# FAAH inhibitors in the limelight, but regrettably

Christophe Mallet, Claude Dubray, Christian Dualé

► To cite this version:

Christophe Mallet, Claude Dubray, Christian Dualé. FAAH inhibitors in the limelight, but regrettably. International Journal of Clinical Pharmacology and Therapeutics, 2016, 54 (07), pp.498 - 501.
10.5414/cp202687. hal-04337687

HAL Id: hal-04337687

https://uca.hal.science/hal-04337687v1

Submitted on 12 Dec 2023

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Distributed under a Creative Commons CC BY 4.0 - Attribution - International License
**Key words**

fatty acid amide
hydroxylase – endocan-
nabinoids – phase I –
serious adverse event
– brain injury

Received
April 7, 2016;
accepted
April 13, 2016

Correspondence to
Dr. Christian Dualé
CHU Clermont-Ferrand,
Centre de Pharmacolo-
gie Clinic, 28, Place
Henri-Dunant BP 38,
63001 Clermont-Fer-
rand, France
cduale@chu-clermont-
ferrand.fr

FAAH inhibitors in the limelight, but regrettably

Christophe Mallet<fnref n="1" />,<fnref n="2" />, Claude Dubray<fnref n="1" />,<fnref n="2" />,³, and Christian Dualé<fnref n="1" />,³

¹Inserm U1107 «Neuro-Dol», ²Univ-Clermont1, and ³CHU Clermont-Ferrand,
Centre de Pharmacologie Clinique (Inserm CIC1405), Clermont-Ferrand, France

**Abstract.** This short review focuses on the recent drug development of FAAH inhibitors, as recent serious adverse events have been reported in a phase I study with a compound of this class. The authors overview the potential interest in targeting FAAH inhibition, the current programs, and the available information on the recent dramatic events.

In January 2016, we were informed of the exceptional occurrence of serious adverse events (SAEs) in a phase I clinical trial conducted by the Biotrial Pharmacology Center (Rennes, France) on behalf of Bial-Portela & Ca. SA (São Mamede do Coronado, Portugal). The trial involved the compound BIA 10-2474, a drug designed to inhibit fatty acid amide hydrolase (FAAH). After two initial phases (single escalating doses up to 100 mg, and kinetics-food interaction studies) without any untoward SAE, the phase in question, which intended to examine the effect of multiple doses (5 or 6 daily doses), resulted in SAEs in 6 participants, who had all been administered the highest tested dose (50 mg). This was a threshold effect, since no SAE had been reported with the lower dose of 20 mg given to the volunteers previously. The most serious symptoms had central neurological features, the worst being those associated with a single case of coma which rapidly lead to brain death. Of the other 5 hospitalized participants, 2 had serious neurological damage (with clinical improvement apparently occurring within a few days). Because of these events, the trial was immediately suspended. Further information (including the protocol of the trial) is available on the website of the French National Agency for Medicine and Health Product Safety (ANSM)<fnref n="1" />. The agency has also recently published the summarized

conclusions of a temporary specialized scientific committee<fnref n="2" />. Although no definitive conclusion can be drawn at the present time regarding the causes, the seriousness of the events has undoubtedly and, in this case regrettably, brought the development of FAAH inhibitors/inactivators into the limelight.

FAAH inhibitors/inactivators have been developed because of their ability to increase the concentration of endocannabinoids. Endocannabinoids are lipid mediators released on demand from membrane phospholipid precursors. Their targets are the cannabinoid receptors CB₁ and CB₂, but other receptors can be involved in their action, such as GPR₅₅, peroxisome proliferator-activated receptors (PPARs) and vanilloid receptors (TRPV₁). This system has been implicated in a wide range of physiological processes such as those associated with chronic pain, metabolic disorders, psychoses, nausea and vomiting, depression, and anxiety disorders (see [1, 2, 3, 4, 5] for reviews). Some exogenous cannabinoids acting on CB₁-₂ are currently used in therapeutics (e.g., Bedrocan®, Bedrobinol®, Bediol®, Bedica®, Cesamet®, Marinol®, Sativex®) involving a variety of indications such as anorexia, neuropathic pain and multiple sclerosis, depending on the country in which the drugs are marketed. However, such treatments may have neurological side effects (including impairment of cognition and motor functions and a predisposition to psychoses), notably when these agents are used for long-term treatment [6, 7].

<footnote n="1">¹http://ansm.sante.fr/S-informer/Actualite/
Essai-clinique-BIA-102474-101-Bial-Biotrial-Chro-
nologie</footnote>

<footnote n="2">²http://ansm.sante.fr/Dossiers/Essai-Clinique-Bial-
Biotrial/Essai-clinique-BIA-102474-101-du-labora-
toire-BIAL/(offset)/0</footnote>
Increasing the concentration of endo-
cannabinoids, rather than administering
exogenous agonistic agents, would reduce
cannabinoid-like adverse events. This strat-
egy can be achieved through the inhibition
of catabolic enzymes, notably FAAH, an
integral membrane enzyme that hydrolyzes
the fatty amide family of lipid transmitters
including the most thoroughly studied endo-
cannabinoid, N-arachidonoylethanolamide
(anandamide) [8]. FAAH also degrades sev-
eral related fatty acid amides which have di-
verse biological functions and mechanisms
of action [9]. FAAH-deficient mice have
enhanced levels of anandamide and display
a CB₁ receptor-mediated hypoalgesic pheno-
type [10, 11]. Pharmacological inhibition of
FAAH increases fatty acid amide concentra-
tions in both rats and humans [12, 13]. This
strategy seems to be successful in animal
models of anxiety and depression [3], sleep
disorders [14], and nociceptive or neuropath-
ic pain [12, 15, 16]. Interest in this pharmaco-
logical pathway is illustrated by the numer-
ous molecules under development. Among
the most advanced programs are those con-
cerning the compounds PF-04457845, JNJ-
42165279, SSR-411298, V-158866, and
URB597³. The disorders for which these
agents are being tested are mostly neuropsych-
iatric, such as pain conditions, depression,
anxiety disorders, and phobias, Tourette syn-
drome, and symptoms associated with can-
nabis withdrawal. The available data from
completed clinical trials indicate that FAAH
inhibitors are well tolerated. A phase I study
of PF-04457845 (developed by Pfizer, New
York, NY, USA) showed that, compared to
placebo, the increase in somnolence was
only mild, and that there were no effects on
cognitive function [13]. The corresponding
phase II study demonstrated that this agent
had a safety profile indistinguishable from
placebo, where the main treatment-related
side effect was dizziness [17]. A phase I
study of JNJ-42165279 (developed by John-
son & Johnson Pharmaceutical, New York,
NY, USA) found few side effects and all
were of mild intensity. A slight and transient

increase in liver transaminases was observed
at the highest doses in a few cases [18]. In
a phase II study with SSR-411298 (Sanofi,
Gentilly, France) in patients with depression,
the rate of adverse events was similar in the
treatment and the placebo group. Headache,
suicidal ideation, diarrhea, dizziness, and
nausea were the most frequent adverse ef-
fects observed in the treatment group [19]. A
major observation was that FAAH inhibitors
do not apparently induce those adverse ef-
fects commonly associated with exogenous
cannabinoids, such as impairment in cogni-
tion, motor coordination, and psychoses.
However, it must be noted that the effects of
chronic treatment are still largely unknown.
It is also of interest that in two randomized,
double-blind, placebo- and active drug-con-
trolled clinical trials, no clinical efficacy of
the tested FAAH inhibitor could be demon-
strated. This was the case with PF-04457845
on pain due to osteoarthritis [17], and with
SSR-411298 in elderly patients with major
depressive disorders [19]. Following an-
nouncement of the accident at Biotrial, the
two JNJ-42165279 trials were also suspend-
ed as a precautionary measure.

Since these events came to light, many
researchers and clinicians have questioned
whether the type of adverse events observed
are directly related to an inhibition of FAAH,
and speculate that they may result from an
interaction with other pharmacological tar-
gets, specific to BIA 10-2474 and which only
become important above a certain concentra-
tion threshold. An answer to this question is
highly important since on the one hand, this
type of adverse reaction could potentially
occur with all substances belonging to this
class of drugs but on the other, this would
not apply if a different target, specific to this
particular drug was involved. The putative
role of a metabolite has also been mentioned
by the experts commissioned by the ANSM.
They have since rejected the hypothesis of
a manufacturing defect, and state that the
preclinical studies – including that in which
dogs died – had met the prerequisites for a
first-in-man study.

The protocol document of the above
mentioned phase I study of BIA 10-2474
shows that the study design is conventional
and was apparently strictly adhered to. How-
ever, more precise information concerning

<footnote n="3">³See refs. on Clinicaltrials.gov: NCT02134080, NCT01618656, NCT00981357, NCT02498392, NCT02432703, NCT00822744, NCT01439919, NCT01748695 & NCT00916201.</footnote>
the extent of the brain damage in the healthy
study volunteers who suffered neurological
symptoms in the days following the first 5 or
6 BIA 10-2474 administrations is still await-
ed. The short report which has so far been
published by ANSM mentions symptoms
related strictly to cerebral functions, with
“very fast appearance”, with homogeneous
aspects but where there are between-subject
differences in severity and progression. MRI
observations showed the presence of “micro-
cerebral tissue damage of varying severity
and with unusual topography”. On the other
hand, this report has not provided a credible
lead concerning possible mechanisms in-
volved.

The fact that the adverse events were ob-
served in 5 out of the 6 subjects who received
50 mg per day of BIA 10-2474 excludes the
possibility of an idiosyncratic reaction in an
individual with a particular phenotype. Thus,
a concentration-dependent effect, with some
between-subject variability, seems more
likely. In animals, the pharmacokinetic half-
life is relatively long and the fact that the
accident happened after several administra-
tions, argues for a product accumulation in
which toxic levels are reached within a few
days. This may result from low clearance
rates and elimination pathways in humans
that differ from those in the experimental an-
imals used during product development. Al-
though this hypothesis cannot be excluded, it
does not appear to be a likely explanation be-
cause BIA 10-2474 does not interact directly
with receptors, but rather inhibits an enzyme
involved in the catabolism of endocannabi-
noids. In biological systems, inhibition of
one metabolic pathway is often compensated
by activation of alternative pathways in order
to restore or at least partially restore the sub-
strate balance and status quo. In support of
this viewpoint is the fact that phenomena re-
sembling those seen in humans with BIA 10-
2474 have not been reported in the literature
in any of the numerous animal studies with
various inhibitors of FAAH, even when high
doses have been used or, as in the case of
rodents, when endocannabinoids have been
administered by intracerebral injection. That
FAAH-deficient mice (knock-out) thrive and
exhibit no abnormal behavioral symptoms
supports the hypothesis even though not
yet conclusive, that BIA 10-2474 itself or a

metabolite thereof and not the inhibition of
FAAH is the cause of the adverse reactions.
The analysis of BIA 10-2474 plasma con-
centrations in the healthy subjects who were
included in the repeated-dose study should
provide information important for answering
two fundamental questions, namely: (i) Does
drug or metabolite accumulation occurring
in humans result from low clearance or the
presence of saturable metabolic pathways?
(ii) Is there a relationship between the mag-
nitude of blood concentrations and the se-
verity of neurological symptoms in subjects
who received the highest dose of 50 mg? In
the course of the coming weeks or months it
is hoped that information will come to light
enabling a distinction to be made between the
possible target specificities of BIA 10-2474
and those of other FAAH inhibitors. This in-
formation is vitally important since the fate of
this class of drug and the marketing potential
of FAAH-inhibitors depend on it.

Conflict of interest

The authors have no conflict of interests
to declare.

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