Ben Van Handel1, Candace Flynn2, Emma Lamoure2, Nancy Liu3, Jinxiu Lu3, Nancy Lane4, Mark Hurtig2 and Denis Evseenko3, 1CarthroniX, Inc., Los Angeles, CA, 2University of Guelph, Guelph, ON, Canada, 3University of Southern California, Los Angeles, CA, 4University of California Davis, Hillsborough, CA
Background/Purpose: The pathogenesis of 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; this promotes matrix degradation leading to the destruction of cartilage. Currently, there are no agents that efficiently slow or inhibit this process. Here, we unveil an advanced late pre-clinical candidate CX-011 that has significant, dose-dependent effects on joint structure, function and pain via modulation of gp130.
Methods: Twenty-four purpose bred dogs were chosen for this study. All dogs underwent CT imaging of both knee joints then general anesthesia and arthroscopic surgery to induce osteoarthritis (OA) by medial meniscal release. Dogs were allocated into four experimental groups (n=6). 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. Knee joint CT imaging was repeated at 4 weeks and again at 16 weeks. Pain was mild throughout the study and was scored using the Colorado Pain Scale (0- 3). Sixteen weeks after OA induction the dogs were sacrificed and both the operated and contralateral knee joints underwent detailed macroscopic assessments. MicroCT imaging of the knee joints was conducted. H&E and safranin O stained tissue sections were produced for blinded OARSI histological scoring.
Results: Histological scoring was done using the OARSI method. In the highest dose (10 μg) group, there was highly significant chondroprotection (p = 0.012) as lesions were limited to superficial fibrillation and mild proteoglycan loss with minimal alterations in the deeper tissues, while control and 0.1 μg treated dogs had larger, deeper more extensive cartilage loss with widespread proteoglycan depletion and involvement of the subchondral plate indicating severe dysregulation of the synovial environment and metabolism. In parallel, there was clear evidence that synovial inflammation and pathologic change in the synovial membrane was significantly limited by the two highest dose rates (p = 0.016) of the test article. By co-registering CT images from different time points, a dramatic, statistically significant reduction (p < 0.001) in medial compartment shape alteration in dogs treated with the two highest dose levels of CX-011 compared to controls was observed. Finally, qualitative scoring of lameness by was performed by trained observers on a daily basis. The two highest doses had significantly reduced lameness, indicating lower pain levels with increasing test article concentration.
Conclusion: Taken together, these data suggest efficacy in controlling joint disease progression and its symptoms as well as a good safety profile for CX-011. We have shown that the high 10 μg and medium 1 μg dose groups prevent some of the most important pathophysiological changes promoting osteoarthritis progression. Notably, bone remodeling and shape change is prevented. 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.
Disclosures: B. Van Handel, CarthroniX, Inc.; C. Flynn, None; E. Lamoure, None; N. Liu, None; J. Lu, None; N. Lane, Amgen, GlaxoSmithKlein(GSK); M. Hurtig, None; D. Evseenko, CarthroniX Inc..
