Pharmacology and the Rise and Fall of the Obesity Wonder-Drug




(SR141716) was a novel
antagonist/inverse agonist at the CB1 receptor developed to aide weight loss in
obese patients. Despite showing efficacy for its indication in phase III and IV
studies, rimonabant caused significant increases in adverse psychiatric effects
in patients, including an increase in suicide ideation, and was subsequently
withdrawn from the market.  Rimonabant
was born out of exploratory research into the cannabinoid signalling system,
and was the first pharmacological modulator of this system to be approved in
Europe for human use. The FDA never approved rimonabant for the US market.
Besides the intrinsic safety issues of the drug itself, the story of rimonabant
is also associated with faults in trial design and an inferred lack of
appreciation for arguably predictable adverse central effects. Whilst the
failure of rimonabant was a significant blow to the development of CB1
antagonists, recent research has offered the potential of a second life for
rimonabant and its analogues.



Rimonabant was a first-in-class anorectic drug developed
by Sanofi-Aventis (now Sanofi) and indicated to treat obesity.  Rimonabant was the first specific cannabinoid
receptor 1 (CB1) inverse agonist to be licenced for human use, and, under the
trade name Acomplia, received approval for sale in Europe by the European
Medicines Agency (EMA) in June 2006 to be used as an adjunct to diet and
exercise for the treatment of obese patients (BMI ? 30kg/m2), or overweight
patients (BMI > 27 kg/m2) with other associated risk factors such
as type 2 diabetes or dyslipidaemia (European
Medicines Agency, 2009) (Fong and
Heymsfield, 2009). The application for rimonabant to be sold in the United
States under the trade name Zimulti was not approved by the US Food and Drug
Administration (FDA) (FDA, 2007).

Obesity is a significant worldwide health issue. A report
published in 2016 by researchers from the UK Parliament House of Commons
Library found that in England 27% of people are obese (BMI ? 30kg/m2)
and a further 36% are overweight (BMI = 25.0 – 29.9kg/m2) (figure 1). (House of Commons Library, 2017). 
A writer from the World Health Organisation (WHO) coined the term
”Globesity” in 2002 to reinforce the scale of the problem, and the WHO
estimates that in 2016 1.9 billion adults were overweight, with more than 650 million
of these qualifying as obese. The global prevalence of obesity has almost
tripled since 1975. Obesity is a major cause of preventable death, and a raised
BMI is major risk factor for other non-communicable major causes of premature
deaths worldwide, including stroke, heart disease, diabetes mellitus and some
types of cancer (World Health Organisation, 2017). In the US alone the
estimated annual cost of obesity-related illness has been estimated to be over
$200 billion. (Hammond and Levine, 2010)
(Cawley and Meyerhoefer, 2012). Therefore the need and market for effective
anti-obesity drugs is huge.

Despite displaying efficacy for the
reduction of weight in pre-clinical and clinical studies (Muccioli and Lambert, 2005), rimonabant (Acomplia) was suspended
from the European market in 2008 before being withdrawn in 2009 after post-marketing
surveillance by the European Union’s Committee for Medicinal Products for Human
Use (CHMP) discovered that the use of rimonabant doubled the risk of
psychiatric disorders in overweight and obese patients who were taking the drug
(European Medicines Agency, 2009)
(Moreira and Crippa, 2009).


Endocannabinoid System

The elucidation of the endocannabinoid system
(ECS) is a result of research stemming from the initial study of the
recreational drug now known as cannabis. The recreational use of preparations
from the plant Cannabis sativa for
their psychotropic effects has been documented for thousands of years, but the
primary psychoactive chemical of cannabis was not isolated and synthesised until
1964, when a research group led by the Israeli organic chemist Raphael
Mechoulam identified it as ??-tetrahydrocannabinol (??-THC) (Mechoulam and Gaoni, 1967) (Mechoulam,
Braun and Gaoni, 1967) (Howlett et al.,

The two identified cannabinoid receptor subtypes, CB1 and
CB2, are components of the ECS, along with their endogenous ligands and the
synthesis and degradation pathways of these ligands. The CB1 receptor is widely
expressed in the brain and peripheral tissues, whilst the CB2 is mostly
expressed in the peripheral tissues of the immune system (Simon and Cota, 2017). There has been debate as to whether or not
CB2 receptors were also present in the brain, and for over a decade the general
consensus was that they were not, and were exclusively expressed peripherally.
More recent research has determined that this is not the case, and CB2
receptors are indeed expressed in the brain (Onaivi,
2006.) It is, however, the CB1 receptor that is involved in the central
regulation of feeding behaviour through which rimonabant mediates its effect.



CB1 Receptor



The CB1 receptor (figure
2) is a Class A (Rhodopsin-like) G-protein coupled receptor (GPCR), and consists
of 7 transmembrane ?-helices. These transmembrane domains are linked by 3
extracellular and 3 intracellular loops. The N terminal is located outside of
the cell and the C terminal is inside. The CB1 receptor is among the most
abundantly expressed GPCRs in the brain (Hua
et al., 2016) (Shao et al., 2016). The receptor is coupled to the G?i/o
guanine nucleotide-binding protein (G protein) (Howlett et al., 2004).


Protein Signalling



The coupling of CB1 to G?i/o
was proven when a team led by Allyn Howlett reported that the binding of ??-THC
causes a specific inhibition of cyclic adenosine monophosphate (cAMP) in
neuronally-derived cells by inhibiting of basal and hormone-stimulated
adenylate cyclase activity. This effect was found to be inhibited by pertussis
toxin, which disables the G?i subunit.  (Howlett, 1984).

CB1 activation inhibits the adenylate cyclase isoforms 5
and 6 to reduce the activity of the cAMP-stimulated protein kinase A (PKA). PKA
normally acts to phosphorylate and therefore inactivate A-type potassium
channels, so the deactivation of this enzyme enhances the activity of the
potassium current to decrease the duration of presynaptic action potentials.
The ultimate effect of this is to decrease the amount of neurotransmitter
exocytosed into the synaptic cleft by speeding up the repolarisation of the
cell after an action potential has fired (Deadwyler
et al., 1995) (Howlett, Blume and Dalton, 2010).

CB1 receptor activation also leads to the phosphorylation
and subsequent activation of the mitogen activated protein kinases 1 and 3
(MAPK1 and MAPK3), also called ERK2 and ERK1. Derkinderen et al (2003) demonstrated that this happens
in vivo using an immunocytochemical
assay involving phosphorylation-state specific antibodies in rat hippocampal
slices to assess the degree of ERK phosphorylation. A strong phosphorylated
ERK-like immunoreactivity was seen in pyramidal cell layers of the hippocampus
10 minutes after the live rats were injected with ??-THC. ERK responses   are
involved in complex signalling pathways which ultimately function to regulate
transcription factors in cell nuclei to alter gene transcription (Derkinderen et al.,
2003) (Howlett, 2005).


Ligands for the CB1 Receptor

The discovery of the CB1 receptor and some of its
signalling pathways prompted the search for its naturally occurring ligands.
The first 2 endogenous CB1 ligands to be identified were the eicosanoids
anandamide (N-arachidonoylethanolamide, AEA) and 2-arachidonyl glycerol (2-AG).
These molecules are synthesised on demand rather than stored for release, and
are degraded primarily by the enzymes fatty acid amide hydrolase (FAAH) and
monoacylglycerol lipase (MGL) respectively (figure
3) (Pertwee, 2006) Petrocellis,
Cascio and Marzo, 2004).




3: the synthesis and
breakdown pathways of AEA and 2-AG, the first identified and most-studied
endocannabinoid molecules











of the ECS in Food Intake

ECS has been well characterised as a modulator of feeding behaviour in humans
and other animals. Early controlled human studies found that smoking cannabis
significantly increased calorific intake and weight gain (Greenberg et al.,
1976) (Foltin, Fischman and Byrne, 1988)  due to an increase in appetite known
colloquially as the ”munchies” (Devlin, 2015). The
??-THC-mediated increase in appetite and feeding behaviour is also seen in rats
(Koch, 2001).

CB1 receptor is widely expressed in the hypothalamus of the brain, an area
associated with the control of homeostasis within the body. Animal studies have
demonstrated that the injection of ??-THC increases the feeding behaviour
induced by electrical stimulation of the hypothalamus (Trojniar and Wise, 1991), suggesting that these
receptors in this specific brain area are involved in the control of food
intake. Injection of the endocannabinoid AEA into the ventromedial hypothalamus
also stimulates the intake of food (Jamshidi
and Taylor, 2001), providing more evidence of the involvement of the
hypothalamus in the ECS-mediated feeding behaviour. In genetic mouse models of
obesity (ob/ob and db/db mutants) there are elevated levels of endocannabinoids
in the hypothalamus compared to normal-weight controls whilst there are were no
differences between endocannabinoid levels in the cerebellum (Di Marzo et al., 2001). In rats, levels of 2-AG in the
hypothalamus and limbic forebrain decrease when upon feeding, and AEA and 2-AG
levels in the limbic forebrain decrease when fasting (Kirkham et al., 2002). In
their review, Gamage and Lichtman interpret these animal data to suggest that
the general mechanism through which cannabinoids induce feeding behaviour is a
negative feedback loop whereby CB1 stimulation mediates a disinhibition of
orexigenic (appetite-stimulating) neurones in the lateral hypothalamus whilst
inhibiting anorectic (satiety-inducing) neurones in the paraventricular nucleus
(Gamage and Lichtman, 2011).

initially codenamed SR141716, was first used in animal experiments to inhibit CB1
signalling during investigations of the actions of cannabinoids on CB1
receptors. At the same time, the ECS became associated with leptin, an
appetite-suppressing hormone whose gene is knocked out in mice (ob/ob mutants, figure 4) to model excessive food
intake and resultant obesity. Research groups began to shift their focus onto rimonabant
as a potential therapeutic agent in obesity after it was found to reduce
obesity in this model (Ravinet Trillou et
al., 2002) as well as in the alternative diet-induced obesity (DIO) model (Liu et al., 2004).

The underlying pharmacology therefore suggested that SR141716
could be a useful therapeutic for the reduction of weight in obesity, and
SR141716 entered the development pipeline as a novel drug for this indication.


Rimonabant: Clinical Trials and Market Approval

received market authorisation from the EMA in Europe in 2006 on the back of its
pivotal RIO (Rimonabant in Obesity) phase III trials; these were RIO North
America, RIO Europe, RIO Diabetes, and RIO Lipid (Sam, Sale and Ghatei, 2011).

RIO North-America study found that rimonabant, in addition to lifestyle
modification, produced sustained reductions in weight and other favourable
improvements in cardiovascular and metabolic endpoints over a 2 year period.
However there was an unusually high drop-out rate, with 47% of patients
withdrawing from treatment (Pi-Sunyer et
al, 2006). RIO Europe reported similar successes in weight loss whilst also
recording that rimonabant was ”generally well tolerated with mild and
transient side-effects” (Van Gall et
al., 2005).

RIO Lipids trial found that rimonabant at 20mg was associated with a
significant decrease in weight, waist circumference and triglyceride levels,
and an increase in the proportion of HDL cholesterol, in overweight or obese
patients with dyslipidaemia. This study reported that depression, anxiety and
nausea were the primary reasons for patients discontinuing the trial (Després et al., 2005). The RIO Diabetes
trial tested rimonabant in overweight or obese patients with type 2 diabetes,
and found a similar result to the lipid trial; a clinically ‘successful’
efficacy result where the drug improved weight loss and cardiovascular and
metabolic risk factors, but there was a presence of central nervous system
adverse events including depressive mood disorders (Scheen et al., 2006).

it seems that there was already evidence of the ability of rimonabant to induce
a potentially-dangerous increase in mood disorders. Two meta-analyses put forward
worries about the safety of rimonabant soon after it was approved in Europe; a
Cochrane review by Curioni and André (2006) found that 20mg per day rimonabant
caused significant nervous-system and psychiatric adverse effects, and called
into question the unusually high drop-out rate of approximately 40% after 1
year of dosing (Curioni and André, 2006)
– the average drop-out rate in phase III studies is normally closer to 30% (Alexander, 2013). Christensen et al.
(2007) also found that 20mg per day rimonabant increased the risk of
psychiatric adverse events including depression and anxiety disorders, and even
recommended physicians have ”increased alertness” to the potential
psychological effects of Rimonabant (Christensen
et al., 2007).

conclusions of these meta-analyses alongside the rejection of rimonabant by the
FDA on the grounds of worrying and poorly-characterised safety data would
foreshadow the demise of rimonabant in the years following its approval in



Soon after rimonabant was made available on the European
market, the manufacturer and regulator were inundated with complaints of the
increased incidence of depressive and anxiety symptoms in patients, as well as
reports of an increase in suicide ideation. Rimonabant was eventually suspended
by the EMA in November 2008 once it had become clear that the psychiatric risks
of the drug outweighed the therapeutic benefit, and in January 2009 it was formally
withdrawn from the European market (Simon and Cota, 2017).

The ban on Rimonabant also ended the ongoing CRESCENDO
(Comprehensive Rimonabant Evaluation Study of Cardiovascular Endpoints and
Outcomes) trial. Despite early termination of the studies, four participants
taking rimonabant had committed suicide compared to only one in the placebo
control group, and an analysis of the data revealed that rimonabant produced
significantly more neuropsychiatric and serious psychiatric adverse effects
than placebo (Topol et al., 2010). The
withdrawal of Rimonabant by the EMA was therefore proven to be appropriate and
justified, and the caution of the FDA vindicated.



Could the problems of Rimonabant have
been predicted?


Depression and
anxiety-related adverse effects can be predicted of CB1 antagonism/inverse
agonism simply by considering the common effects of recreational cannabis use. The
rationale of rimonabant was to reduce appetite in an opposite manner to the
increased appetite observed with recreational cannabis use (CB1 agonism). Given
that cannabis (e.g. when smoked) can also induce states of relaxation,
well-being, reduced anxiety, happiness and even increased enjoyment of visual
and auditory stimuli (Moreira and Crippa,
2009) (nhs.uk, 2017), it is logical to presume that rimonabant may cause
the converse psychiatric effects of stress, depression and anxiety.


Indeed, this was
confirmed in preclinical animal studies. Rimonabant was found to cause
”anxiety-like responses” in rats (Navarro
et al., 1997) as well exacerbating stress responses (Moreira, Grieb and Lutz, 2009). Drawing on such animal data,
Moreira and Lutz (2008) even suggested that a disruption in endocannabinoid
functioning may result in depression and anxiety (Moreira and Lutz, 2008). The potential for rimonabant to cause
significant psychiatric adverse effects should have therefore been anticipated,
and this risk should have been integrated into all stages of rimonabant’s


mistakes with patient selection and data stratification

The RIO trials excluded individuals with depression or
other neuropsychiatric conditions (Sam,
Sale and Ghatei, 2011). The reason for this is likely to be
that Sanofi-Aventis were aware of the propensity of rimonabant to induce
psychiatric adverse effects, and therefore did not want to worsen the condition
of those with pre-existing depression. This would also allow them to see if,
and to what extent, rimonabant would induce its psychiatric adverse effects in
otherwise mentally healthy participants.

this meant that the safety data from the RIO studies was not generalisable to
the true patient population.  Depressive
disorders are common and are co-morbid with obesity (Carey et al., 2014), so for phase III safety data to be
appropriate they must come from a participant population reflective of the
patient population. The participant design of the RIO studies also meant that
there were no data examining the effect of rimonabant on existing depressive
disorders; it would have been invaluable and potentially lifesaving if the
drug-induced increase in suicidal ideation had been appropriately characterised
before the market authorisation and CRESCENDO trial.

if the trials had included participants with depressive and anxiety disorders,
the unacceptable frequency of psychiatric adverse effects, including the
increased risk of suicide ideation and completion, would have been demonstrated
before the drug was approved and distributed to a much wider population of
at-risk patients.

issue with the RIO trial data highlighted by the FDA is that the commonly
reported adverse effect of ‘irritability’ was not classed as psychiatric. This
may have led to an underestimation in the ability of rimonabant to cause
psychiatric symptoms because irritability, a symptom indicative of depressive
and anxiety disorders, was excluded from the pool of psychiatric complaints (FDA,


Aftermath and the Future of CB1 Antagonists

The failure
of rimonabant severely hindered the study of CB1 antagonists and many research
projects and in-progress trials were terminated. However, revisitation of
preclinical data showed that the therapeutic benefits of CB1 antagonists
involve a peripherally-mediated component, whilst the psychiatric side-effects
that brought about the downfall of rimonabant are centrally-mediated. This
prompted novel research into peripherally selective CB1 inhibitors to treat
obesity (Klumpers et al., 2013).  

this end, TM38837 is a newer CB1 antagonist which, unlike rimonabant, acts
selectively in the periphery. In a phase I trial in healthy volunteers, TM38837
at a dose of 100mg had no effect on the central nervous system and did not
cause any psychiatric side effects, suggesting that this dose does not cross
the blood-brain-barrier to antagonise central CB1 receptors. The authors of
this trial report that animal models predict this molecule to have an equal
potency to rimonabant in terms of treating metabolic disorders, suggesting that
this molecule has future potential for treating obesity without the psychiatric
adverse effects associated with rimonabant (Klumpers et al., 2013).  However, there has been little news and no
published data from the parent company of TM38838, (‘7TM Pharma’) since 2013,
which suggests that the molecule has not performed as well as expected in
further trials.

In a
paper published only months ago, rimonabant was found to produce positive
changes in the gut microbiota of obese mice modelled with the Diet-Induced
Obesity (DIO) model, as well as inducing an anti-inflammatory state in the
adipose tissue by attenuating the trafficking of M1 macrophages into it. Therefore
this study revealed that the therapeutic mechanism of rimonabant in treating
obesity may involve anti-inflammatory and microbiological components (Mehrpouya-Bahrami et al., 2017). With
this information, researchers may be able to identify novel targets or pathways
upon which to design new drugs to treat obesity.

Finally, rimonabant may yet
experience success for a different indication entirely.  Low (µM ) dose rimonabant has been found to
directly affect the function of the kappa opioid receptor (KOR) in-vitro, and
to produce anxiolytic effects in mice performing the elevated plus maze. (Zádor et al., 2015). Therefore, counterintuitively,
low-dose rimonabant may have potential as a novel anxiolytic by acting through
a completely different mechanism to that behind its therapeutic efficacy in
reducing weight in obesity.


Conclusions and Lessons Learned

Rimonabant revealed the dangers
of the use drugs which act on metabolic and neurological systems which are not
fully understood. Whilst the clinical failure of rimonabant may have been
inevitable from the start, the suffering of patients due to its intrinsic
psychiatric adverse effects was not, and could have been avoided had the
manufacturer treated the CNS liability of the drug with greater caution and
respect, and designed their trials accordingly.

The story of rimonabant also
highlights the importance of regulatory vigilance, and serves as a lesson for
European regulators in that they should be more stringent in their review
processes, especially in the case of novel drugs such as rimonabant, where
there are not comparable phase IV safety data from other approved drugs that
work by similar mechanisms. Perhaps an increase in harmonization between the
EMA and the FDA could have prevented the entry of rimonabant into the European market
and the harm to patients that followed. 


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