Nearly two weeks after the death and hospitalisations of participants in a phase I study of Bial’s BIA 10-2474 very few details have been disclosed about the compound, the study design or the specific nature of the catastrophic adverse events.
However, it is known that the Bial project was a fatty acid amide hydrolase (FAAH) inhibitor, and despite the lack of further information Johnson & Johnson has already moved to suspend trials of its similarly acting antidepressant JNJ-42165279. EvaluatePharma reveals several other FAAH inhibitors whose developers likewise have an important decision to make (see table below).
Among the most advanced are those owned by the UK’s Vernalis and Faah Pharma, a private group formed specifically to take on development of an Infinity Pharmaceuticals asset. There are also at least two academic groups with clinical projects, as well as additional assets that have already been ditched.
There is no clear link between FAAH inhibition and the kind of toxicity seen in the Bial study, in which five of six volunteers given the highest BIA 10-2474 dose suffered haemorrhagic and necrotic brain lesions, and one subsequently died. Moreover, preclinical studies have suggested that the therapeutic potential and side effects of FAAH inhibitors vary widely.
That said, J&J can hardly be blamed for immediately suspending its phase II studies, in which JNJ-42165279 was being tested for social anxiety disorder and major depressive disorder. The company said earlier trials had not shown any serious adverse events, but it was taking the move as a precaution.
Interestingly there are already two approved FAAH-inhibiting products: Cipher Pharmaceuticals’ Dermadexin and Pruridexin are topical creams that have been cleared in the EU as medical devices that serve as barrier repair creams. They both contain pyridine-3-carboxamide glyceryl monocaprylate, which inhibits FAAH as well as NF-kappaB-mediated inflammatory gene expression.
|Fatty acid amide hydrolase (FAAH) inhibitors|
|PF-04457845||Phase II||Yale University||NCT02134080|
|JNJ-42165279||Phase II (suspended)||Johnson & Johnson||NCT02432703, NCT02498392|
|IPI-940||Phase I||Faah Pharma||–|
|BIA 10-2474||Phase I (suspended)||Bial||–|
|URB597||Phase I (not yet recruiting)||Max-Planck Institute||NCT00916201|
|FAAH research program||Preclinical||Advinus Therapeutics||–|
|SAR411298||Abandoned - phase II||Sanofi||NCT00822744, NCT01439919 (terminated)|
|IW-6118||Abandoned - phase II||Ironwood Pharmaceuticals||NCT01107236|
|SSR 101010||Abandoned - phase I||Sanofi||–|
|IW-7229||Abandoned - phase I||Ironwood Pharmaceuticals||–|
|MK-4409/Org 231295/KDS-4103||Abandoned - phase I||Merck & Co||–|
|FAAH antagonist||Abandoned - preclinical||Evotec||–|
|PF2||Abandoned - preclinical||LG Life Sciences||–|
|AM374||Abandoned - preclinical||MAKScientific||–|
FAAH is a membrane protein that catalyses breakdown of the endocannabioid anandamide, which normally produces an analgesic effect. Inhibition of FAAH thus elevates anandamine levels, hence the application in pain relief and depression.
As for clinical projects, Vernalis has for some time been seeking a partner for V158866, while it is not clear whether Faah Pharma has carried out any further work on the Infinity asset since acquiring it in 2014. Pfizer abandoned PF-04457845, though work continues in studies sponsored by Yale University.
Pfizer’s discontinuation might hint at earlier fears over FAAH inhibitors’ risk/benefit balance. Ironwood and Sanofi abandoned FAAH inhibitor portfolios, the latter terminating one phase II study of SAR411298 for “strategic reasons” after recruiting just five breakthrough cancer pain patients.
The spotlight might also fall on Bial’s contract research partner, Biotrial, though there has of course been no suggestion of impropriety. Biotrial is known also to be running the clinical studies of Arno Therapeutics’ onapristone, for instance.
For obvious reasons the BIA 10-2474 disaster has been compared with the serious adverse events seen 10 years ago in a Parexel-run phase I trial of Tegenero’s CD28-agonist MAb TGN1412. There are key differences, however, since that had concerned the first human administration of TGN1412, and those running it came under considerable criticism for dose escalating too quickly.
In contrast the Bial trial, which recruited 116 volunteers, had already seen 84 of them receive BIA 10-2474 with no severe adverse events. Tegenero ended up going out of business, though curiously TGN1412 was later picked up by the Russian company Theramab, and is in phase II development as TAB08.
It was only three days ago that Bial issued a statement on its catastrophe; moreover there still appears to be no record of the study in question on Clinicaltrials.gov or EudraCT. With so many unknowns it makes perfect sense for others to play it safe.