The pathogenesis of osteoarthritis (OA) often begins from an injury to articular cartilage, which establishes chronic, low-grade inflammation principally mediated by IL-6 family cytokines that signal through the obligate receptor gp130. However, we and others have shown that gp130 can also regulate anabolic responses in chondrocytes and immune system. Here, we unveil an advanced late pre-clinical regeneration-promoting candidate CX-011 that modulates, rather than completely inhibits, gp130 signaling.
Twenty-four purpose bred Foxhound dogs (12 females, 12 males), 10 months of age, (Marshall BioResources) were chosen for this study. All dogs underwent CT imaging of both knee joints then general anesthesia and arthroscopic surgery to induce OA by medial meniscal release (MMR). Three groups received CX-011 by intra-articular injection into the operated limb and the fourth control group (n=6) received an equal volume of vehicle. Injections were done four weeks post-operatively and again at 6 weeks after initial injection. The three experimental groups given the test article received doses of 10 μg, 1 μg or 0.1 μg in a 0.5 mL volume.
Dose dependent effects of CX-11 were documented. In the highest dose of CX-011 (10 mg) group, there was highly significant chondroprotection (p = 0.012). Synovial inflammation was significantly limited by the two highest dose rates (p = 0.016) of the test article. CT imaging showed a dramatic, statistically significant reduction (p < 0.001) in shape alteration in dogs treated with the two highest dose levels of CX-011 compared to controls. Finally, the two highest doses had significantly reduced lameness, indicating lower pain levels with increasing test article concentration (p < 0.001).
The current study has nominated the gp130 modulator CX-011 as an excellent candidate for clinical progression as a disease modifying agent for OA with concurrent reduction in pain.