Background/Purpose: SM04690, a small molecule, intra-articular (IA) Wnt pathway inhibitor, is in development for knee OA treatment. A phase 2, 52-week, trial evaluated changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain & Function and medial joint space width (mJSW) by x-ray. Health-related quality of life (HRQoL) was measured by Short Form Survey SF-36. The objective of this study was to assess the effect of SM04690 treatment on HRQoL.

Methods: Subjects with ACR-defined knee OA, Kellgren-Lawrence grades 2-3, received 2 mL IA SM04690 (0.03, 0.07, 0.23 mg) or placebo (PBO) in the target (most painful) knee. SF-36 was assessed (Weeks 0, 4, 13, 26, 39, 52). Baseline-adjusted analysis of covariance (with multiple imputation for missing data) was conducted in the intent-to-treat (ITT) population, with improvements ≥ minimum clinically important differences (MCID) noted. Two subgroups were explored: 1) unilateral symptomatic knee OA (pre-specified: UNI) and 2) unilateral symptomatic knee OA without widespread pain or comorbid symptoms (Widespread Pain Index ≤4 and Symptom Severity ≤2, post-hoc: UNI-WP).

Results: 455 subjects (mean age 60.3 [±8.7] years, BMI 29.9 [±4.6] kg/m², female 58.9%, KL 3 [64.4%], with UNI OA [36.0%]) were enrolled (n=402 [88.4%] completers).

In ITT, improvements from baseline were reported in 0.03 mg (n=112), 0.07 mg (n=117), 0.23 mg (n=110) and PBO (n=116) groups, with scores ≥ MCID in Physical Component Summary (PCS), Physical Functioning (PF), Role-Physical (RP), and Bodily Pain (BP) domains at Weeks 13 to 52. Improvements vs PBO reported in 0.07 mg at Week 13 were significant in Mental Component Summary (MCS [P=0.024]) and Role-Emotional (RE [P=0.036]) domains.

In UNI subgroup, at Week 52, all groups reported improvements ≥ MCID as in the ITT across all domains with 0.07 mg (n=35) significant vs PBO (n=39) in MCS (P=0.015), General Health (GH [P=0.028]), RE (P=0.009), and Mental Health (MH [P=0.011]) domains.

In UNI-WP subgroup at Week 52, all groups reported changes ≥ MCID in PCS, PF, RP, and BP domains, and across all domains with 0.07 mg. Improvements vs PBO (n=32) with 0.03 mg (n=34) were significant in PF (P=0.025), and with 0.07 mg (n=29) in MCS (P=0.002) and all domains excluding BP (PF [P=0.025], RP [P=0.027], GH [P=0.035], Vitality (VT [P=0.014]), Social Functioning (SF [P=0.028]), RE [P=0.003], MH [P=0.003]), which met or exceeded normative scores across all domains, except PF (Figure).

Conclusion: In this phase 2 trial, subjects receiving 0.07 mg SM04690 reported statistically significant and clinically meaningful HRQoL improvements in the ITT and subgroup analyses compared with PBO. In the UNI and UNI-WP subgroups at Week 52, HRQoL improvements mirrored changes observed from analyses in WOMAC Pain and Function and mJSW (Yazici et al., Arthritis Rheumatol 2017) and support further investigation of SM04690 for treatment of knee OA.