AB0070 LORECIVIVINT (SM04690), A POTENTIAL DISEASE-MODIFYING TREATMENT FOR KNEE OSTEOARTHRITIS, DEMONSTRATED CARTILAGE-PROTECTIVE EFFECTS ON HUMAN OSTEOARTHRITIC EXPLANTS

Background: Wnt pathway upregulation contributes to knee osteoarthritis (OA) through osteocyte differentiation, cartilage thinning, and inflammation. Lorecivivint (LOR; SM04690), a novel, small-molecule CLK/DYRK1A inhibitor that modulates the Wnt pathway, demonstrated disease-modifying potential for knee OA in preclinical studies.1 However, the specific mechanisms by which LOR protects cartilage in knee OA are unclear. Objectives: To evaluate the cartilage-protective effects of LOR on human OA explants from total knee replacement (TKR) donors. Methods: Knee joint tissue from 22 TKR donors was obtained. IRB approval was obtained from Scripps Health. Cartilage was scored using the Outerbridge classification system based on gross appearance (grade 1=least-damaged tissue, grade 4=most-damaged tissue). Cartilage explants (4 mm in diameter) with Outerbridge grades 2–3 were harvested and cultured for 48 hours to reach metabolic stability. They were then treated with LOR (10 nM, 30 nM) or DMSO and stimulated with either IL-1β (10 ng/ml) or TNF-α (20 ng/ml)+oncostatin M (OM) (10 ng/ml) or left unstimulated. After 72 hours, supernatants and explants were collected. Gene expression of matrix metalloproteinases (MMPs) 1, 3, and 13 was measured by qPCR and protein levels of MMP-1, MMP-3, MMP-13, and thrombospondin-motif-containing disintegrins/metalloproteinases ADAMTS-4 and ADAMTS-5 were measured in supernatants by ELISA. Glycosaminoglycan (GAG) and nitric oxide (NO) levels were measured in supernatants using the dimethylmethylene blue assay and Griess assay, respectively. One-way ANOVA was used for multiple group comparisons. Results: Treatment with IL-1β or TNF-α+OM led to statistically significant increases in gene expression of MMP1, MMP3, and MMP13 and increased secretion of GAG, MMP-1, MMP-3, MMP-13, ADAMTS-4, ADAMTS-5, and NO in supernatants compared to unstimulated control. Treatment with LOR decreased both IL-1β-stimulated and TNF-α+OM-stimulated gene expression of MMP1, MMP3, and MMP13 and secretion of GAG, MMP-1, MMP-3, MMP-13, ADAMTS-4, ADAMTS-5, and NO in supernatants compared to treatment with DMSO. Conclusion: LOR demonstrated potent inhibition of cartilage catabolism enzyme production in human OA explants compared to controls. These cartilage-protective effects support the development of LOR as a potential disease-modifying treatment for knee OA. Human trials are ongoing. References: [1]Deshmukh V, et al. Osteoarthr Cartil. 2019. Disclosure of Interests: Vishal Deshmukh Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Shawn Grogan: None declared, Tim Seo Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Deepti Bhat Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, William Bugbee: None declared, Darryl D’Lima: None declared, 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