An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee.
The effect of PF-04457845, a potent and selective fatty acid amide hydrolase-1 (FAAH1) inhibitor, on pain due to osteoarthritis of the knee was investigated in a randomised placebo and active-controlled clinical trial. The trial involved 2 periods (separated by a 2-week washout) consisting of a 1-week wash-in phase followed by 2weeks double-blind treatment. Patients received single-blind placebo throughout the wash-in and washout periods. Patients were randomised to receive either 4mg q.d. PF-04457845 followed by placebo (or vice versa), or 500mg b.i.d. naproxen followed by placebo (or vice versa). The primary end point was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score. The trial had predefined decision rules based on likelihood that PF-04457845 was better or worse than the standard of care (considered to be a 1.8 reduction in WOMAC pain score compared to placebo). A total of 74 patients were randomised to 1 of 4 treatment sequences. The mean differences (80% confidence intervals) from placebo in WOMAC pain score were 0.04 (-0.63 to 0.71) for PF-04457845 and -1.13 (-1.79 to -0.47) for naproxen, indicating that whilst naproxen seemed efficacious, PF-04457845 was not differentiated from placebo. The study was stopped at the interim analysis for futility. PF-04457845 decreased FAAH activity by >96% and substantially increased 4 endogenous substrates (fatty acid amides). PF-04457845 was well tolerated in osteoarthritis patients, and there was no evidence of cannabinoid-type adverse events. The lack of analgesic effect of FAAH1 inhibition in humans is in contrast to data from animal models. This apparent disconnect between species needs further study.
Pfizer Global Research and Development, Sandwich, UK.
John P
JP
Huggins
Trevor S
TS
Smart
Stephen
S
Langman
Louise
L
Taylor
Tim
T
Young
D000328:Adult; D000368:Aged; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000700:Analgesics / Q000627:therapeutic use*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D018771:Arthralgia / Q000188:drug therapy* / Q000209:etiology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D063388:Endocannabinoids / Q000378:metabolism; D005260:Female; D006801:Humans; D007719:Knee Joint; D008297:Male; D018447:Medical Futility; D008875:Middle Aged; D009288:Naproxen / Q000627:therapeutic use; D020370:Osteoarthritis, Knee / Q000150:complications; D010147:Pain Measurement; D011724:Pyridazines / Q000627:therapeutic use*; D016037:Single-Blind Method; D016896:Treatment Outcome; D014508:Urea / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D063388:Endocannabinoids; D009288:Naproxen; D011724:Pyridazines; D014508:Urea; D000099252:Fatty Acid Amide Hydrolases; C560620:N-pyridazin-3-yl-4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzylidene)piperidine-1-carboxamide