OP0061 Treatment of knee osteoarthritis with sm04690 improved womac a1 ‘pain on walking’ – results from a 52 week, randomised, double-blind, placebo-controlled, phase 2 study of a novel, intra-articular, wnt pathway inhibitor

Background Knee osteoarthritis (OA) is characterised by pain, disability and joint deformity due to articular cartilage degradation and bone remodelling. Wnt signalling is involved in these cellular processes. SM04690, a small molecule, intra-articular (IA), Wnt pathway inhibitor, is in development for treatment of knee OA as a potential disease modifying drug. Objectives A phase 2, multicenter, 52 week, randomised, double-blind, placebo-controlled (PBO) trial of SM04690 was conducted. Safety and efficacy outcomes including the Western Ontario and McMaster Universities Arthritis Index (WOMAC) question A1 were evaluated. Methods Subjects with ACR-defined knee OA, Kellgren-Lawrence (KL) grades 2–3, received a single 2 mL IA injection of SM04690 (0.03, 0.07 or 0.23 mg) or PBO in the target (most painful) knee. WOMAC was assessed at baseline and 4, 13, 26, 39 and 52 weeks post-injection. WOMAC question A1, (‘how much pain have you had when walking on a flat surface? ’), was analysed as an exploratory outcome. Analysis of covariance adjusted for WOMAC A1 baseline in the intent-to-treat (ITT) population was conducted. Two subgroups identified in the primary analysis1 were also explored: 1) subjects with unilateral symptomatic knee OA (pre-specified) and 2) subjects with unilateral symptomatic knee OA without widespread pain or comorbid symptoms (Widespread Pain Index≤4 and Symptom Severity≤2 [WP-], post-hoc). Abstract OP0061 – Figure 1 Change and ladder plots deploting average WOMAC A1 improvement in SM04690 over placebo adjusted for baseline WOMAC A1. *Minimal clinicaly improvement difference (MCID) difined as 10% of WOMAC A1. Results 455 subjects, mean age 60.3 [±8.7] years, BMI 29.9 [±4.6] kg/m2, female 58.9%, KL 3 [64.1%], with unilateral symptomatic OA [36.0%]) were enrolled (n=402 [88.4%] completers). No safety signals were observed. For WOMAC A1, in the ITT population, no statistically significant differences between treatment groups and PBO were seen, although the 0.07 mg dose demonstrated improvements compared to PBO at all timepoints (figure 1). In unilateral symptomatic subjects, 0.07 mg showed statistically significant improvements in WOMAC A1 compared to PBO at Weeks 39 (-1.2, 95% CI: [−2.3 to −0.0], p=0.043) and 52 (-1.1, 95% CI: −2.0 to −0.1, p=0.027). In unilateral symptomatic WP- subjects, the 0.07 mg dose showed statistically significant improvements in WOMAC A1 compared to PBO at Week 26 (-1.2, 95% CI: −2.1 to −0.2, p=0.015), through Weeks 39 (-1.8, 95% CI: −3.0 to −0.6, p=0.004) and 52 (-1.4, 95% CI: −2.5 to −0.4, p=0.010). Conclusions In this phase 2 study, improvements compared to PBO in WOMAC A1 were seen in clinically relevant unilateral symptomatic and unilateral symptomatic WP- subgroups. The improvements seen in this combined, multi-dimensional outcome of pain and function suggested SM04690 has a potential role in the treatment of signs and symptoms of knee OA. Reference [1] Yazici Y, et al. Arthritis Rheumatol2017;69(SupplS10):935. Disclosure of Interest S. Kennedy Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, H. Ghandehari Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, C. Swearingen Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, J. Tambiah Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, M. Hochberg Consultant for: Bioberica, EMD Serono, Novartis Pharma AG, Plexxikon, Pfizer, Proximagen, Regeneron, Samumed, LLC, Theralogix LLC