A novel Wnt pathway inhibitor, SM04690, for the treatment of moderate to severe osteoarthritis of the knee: results of a 24-week, randomized, controlled, phase 1 study

Abstract
Objective: This study aimed to evaluate the safety, pharmacokinetics, and preliminary efficacy of SM04690, a new Wnt pathway inhibitor, as a potential disease-modifying treatment for knee osteoarthritis (OA).Design: Participants with Kellgren-Lawrence grade 2-3 knee OA were randomly assigned to receive intra-articular injections of either 0.03, 0.07, or 0.23 mg SM04690 or a placebo, in a 4:1 ratio. Safety, pharmacokinetic data, and efficacy measures (WOMAC Total/Function/Pain, Pain VAS, Physician Global Assessment [MDGA], OMERACT-OARSI Response) were assessed, along with OA-related biomarkers (P1NP, ß-CTX, and cartilage oligomeric matrix protein [COMP]) and radiographic/imaging data, at baseline and after 24 weeks.
Results: A total of 61 subjects were enrolled (50 receiving SM04690 and 11 receiving placebo). In the 0.07 mg cohort, two dose-limiting toxicities (DLTs) were reported: increased pain following injection and paroxysmal tachycardia (the only serious adverse event). Overall, 72 adverse events (AEs) were noted, with 16 (in eight participants) considered related to the study medication. Three participants discontinued the study, one due to an AE in the 0.03 mg group. Bone marrow edema (BME) remained stable for most participants. No doses were excluded based on DLT criteria, and plasma levels of SM04690 were undetectable at all time points. By Week 24, all cohorts showed improvements from baseline in exploratory measures such as WOMAC Total, WOMAC Function, WOMAC Pain, MDGA, Pain VAS, and OMERACT-OARSI response. Notably, the 0.07 mg cohort demonstrated a significant improvement in joint space width (JSW) compared to placebo (P = 0.02).

Conclusion: SM04690 appeared to be safe and well-tolerated, with no signs of systemic exposure. Preliminary efficacy analyses indicated promising trends in OA pain, function, and potential disease-modifying Adavivint properties.