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

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

doi:10.3389/fphar.2018.00471

Abstract

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.

Highlights

Gemcabene calcium is a small molecule and is the monocalcium salt of a dialkyl ether dicarboxylic acid [6,6 -oxybis (2,2-dimethylhexanoic acid)] and is currently in late-stage clinical development
Using these animal efficacy models of inflammation, we showed that gemcabene attenuates monosodium iodoacetate (MIA), monoclonal antibody-induced arthritis (MAIA), and IL-6/IL-6sR induced hyperalgesia, OA, and hind paw weight distribution, respectively
A COX-2 inhibitor, with gemcabene either alone or in combination and the results shown in Figure 5D suggest that 3 mg/kg dose of rofecoxib was comparable to 30 mg/kg gemcabene in acute hyperalgesia model

Summary

INTRODUCTION

Gemcabene calcium ( known as gemcabene, CI-1027 and PD 72953-0038) is a small molecule and is the monocalcium salt of a dialkyl ether dicarboxylic acid [6,6 -oxybis (2,2-dimethylhexanoic acid)] and is currently in late-stage clinical development. Clinical studies in humans demonstrated that, in addition to LDL lowering, gemcabene reduces plasma levels of C-reactive protein (CRP) in patients by 53.5% in monotherapy and by 71% in combination with statins (Stein et al, 2016), indicating that this compound may have anti-inflammatory properties. In the MAIA model, we found that 129/SvJ, BALB/c, C3H/FeJ, and C57BL/6 strains were responsive as the DBA/1 mice Since all these animal models represent inflammation-induced progression of disease, gemcabene efficacy to attenuate pathological conditions resulting from inflammation was evaluated in these animal models. Using these animal efficacy models of inflammation, we showed that gemcabene attenuates MIA, MAIA, and IL-6/IL-6sR induced hyperalgesia, OA, and hind paw weight distribution, respectively

EXPERIMENTAL PROCEDURES

Findings

DISCUSSION