RT Journal Article
SR Electronic
T1 A randomized clinical efficacy study targeting mPGES1 or EP4 in dogs with spontaneous osteoarthritis
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP eaaw9993
DO 10.1126/scitranslmed.aaw9993
VO 11
IS 516
A1 Robertson-Plouch, Carol
A1 Stille, John R.
A1 Liu, Peng
A1 Smith, Claire
A1 Brown, Dorothy
A1 Warner, Margaret
A1 Hu, Leijun
A1 Fisher, Matthew J.
YR 2019
UL http://stm.sciencemag.org/content/11/516/eaaw9993.abstract
AB 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.