Background: Lorecivivint (LOR; SM04690) is a small-molecule, intra-articular (IA) CLK/DYRK1A inhibitor that modulates the Wnt pathway ¹ and has demonstrated some beneficial effects on patient-reported outcomes (PROs) relative to placebo (PBO) in two Phase 2 knee OA trials. With subjective measures such as PROs, meaningful benefits may be better characterized by representation as discrete threshold responses rather than by changes in mean point estimates.

Objectives: To conduct a post hoc analysis of subjects in a 24-week Phase 2b study by measuring the proportions of subjects treated with LOR and placebo (PBO) who achieved 30%, 50%, or 70% threshold responses of improvement over baseline in Pain Numeric Rating Scale (NRS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Function, and Patient Global Assessment (PtGA) at Week 12. Results from the Phase 3-selected dose of 0.07 mg LOR are presented here.

Methods: Subjects had ACR-defined knee OA, Kellgren-Lawrence (KL) grades 2–3, and Pain NRS scores ≥4 and ≤8 in the target knee and <4 in the contralateral knee. A single 2mL IA injection of 0.03 mg, 0.07 mg, 0.15 mg, or 0.23 mg LOR, or vehicle PBO was given in the target knee at baseline. The proportion of subjects meeting 30%, 50%, or 70% threshold responses over baseline in the weekly average of daily Pain NRS [0–10], WOMAC Pain [0–100], WOMAC Function [0–100], and PtGA [0–100] at Week 12 was determined. The odds ratios (OR [95% CI]) of achieving each threshold response level were calculated and compared between LOR and PBO.

Results: In total, 635 subjects (91.4%) completed the study (mean age 59.0±8.5 years, BMI 29.0±4.0 kg/m ² , female 58.4%, KL grade 3 57.3%). At Week 12, treatment with 0.07 mg LOR significantly ( P <0.05) increased the odds of a 30% threshold response in Pain NRS (OR 2.47 [1.45, 4.19]) and WOMAC Function (OR 1.86 [1.10, 3.12]) and a 50% threshold response in WOMAC Pain (OR 1.79 [1.06, 3.03]) and PtGA (OR 2.28 [1.25, 4.16]). Numerically, more (not statistically significant) subjects achieved a 70% threshold response in all PROs. All improvements were maintained through Week 24.

Conclusion: In this post hoc analysis, LOR-treated subjects reported greater improvements in PRO threshold responses versus PBO from Week 12 through Week 24. LOR demonstrated significantly higher odds of achieving and maintaining improvements in PROs at 30% and 50% thresholds. Phase 3 studies of 0.07 mg LOR are ongoing.

REFERENCES:

[1]Deshmukh V, et al. Osteoarthr Cartil . 2019.

Disclosure of Interests: Yusuf Yazici Shareholder of: Samumed, LLC, Grant/research support from: Bristol-Myers Squibb, Celgene, and Genentech, Consultant of: Celgene and Sanofi, Employee of: Samumed, LLC, Sarah Kennedy Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Christopher Swearingen Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Jeyanesh Tambiah Shareholder of: Samumed, LLC, Employee of: Samumed, LLC