BIA 10-2474: Beyond the Finger Pointing and Speculation, Many Questions

The tragedy that happened during a Phase I first-time-in-man trial in France a few days ago has received widespread attention in the media, as had to be expected when you have five trial participants hospitalized with neurological symptoms of varying degrees, and one dead. It has also highlighted how the interaction between mainstream media, the so-called social media, and members of the scientific community fuel speculation in the absence of corroborated facts.

Nonsense was rampant from the day the news broke (January 15th). The first things the public learned through the media was that the tested agent was a “cannabis derivative” that “had been looked at in chimpanzees before.” Wrong as both statements were, anti-cannabis campaigners, animal rights activists, and pharma industry foes immediately latched onto them. H.M. Pharma Consultancy was among the first trying to set the facts right in the social media (as e.g. here on Twitter): the investigational compound, Bial-Portela’s BIA 10-2474, is an inhibitor of fatty aminoacid hydrolase (FAAH). There is not much more of any substance that we know even today (Jan 20th). Bial has not disclosed the structure of BIA 10-2474, the outline of the trial protocol that was leaked to the media shows nothing out of the ordinary for a Phase I (contrary to some reports, using a placebo group in f.t.i.m. trials is not unheard of), and virtually the only other information is that the affected participants’ MRIs showed brain hemorrhages and deep necrosis – and that they all had received one drug dose before the events.

Sadly, but not unexpectedly, some members of the scientific community whom the media approached for comments would not refuse to pile speculation upon speculation in this near-total absence of hard data. This and that, or maybe another, moiety of the presumed drug structure (based on formulas or Markush structures in Bial’s patent applications) could have caused all that. But maybe not by itself. Or maybe only after some time. Or maybe because BIA 10-2474 is an irreversible inhibitor – if it really is.

But none of the few FAAH inhibitors that have been clinically investigated so far has shown any known problems with cerebral hemorrhages or necrosis, and what we know about this pathway does not suggest such danger potential at any reasonable drug doses. Given the broad safety margin that has to be applied when the human starting dose for a small molecule is defined on the basis of preclinical studies in several animal species, it seems extremely unlikely that a fundamentally unsafe dosing scheme had been chosen and approved.

As it happens so often when the public clamor is loudest, it pays to look at what is not being discussed. In the present case, nobody is talking about the clinical supplies: Who manufactured, quality-controlled and released them? Was it Bial, the originator of the drug and the sponsor of the trial, or did they outsource this non-standard mini-scale manufacturing? The CRO, Biotrial, is also getting massively damaging media heat – but apparently it was the Centre Hospitalier Universitaire de Rennes (to which Biotrial has very close ties) where the patients were actually dosed. Why did 84 other volunteers who were exposed to the test drug show no clinically manifest adverse effects at all – or did they? (Remember: trial participants are encouraged, and even prompted, to report even the most trivial discomfort.)

Obviously we won’t add speculations of our own at this stage; but there are many questions that just do not seem to have been publicly asked so far.