Background Inflammation is a known contributor to osteoarthritis (OA) pain in animals and humans. While translation of human treatments to companion dogs is common, translation from companion dogs to humans is less frequent. We present results of a clinical study, in client-owned canines with moderate OA pain, which evaluated the efficacy of 2 molecules targeting the actions of prostaglandin E, either by modulating its production (mPGES1 inhibitor; LYA), or subsequent pharmacology through 1 of its 4 receptors (EP4 antagonist, LYB).
Objectives To provide translational and comparative data to inform the potential utility of each of these mechanisms for treatment of chronic OA pain in humans and dogs.
Methods A multicenter, randomized, double-blind, placebo (PBO)- and active-controlled trial in client-owned canine patients with moderate OA pain in ≥1 hindlimb/forelimb joint. Dogs ≥2 years of age with Liverpool Osteoarthritis in Dogs (LOAD) Mobility total score ≥13 to <46 were randomized (1:1:1:1) to 2 weeks of LYA (1.5 mg/kg/day), LYB (25 mg/kg/day), carprofen (4.4 mg/kg/day), or PBO. Efficacy versus PBO was assessed by mean change from baseline (CFB) to Week 2 in the Canine Brief Pain Inventory (CBPI) Pain Interference (PI) Score (primary endpoint), and for secondary endpoints: CBPI Pain Severity (PS) and Overall Impression (OI) subscores, and LOAD Mobility score. Data were analyzed by mixed-effect model for repeated measures with treatment, time, and interaction of treatment and time as fixed effects, and with baseline score, site, and weight as covariates. Posterior probability of treatments being superior to PBO was calculated with Bayesian methods.
Results Of 163 dogs randomized, 158 (96.9%) completed the study. Treatment arms were well-balanced for baseline characteristics (mean [standard deviation] age: 9.3 [3.0] years, weight: 54.6% 15–32 kg, 45.4% >32–50 kg, CBPI PI: 5.1 [2.1]; CBPI PS: 4.2 [1.9]; LOAD Mobility: 24.1 [5.6]). Improvements (CFB) in CBPI PI were observed in all treatment groups after 2 weeks (Table). For LYA, the probablility of superiority to PBO was 80% for CBPI PI and 89% to 96% for secondary endpoints. LYB showed inconsistent separation from PBO across the endpoints, with probablilty of superiority to PBO 54% to 89%. The separation of carprofen and PBO arms demonstrated assay sensitivity. The incidence of adverse events for LYA (35.9%) was comparable to that of carprofen (25.6%) and PBO (32.6%). For LYB, the incidence was significantly higher versus PBO (59.5%, P=.017).
Conclusions The study results support an efficacy proof-of-concept signal for the mPGES1 inhibitor mechanism for treatment of chronic OA pain in canine patients.
Acknowledgements We also thank Leijun Hu, Alain Frix, and Claire Smith of Eli Lilly and Company for their contributions to the study.
Disclosure of Interest C. Robertson-Plouch Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, J. Stille Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, P. Liu Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, S. Malcolm Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, D. Brown Grant/research support from: AlcheraBio, Centrexion Corporation, Enceladus, Integrated Chinese Medicine Holdings, and Regeneus, M. Warner Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, M. Fisher Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company