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Discovery & Development Drug Delivery, Small Molecules, Trends & Forecasts

Casing the Joint

Paul Rennie, Managing Director at Paradigm Biopharmaceuticals, Australia, was instrumental in leading the commercial development of Recaldent – a new adjunctive dental therapy originating from the Melbourne Dental School, into a commercial product. He co-developed pentosan polysulfate sodium (PPS), a non-opioid pain relief alternative, alongside Peter Ghosh based at Monash University. Through this collaboration, he reached out to Germany-based bene pharmaChem, the only manufacturer of PPS for human use, to negotiate a supply agreement for the use of injectable (subcutaneous) pentosan polysulfate sodium (iPPS) for a number of indications. Thus, Paradigm Biopharmaceuticals was born. 

Rennie knew the company had “something really exciting” in terms of pain relief alternatives, and decided to move beyond the dental industry, with an initial focus on osteoarthritis (OA). We asked Rennie to walk us through the unmet need and the future of OA.

How does OA affect sufferers?

Almost everyone knows someone who is affected by OA; recent estimates calculate that about half a billion people (400-500 million people) worldwide are affected by this disease. Knee and hip account for approximately 70 percent of all OA cases because of the load-bearing nature of these joints. 

OA is a progressive, debilitating disease in which the cartilage gradually wears away so that patients end up with bone-on-bone friction, which results in a lot of pain and inflammation. The gradual stiffening and immobilization of joints with increasing pain greatly affects the ability to work and live normally, with severe negative effects on mental health and quality of life. Current therapies only help manage the symptoms. There are no registered medicines that can slow, stop, or reverse it.

How effective is iPPS against OA symptoms?

In a double-blind randomized placebo-controlled phase IIb clinical trial of 126 participants with moderate to severe knee OA, we showed that a six-week course of twice-weekly iPPS demonstrated strong signals that pain was reduced compared with placebo. We also saw reductions in bone marrow lesions thought to be caused by joint overloading, causing bone microtrauma, and we observed biomarker signals indicating that iPPS could be altering disease progression. The FDA has now approved a phase III clinical trial to investigate effects on pain and function in over 900 patients worldwide.

In addition to the clinical trials, iPPS has been provided to prescribing doctors through expanded access programs, such as the Australian Therapeutic Goods Administration’s (TGA) Special Access Scheme and the FDA’s Expanded Access Program. In total, iPPS has been provided to over 600 sufferers with severe OA of a variety of joints (including knee, hip, hands, shoulder, back, cervical). The results so far are positive.

How significant is it that iPPS is a non-opioid drug?

We know that there’s a global need for effective non-addictive treatments to replace opioids for chronic pain conditions, and we know of the problems associated with long-term opioid use. With iPPS, we’ve seen how it can reduce pain and improve function in knee OA. We think iPPS is an excellent candidate as an effective alternative option or as a replacement for opioids. 

But it’s not just opioids that are a problem. In Australia, the TGA recently announced reductions in the availability of paracetamol because of high numbers of hospitalizations and deaths from overdose each year. The US FDA also has warnings about the potential for severe liver failure on the label of all products containing paracetamol (acetaminophen).

What are you doing to minimize the invasiveness of the injections?

The iPPS treatment course is administered via subcutaneous injections. These are completely different to injections of steroids (cortisone) into the knee joint itself (intra articular injections) that require radiographic guidance. The treatment is minimally invasive, similar to some vaccinations, but we are investigating the suitability of autoinjectors to improve patient comfort and convenience during the treatment phase. 

The potential disease modifying capabilities of iPPS sound exciting… 

Though our phase III trial is looking at improving pain and function outcomes in knee OA, we’ve also conducted a focused exploratory phase II trial to provide data on the disease modifying potential of iPPS. We recently released data showing that iPPS improved cartilage via magnetic resonance imaging compared with the placebo group and that there were reductions in key biomarkers associated with cartilage breakdown. We’re currently completing the manuscript for eventual publication but top-line results can be found in two announcements released in October 2022 and April 2023. Positive clinical signals were also seen out to six months.

We will continue to pursue the disease-modifying pathway with regulators to help define which endpoints will be needed to prove a disease-modifying label. If iPPS holds to its potential, this new therapy would be a world first in OA therapies, and a phenomenal life-changing medication for the millions of patients with OA worldwide.

How do you foresee discussions with regulators going?

In April last year, Paradigm was granted fast track designation from the FDA as they acknowledge OA as a serious disease with unmet need. This designation enables Paradigm to interact and collaborate with the FDA more frequently as we progress the clinical development program. It should also provide potential opportunities for shorter review timelines.

Early on, during the creation of our clinical program, we made the important decision to harmonize our conversations with global regulators. And that enabled us to develop our clinical trials globally, following  collaboration and approval from five key regulatory bodies in Australia, Canada, Europe (EMA), the UK (MHRA), and the US (FDA). They provided expert insight into primary endpoints and other clinical trial aspects, such as trial size. Our goal is to obtain simultaneous registration on the results of these late-stage clinical trials in multiple jurisdictions. We anticipate several more rounds of discussion with regulators as we progress through the regulatory process.

How else can governments and regulatory bodies help accelerate processes?

Currently, joint/parallel discussions with two or more regulatory agencies are limited to the development of drugs for specific indications (for example, oncology or rare diseases). Widening the opportunity for concurrent dialogue with multiple regulatory bodies could help harmonize the drug development process more efficiently to facilitate global concurrent registration. 

Governments could also widen reimbursement considerations for non-opioids. This would enable patients to have easier access to life-changing medications, as well as reducing reliance on opioids.

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About the Author
Paul Rennie

Paul Rennie, Managing Director has extensive sales, marketing, business development, operational and IP commercialisation experience in the biopharmaceutical sector. His experience includes working for Boehringer Mannheim (now Roche Diagnostics), Merck KGGA as national sales and marketing manager and Soltec (FH Faulding Ltd) as their director of business development. Paul also led the commercialisation of Recaldent, a novel biopharmaceutical arising from research at the Melbourne Dental School, University of Melbourne. Paul took this R&D project from the laboratory bench to a commercial product now marketed globally as an additive to oral care products. More recently he worked in a number of positions with Mesoblast Ltd. He was the inaugural COO and moved into Executive Vice President New Product Development for the adult stem cell company. Paul founded Paradigm Biopharmaceuticals in early 2014 and subsequently listed the Paradigm on the Australian Stock Exchange in 2015.

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