SAT0586 Results from a 52 week randomised, double-blind, placebo-controlled, phase 2 study of a novel, wnt pathway inhibitor (SM04690) for knee osteoarthritis treatment
Authors: Y. Yazici, T. McAlindon, A. Gibofsky, N. Lane, D. Clauw, C. Swearingen, A. DiFrancesco, J. Tambiah, M. Hochberg
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> 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 Wnt pathway inhibitor, is in development as a potential disease modifying OA drug (DMOAD) for knee OA. <h3>Objectives</h3> A phase 2, multicenter, 52 week, placebo-controlled (PBO) trial was conducted to identify a target population, determine optimal dose and assess safety. <h3>Methods</h3> Knee OA subjects, Kellgren-Lawrence (KL) grades 2–3, received a single 2 mL injection of SM04690 0.03 mg, 0.07 mg, 0.23 mg or PBO in target (most painful) knee. WOMAC Pain and Function were assessed (Weeks 0, 4, 13, 26, 39, 52) and fixed flexion radiographs (QuAP positioned; Weeks 0, 26, 52) assessed medial joint space width (mJSW). Analysis of covariance adjusted for baseline was conducted using multiple imputation for missing data. Exploratory subgroups included: 1) unilateral symptomatic subjects (pre-specified; determined by history and examination) and 2) unilateral symptomatic subjects without comorbid pain (post-hoc; Widespread Pain Index≤4, Symptom Severity≤2 [WP-]). <h3>Results</h3> 455 subjects (mean age 60.3 [±8.7] years, BMI 29.9 [±4.6] kg/m<sup>2</sup>, female 58.9%, KL grade 3 [64.4%], unilateral symptomatic OA [36.0%]) were enrolled, 91% with radiographic bilateral OA. Seventeen serious adverse events, all unrelated to SM04690, were reported. The primary endpoint of Week 13 change from baseline in WOMAC Pain was not met. In ITT, at all timepoints, minimal clinically important differences (&gt;10% full range) in WOMAC Pain and Function compared to baseline were seen in all groups. In 0.07 mg unilateral symptomatic subjects, at 52 weeks, WOMAC Pain (4.4, p=0.049), and Function (17.5, p=0.035) were significantly improved compared to PBO. In 0.07 mg unilateral symptomatic WP- subjects at Weeks 26, 39, and 52, WOMAC Pain (4.6, p=0.039; 5.9, p=0.042; and 5.6, p=0.025, respectively) and Function (16.3, p=0.027; 19.7, p=0.035; and 22.8, p=0.017, respectively) were significantly improved compared to PBO (Abstract SAT0586 – figure 1). At 26 and 52 weeks, 0.07 mg unilateral symptomatic (0.5 mm, p=0.006 and 0.4 mm, p=0.021, respectively) and 0.07 mg unilateral symptomatic WP- (0.5 mm, p=0.016 and 0.4 mm, p=0.032, respectively) subgroups demonstrated significant increases from baseline in mJSW compared to PBO (figure 1). <h3>Conclusions</h3> A target subgroup of unilateral symptomatic knee OA subjects and potential optimal dose (0.07 mg) of SM04690 were identified. Clinical and radiographic outcomes suggested that SM04690 has potential as a DMOAD, especially in subjects with unilateral symptomatic WP- knee OA. Further studies are ongoing. <h3>Disclosure of Interest</h3> Y. Yazici Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, T. McAlindon Grant/research support from: Samumed, LLC, Consultant for: Samumed, LLC, Astellas, Flexion, Pfizer, Regeneron, Seikugaku, A. Gibofsky Shareholder of: AbbVie, Amgen, Johnson and Johnson, GSK, Regeneron, Consultant for: AbbVie, Pfizer, Horizon, Iroko, Celgene, Novartis/Sandoz, Samumed, LLC, Speakers bureau: AbbVie, Celgene, Pfizer, N. Lane Consultant for: Samumed, LLC, D. Clauw Consultant for: AbbVie, Astellas, Cerephex, Eli Lilly, Forest Laboratories, Johnson and Johnson, Merck, Pfizer, Purdue, Samumed, LLC, Theravance, Tonix, UCB, Williams and Connolly LLP, Zynerba, C. Swearingen Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, A. DiFrancesco 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