A randomized clinical efficacy study targeting mPGES1 or EP4 in dogs with spontaneous osteoarthritis

Abstract

An inhibitor of microsomal prostaglandin E synthase-1 demonstrates proof-of-concept clinical efficacy in dogs with osteoarthritis. Paws on pain Canines experience osteoarthritis similar to humans, and studies testing therapeutics in companion animals can provide valuable support for clinical trials. Robertson-Plouch and colleagues evaluated efficacy of inhibitors of the prostaglandin E (PGE) pathway in reducing pain in dogs with spontaneously occurring osteoarthritis. A microsomal PGE synthase-1 inhibitor showed promising results for reducing pain scores compared to a nonsteroidal anti-inflammatory targeting cyclooxygenase-2 and a downstream antagonist of the E-type prostanoid receptor 4, although consistent superiority compared to placebo did not reach the study’s predetermined threshold. Results from this proof-of-concept study support further investigation of microsomal PGE synthase-1 inhibition for analgesia. Canine studies of spontaneous osteoarthritis (OA) pain add valuable data supporting drug treatment mechanisms that may translate to humans. A multicenter, randomized, double-blind, placebo- and active-controlled study was conducted in client-owned dogs with moderate OA pain to evaluate efficacy of LYA, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES1), an EP4 antagonist (LYB), and carprofen, versus placebo. Of 255 dogs screened, 163 were randomized (placebo/LYA/LYB/carprofen: n = 43/39/42/39) and 158 completed treatment. Efficacy versus placebo was assessed using Bayesian mixed-effect model for repeated measure analyses of the Canine Brief Pain Inventory (CBPI) pain interference score (PIS; primary endpoint), pain severity score, and overall impression, as well as the Liverpool Osteoarthritis in Dogs (LOAD) mobility score. The posterior probability that the difference to placebo was <0 at week 2 was 80% for LYA and 54% for LYB for CBPI PIS (both <95% predefined threshold). For secondary endpoints, the posterior probability that the difference to placebo was <0 at week 2 ranged from 89 to 96% for LYA and from 56 to 89% for LYB. The posterior probabilities comparing carprofen to placebo groups were ≥90% for all efficacy endpoints. The proportion of dogs with one or more adverse event was not significantly different from placebo (32.6%) for LYA (35.9%) or carprofen (25.6%), but the rate for LYB (59.5%) was higher versus placebo (P = 0.017). LYA treatment demonstrated consistent improvement in all efficacy measures, suggesting that inhibition of mPGES1 may be an effective treatment for chronic pain associated with OA.