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

Abstract

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.

The intra-articular administration of triamcinolone hexacetonide in the treatment of osteoarthritis. Its effects in a naturally occurring canine osteoarthritis model

“…Besides changes in different CMI scores, particularly pain scores calculated with the CBPI, were observed. This is of particular interest, since pain is a hallmark of OA, and its characterization produces valuable data that may translate to humans [21,73,74]. Individual CMI scores in THG improved for a majority of animals were observed with several of the considered questionnaires, in many cases up to the last evaluation.…”

Management of Osteoarthritis Using 1 Intra-articular Platelet Concentrate Administration in a Canine Osteoarthritis Model

“…41 Pain and functional ability are the most important parameters in the evaluation of OA treatment efficacy, with canine studies offering valuable data that may translate to humans. 16,45,56 We used several CMIs to try to capture multiple dimensions of OA, and we observed significant improvements with several of them—in some cases, up to the last evaluation moment. A previous report has described similar long-lasting effects of a single administration of platelet concentrate, 1 but further studies should be done to evaluate if different treatment frequencies can lead to better results.…”

G Protein-Coupled Receptors in Osteoarthritis

“…Grapiprant, an EP4 antagonist, has been approved for by the FDA treating OA pain in dogs (132,133). A multicenter, randomized study demonstrated that the inhibitor of microsomal prostaglandin E synthase-1 (LYA) but not the EP4 antagonist (LYB) improved clinical signs of OA pain in dogs (134). Although there are animal model studies and clinical applications in effects of EP receptors in OA, the in vivo functions and molecular mechanisms of EP receptors in cartilage homeostasis and OA need further investigation.…”