Paradigm’s iPPS biomarker study earns peer-reviewed validation in leading rheumatology journal
Paradigm Biopharmaceuticals (ASX: PAR) has secured independent scientific validation of its Phase 2 iPPS biomarker study through publication in Arthritis Research & Therapy, a leading international rheumatology journal with an impact factor of approximately 4.6. The peer-reviewed publication reports findings from the company’s PARAOA008 Phase 2 trial, demonstrating favourable changes in synovial fluid biomarkers associated with cartilage degradation, inflammation, and pain in patients with moderate to severe knee osteoarthritis treated with injectable pentosan polysulfate sodium (iPPS).
Publication in Arthritis Research & Therapy represents independent validation of the scientific rigour, study design, biomarker methodology, and statistical analysis underpinning the Phase 2 trial. Manuscripts accepted by the journal undergo stringent peer review focused on clinical relevance and translational significance in rheumatology. The publication strengthens the scientific foundation for Paradigm’s ongoing pivotal PARAOA012 Phase 3 clinical trial of iPPS in knee osteoarthritis.
Dr Donna Skerrett, First Author and Chief Medical Officer of Paradigm Biopharmaceuticals, commented: “Acceptance and publication of this manuscript by Arthritis Research & Therapy is an important validation of the quality and depth of the PARAOA008 study. Conducting a trial of this complexity, involving repeated synovial fluid sampling and detailed biomarker analysis, required a significant collaborative effort by investigators, laboratories, and Paradigm’s clinical team. The peer-reviewed findings provide valuable insight into the biological activity of iPPS within the osteoarthritic joint and further strengthen the scientific foundation underpinning our ongoing Phase 3 program.”
What the biomarker data revealed
Treatment with iPPS was associated with biologically meaningful changes across multiple biomarker categories relevant to osteoarthritis. Importantly, several of these effects were observed directly in synovial fluid, reflecting biological activity at the site of disease. Some biomarker changes persisted months after completion of dosing, suggesting durable biological effects beyond the active treatment period.
Cartilage degradation and bone turnover markers
The study demonstrated significant effects on biomarkers associated with cartilage degradation and bone turnover. Synovial fluid ARGS (aggrecanase-derived aggrecan neoepitope), a direct marker of cartilage matrix breakdown, was significantly reduced in iPPS-treated patients versus placebo at Day 56 (p=0.028) and remained significantly reduced at Day 168 (p=0.024). Serum C2C (Type II Collagen Cleavage Neoepitope), a marker of type II collagen degradation, showed a statistically significant reduction at Day 168 versus placebo (p=0.024).
| Biomarker | Sample Type | Timepoint | Statistical Significance |
|---|---|---|---|
| ARGS | Synovial Fluid | Day 56 | p=0.028 |
| ARGS | Synovial Fluid | Day 168 | p=0.024 |
| C2C | Serum | Day 168 | p=0.024 |
| CTX-I | Serum | Day 56 | p=0.022 |
| CTX-I | Serum | Day 168 | p=0.025 |
Serum CTX-I (C-terminal Telopeptide of Type I Collagen), which is released into the bloodstream when bone is being broken down and remodelled, demonstrated a statistically significant increase at Day 56 (p=0.022) and Day 168 (p=0.025), consistent with altered bone and cartilage remodelling dynamics.
Inflammation and pain biomarkers
Favourable changes were observed in key synovial fluid inflammatory mediators, including TNF-α (tumour necrosis factor alpha) and IL-6 (interleukin-6). These proteins drive inflammatory processes within the osteoarthritic joint. Increases in TIMP-1 (tissue inhibitor of metalloproteinases-1), an endogenous inhibitor of cartilage-degrading enzymes, were observed, consistent with a shift toward reduced tissue breakdown.
Reductions were also observed in NGF (nerve growth factor), a biomarker involved in pain sensitisation and nociceptive signalling within the osteoarthritic joint. This finding suggests iPPS may influence pain pathways at a molecular level.
Evidence of activity on inflammation, cartilage metabolism, and pain pathways addresses key disease processes, demonstrating iPPS is targeting underlying biology.
Understanding biomarkers in osteoarthritis drug development
Biomarkers are objective, measurable indicators of biological processes occurring inside the joint, beyond what a patient feels or reports as pain. They fall into two broad categories that provide complementary information about disease activity and treatment effects.
Molecular biomarkers are measured in biological samples:
- Joint (synovial) fluid directly from the knee
- Blood (serum) samples
- Urine samples
- These indicate inflammation, cartilage breakdown or repair, and biological processes linked to pain signalling
Imaging biomarkers are assessed using medical imaging:
- MRI (Magnetic Resonance Imaging)
- X-ray
- These show structural changes in cartilage and bone, joint space narrowing, bone marrow lesions, and other physical features
Synovial fluid is particularly valuable because it sits directly inside the joint. Changes measured there provide strong evidence of local activity at the site of osteoarthritis disease, even when the treatment is administered subcutaneously rather than directly into the joint. Together, molecular and imaging biomarkers help researchers and clinicians understand how a treatment affects the underlying disease process, not just whether pain scores improve.
Clinical outcomes and safety profile
Clinical outcomes including pain, physical function, stiffness, and patient global impression of change assessments were followed for up to 12 months (Day 365). While the study was exploratory and not powered to demonstrate long-term statistical separation versus placebo, patients treated with iPPS generally maintained improvements from baseline over the 12-month follow-up period.
Early improvements in pain and function observed in the twice-weekly iPPS dosing group were consistent with the biological activity demonstrated through synovial fluid and systemic biomarker changes. The durability of clinical outcomes over extended follow-up provides supportive clinical context for the mechanistic findings reported in the study.
iPPS was generally well tolerated, with no serious treatment-related adverse events reported.
Strengthening the Phase 3 foundation
While PARAOA008 was not designed to support drug registration, the biomarker findings provide important mechanistic support for Paradigm’s ongoing pivotal PARAOA012 Phase 3 clinical trial in knee osteoarthritis. The data strengthen the biological rationale for iPPS by demonstrating effects on pathways associated with inflammation, cartilage metabolism, and pain processes, which are increasingly recognised by clinicians and researchers as central to osteoarthritis disease progression.
The publication further enhances Paradigm’s scientific credibility and supports ongoing engagement with regulatory authorities, investigators, and potential strategic partners. Peer-reviewed mechanistic evidence arriving mid-Phase 3 is strategically valuable as it bolsters the scientific narrative for regulatory submissions and partnership negotiations.
In addition to the published biomarker manuscript, Paradigm notes that the MRI outcomes from the PARAOA008 study demonstrated clinically meaningful findings. A separate manuscript focusing on these imaging-based results is in preparation and once complete, will be submitted to a relevant scientific journal for peer review.
Near-term catalysts for investors:
- Phase 3 trial progress: Ongoing PARAOA012 pivotal trial in knee osteoarthritis
- MRI manuscript submission: Separate publication on imaging outcomes from PARAOA008 in preparation
- Regulatory engagement: Enhanced scientific credibility supports ongoing discussions with regulatory authorities
- Partnership opportunities: Peer-reviewed mechanistic data strengthens positioning for strategic partnership negotiations
The publication in Arthritis Research & Therapy represents independent validation of Paradigm’s Phase 2 biomarker work, demonstrating rigorous study design, robust execution of complex synovial fluid sampling protocols, and coordinated multi-site clinical operations. This credibility milestone arrives at a strategically valuable point in the company’s development timeline, providing mechanistic support as the pivotal Phase 3 program progresses.
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