One volunteer for a phase 1 trial of the oral analgesic BIA 10-2474 died and five others were hospitalized at Rennes University Hospital in France with serious neurological symptoms in January. The trial testing a drug from Bial-Portela of São Mamede do Coronado, Portugal, in healthy volunteers was halted on January 11. The incident has cast a pall over inhibitors of fatty acid amide hydrolase (FAAH), the drug class to which the compound belongs. Although it is still unclear what may have caused the neurological damage, the Bial trial has prompted Janssen, a research unit of Johnson & Johnson, based in New Brunswick, New Jersey, to suspend its own phase 2 trials of a different FAAH inhibitor as a precaution.

Marisol Touraine, French health minister, holds a press conference on February 4 about the Bial affair. Credit: Kenzo Tribouillard AFP/Getty Images

French authorities, in a report published on January 29, faulted Biotrial, the Rennes-based contract research organization conducting the BIA 10-2474 trial. French health minister Marisol Touraine stated that the contract researchers continued to administer the highest dose of the drug after the first volunteer fell ill, failed to notify the authorities promptly and kept the incident from the remaining volunteers. Bial said 90 volunteers received varying doses of BIA 10-2474 starting in the summer of 2015. The six hospitalized volunteers, one of whom did not show any symptoms but was under observation, were in the group receiving the highest dose.

BIA 10-2474 is a small-molecule FAAH inhibitor. FAAH is an enzyme that degrades endocannabinoids, the best known of which is anandamide. Blocking the enzyme could slow the breakdown of such endogenous cannabinoids, which could help treat pain as well as other conditions including, anxiety, multiple sclerosis and motor problems in Parkinson's disease.

The preliminary report did not investigate the role of the compound itself. Even if the class is cleared, patients may remain wary of FAAH inhibitors. “If it is indeed a class effect, then FAAH inhibitors are doomed,” says Christopher Fowler, a professor of pharmacology, at Umeå University in Umeå, Sweden. “It may be damaging regardless of how this turns out.” Johnson & Johnson has suspended two phase 2 clinical trials of its FAAH inhibitor JNJ-42165279 in patients with social anxiety disorder and in major depressive disorder with anxious distress “as a precaution.” The company said it did not receive reports of adverse events in its tests of the compound.

The disastrous outcome of the Biotrial study was unexpected. Previous early-stage clinical trials of FAAH inhibitors showed no such effects, according to Steve Alexander, associate professor of molecular pharmacology at the University of Nottingham. “What we don't have is clarity; it is possible that this is an off-target effect.''

At least five other compounds targeting FAAH have been developed with limited success over the past several years. New York–based Pfizer had begun testing an FAAH inhibitor PF-04457845 in patients with osteoarthritis of the knee in 2009. Although there were no untoward effects, the drug was no better than a sugar pill in controlling pain. The company abandoned mid-stage studies of the drug in patients with Tourette syndrome and as a cannabis withdrawal treatment due to business reasons, says Susanne Straetmans, a Pfizer spokeswoman based in Berlin. In August 2014, the venture capital firm TVM Capital, based in Munich and Montreal, established FAAH Pharma in Montreal to develop FAAH inhibitor IPI-940, in-licensed from Infinity Pharmaceuticals of Cambridge, Massachusetts. Commenting on the impact these recent events may have on the biotech's future, Hubert Birner, a TVM Capital managing partner, says, “What happened was very tragic, and we are still in the middle of evaluating our options.” The compound is currently in preclinical trials.

Another FAAH inhibitor, V158866 from Winnersh, UK–based Vernalis, in August 2015 missed the primary endpoint in a phase 2 study to treat neuropathic pain resulting from spinal cord injury. Vernalis, which once valued the drug at annual peak sales of over $500 million, will cease further investments into the treatment. Mike Wood, the company's research director, declined to comment on the future of the compound “until the facts are clear.”

Touraine expects a complete report on the incident from France's General Inspectorate of Social Affairs before the end of March.