This is a black Friday for Pharma drug development in general and for endocannabinoid research in particular. One would expect that the extensive preclinical development with small molecules ensures the lack of severe toxicity in humans once the experimental drug is taken into the develomental phase I in humans. This was not the case with the irreversible (covalent) FAAH inhibitor BIA-10-2474 from Bial, which was tested by Laboratoire Biotrial in Rennes, France. As Reuters reported "French drug trial disaster leaves one brain dead, five injured". Apparently the high chronic doses caused this effect in some humans. The question now is whether this toxicity is due to the mechanism of action (via inhibiting the degradation of endocannabinoids in the brain), or whether this is a severe aversive effect specific to the drug developed by Bial? Given that Pfizer already entered phase II clinical trials with the same or similar concept (potent, irreversible and selective FAAH inhibitor PF-04457845) and also Merck (MK-4409), the disaster may rather have been caused by the toxicity of this particular drug from Bial. Yet, how selective is BIA-10-2445 towards FAAH over other enzymes at higher concentrations? More information about the full spectrum of pharmacological effects of BIA-10-2472 is awaited and will have to be carefully analyzed by the research community. Furthermore, formation of haptens with serine residues in certain proteins like hydrolases (lipases, proteases or esterases) which in humans may lead to a strong and exacerbated immune reaction cannot be excluded without more detailed information about the cause of damage and lethality.
FAAH inhibition, leading to dramatically increased levels of the endocannabinoid anandamide and other N-acylethanolamines, may be a feasible novel therapeutic option to treat certain types of neuropsychiatric disorders and maybe certain forms of pain, but irreversible blockage of FAAH may likely also cause severe side effects in the kidney and liver, especially upon prolonged treatment. The fate of the covalent irreversible FAAH inhibitors for clinical development just got another blow by this sad report from Rennes, despite the fact that the toxic effect of BIA-10-2445 may be unrelated to the effect on the endocannabinoid system.