FAAH inhibitors aren’t relatively new drugs, researchers have been using them to modulate the endocannabinoid system for several years (see reviews here and here).

In general, enzyme inhibitors can sometimes be favourable therapeutic target in that they can have fewer adverse effects compared to directly manipulating the target receptor. FAAH inhibitors, in particular, are advantageous over directly activating cannabinoid receptors in that they shouldn’t induce the same type of side effects one would expect with direct cannabinoid receptor activation; namely, the psychotropic, cataleptic, and euphoric effects after activating CB1 beyond “normal,” or physiological, ranges (ie, without adding any type of drug into the system). This results in less risk for drug abuse, and in general, better safety profiles (review here). In fact, you can completely knock out the gene that produces FAAH, and still get relatively normal mice, at least while they’re healthy.

What happened?

Even before starting a human clinical trial (but after pre-clinical trials, eg, in laboratory animals), drug companies must request approval from a governing body — in Canada, Health Canada; the US, the FDA, etc. In this case, approval was granted from the French regulatory authority was the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM) and approval from an independent ethics committee.

Human clinical trials follow defined stages. Phase 1 (aka, first-in-human trials) involves testing the drug in a small set of healthy volunteers — this phase is typically to establish safety margins. Phase 2 involves testing in a small group of the patient population in which the drug was intended (eg, a pain drug in those experiencing pain). In general, the aim of phase 2 is to identify dose and potential side effects. In phase 3, a large sample in the intended population is administered the drug, and the effectiveness is evaluated. The Bial trial was in the last stage of phase 1 testing — multiple dosing (10 days) in healthy volunteers.

Prior to the first appearance of issues, 72 volunteers had been exposed to various doses of BIA 10–2474 (0.25–100 mg in either single or repeated administration) without serious issue. However, on the 5th day of administration of 50 mg, one of the six volunteers in this cohort of volunteers was hospitalized in serious condition, and three days later becoming brain dead. All five other volunteers in this cohort were hospitalized in the three days after the first, and two have lasting neurological issues.

Why was this time different?

What was peculiar about the outcome of this drug trial is that at least four other companies (Pfizer, Janssen, Sanofi, and Vernalis) have previously run clinical trials on FAAH inhibitors (Merck, Bristol-Myers Squibb, and Eli Lilly have also performed pre-clinical studies). The reason why you probably haven’t heard about them is because they didn’t make it very far in the trials — not because they had adverse effects, but because they didn’t seem to have much of a clinical effect. This was rather surprising given that, at least in the case of the Pfizer drug, blood tests showed a >97% inhibition of FAAH activity.

If all previous FAAH inhibitors seemed to be relatively tame, what was the difference with this one? The consensus of most discussion in this area seems to point to two issues: 1. The pharmacological properties of this particular FAAH inhibitor, and 2. the study design.

1. The pharmacological properties

BIA 10–2474 is different from other FAAH inhibitors: it lacks of specificity and strength, yet has a longer duration of action.

In some instances, a drug that binds to a few similar targets can be beneficial; however, the majority of the time, specificity is best. The less specific a drug is to its target, the more easily it can bind to other things and result in unwanted side effects. Compared with other FAAH inhibitors, BIA 10–2474 was much less specific to FAAH.

The strength of a drug, measured by the affinity and efficacy of the drug at its target, is also important, and will play a major role in determining dosing. BIA 10–2474 is particular in that it has a very steep concentration curve — it goes from no effect to full effect within a very small window. This type of effect can make adjusting doses in humans more difficult. BIA 10–2474 was also much weaker than other drugs in the class - it took much more to have the same effect.

72 hours after administration of BIA 10–2474, even though the drug was no longer in the blood, FAAH was still inhibited. Longer isn’t always bad, for example some of our newer antibiotics (like azithromycin) last a very long time, and translates to less frequent administration. But, such a long duration of action comes with important considerations when giving multiple doses – too frequent administration can lead to overlap, and presents greater risk of side effects.

For more specific information on the chemistry of BIA 10–2474, see Dr. Christopher Southan’s very extensive blog post. PK and PD data are summarized in the TSSC’s report.

2. Study design

Extrapolating data from animals to humans is not always a perfect science, so first in human trials are designed to reduce risk as much as possible. Doses would typically range from very low, to slightly above what would be required to achieve target (in this case inhibition of FAAH), but still far below the estimated dose which would cause observable events (based on animal data).

In ascending dose drug studies, doses are escalated in a specific pattern, typically based on international guidelines, but guided by pre-clinical data and initial human findings. Typically, the higher the dose, the smaller the increment (as the target becomes saturated, any excess drug is left open to bind to other things, presenting possible toxicity).

Volunteers in this part of the study were given either 2.5, 5, 10, 20 mg once per day for 10 days (initiated sequentially, without overlap). In the single dose study neither 50 mg nor 100 mg produced adverse events. Nevertheless, the jump from 10 to 20 mg is substantial, especially given that initial studies found that maximal FAAH inhibition was reached at 5 mg. Taking the rates of drug elimination into account, there was no reason to even administer such a high dose repeatedly.

However, according to the final report by the TSSC, there was nothing of particular concern in the initial toxicity data which would raise concerns for the administration in humans. Prior to administration in humans, Bial had actually performed toxicity testing in four species, which is more than required, and more than what had been screened in any other FAAH inhibitor gone to trial. This group did note that compared with other FAAH inhibitors, BIA-102474 did not seem to produce the same toxicity profile (they said it was “under par”, but still not enough to raise concerns).

“It is therefore highly likely, not to say almost certain, that the mechanism causing the accident in Rennes should be looked for outside the endocannabinoid system, especially as stimulation of endocannabinoid receptors by anandamide cannot theoretically cause this type of toxicity.” (TSSC)

It seems clear that while Bial didn’t “break” any rules, there was more they could have done. They could have performed more specificity testing pre-clinically (especially since this compound seem to be less selective than others in the class). But they should have revised dosing after initial human findings. Hopefully, the new recommendations put forth by the TSSC will prevent instances like this from occurring in future.

What does this mean for cannabinoid-related research?

The Bial tragedy wasn’t a cannabinoid-related issue, but cannabinoid-related research will still be (and is) affected.

We still don’t actually know exactly what happened to cause the toxicity, and as of writing this post, Bial has yet to release BIA 10–2474 to others for study (which isn’t required). Without knowing what else this drug may have targeted, it’s difficult to design and screen other drugs for similar potential. Therefore, out of concern for safety, at least one company investigating FAAH inhibitors (Janssen) has currently suspended their clinical trials.

Since the TSSC report was released, it has received very little media attention, especially given the substantial attention the initial (sometimes erroneous) reports received. Where there was a follow up story (see CBC, NYT, the Independent), little explanation was given as to why Bial and BiotriaL were found at fault. Citing the French Health Minister and the findings from France’s social affairs inspectorate (IGAS), dosage and time to report event was given as the cause, without mention of anything related to the specifics of the drug. In fact, I’ve only found two major English media outlets (NPR, and vaguely in the WSJ) where the TSSC report was even mentioned (but note that the WSJ was oversimplified, and inaccurate in places).

For all the mention of cannabis and cannabinoids in relation to this trial, not a single news piece that I could find has explicitly stated TSSC’s findings that this was not an cannabinoid-related issue. A few articles have danced around it (simply stating that the drug was “toxic”), but most no longer have any mention of cannabinoids at all (mentioning only FAAH, if at all).

This is a big problem for cannabinoid-related research. This type of biased reporting contributes to the negative perception of the public, and again, is precisely why I don’t tell people what I do.

Since public funding is becoming more difficult to acquire (due to cuts in the US, and major problems with the CIHR funding scheme in Canada), more and more basic researchers are forced to seek out private funding. However, private funding classically favours “trendier” science, which doesn’t bode well for an area that gets repeatedly portrayed in a negative light. This negative media attention can also drive large pharma companies away from performing future clinical trials (see Janssen reference above). Regardless of sound science to back these compounds, generally risk adverse companies will tend to avoid this field. Ultimately, this trickles down and slows progress in the cannabinoid field as a whole.

So, yes, Bial has come and gone. But the news reports are still out there, uncorrected, or for the most part unreported. This is why we need advocates for good cannabinoid research, based on solid research that is disseminated appropriately.

Tell me, what did you think of the coverage? Had you seen the updated press releases or any statements? Have more questions on how FAAH inhibitors work? Leave me a comment and let me know.