Background/Purpose: Osteoarthritis (OA) is an inflammatory joint disease, causing chronic pain, disability, and reduced quality of life. Affected joints may include the knee, hip, and hands. This study evaluated clinical and disease modifying biomarker and structural changes in subjects with knee OA pain treated with injectable pentosan polysulfate sodium (iPPS) or placebo.

Methods: In this phase 2, double-blind study, subjects were randomized to iPPS 2.0 mg/kg ideal body weight (IBW) twice weekly, 2.0 mg/kg IBW PPS once weekly + placebo once weekly, or placebo twice weekly for 6 weeks, followed by a 46-week follow-up. Subjects were evaluated at baseline, days 56 and 168 for clinical outcomes using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and synovial fluid (SF), serum and urine samples were obtained for biomarker assays. Magnetic resonance imaging (MRI) was performed at Day 168 to assess joint structure changes.

Safety was evaluated by assessing adverse events (AEs).

All comparisons were exploratory at 5% significance. The percentage change from baseline to Day 56 and Day 168 were compared between treatment groups using a mixed model for repeated measures (MMRM) analysis. Biomarkers were quantitated using verified ELISA kits. Whole-Organ MRI Scoring (WORMS) was used to assess changes in the joint structures.

Results: 61 subjects were randomized (17, 15 and 21 to twice weekly iPPS, once weekly iPPS and placebo respectively. Median age was 60 years; 57% were male; median BMI was 28.8 and KL 3-4 was 78% overall. Baseline clinical values were similar among groups. At Day 56, significant improvements in WOMAC pain (p=0.05), function (p=0.017) and overall (p=0.022) scores were observed in subjects treated with iPPS twice weekly vs placebo and all improvements continued through Day 168. Once weekly iPPS showed improvement but differences from placebo did not reach statistical significance. At Day 56 favorable changes were observed in 6 SF biomarkers (IL-6, TNF-α, βNGF, COMP, ARGS [p=0.036], TIMP-1) in iPPS-treated subjects vs placebo. At Day 168, SF biomarkers ARGS and COMP, serum biomarker ARGS (p=0.024), COMP and C2C (p=0.024), and urine biomarker CTX II demonstrated favorable changes in iPPS-treated subjects vs placebo.

MRI results showed improvements in structural disease features, most apparent in the once-weekly iPPS treated subjects: a 21% improvement in cartilage loss score in the medial femur vs 4% worsening in placebo (p=0.065), and a 17% decrease of bone marrow edema lesions in the lateral tibiofemoral compartment with an increase of 56% in the placebo (p=0.028).

Related AEs occurred in 55.0%, 73.7% and 36.4% of subjects in the iPPS once weekly, iPPS twice weekly, and placebo-treated subjects, respectively. There were no serious AEs or AEs of special interest. The majority of AEs were mild to moderate in severity. The most common related AEs were headache and injection site reactions.

Conclusion: These findings show promising effects of iPPS for pain relief and improved function while changes in biomarkers and MRI assessments show potential DMOAD effects of iPPS in patients with knee OA. Paradigm is conducting larger global studies to confirm the observed clinical and DMOAD effects of iPPS.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/therapeutic-effects-of-pentosan-polysulfate-sodium-on-clinical-and-disease-modifying-outcomes-in-subjects-with-knee-osteoarthritis/