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Published on: September 29, 2018
A Phase 2b randomized trial of lorecivivint, a novel intra-articular CLK2/DYRK1A inhibitor and Wnt pathway modulator
Y Yazici1, T E McAlindon2, A Gibofsky3
1Samumed, LLC, San Diego, CA, USA; New York University School of Medicine, New York, NY, USA.
Objective:
Lorecivivint (LOR; SM04690), an investigational Wnt pathway modulator, previously demonstrated patient-reported and radiographic outcome improvements vs placebo in clinically relevant subjects with moderate to severe knee osteoarthritis (OA). This study's objective was to identify effective LOR doses.
Design:
Subjects in this 24-week, Phase 2b, multicenter, randomized, double-blind, placebo (PBO)-controlled trial received an intra-articular injection of 2 mL LOR (0.03, 0.07, 0.15, or 0.23 mg), PBO, or dry-needle sham. The primary efficacy endpoints were changes in Pain NRS [0-10], WOMAC Pain [0-100], WOMAC Function [0-100], and radiographic mJSW outcomes, which were measured using baseline-adjusted analysis of covariance at Week 24. Multiple Comparison Procedure-Modeling (MCP-Mod) was performed for dose modeling.
Results:
In total, 695/700 subjects were treated. Pain NRS showed significant improvements vs PBO after treatment with 0.07 mg and 0.23 mg LOR at Weeks 12 (-0.96, 95% CI [-1.54, -0.37], P = 0.001; -0.78 [-1.39, -0.17], P = 0.012) and 24 (-0.70 [-1.34, -0.06], P = 0.031; -0.82 [-1.51, -0.12], P = 0.022). Additionally, 0.07 mg LOR significantly improved WOMAC Pain and Function subscores vs PBO at Week 12 (P = 0.04, P = 0.021), and 0.23 mg LOR significantly improved both WOMAC subscores at Week 24 (P = 0.031, P = 0.017). No significant differences from PBO were observed for other doses. No radiographic progression was observed in any group at Week 24. MCP-Mod identified 0.07 mg LOR as the lowest effective dose.
Conclusion:
This 24-week Phase 2b trial demonstrated the efficacy of LOR on PROs in knee OA subjects. The optimal dose for future studies was identified as 0.07 mg LOR.
Insights
Lorecivivint (LOR) effectively reduced knee osteoarthritis pain and improved function in a Phase 2b trial. The lowest effective dose identified for future studies was 0.07 mg LOR.
Area of Science:
- Orthopedics
- Pharmacology
- Clinical Trials
Background:
- Knee osteoarthritis (OA) is a significant cause of pain and disability.
- Lorecivivint (LOR), a Wnt pathway modulator, has shown promise in improving patient-reported and radiographic outcomes in OA.
- Identifying optimal dosing is crucial for therapeutic development.
Purpose of the Study:
- To determine the effective doses of Lorecivivint (LOR) for treating moderate to severe knee osteoarthritis (OA).
- To evaluate the efficacy of different LOR doses on pain, function, and radiographic measures.
Main Methods:
- A 24-week, Phase 2b, multicenter, randomized, double-blind, placebo-controlled trial.
- Subjects received intra-articular injections of LOR (0.03, 0.07, 0.15, or 0.23 mg), placebo, or dry-needle sham.
- Primary endpoints included changes in Pain NRS, WOMAC Pain, WOMAC Function, and radiographic mJSW; MCP-Mod was used for dose modeling.
Main Results:
- Significant improvements in Pain NRS were observed with 0.07 mg and 0.23 mg LOR versus placebo at Weeks 12 and 24.
- 0.07 mg LOR improved WOMAC Pain and Function at Week 12, while 0.23 mg LOR showed improvements at Week 24.
- No significant differences were seen with other doses, and no radiographic progression occurred in any group.
Conclusions:
- Lorecivivint (LOR) demonstrated efficacy in improving patient-reported outcomes for knee OA over 24 weeks.
- The lowest effective dose of LOR for knee OA was identified as 0.07 mg.
- This dose represents a promising option for future clinical studies in knee OA management.
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