Paradigm Biopharmaceuticals Ltd. announced that the primary endpoint has been met and additionally significant improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function scores were demonstrated for injectable iPPS in the PARA_OA_008 phase 2 clinical trial. The day 56 data analysed by an independent clinical research organisation, demonstrates synovial fluid biomarker change from baseline for the iPPS treatment group. iPPS impacted multiple biomarkers measured in the synovial fluid.

Reductions in nerve growth factor (NGF) indicate iPPS mechanisms related to pain reduction. Reductions in TNF- and IL-6 indicate mechanistic effects on inflammatory pathways. Reductions in COMP and ARGS and an increase in TIMP-1 provide important insights into iPPS mechanisms of action impacting cartilage preservation and potential disease modification.

In all cases, the synovial biomarker changes in iPPS-treated subjects at day 56 were favourable compared to placebo controls. WOMAC data has also been collected from baseline. iPPS treatment showed statistically significant improvements at day 56 in pain, function, stiffness, and overall WOMAC scores for twice-weekly iPPS compared to the placebo arm.

The proportions achieving 30% and 50% improvement in pain were 73% and 60%, respectively. iPPS was well tolerated in this randomised, placebo-controlled study. There were no serious adverse events and no adverse events of special interest in any patient receiving iPPS or placebo.

The most common adverse reactions were injection site reactions, all of which were mild in intensity and self-limiting. Paradigm is also pleased to present preliminary data from nine dogs treated with iPPS in the ongoing canine model of naturally occurring OA. Initial data in this study demonstrates a trend towards functional improvement in osteoarthritic dogs following iPPS treatment as well as a trend towards reductions in cartilage degrading biomarkers locally within the joint (synovial fluid) and systemically (serum).

Current OA therapies, such as paracetamol, opioids, and nonsteroidal anti-inflammatory drugs (NSAIDs), as well as intra-articular medications, such as corticosteroids and hyaluronic acid, are solely focused on symptom management, as there are no established disease modifying therapies (3). Due to patient dissatisfaction with current OA treatments(4), there is a high unmet medical need for new therapies that can effectively reduce pain, improve joint function, and impede OA progression in tandem with symptomatic improvement. A DMOAD is defined as a drug that will "alter the natural history of disease progression by arresting joint structural change and ameliorate symptoms, either by reducing pain or improving physical function"(3).

The PARA_OA_008 phase 2 clinical trial is designed to evaluate the treatment effects of iPPS on synovial fluid biomarkers associated with OA-related pain, inflammation, and disease progression in humans. The study also evaluates the effect of iPPS on these biomarkers in serum and urine and investigates any correlation with synovial fluid biomarkers. In a prior phase 2b clinical trial, Paradigm observed serum and urine changes in biomarkers COMP, ADAMTS-5, and CTX-II, providing promising signals of iPPS mechanisms of action on joint preservation.

In the PARA_OA_008 clinical trial, subjects (n=61) were randomised and received either a subcutaneous injection of 2 mg/kg iPPS twice weekly, iPPS once weekly plus one placebo injection, or two placebo injections for 6 weeks. Patients had moderate to severe arthritis with Kellgren Lawrence (KL) grade 2-4 (where 4 is the maximum indicating severe OA), and baseline WOMAC pain scores of 4.6 to 10. This phase 2 clinical trial is an exploratory study and was not intended to be powered to obtain statistical significance.

The aim is to provide novel scientific evidence to test the hypothesis that iPPS acts locally in the knee joint of OA subjects as well as provide data on whether biomarker changes correlate with clinical outcome (WOMAC pain and function assessments). Further evaluation on serum and urine biomarker correlations, and further longer-term clinical outcomes are in progress. The Australian clinical trial operating at two sites in Victoria and NSW aims to gather data on the medium-term structure-modifying and symptom-modifying effects of iPPS on knee OA.

Participants have been randomised into three treatment groups according to a 1:1:1 ratio (19 randomised to iPPS twice-weekly, 20 randomised to iPPS once-weekly plus a placebo injection once-weekly, 22 randomised to placebo twice-weekly). Of the 61 patients, 48 (78%) had KL grades 3-4, and the average median baseline WOMAC scores were 6.6 for pain and 6.9 for function. iPPS has been shown to exert anti-inflammatory activity by blocking the effects of proinflammatory cytokines, such as TNF and IL-1, in a cellular model of canine OA(5); inhibiting the expression of NGF, a pain mediator, in differentiated human osteocytes derived from subchondral bone samples obtained during arthroplasty for knee OA(6); and by inhibiting cartilage degrading enzymes known to play a key role in OA disease progression(7).

In small clinical studies of 114 and 20 participants respectively, PPS has been shown to reduce pain and improve joint function in patients with knee OA(8,9).