Death from French drug trial likely due to high doses of compound
- The death of a man and hospitalization of five others after participating in a French drug trial has been tentatively linked to the specific compound being tested, rather any manufacturing problems.
- French health regulators had set up a "Temporary Specialist Scientific Committee" to investigate the cause of the adverse reactions. In a report, the TSCC highlighted the "astonishing and unprecedented nature of the accident." According to the Guardian, the committee ruled out manufacturing and shared genetic weakness among the affected patients.
- Conducted by the CRO Biotrial, the clinical trial was testing a FAAH-enzyme inhibitor known as BIA 10-2474 for treatment of pain and mood disorders. The Portuguese drug company Bial was developing the drug.
The severe adverse reactions in the six men called into question FAAH-enzyme inhibitors as a class. Johnson and Johnson's Janssen halted a separate FAAH inhibitor trial soon after the Bial disaster. Both Sanofi and Pfizer had worked with similar compounds in the past.
FAAH inhibitors work by slowing the degradation of anandamide, a "feel-good" molecule, as well as several related endocannabinoids. Up until the Bial trial, the compounds had been considered an attractive target by researchers because of their potential to address neurological and psychiatric conditions. No serious adverse events had occurred in the phase 1 and phase 2 trials conducted by Sanofi, Pfizer, and Janssen.
Over 100 volunteers participated in the study, and no others suffered from similar negative reactions.
The committee presented several more likely hypotheses to explain why the six men (who had received higher dosing), including off-target effects and toxicity from the BIA 10-2474 metabolite. High dosing in the trial was also called into question.
"It appears unjustified to plan to test a dose (100 mg) 80 times higher than that presumed to induce complete and prolonged FAAH inhibition," the report said.
In concluding, the committee advocated for legislation to be instituted to require neuropsyhcological assessments before clinical trials related to central nervous system tropism. They also recommended better Phase dose-escalation strategies.
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