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Objectives: To assess the efficacy and safety of an intra-articular (IA) CLK/DYRK inhibitor, lorecivivint (LOR), for the treatment of moderate to severe symptomatic knee osteoarthritis (OA)., Methods: This was a Phase 3, 28-week, multicentre, double-blind, placebo-controlled study evaluating the efficacy and safety of a single IA injection of LOR. Patients with ACR-defined knee OA, Kellgren-Lawrence (KL) grades 2-3, and pain Numeric Rating Scale (NRS) ≥4 and ≤8 in the target knee were randomised (1:1) to receive LOR 0.07 mg or vehicle placebo (PBO) on Day 1. The primary endpoint was the change from baseline in Pain NRS at Week 12 between LOR and PBO. Additional outcomes included the change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Function, WOMAC Pain, Patient Global Assessment and safety., Results: 498 patients were randomised, and 51.9% had KL Grade 3 severity. In the full analysis set (FAS), LOR failed to meet the primary endpoint when compared to PBO. No significant treatment differences were noted in other efficacy endpoints. A post-hoc analysis demonstrated a positive treatment effect of LOR relative to PBO in the KL Grade 2 subgroup; the difference in weekly Pain NRS between LOR and PBO groups showed nominal statistical significance at Week 4 (p<0.05). Incidences, seriousness, and severity of adverse events were similar across the treatment groups., Conclusions: LOR was well tolerated despite not meeting the primary endpoint. Efficacy signals were identified in patients with less severe structural knee OA disease, suggesting earlier intervention may be more effective.

Objectives: To determine the efficacy, safety, and tolerability of intraarticular (IA) lorecivivint (LOR) in the treatment of knee osteoarthritis (OA)., Methods: Patients with American College of Rheumatology criteria-defined knee OA, Kellgren-Lawrence (KL) grades 2-3, and medial Joint Space Width (JSW) by radiograph between 1.5 and 4 mm in the target knee were enrolled in this phase 3, 56-week, multicentre, double-blind, placebo-controlled study. Patients were randomised (1:1) to receive a single IA injection of 0.07 mg LOR or vehicle placebo (PBO) on Day 1. The primary endpoint was the change from baseline in pain Numeric Rating Scale (NRS) at Week 12. Additional outcomes included the change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Function, WOMAC Pain, Patient Global Assessment, medial JSW, and safety., Results: 513 patients were randomised. Baseline mean medial JSW was 2.61 (±0.7) mm. The mean change from baseline in weekly average of daily Pain NRS at Week 12 was LOR -2.24 (± 0.13) compared with PBO -2.49 (± 0.13); p=0.185, 95% confidence interval (CI) (-0.12, 0.62). No discernable treatment effects of LOR compared with PBO were revealed by the analysis of other endpoints. Neither treatment group showed meaningful medial JSW loss over 52 weeks. Incidences, severity, and relationship to study treatment of AEs were similar between LOR and PBO treatment groups., Conclusioins: In this study, LOR was well tolerated although it did not meet the primary endpoint of change from baseline in target knee Pain NRS at Week 12.