One person is dead and five others are hospitalized in a phase I trial that went badly wrong. Three of the survivors may have suffered irreversible brain damage, according to Dr. Gilles Edan, head of neurology at the Centre Hospitalier Universitaire de Rennes, France, as quoted in the New York Times (Chanjan S. NY Times, Jan. 15, 2016). Preliminary MRI results showed cerebral hemorrhage and brain necrosis in some study participants.
The affected subjects were males aged 28 to 49 years. All were participating in a phase I trial of BIA 10-2474, in development by Bial-Portela, Portugal, for the treatment of pain, and mood, anxiety and motor disorders associated with neurodegenerative conditions. The study was not listed on clinicaltrials.gov and details of the study protocol are lacking.
BIA 10-2474 inhibits fatty acid amide hydrolase (FAAH), a key modulator of the endocannabinoid system. The FAAH enzyme degrades fatty acid amides such as anandamide (N-arachidonoyl ethanolamide), N-palmitoyl ethanolamide (PEA),
N-oleoyl ethanolamide (OEA), N-stearoyl ethanolamide (SEA), and N-linoleoyl ethanolamide (LEA). Anandamide, named for the Sanskrit word for ‘bliss’ (Ananda), was the first ligand found to bind to the CB1 and CB2 cannabinoid receptors. BIA 10-2474 blocks the conversion of anandamide to ethanolamine and arachidonic acid and elevates anandamide levels in the CNS and periphery. FAAH inhibition is one of the mechanisms of action of some anesthetics, such as propofol (Patel et al. Br J Pharmacol 2003;139):1005-1013). Pre-clinical studies have also reported that FAAH inhibitors promote neuronal survival in animal models of traumatic brain injury (Tchantchou et al. Neuropharmacology 2014;85:427-439).
A first-in-human study of BIA 10-2474 was launched on July 9, 2015, with a planned enrolment of 128 healthy volunteers (90 on active drug, 38 on placebo). Following single-dose testing, multiple-dose testing was initiated in the first week of January 2016. The first adverse reactions were observed on January 10, when a subject presented with severe neurological symptoms that were initially diagnosed as a stroke, according to an interview with Dr. Edan on French radio. The trial was stopped the next day. The patient went into a coma, and died on January 17. Five others were hospitalized between January 10-13. Four had hemorrhagic and necrotic lesions on brain MRI (three with severe neurological symptoms), and one was asymptomatic. The six subjects had received the highest cumulative drug dose. According to a Bial media release on January 19, four subjects remain hospitalized and one has been able to return home.
The cause of mortality and morbidity has not been determined. Some have speculated that adverse effects may be due to drug impurities; that the compound may have promoted an autoimmune response; or that reactions were due to unidentified off-target effects of the drug.
France’s Agence national de securité du medicament et des produits du santé (ANSM), which oversees drug safety, has launched an investigation.
Several other FAAH inhibitors have been investigated in phase I and II trials, but no deaths or severe adverse events have been reported (for a review of the drug class see Lodola et al. Expert Opin Ther Pat 2015;25:1247-1266). A phase II trial of PF-04457845 for osteoarthritis knee pain reported that treatment was well tolerated, although the drug was ineffective (Huggins et al. Pain 2012;153:1837-1846). Merck (MK4409), Sanofi-Aventis (SSR411298) and Vernalis (V158866) also have FAAH inhibitors in various stages of development.
Following news reports of the Bial deaths, a phase II trial of a Janssen compound, JNJ-42165279, was voluntarily suspended pending further safety analyses. The study was investigating the efficacy of the drug in social anxiety disorder and depression. A phase I study of drug kinetics in the brain has been completed but results have not yet been published (for a review of preclinical data see Keith et al. ACS Med Chem Lett 2015;6:1204-1208). Recent studies have examined the utility of combined FAAH inhibition and cyclo-oxygenase (COX) inhibition for inflammatory and pain syndromes (Migliore et al. Eur J Med Chem 2015;109:216-237).
Deaths or severe adverse events among healthy volunteers in phase I testing are extremely rare. A recent meta-analysis of Pfizer healthy volunteers (n=11,028) enrolled in non-oncology phase I studies found that the incidence of severe adverse events was 0.31%, with no deaths reported (Emanuel et al. Br Med J 2015;350:h3271).
Severe adverse effects occurred in a first-in-man study of TGN1412, a monoclonal antibody that acted as a CD28 agonist. In what became known as the Elephant Man trial, six patients were hospitalized within hours of drug infusion with severe immune reactions and multiple organ dysfunction in March 2006. That study led to a series of new recommendations (the Duff Report) for phase I drug testing in the U.K. (http://webarchive.nationalarchives.gov.uk/20130107105354/http://dh.gov.uk/en/publicationsandstatistics/publications/publicationspolicyandguidance/dh_063117).