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Expert opinion: What is wrong with BIA 10-2474?


Thankfully major adverse effects of experimental drugs in Phase 1 clinical trials are rare, so we are very shocked by the news that six volunteers who were given the Bial drug BIA 10-2474 are seriously ill.

BIA 10-2474 is designed to be a FAAH inhibitor. Fatty Acid Amide Hydrolase (FAAH) is an enzyme found throughout the body, and is particularly important in the central nervous system. This enzyme is responsible for the hydrolysis (breakdown) of a number of important naturally occurring bioactive lipids, including anandamide, the brain's natural cannabinoid.

FAAH is a potentially important therapeutic target, in particular for pain relief. The idea is that blocking the enzyme increases anandamide and there is more anandamide available to bind to cannabinoid (CB1 and CB2) receptors, and these receptors can activate the body's pain control system. There is very strong evidence from biomedical research that this is the case.

The news reports suggest that volunteers given lower doses of the experimental drug had no adverse effects, and that FAAH inhibitors that have been developed previously by other companies (Pfizer, Merck) have been abandoned, not because they were toxic but because they were not effective. So it is entirely unexpected that the Bial compound has had such major effects on these volunteers.

So what's the problem with this particular drug? Quite simply, we don't know right now, and it is likely to take time to find out. One likely explanation is related to off-target effects, Technically, that as well as binding to FAAH there is drug engagement with another protein target that has lower affinity for BIA 10-2474 than FAAH. This would mean at higher doses a new effect is switched on through blocking the second protein. These off-target effects cannot easily be predicted, and in most cases off-target effects are not toxic. Unfortunately the the toxic effects are generally only detected once adverse effects are identified in people, because they are completely unknown before the effects are observed.

Another possibility is that there is no off-target engagement, but that there are detrimental effects caused by switching off FAAH in man, in other words too much anandamide may cause problems in people.

Finally the problems may be systemic, relating to an unpredicted effect of the drug on other organ systems, for example liver or kidney to cause a rapid development of serious illness.

Does this mean that clinical trials are unsafe?

Phase 1 trials are highly regulated across Europe, with volunteer safety at the heart of the rules. Currently there is no reason to suppose that there were errors made in the trial design. Despite the precautions built into the systems used, the truth is that no drug can ever be completely safe. Thankfully among the thousands of people who volunteer for drug trials each year there are very few serious effects, which suggests that the systems used work well. While a huge amount of work is carried out to demonstrate safety before an experimental medicine can be given to people, unpredicted effects sometimes occur, as in this case. Just as when a plane crash occurs we don't always think of the millions of people who take off and landed safely, a trial that goes wrong can cast doubt on the systems we use to develop much-needed new medicines.

Our thoughts are with the trial volunteers who are currently in hospital and their families.

Image: Structure of BIA 10-2474 (source Wikipedia)

Professor Marcus Rattray, Head of School of Pharmacy, reacting to article in The Guardian

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