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Purpose:Osteoarthritis (OA) is an inflammatory joint disease, causing chronic pain, disability, and reduced quality of life. Currently approved drug treatments for OA are only palliative. Injectable pentosan polysulfate sodium (iPPS, Zilosul™- Paradigm Biopharmaceuticals Ltd, Australia) is an investigational drug with disease modifying potential for OA treatment. PPS targets inflammation via inhibition of the transcription factor NF-?B, pain through the inhibition of NGF expression in osteocytes, and tissue preservation by inhibiting the cartilage-degrading enzymes. The purpose of this phase 2, randomized, double-blind, place-controlled study is to investigate changes in synovial fluid (SF) biomarkers in subjects with knee osteoarthritis pain treated with PPS compared with placebo-treated subjects.
Methods:Patients had a radiographic diagnosis of knee OA with Kellgren-Lawrence (K-L) Grade 2, 3, or 4 and OA pain unresponsive to conservative therapy for ?6 months to be eligible for the study. Subjects were randomly assigned to treatment with PPS or placebo. Subjects received iPPS 2.0 mg/kg ideal body weight (IBW) twice-weekly for 6 weeks, 2.0 mg/kg IBW PPS once-weekly + placebo once weekly, or placebo-twice weekly for 6 weeks. Following the 6-week treatment period subjects are being evaluated in a 46-week follow-up period. Subjects were evaluated for changes from baseline at Day 56 in one or more SF biomarkers (primary endpoint), including cartilage oligomeric matrix protein (COMP), neo-epitope of aggrecan ARGS fragment, tissue inhibitor matrix metalloproteinase 1 (TIMP-1), a disintegrin and metalloproteinase with thrombospondin motif 5 (ADAMTS-5), c-terminal telopeptide (CTX) -II, type II collagen (C2C), nerve growth factor (NGF), interleukin (IL) -1?, tumour necrosis factor alpha (TNF?), and IL-6. Subjects were evaluated at Day 56 for clinical outcomes including pain, function and stiffness using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC®) NRS 3.1 Index. Adverse events (AEs) were evaluated for safety.
Results:There were 20, 19 and 22 subjects randomized to iPPS once-weekly, twice-weekly, and placebo, respectively and 17, 15 and 21 subjects completed study treatment, respectively. Of the 61 subjects treated within the study 49 (80%) had K-L Grades 3-4 (moderate/severe) OA. At baseline, mean WOMAC overall scores for iPPS once-weekly, twice-weekly, and placebo were 7.08, 6.43, and 6.75 respectively. The SF biomarkers at Day 56 showed favorable changes from baseline in subjects treated with iPPS compared to placebo. Biomarkers of COMP, ARGS, NGF, IL-6 and TNF? were reduced, while TIMP-1 increased in subjects treated with iPPS compared to placebo. The percentage change from baseline to Day 56 were compared between treatment groups using a mixed model for repeated measures (MMRM) analysis. The MMRM model included factors for treatment group (PPS once-weekly, PPS twice-weekly, placebo), randomization stratification factor (K-L grades 2, 3, 4), age as a continuous variable, treatment-by-time interaction, baseline value of the biomarker, and baseline-by-time interaction. Analysis of SF biomarkers was quantitated using verified ELISA kits and where samples were lavaged correction factors were imputed. Significant improvement in WOMAC NRS 3.1 Index Pain Subscale scores were observed over time in subjects treated twice weekly. The mean percentage change from baseline WOMAC Index Pain score was 49.5% and 29.7%, in participants treated with PPS twice-weekly (mean baseline score was 6.37) and placebo (mean baseline score was 6.69), respectively (p=0.050). The mean percentage change from baseline WOMAC NRS 3.1 Index Function Subscale score was 50.0% and 24.9%, in participants treated with PPS twice-weekly (mean baseline score was 6.43) and placebo (mean baseline score was 6.71), respectively (p-0.017). The proportion of subjects with ?30% and ?50% improvements from baseline WOMAC® NRS 3.1 Index Pain Subscale scores were 73% and 60%, respectively. At Day 56, significant changes in pain and function were not apparent in the once-weekly iPPS group. Treatment with PPS was well tolerated with no serious AEs and no AEs of special interest in any subjects. The most common AE was injection site reactions which were mild to moderate in severity. Additional key biomarker and clinical endpoints under investigation in the study include correlations between SF biomarkers and clinical outcomes, changes in SF biomarkers from baseline to 6 months, changes in WOMAC pain, function and stiffness at 6 months, changes in PGIC at various timepoints, and changes in bone and joint structure assessed by magnetic resonance imaging. The study will continue to monitor all biomarker, clinical and safety data out to 12 months.
Conclusions:These findings demonstrate the favorable effects of iPPS on SF biomarkers which support the in vivo mechanisms of actions of iPPS. The observed reductions in NGF, TNF? and IL-6 suggest effects on pain and inflammatory pathways. Reductions in COMP and ARGS with an increase in TIMP-1 suggest a potential effect on cartilage preservation. Moreover, PPS significantly improved WOMAC pain and function clinical outcomes. The improved biomarker and clinical outcomes indicate that treatment with iPPS shows promise as a potential disease modifying treatment for patients with moderate to severe knee OA.
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