Osteoarthritis and cartilage 2017 07 12() pii S1063-4584(17)31085-3
To assess the safety, pharmacokinetics, and exploratory efficacy of SM04690, a novel Wnt pathway inhibitor, as a potential disease modifying treatment for knee OA.
Subjects with Kellgren-Lawrence grade 2-3 knee OA were randomized in successive dose-escalation cohorts to receive a knee intra-articular injection with 0.03, 0.07, or 0.23 mg SM04690, or placebo (PBO) (4:1 ratio). Safety, pharmacokinetics, efficacy (WOMAC Total/Function/Pain, Pain VAS, Physician Global Assessment [MDGA], and OMERACT-OARSI Response), OA-related biomarker (P1NP, ß-CTX, and COMP), and radiographic/imaging data were collected at baseline and during 24-week follow-up.
61 subjects (SM04690 n=50; PBO n=11) enrolled. Two DLTs, increased pain following injection and paroxysmal tachycardia (also the single serious AE), were reported in the 0.07 mg cohort. A total of 72 AEs were reported; Sixteen (occurring in 8 subjects) were considered related to study medication. There were 3 discontinuations; 1 due to an AE (0.03 mg cohort). Bone marrow edema remained constant for most subjects. No doses were excluded from further study due to DLT criteria. Plasma levels of SM04690 were below the limit of detection at all timepoints. At Week 24, improvements from baseline were seen in all cohorts for the exploratory measures WOMAC Total, WOMAC Function, WOMAC Pain, MDGA, Pain VAS, and OMERACT-OARSI response. Joint space width improvement was observed in the 0.07 mg cohort (P=0.02 vs. PBO).
SM04690 appeared safe and well tolerated, with no evidence of systemic exposure. Exploratory efficacy analyses suggested positive trends for measurements of OA pain, function and DMOAD properties. CLINICALTRIALS.GOV: registration-NCT02095548.