Gemcabene, a First-in-Class Hypolipidemic Small Molecule in Clinical Development, Attenuates Osteoarthritis and Pain in Animal Models of Arthritis and Pain

Rai A. K. Srivastava, Joseph A. Cornicelli, Bruce Markham, Charles L. Bisgaier

Our clinical studies have demonstrated that gemcabene, a small molecule in late-stage clinical development, lowers pro-inflammatory acute-phase protein, C-reactive protein (CRP). This observation was further confirmed in a cell-based study showing inhibition of cytokine-induced CRP production. Based on these observations, in the present study, we tested the hypothesis that gemcabene may possess anti-inflammatory activities in animal models of inflammatory disease. Efficacy of gemcabene was investigated in rat models of carrageenan-induced thermal hyperalgesia (CITH), monosodium iodoacetate (MIA)-induced osteoarthritis (OA), and IL-6/IL-6sR-induced inflammation. We also evaluated efficacy of gemcabene in collagen antibody-induced joint swelling and arthritis in BALB/c mice. In CITH rat model, gemcabene administration attenuated paw withdrawal latency (60% at 30 mg/kg/d and 97% at 100 mg/kg/d) and showed improvement in joint swelling (-50% at 30 mg/kg/d) in MIA model of OA. These findings were further corroborated by IL-6/IL-6sR knee injection model in rat, showing 63 and 71% reduction in hind paw weight distribution at 10 and 30 mg/kg/d doses, respectively. In mouse model of monoclonal antibody-induced arthritis, a dose-dependent attenuation of joint swelling was observed. These results demonstrate that the anti-inflammatory activity of gemcabene previously observed in cell-based and in clinical studies also occurred in animal models of inflammation-induced arthritis and hyperalgesia. Thus, in addition to hypolipidemic efficacy, the anti-inflammatory activity of gemcabene may have additional benefits to patients with elevated vascular inflammation.