosul (iPPS) as a potential first line therapeutic treatment of osteoarthritis and other diseases affecting the musculoskeletal system.  
 
Paradigm will be filing a number of submissions to Global Regulatory Authorities and therefore provides this update on the planned filings being submitted in the next two quarters of CY 2019.  
 
Summary of Expected future market updates prior to end of CY 2019:

• File Expanded Access Program (EAP) for 10 patients with US FDA Q3 CY 2019;
• File initial submission with the TGA for Provisional Approval Application of Zilosul (iPPS) for treatment of osteoarthritis, Q3 CY 2019;
• Pre-IND meeting with US FDA Orphan Indication (MPS) Phase 2/3 clinical Trial Q4 CY 2019;
• Pre-IND Meeting with US FDA Osteoarthritis Phase 3 Clinical Trial Q4 CY 2019;
• Commercial Discussions – ongoing;
• Discussions with US DoD for Ross River/CHIK-V treatment – ongoing.

Paradigm Expanded Access Program  

Paradigm has filed a submission to the US FDA for Expanded Access Program IND (Investigational New Drug) under which ten people from the USA may be treated with Zilosul iPPS and it is anticipated to include some retired NFL players who have early-onset Osteoarthritis who have also failed standard of care. 
 
What is The FDA Expanded Access Program?

“Expanded access”, also called “compassionate use,” provides a pathway for patients to gain access to investigational drugs, biologics, and medical devices used to diagnose, monitor, or treat patients with serious diseases or conditions for which there are no comparable or satisfactory therapy options available outside of clinical trials”.
 
FDA recognizes that osteoarthritis (OA) can be a serious disease with an unmet medical need for therapies that modify the underlying pathophysiology of the disease and potentially change its natural course to prevent long-term disability.  
 
The unmet clinical need

Osteoarthritis (OA) is a disabling disease leading to chronic pain, disability and a decreased quality of life. It is the most common joint disorder in the developed world, with the lifetime risk of developing symptomatic knee osteoarthritis before age 85 years estimated in one US study at 44.7% ([95% CI] 40.0–49.3%). Injury, particularly to the joints, has been identified as a potential risk factor for OA. Annually, sports contribute to 7 million injuries in Americans, and reports have suggested that the development of OA may be more prevalent and occur prematurely in individuals who regularly participate in sports. It is estimated, 31 million people in the USA suffer from OA. The therapeutic market for the treatment of OA is a multibillion-dollar opportunity.
 
Although loss of joint cartilage is a hallmark of OA, it is increasingly recognized that bone marrow edema lesions (BMLs) in the subchondral bone are involved with the pathogenesis of cartilage degeneration in OA. BMLs (as detected on MRI) result from increased blood and interstitial fluid collection in areas of trabecular microfractures and collapse within the bone marrow. The prevalence and severity of BMLs are associated with symptoms of pain, greater cartilage loss and risk of joint replacement. In regard to progressive OA, data have suggested that BMLs are more likely to persist and enlarge in size with an associated increase in cartilage loss.  (Continues)...

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Disclosure:  I hold a small parcel of PAR shares.  High risk, but potentially huge upside if they can prove that this drug (that has already been approved for antithrombotic use in 4 of the 7 major global pharmaceutical markets) can also be used to effectively treat Osteoarthritis (OA) and BML conditions.
 

Zilosul is a registered Trademark of Paradigm Biopharmaceuticals Ltd.

Zilosul is the registered Trademark of the final product i.e. injectable Pentosan Polysulfate Sodium (iPPS).