Paradigm Biopharmaceuticals Ltd (ASX:PAR) plans to take a partnering or licensing track to commercialise the repurposing of pentosan polysulfate sodium (PPS) for a painful arthritic bone condition after a clinically-meaningful successful Phase 2b clinical study.
The company last month released top-line data from its clinical trial in patients with OA-related knee pain and subchondral bone marrow edema lesions (BMELs), revealing the trial met its primary endpoint with a change in the knee injury and OA outcome score (KOOS).
Paradigm then highlighted that the trial had produced a clinically meaningful and statistically significant result of a pain reduction of 50% or more in patients, using their KOOS scores as a measure.
A notable 46.2% of subjects receiving the injectable PPS (iPPS) showed a greater than 50% reduction in pain from baseline compared to 22.5% of subjects receiving placebo, under the KOOS pain sub-scale.
The company highlighted respected opinion on what is considered clinical meaningfulness and statistical significance for pain as an end-point, quoting a Pain Outcomes report from 2010, cross-published to the US NIH NCBI repository, that stated “a 30% reduction of pain can be considered clinically significant.
“This level corresponds with a ‘much improved’ or ‘very much improved’ response from patients on a global impression of change, or 2 points on a 0 to 11 pain intensity numerical rating scale.”
Paradigm opted for a 50% reduction in pain for its endpoint in its study of patents with knee OA and BMELs.
Paradigm chief executive officer Paul Rennie said on December 20, 2018: “I would like to confirm the Paradigm Phase 2b clinical trial met its primary endpoint.
“In addition to that, Paradigm wanted to present top-line results and that Paradigm achieved a clinically meaningful and a statistically significant result between iPPS and placebo in the total population and highly clinically meaningful and highly statistically significant results in the NRS 4-6 strata.”
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Paradigm’s CEO flagged clinically meaningful and statistically significant results during phase 2 studies in humans bode well for the success of the final studies needed to take a drug to regulators for approval to use for a particular indication.
Rennie said: “If you have both a clinically meaningful and statistically significant result you have a high probability that the drug will be successful in a phase 3 clinical trial and once registered, a drug that can penetrate the market.”
Results of the study’s secondary endpoint data are still being evaluated, as is custom, however, two of the datasets have been analysed, the company reported on December 20, 2018.
These show that in comparison with placebo, statistical differences were achieved in NRS pain score (day 39 and 53), patient global impression of change (PGIC, p=0.0062), and proportions of patients with 25% and 50% reductions in time points other than day 53.
To help explain the importance of the data and of having a product that is both clinically meaningful and statistically significant, the company put together a video explanation presented by its principal investigator Professor Andrew Östör, orthopaedic surgeon Dr David Martin, sports physician Dr Phil Bloom and retired AFL footballer Andrew Walker.
Paradigm’s strategic approach
Paradigm’s strategic approach includes repurposing existing drugs with historically strong safety data and using the drugs for new purposes, like treating OA in humans.
The semi-synthetic polysulfated xylan PPS has a long history, being used as a blood thinner and interstitial cystitis or painful bladder syndrome treatment in humans.
The calcium salt of PPS was also one of the first reported disease-modifying OA drugs (DMOADs).
It is used to treat OA in dogs and horses.
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PPS was reported as a chondroprotective drug in 1988, with a detailed rationale of the molecule’s disease-modifying activity published the next year.
The mechanism of PPS in OA is put down to its multifactorial nature of stimulating cartilage matrix synthesis and preventing cartilage breakdown.
Paradigm’s drug repurposing of PPS uses the 505(b)(2) pathway.
A second strategy for Paradigm is to “develop therapeutics targeting multiple pathways”.
Paradigm hopes that by repurposing drugs it can reduce development costs.
It also hopes that by targeting multiple pathways involved in injury or on the road to disease, it can produce better outcomes for patients.
Paradigm’s forecasted timeline development compared to industry standards
1. Khanaoure A, Chuki P & De Sousa A (2014); 2. Ashurn T & Thor K (2004)
PPS safety compared to approved OA drugs
Paradigm drew investors’ attention to the safety profile of PPS, compared to OA drugs on the market for use in humans.
The company reported on December 20, 2018: “Paradigm, would like the reiterate the real and significant commercial potential of iPPS as a safe, effective, durable, repeat (year-on-year) treatment for OA.
“Especially in the context of the nearest comparator treatments currently going through clinical development, the anti-NGF class of small molecules.”
The company compared the six-week dosing schedule of its iPPS to the monoclonal antibody against nerve growth factor as a treatment for pain, Tanezumab (INN, RN624).
Paradigm wrote: “Both iPPS and the anti-NGFs are administered via several sub-cutaneous injections — for example, Tanezumab is intended to be administered at 8-week intervals (seven doses total) for up to about 1 year and iPPS is administered twice-weekly for 6 weeks with SAS data indicating potential durability up to about 12 months.
“We do note 6-month duration of effect data via the phase 2b trial is yet to be collected and therefore cannot be reported on as yet, but the company is very encouraged by the duration of effect witnessed in the TGA SAS patients.”
The company said on December 18, 2018, it was confident the Therapeutic Goods Administration (TGA) special access scheme results, averaging 51.5% of greater pain reduction for knee pain in 125 patients, would be replicable in the US.
Paradigm has executed a 20-year exclusive supply agreement with bene PharmaChem GmbH & Co, the original developer and only FDA-approved manufacturer of PPS.
The agreement grants exclusive supply of only FDA-approved PPS for all orthopaedic including alphavirus respiratory and cardiovascular indications.
Under the agreement Paradigm will pay PharmaChem a single-digit royalty on commercial sales.
Paradigm has also patented its specific indications to a minimum of 2,030 indications, with established regulatory exclusivity and trademarks.
Patent applications have been made for OA and concurrent BMEL, Ross River virus and Chikungunya virus.
iPPS is not currently registered in Australia but is registered in four of the seven major global pharmaceutical markets.
In European markets, iPPS is registered as an antithrombotic agent.
iPPS for human use is not available for sale in Australia and is only available by inclusion into a Paradigm-sponsored clinical trial or via a treating physician applying for its use in patients via the Therapeutic Goods Administration’s SAS category B.
Licensing and partnering potential
Paradigm believes in the attractiveness of iPPS for potential partners or licensees.
It reported: “In the true context of partnering/licensing attractiveness, the safety profile of iPPS versus the anti-NGFs cannot be underestimated.
“The anti-NGFs have all been put on clinical hold by the FDA at various stages due to serious adverse events (AEs) such as rapid joint disintegration or rapidly progressive OA.”
The company highlighted the size of the deals that big pharmaceutical companies had made with companies pursuing OA-drug commercialisation.
Paradigm wrote: “Despite these serious safety issues numerous big pharma transactions have occurred over recent years with one of the largest being Elly Lilly partnering with Pfizer on Tanezumab for US$200 million upfront and up to US$1.6 billion in milestones — that is (a) US$1.8 billion total potential transaction size.
“Paradigm, therefore feels very confident in the partnering/licensing potential of iPPS and ... remains committed to progressing this pathway as part of the commercialisation of its OA program.”
Paradigm has a market capitalisation of $147.85 million.
At the time the company announced its trial results in December 2018 it had $10.5 million cash and no debt.
Paradigm’s quarterly results for the December 2018 half-year are pending, however, the company used $2.2 million on its operating activities in the October 2018 quarter, $21,000 on investments and $1 million on financing activities.
It subsequently ended the quarter with $1.3 million cash and no debt.
Paradigm estimated on October 31, 2018, it would have $2.2 million in cash outflows during the December 2018 quarter.
The company then received a $2.32 million research and development tax incentive refund from the Australian Government in November 2018.
Paradigm's largest investor on December 13, 2018, was its managing director Rennie.
Technology vendor MJGD Nominees had a 4.9% stake while technology vendor Irwin Biotech held 4.5%, JP Morgan Nominees Aust Pty Ltd had 3% and Citicorp Nominees Pty Ltd held 2.3%.
Other board members and management besides Rennie had a collective 5.1% stake.
— with Berkay Erkan