Paradigm Biopharmaceuticals (ASX:PAR) has reached an important scientific milestone with the peer-reviewed publication of results from its Phase 2 biomarker study investigating injectable pentosan polysulfate sodium (iPPS) in patients with moderate to severe knee osteoarthritis.
The manuscript, now published online in Arthritis Research and Therapy, provides independent validation of iPPS's biological activity in the osteoarthritic joint and reinforces the scientific rationale for the company’s ongoing Phase 3 clinical program.
The study, known as PARA_OA_008, was designed as an exploratory, randomised, double-blind, placebo-controlled Phase 2 trial. Its primary purpose was not to demonstrate clinical efficacy for regulatory approval, but rather to examine whether iPPS produces measurable biological effects on disease-relevant pathways in osteoarthritis. The trial employed an unusually detailed biomarker strategy, including repeated ultrasound-guided synovial fluid sampling, along with blood and urine analyses.
Publication in Arthritis Research and Therapy, a leading international journal in rheumatology and joint disease, reflects the rigour of the study’s design, execution, and statistical analysis. Manuscripts accepted by the journal undergo stringent peer review focused on translational relevance, making acceptance a meaningful external endorsement of the work.
One of the most significant aspects of the study is that many of the observed biomarker changes were detected directly in synovial fluid, which is the biological environment within the knee joint itself. Because synovial fluid sits at the centre of osteoarthritis pathology, changes measured there provide strong evidence that a therapy is acting locally at the site of disease.
Patients treated with iPPS showed significant reductions in biomarkers associated with cartilage degradation. Levels of synovial fluid ARGS, a marker of aggrecan breakdown in cartilage, were significantly reduced compared with placebo by Day 56 and remained lower through Day 168. Similarly, serum C2C, a marker of type II collagen degradation, was reduced at later time points, indicating a broader effect on cartilage metabolism.
Changes were also observed in markers linked to bone and cartilage turnover. Serum CTX-I, which reflects bone remodelling dynamics, increased in the iPPS group, suggesting altered tissue remodelling processes consistent with biological engagement rather than simple symptomatic relief.
Inflammation-related biomarkers within the joint also shifted in a favourable direction. Key inflammatory mediators, such as TNF-α and IL-6, were reduced, while TIMP-1, an endogenous inhibitor of cartilage-degrading enzymes, increased. Together, these changes point toward a joint environment less dominated by inflammatory and degradative processes.
Importantly for patients, reductions were also observed in nerve growth factor (NGF), a biomarker closely linked to pain sensitisation in osteoarthritis. This provides a biological explanation for the clinically observed pain improvements and connects molecular findings with patient-reported outcomes.
Several of these biomarker effects persisted months after dosing ended, suggesting that iPPS may induce durable biological changes rather than transient pharmacological effects. Across the study, iPPS was generally well tolerated, with no serious treatment-related adverse events reported.
Although the trial was not powered to demonstrate definitive clinical superiority over placebo, patients were followed for up to 12 months. Over this period, those treated with iPPS generally maintained improvements from baseline in pain, physical function, and stiffness. Early improvements observed in the twice-weekly dosing group aligned with the biological activity demonstrated through synovial and systemic biomarkers, providing a supportive clinical context for the mechanistic findings.
The durability of these outcomes over extended follow-up adds further weight to the biological signals observed during the active treatment phase, even though formal statistical separation was not the primary objective of the study.
Commenting on the publication, Paradigm’s Chief Medical Officer and first author of the manuscript, Dr Donna Skerrett, highlighted the significance of the achievement. She noted that conducting a trial involving repeated synovial fluid sampling and complex biomarker analysis required extensive collaboration among investigators, laboratories, and the company’s clinical team. According to Dr Skerrett, the peer-reviewed findings provide valuable insight into how iPPS may act within the osteoarthritic joint and further validate the company’s development strategy.