French authorities are still investigating the Biotrial-run Phase I study in which one volunteer died and five others were hospitalised on Thursday (one as a precaution).
Little additional information has been provided, but what is clear at this stage is that the injured men had been given multiple doses of the drug.
BIA 10-2474 inhibits an enzyme called fatty acid amide hydrolase (FAAH), which results in the accumulation of fatty acid amides.
One of these compounds – anandamide – activates cannabinoid receptors, which are thought to have a variety of functions including damping down neurones involved in the transmission of pain.
Bial is not the only company to have looked at FAAH inhibition.
Big Pharma and FAAH
Sanofi and Pfizer have researched FAAH inhibitors – PF-0445845 for osteoarthritis pain and trauma and SSR411298 for the treatment of depression, respectively – however both halted development a few years back.
Pfizer spokeswoman Lisa O’Neill told us “we did explore the potential of a FAAH-inhibitor for osteoarthritic pain in Phase 2 trials however no significant efficacy was observed.”
She added that “The FAAH-inhibitor was recently being evaluated in a Phase 2 study in Post-traumatic Stress Disorder but we discontinued this trial in 2015 for business reasons. We do not have any active trials in this area.
Similarly, Jack Cox from Sanofi told us “we have no projects in development that target this enzyme.”
Adverse events
The difference between the Pfizer and Sanofi studies and the Bial trial is the occurrence of serious adverse events.
The reason for this difference has not yet been determined, although it may be to do with the dosing regimen according to Stephen Alexander, associate professor in molecular pharmacology at the University of Nottingham.
“There are a lack of data on the Bial compound, which doesn’t allow us to be certain about its action. It might be due to differences in the way that the body handles the drug compared to other FAAH inhibitors used previously in human.”
But the most likely scenario – according to Alexander – is that in addition to FAAH the Bial compound blocks another unidentified protein, the impact of which is only apparent in people given high and or repeated doses of the drug.
“If the report is correct in that the severe adverse effects were only observed in those individuals that received repeated cumulative doses of the compound, there is a possible explanation, which is more likely in my opinion.
“While this is just speculation, one possibility that presents itself, is that with repeated dosing, not only would the primary target, FAAH, be affected, but also a secondary, as yet unidentified target – the off-target.”
FAAH development
Even if it is confirmed that BIA 10-2474 does act on several enzymes there is not sufficient information to say whether this action is shared by all FAAH inhibitors.
For example, no adverse events of the kind reported in the Bial study occurred during early phase clinical trials of Pfizer’s FAAH inhibitor. Similarly, in the Sanofi study there was no difference in the frequency of adverse events between the treatment and placebo arms.
Even without a definitive view on the safety - or otherwise - of FAAH inhibitors, companies developing such products – like Janssen Research & Development which is trialling JNJ-42165279 for anxiety – are likely to come under event greater regulatory scrutiny.
According to Alexander “Any other FAAH inhibitor in development will be looked at very closely to try to define possible off-target effects, which may be the cause of the problems with the BIAL compound.”