SAT0549 Anti-inflammatory properties of SM04690, a small molecule inhibitor of the wnt pathway as a potential treatment for knee osteoarthritis

Background Osteoarthritis (OA) is characterized by pain, deformity, and reduced function in the knee joint. Upregulated Wnt signaling affects the pathogenesis of OA through increased inflammation, increased subchondral bone and thinning cartilage. SM04690, a novel small molecule, was previously shown to inhibit the Wnt pathway and induce chondrogenesis in vitro and in vivo. 1 Objectives SM04690 was evaluated in preclinical studies to determine its capacity to reduce inflammation, and reduce pain in OA. Methods Anti-inflammatory activity was evaluated by measuring cytokine (IL-6 and TNF-α) secretion using ELISA with IL1-b stimulated synovial fibroblasts. A panel of pro-inflammatory cytokines (TNF-α, IL-1α, IL-1β, IL-2, IL-6, IL-8, IL-17A, IL-17F, IFN-γ and PGE2) was evaluated by ELISA; T and B cell proliferation by flow cytometry in peripheral blood mononuclear cells (PBMCs), and T and B cell co-cultures stimulated with super-antigen (SAg) or lipopolysaccharides (LPS), compared to vehicle or benchmark immunosuppressant or steroid (cyclosporin A and prednisolone). SM04690 effects on LPS-induced expression and phosphorylation of JNK, NFkB, Erk, cJun, Akt, Stat3 in THP-1 cells were measured by qPCR and Western Blot. In vivo SM04690 activity was evaluated in a rat monosodium iodoacetate (MIA) injection-induced OA model, immediately followed by a single intra-articular SM04690 or vehicle injection. Joint inflammation was evaluated by measuring synovial thickness and infiltrating cells histology; inflammatory cytokines (IL-1α, IL-1β, IL-2, IL-5, IL-6, IL-8, TNF-α and IFN-γ) by qPCR and ELISA and cartilage protection by qPCR for matrix metalloproteinases (MMPs). Pain was measured as paw withdrawal threshold using Von Frey apparatus. Results SM04690 inhibited IL-1b-induced TNF-α and IL-6 secretion in synovial fibroblasts (EC 50 @30nM). SM04690 significantly inhibited ( p p Conclusions SM04690 demonstrated potent anti-inflammatory properties, comparable to or greater than cyclosporin A and prednisolone. In a rat knee OA model, SM04690 injection reduced inflammation, protease production and pain compared to vehicle. The anti-inflammatory properties of SM04690 may provide beneficial effects in the treatment of OA. Clinical studies are ongoing. References Hood et al. OAC 2016, s187. Disclosure of Interest V. Deshmukh Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, C. Barroga Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, M. Ibanez Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, T. Seo Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, S. KC Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Y. Yazici Shareholder of: Samumed, LLC, Employee of: Samumed, LLC