Paradigm Biopharmaceuticals Ltd (ASX:PAR) has received ethics approval for its phase 2 clinical trial to evaluate the treatment effects of Pentosan Polysulfate Sodium (PPS) against placebo on synovial fluid biomarkers in participants with knee osteoarthritis (OA) pain.
The randomised, double-blind, placebo-controlled phase 2 study will investigate PPS or placebo treatment in a total of 60 patients with primary endpoint data expected to read out in the third quarter of 2021.
PAR hopes to provide further evidence that certain biomarkers are more prevalent in the synovial fluid of symptomatic OA patients with radiographic evidence of joint damage, determine if biomarker concentrations change in the synovial fluid with PPS treatment, and to assess possible disease modifying effects of PPS on patients with knee OA pain.
“Important data for regulatory filing”
Paradigm chief executive officer Paul Rennie said: “Investigating the disease modifying effects of Zilosul® in subjects with osteoarthritis is important for our regulatory filing in Australia (TGA provisional approval) and our clinical and regulatory filings in the USA and Europe.
“The two unmet medical needs for osteoarthritis are (i) safe and effective pain relief and (ii) therapies that can slow or halt the disease progression.
“Biomarkers are an excellent way to assess the stage of the disease and the disease progression.
“We look forward to announcing the top-line results of this clinical trial in Q3 2021.”
Biomarker anaylsis
The biomarker analysis in synovial fluid samples will provide key scientific evidence as to whether PPS is acting locally in the knee joint of OA subjects and may further support the multiple actions of PPS in OA.
Biomarkers analysed will include inflammatory cytokines (TNF-α, IL-1β and IL-6); pain mediator NGF and cartilage degrading enzymes ADAMTS4 and 5 in association with other molecular biomarkers potentially associated with disease modification.
The data will be part of the submission package to the TGA for provisional approval.
Primary endpoint
Primary endpoints will assess a change from baseline at day 56 (two weeks post final injection) in one or more synovial fluid biomarkers.
The biomarkers that will include but are not limited to:
- Cartilage Oligomeric Matrix Protein (COMP);
- C-Terminal Telopeptide (CTX) -II;
- Nerve Growth Factor (NGF);
- Interleukin (IL) -1 β;
- 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 fragment (C2C).
Secondary and exploratory endpoints
Secondary endpoints will include:
- Correlation between synovial fluid biomarker changes and clinical outcomes - The change from baseline of synovial fluid biomarkers will be assessed to investigate whether the down regulation of certain biomarkers post PPS treatments is related to patient reported outcomes compared to placebo;
- Changes from baseline at 6 months in one or more synovial fluid biomarker - Changes of one or more synovial fluid biomarkers from baseline out to Day 168 will be measured to provide Paradigm important data on the durability of effect of PPS against placebo;
- Changes from baseline at designated timepoints of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)® Pain, Function, Stiffness and Quality of life (PGIC) - Participants in the study will be asked to provide baseline pain scores at predetermined timepoints out to day 168; and
- The exploratory endpoints will assess radiographic changes in the bone and joint of participants from baseline to day 168 - This data will provide Paradigm with important information on the disease modifying potential of PPS over six months.
Trial design
The purpose of Paradigm’s Phase 2 study is to measure the change in synovial fluid biomarkers associated with inflammation and osteoarthritis disease progression following treatment with subcutaneous injections of pentosan polysulfate sodium compared with subcutaneous injections of placebo in participants with knee OA.
Patient recruitment and screening will begin imminently, with first patient dosing expected in the second quarter of 2021.
Sixty participants with Kellgren-Lawrence grade 2, 3 or 4 and have OA pain will be enrolled and randomised 1:1 to receive either PPS (n=30) or placebo (n=30) and will receive twice weekly subcutaneous injections for six weeks.
Paradigm believes biomarker data collected from this study will strengthen the application package to be submitted to the TGA for provisional approval.
Looking forward, the company is on track to submit its Investigational New Drug (IND) application to the FDA during the quarter.