What is the prognosis for new centrally-acting anti-obesity drugs? , Invited review

Transcription

Neuropharmacology xxx (2012) 1e15
Contents lists available at SciVerse ScienceDirect
Neuropharmacology
journal homepage: www.elsevier.com/locate/neuropharm
Invited review
What is the prognosis for new centrally-acting anti-obesity drugs?
David J. Heal*, Jane Gosden, Sharon L. Smith
RenaSci Consultancy Limited, Biocity, Pennyfoot Street, Nottingham, NG1 1GF, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 November 2011
Received in revised form
17 January 2012
Accepted 20 January 2012
Obesity is a global problem that is predominantly caused by the increasing adoption of a low-cost,
Westernised diet that is rich in fat and sugar and a more sedentary lifestyle. The costs of this
epidemic are substantial increases in Type 2 diabetes, cardiovascular disease and some types of cancer
that are certain to place a huge burden on individuals, healthcare providers and society. In this review,
we provide an overview of the chequered history of pharmacotherapy for the treatment of obesity and an
analysis of the regulatory and commercial challenges for developing new centrally-acting drugs in this
metabolic indication. The efficacy and safety of the drug candidates that are currently at the preregistration phase, i.e., lorcaserin, Qnexa and Contrave, are critically assessed. The main focus,
however, is to provide a comprehensive review of the wide range of novel CNS compounds that are in the
discovery phase or early clinical development. The profiles of various clinical candidates in animal
models of obesity predict that several new CNS approaches in the clinic have the potential to deliver
greater weight-loss than existing agents.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Obesity
CNS drugs
Drug targets
Animal models
Clinical trials
1. Introduction
The accepted definition of obesity is a body mass index (BMI;
weight in kg/height in m2) of greater than 30. According to the
latest figures from IASO (International Association for the Study of
Obesity) and IOTF (International Obesity Task Force), 475 million
adults and up to 50 million children in the world are now obese
(IOTF, 2010). Using data for England in 2008 as an example, w25%
of adult males and females were obese and w30% of boys and girls
(2e15 years of age) were either overweight (BMI ¼ 25e30) or obese
(Health Survey for England, 2008). If obesity in the UK continues to
increase at its current rate, the UK Government estimates that
50e60% of British adults and 25% of children will be obese by 2050
Abbreviations: AgRP, agouti-related peptide; BD or bid, twice daily; BMI, body
mass index; CB, cannabinoid; mCPP, m-chlorophenylpiperazine; DBP, diastolic
blood pressure; DIO, dietary-induced obesity; DPP-4, dipeptidyl peptidase-4; EMA,
European Medicines Agency; FDA, Food and Drugs Administration; GLP-1,
glucagon-like peptide-1; GPCR, G-protein coupled receptor; hERG, human ether-àgo-go related gene Kþ channel; IASO, International Association for the Study of
Obesity; IOTF, International Obesity Task Force; ip, intraperitoneal; MC, melanocortin; MTII, melanotan-II; MCH, melanin-concentrating hormone; MSH, melanocyte stimulating hormone; MTP, microsomal triglyceride transfer protein; NEFA,
non-esterified fatty acid; NPY, neuropeptide Y; OD, once daily; PYY, peptide YY; po,
oral dosing; qd, once daily; SBP, systolic blood pressure; sc, subcutaneous; TAG,
triacylglycerol; WHO, World Health Organisation.
* Corresponding author. Tel.: þ 44 0 115 9124261; fax: þ 44 0 115 9124263.
E-mail address: [email protected] (D.J. Heal).
(UK Government Foresight Report, 2007). The major contributors to
the increased level and severity of obesity are easy access to a diet
rich in fat, sugar and salt together with a much more sedentary
lifestyle than in previous times (Prentice and Jebb, 1995;
Deedwania, 2004). However, recent epidemiological data in children indicates that the amount of exercise taken has relatively little
influence on the occurrence and degree of obesity (Metcalf et al.,
2011), whereas there is a very strong association between daily
calorie intake, consumption of “fast food” and obesity (Block et al.,
2004; Bowman et al., 2004). Although unhealthy, Western, eating
habits are believed to be a pivotal cause of obesity, the epidemic has
become a global problem because of the rising popularity of a fast
foods and a Western lifestyle in many developing nations (particularly in urban locations) (International Obesity Task Force [IOTF],
2010). Moreover, in many populations, e.g., Asians, the health
risks occur at BMI values below the 25 cut-off for overweight, and
at any given BMI above 25, Asians suffer a disproportionately
greater burden of disease than Caucasians (World Health
Organisation [WHO] Expert Consultation, 2004).
Obesity is not merely a cosmetic issue because it is causal factor
in many serious diseases including dyslipidaemia, hypertension,
stroke, myocardial infarction, Type 2 diabetes and some cancers
(IASO, 2012). For this reason, the rapidly increasing level of obesity
is likely to result in substantial health, financial and social burdens
across the world unless effective interventions are employed.
For many obese subjects, attempts to adhere to a healthy diet
and lifestyle have not addressed this problem. In these cases
0028-3908/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neuropharm.2012.01.017
Please cite this article in press as: Heal, D.J., et al., What is the prognosis for new centrally-acting anti-obesity drugs?, Neuropharmacology
(2012), doi:10.1016/j.neuropharm.2012.01.017
2
D.J. Heal et al. / Neuropharmacology xxx (2012) 1e15
supplementation with pharmacotherapy or bariatric surgery will
be required.
In this review, we discuss the challenges for the development of
centrally-acting anti-obesity drugs arising from a conservative
regulatory environment, difficult marketing conditions and unrealistic patient expectations. We also critically assess the three drug
candidates that are currently at the pre-registration phase in the
USA and review a wide range of novel compounds and drug targets
that are in discovery or early clinical development.
2. A brief history of centrally-acting anti-obesity
2.1. The first generation of weight-loss drugs
Anti-obesity drugs should be used only as an adjunct to first-line
treatment for obesity treatment, which is a healthy diet, exercise and
lifestyle modification. At present, there are no centrally-acting drugs
which are on the market for the treatment of obesity in Europe
(Table 1). In the USA, the only central nervous system (CNS) drugs
that can be used to treat obesity are the sympathomimetic, appetite
suppressants that are only approved as short-term (12 weeks)
treatments. These drugs have been marketed for many years and
include phentermine, phendimetrazine, diethylpropion and benzphetamine. Fifty years ago, D-amphetamine (dextroamphetamine)
and even methamphetamine were prescribed as appetite suppressants, but their frequent diversion and abuse led to them becoming
highly restricted Controlled Drugs. In the 1990’s, the 5-HT releasing
agents, fenfluramine and D-fenfluramine, were withdrawn from the
market because their prolonged use was linked to life-threatening
primary pulmonary hypertension and cardiac valvulopathy.
shown to be efficacious in treating obesity with or without its
associated comorbidities (Déspres et al., 2005; Van Gaal et al.,
2005; Scheen et al., 2006; Pi-Sunyer et al., 2006) and it was
approved as an anti-obesity drug by the European Medicines
Agency (EMA) in 2006. However, later reports of severe depression
and suicidal thoughts in patients taking rimonabant (Pi-Sunyer
et al., 2006; Christensen et al., 2007) led to a recommendation for
non-approval by the US Food and Drugs Administration (FDA)
Advisory Committee that prompted Sanofi-Aventis to withdraw
rimonabant’s licensing application in the USA. Although the drug
remained on the European market for some while afterwards, an
ever increasing number of reports of psychiatric adverse events
associated with rimonabant use eventually led EMA to suspend the
European marketing authorisation for rimonabant in 2008.
2.4. Other anti-obesity drugs
In the absence of any centrally-acting anti-obesity drugs in
Europe, prescription pharmacotherapy in this indication is
restricted to orlistat, which has a peripheral mechanism of action.
Orlistat, an inhibitor of gastric and pancreatic lipases that blocks fat
absorption from the gut (McNeely and Benfield, 1998), is approved
as a prescription medicine in most countries around the world. This
drug has recently been granted an “over the counter” licence (albeit
at reduced strength) in Europe and the USA. Cetilistat is a newer
inhibitor of gastric and pancreatic lipases that is currently under
development for the management of weight loss in obese patients
with or without medical complications. Cetilistat is reported to
have fewer adverse side-effects than orlistat (Kopelman et al., 2007,
2010).
2.2. Sibutramine
3. Late-stage, centrally-acting, anti-obesity drug candidates
Sibutramine, which is a centrally-acting noradrenaline/serotonin reuptakeinhibitor (Heal et al., 1998), is the most recent
anti-obesity drug casualty. Results from large, Phase 4, cardiovascular outcome trial found sibutramine was linked to an increase
in non-fatal heart attacks and strokes in subjects with preexisting cardiovascular problems (James et al., 2010). For this
reason, sibutramine was withdrawn from the European and North
American markets in 2010.
In 2009e10, three new CNS medications for obesity were
submitted to the Food and Drugs Administration (FDA) for regulatory
evaluation, viz the 5-HT2C receptor agonist, lorcaserin (LorqessÒ),
and fixed-dose, drug combinations of phentermine þ topirimate
(QnexaÒ) and bupropion þ naltrexone (ContraveÒ).
2.3. Rimonabant
Rimonabant is a centrally-acting cannabinoid CB1 receptor
inverse agonist. In pivotal Phase 3 clinical trials, rimonabant was
3.1. Lorcaserin
The scientific rationale for the use of 5-HT2C agonists to treat
obesity is based on the observation that the hypophagic effect of
fenfluramine is believed mediated by indirect activation of these
receptors (Lee et al., 2004; Vickers et al., 2001), and this finding
prompted several companies to explore the development of 5-HT2C
Table 1
A summary of current antieobesity drugs and late-stage drug candidates.
Drug
Trade name
Mode of action
Company
USA
European Union
Orlistat
Orlistat
Phentermine
Methamphetaminea
Phendimetrazine
Diethylpropion
Benzphetamine
Sibutramine
Rimonabant
Bupropion/naltrexone
Topiramate/phentermine
Lorcaserin (APD356)
Zonisamide þ bupropion
Xenical
Alli (OTC)
Ionamin, Duromine
Desoxyn
Tepanil, Bontril
Tenuate, Apisate
Didrex
Reductil, Meridia
Accomplia
Contrave
Qnexa
Lorqess
Empatic
Lipase inhibitor
Lipase inhibitor
Noradrenaline (NA) þ dopamine (DA) releasing agent
DA þ NA releasing agent
Sympathomimetic
Sympathomimetic
Sympathomimetic
Noradrenaline (NA) þ 5eHT reuptake inhibitor
Cannabinoid CB1 antagonist
DA reuptake inhibitor/opioid antagonist
Unknown/NA þ DA releasing agent
5-HT2C agonist
Unknown/DA reuptake inhibitor
Roche
Roche
Generic
Generic
Generic
Generic
Generic
Abbott
Sanofi-Aventis
Orexigen/Takeda
Vivus
Arena/Eisai
Orexigen
Marketed
Marketed
Marketed
Marketed
Marketed
Marketed
Marketed
Withdrawn in 2010
Not approved
Non-Approvable
Pre-registration
Pre-registration
Phase 2
Marketed
Marketed
Withdrawn in 2001
Withdrawn in 2000
Withdrawn in 2000
Withdrawn in 2000
Withdrawn in 2000
Withdrawn in 2010
Withdrawn in 2008
Phase 3
Pre-registration
Phase 3
Phase 2
OTC ¼ Over the counter (non-prescription) medicine.
Sources: MedTrackÒ and information posted by companies, FDA and EMA on official websites.
a
Approved only for the treatment of refractory obesity.
(2012), doi:10.1016/j.neuropharm.2012.01.017
agonists as novel anti-obesity drugs. 5-HT2C agonists to have
undergone preclinical or clinical evaluation include Ro 60-0175,
VR 1065, and VER-8775 (Vernalis/Roche), LY 448100 (Lilly) as
well as lorcaserin (Arena Pharmaceuticals). Lorcaserin is a high
affinity 5-HT2C receptor full agonist (Ki: h5-HT2C ¼ 15 hM;
r5-HT2C ¼ 29 hM) that is devoid of affinity for a wide panel of other
G-protein coupled receptors (GPCRs) and ion channels (Thomsen
et al., 2008). With respect to the 5-HT2A and 5-HT2B receptor
subtypes, lorcaserin has selectivity ratios of w15-fold and 100-fold,
respectively (Thomsen et al., 2008). The benefits of lorcaserin have
been evaluated in three, pivotal, Phase 3 clinical trials, i.e., two in
obesity without major medical complications (so called “healthy
obese” subjects) and one in overweight or obese adults with Type 2
diabetes. At Week-52, the placebo-subtracted weight-loss
produced by locaserin was 3.6 kg (Smith et al., 2010) and 2.9 kg in
healthy obese subjects (Lorcaserin NDA, 2010) and 3.1 kg in obese
diabetics (Arena Pharmaceuticals Press Release, 2010) (Table 2). The
corresponding responder analyses revealed that 5% weight-loss
was achieved by 27.2% (Smith et al., 2010) and 22.2% (Fidler et al.,
2011) in subjects with obesity and 21.4% in obesity with Type 2
diabetes (Arena Pharmaceuticals Press Release, 2010). In spite of
the widespread belief that having a selective 5-HT2C full agonist
would increase efficacy, the weight-loss produced by lorcaserin was
remarkably similar to the 3.5 kg weight-loss at 1-year that was
reported for the indirect 5-HT2C receptor agonist, D-fenfluramine
(Guy-Grand et al., 1989). Lorcaserin’s clinical efficacy was described
by the FDA as “minimal” in its non-approvable letter (Arena
Pharmaceuticals Press Release, 2010). Lorcaserin’s ability to
decrease weight is almost certainly inferior to rimonabant (Déspres
et al., 2005; Van Gaal et al., 2005; Scheen et al., 2006; Pi-Sunyer
et al., 2006) or sibutramine (Apfelbaum et al., 1999; James et al.,
2000) which have been withdrawn from the market. The effect of
lorcaserin on a range of cardiometabolic risk factors is reported in
Table 2 and while many of the differences are highly significant
when statistically analysed, their small size, which is consistent
with the very modest degree of weight reduction, indicates they are
likely to be of minimal clinical benefit.
3
As discussed earlier in this review, safety is of primary concern
to the regulatory agencies. Common adverse events associated with
lorcaserin use are consistent with its serotonergic mechanism of
action, ie an increased incidence of blurred vision, dizziness,
somnolence, headache, gastrointestinal disturbance and nausea
(Smith et al., 2010; Fidler et al., 2011). Concern that lorcaserin’s
serotonergic mechanism might cause cardiac valve damage
appears to have been allayed by results from extensive echocardiographic monitoring throughout its clinical development.
However, 5-HT2A receptor agonists are hallucinogenic (Fiorella
ska, 1997) and in a clinet al., 1995; Chojnacka-Wójcik and K1odzin
ical trial in drug-experienced human volunteers the two highest
doses of lorcaserin produced subjective effects of “floating”,
“spaced out” and “euphoric mood” (Shram et al., 2010) leading the
FDA to state that if the drug is approved lorcaserin will become
a Schedule 4 Controlled Drug in the USA (Arena Pharmaceuticals
Press Release, 2010). The other major safety concern highlighted
by the FDA in its non-approvable letter was an increased incidence
of mammary adenocarcinomas in female rats and brain astrocytomas in male rats. In January, 2012, Arena announced that it had
prepared and submitted its responses to the FDA on safety concerns
relating to lorcaserin with a view to resubmitting its NDA (Arena
Pharmaceuticals Press Release, 2012).
3.2. Onexa
Fixed-dose drug combinations to treat obesity have been
pursued by Orexigen and Vivus on the basis that using already
approved CNS compounds would help allay the safety concerns of
the regulatory agencies. Furthermore, by employing drugs with
complementary mechanisms it may be possible to achieve additive
or even synergistic weight-loss with such combination therapies.
QnexaÒ (Vivus) consists of phentermine, which is a generic, nonselective, monoamine releasing agent (Prow et al., 2001; Tao
et al., 2002; Rowley et al., 2000) that has been widely prescribed
as a short-term appetite suppressant, combined with topirimate,
which is a marketed anticonvulsant that was also clinically
Table 2
A comparison of the metabolic benefits of treatment with lorcaserin, ContraveÒ and QnexaÒ determined 1-year after treatment commencement.
Placebo-subtracted effect
Weight-loss (kg)
D BMI
Categorical analysis of weight-loss
5%
10%
Waist (cm)
Lipid parameters
Triglycerides (% change)
Total cholesterol (% change)
LDL-C (% change)
HDL-C (% change)
Glycaemic control
Fasting glucose (mg/dL)
Fasting insulin (mIU.mL)a
HoMA (%)a
HbA1C
Blood pressure
Systolic (mmHg)
Diastolic (mmHg)
ContraveÒ
Lorcaserin
QnexaÒ
NDA (pooled data)
(n ¼ 3097)
BLOOM-DM
(n ¼ 256)
NB-301
(n ¼ 1742)
NB-303
(n ¼ 1496)
NB-302
(n ¼ 793)
OB-302
(n ¼ 1267)
OB-303
(n ¼ 2487)
(10 mg bid)
(10 mg bid)
(32/360 mg)
(32/360 mg)
(32/360 mg)
(92/15 mg)
(92/15 mg)
3.25 (3.3%)
1.19
3.10 (3.0%)
ND
4.8 (4.8%)
1.7
5.2 (5.2%)
2.21
4.2 (4.2%)
1.5
10.9 (9.4%)
3.94
8.9 (8.6%)
3.15
24.5%
13.7%
2.5
21.4%
11.9%
DNA
32%
18%
3.7
37%
22%
4.6
24%
21%
3.2
49.4%
39.8%
7.1
49.2%
40.2%
6.5
4.61
0.47
þ1.33
þ1.23
c
c
c
c
9.6
ND
1.0
þ6.7
9.3
ND
3.3
þ8.7
8.1
ND
2.5
þ6.0
14.3
2.5
2.8
þ3.5
15.3
3.0
2.8
þ5.6
0.69
2.05
0.24
0.06
DNA
c
DNA
0.5%
1.9
1.6
0.38
ND
1.5
1.7
0.20
ND
1.3
1.5
0.26
ND
2.5
ND
ND
ND
3.6
4.7
1.53
0.13
0.68
0.40
c
c
3.8
1.9
3.2
1.1
þ1.5b
þ0.6b
ND ¼ Not determined; DNA ¼ Data not available; HoMA ¼ homeostasis model assessment; HbA1C ¼ Haemoglobin A1C.
Sources: Lorcaserin new drug application [NDA] (2010); Arena Press Release (2010); Contrave NDA (2010); Qnexa NDA (2010).
a
Result calculated from APD356e009 [BLOOM] data.
b
Pooled result for all Phase 3 trials.
c
Stated to be unchanged in Arena Press Release (2010).
(2012), doi:10.1016/j.neuropharm.2012.01.017
4
evaluated for the treatment of obesity (Astrup and Toubro, 2004;
Bray et al., 2003; Rosenstock et al., 2007) until its development in
this indication was halted because of unacceptable side-effects. The
pharmacological mechanism underpinning topirimate’s weightloss effect has not been fully elucidated, but may derive in part
from potent inhibition of mitochondrial carbonic anhydrase V
(Vullo et al., 2004). Jackson et al. (2007) demonstrated that either
phentermine or topiramate produced substantial weight-loss in the
cafeteria-fed dietary-induced obese (DIO) rat when given alone and
when given in combination their effects were additive, but not
synergistic. The weight-loss of the phentermine/topiramate
combination in the DIO rat was greater than that observed previously with sibutramine, rimonabant or orlistat (Jackson et al.,
2007). Three different dosage combinations of Onexa have been
clinically evaluated, i.e., phentermine (mg)/topirimate (mg): 3.75/
23 (low dose), 7.5/46 (mid dose) and 15/92 (full dose). Consistent
with the animal data, the weight-loss effects of combined phentermine and topirimate were shown to be approximately additive
in a 6-month, Phase II trial (Vivus Press Release, 2010) and with 42%
of patients achieving 10% placebo-subtracted weight-loss, the
efficacy of Qnexa was considerably better than that reported for
orlistat, sibutramine or rimonabant (Van Gaal et al., 1998; Bray
et al., 1999; Van Gaal et al., 2005; Despres et al., 2005; Pi-Sunyer
et al., 2006). Two, large, 1-year Phase 3 pivotal trials have been
performed with Qnexa. The first (OB-302) was in severely obese
subjects (BMI 40 kg/m2) and the second (OB-303) was in overweight or obese subjects with co-morbid disorders, i.e., hypertension, dyslipidaemia or Type 2 diabetes together with abdominal
adiposity. The placebo-subtracted weight-loss at 1-year observed
after treatment with the full doses of Qnexa was 10.9 kg (9.4%) and
8.9 kg (8.6%) in OB-302 and OB-303, respectively (Table 2). After
correction for placebo, the proportion of subjects on the full dose of
Qnexa who achieved a 10% reduction in bodyweight from baseline was w40% in both trials (Table 2). A summary of the benefits of
Qnexa on cardiovascular risk factors is summarised in Table 2. The
observed improvements in plasma lipid profiles, glycaemic control
and blood pressure were consistent with the high degree of weightloss and are substantially greater than those produced by lorcaserin
because of Qnexa’s superior weight-loss effect (Table 2). Adverse
events associated with Qnexa treatment were generally consistent
with those reported for phentermine, i.e., dry mouth, constipation,
insomnia, and palpitations, and for topirimate, i.e., dizziness,
paresthesia, and disturbances in attention, together with headache,
dysgeusia (distortion of sense of taste), alopecia and hypokalemia
(Qnexa NDA, 2010). In addition, phentermine is a Controlled Drug
(Schedule 3 and 4 in USA and UK, respectively). In spite of Qnexa’s
impressive efficacy as an anti-obesity treatment, the FDA declined
to approve the drug because of safety concerns.
Many antiepileptic drugs including topiramate are known to
cause birth defects in humans and as the prescribing of anti-obesity
drugs is predominantly to females in the 35e55 year age group, the
safety concerns of FDA were well founded. However, the issue is
complex because the doses of topiramate used in Qnexa are much
lower than those required for the management of epilepsy, there
were significant differences across the epidemiological data-bases
that have estimated the teratological risks of antiepileptic drugs,
and epilepsy itself is associated with an increased number of birth
defects. Vivus is addressing these questions by conducting a retrospective review of the incidence of birth defects in woman taking
topiramate during pregnancy. In the meantime, the company
submitted a revised NDA in October 2011 for the use of Qnexa in the
treatment of obesity in men and women without child-bearing
potential (Vivus Press Release, 2011) with a view to extending the
labelling to include all women if the results from its retrospective
analysis are supportive. In terms of weight-loss and metabolic
benefits, Qnexa is the leader of the current crop of pre-registration
drug candidates and is almost certainly superior to orlistat, rimonabant and sibutramine.
3.3. Contrave
Contrave (Orexigen) is a fixed-dose combination of bupropion þ naltrexone. Bupropion is a weak, selective dopamine
reuptake inhibitor (Richelson and Pfenning, 1984) used to treat
depression (WelbutrinÒ) and as an aid to smoking cessation
(ZybanÒ) and naltrexone is a non-selective opioid receptor antagonist used to treat opiate and alcohol dependence syndromes
(VivitrolÒ). Four pivotal trials have been conducted to evaluate
Contrave in obesity. NB-301 to NB-303 were in subjects with
uncomplicated obesity, or overweight/obesity combined with
controlled hypertension and/or dyslipidaemia. NB-304 was a trial
in overweight and obese subjects with Type 2 diabetes. At Week56, the placebo-subtracted weight reductions observed with Contrave (naltrexone 32 mg þ bupropion 360 mg) were 4.8 kg and
5.2 kg in NB-301 and NB-303 (Table 2). In NB-302 that included
intensive dietary and behavioural support, the drug produced
a 4.2 kg reduction in weight and in obese subjects with Type 2
diabetes, Contrave produced a 3.4 kg weight-loss. The proportion of
subjects in NB-301 e NB-303 who achieved a 10% reduction from
baseline bodyweight was 18e22% (Contrave NDA, 2010; Table 2).
In general, the improvements in various obesity-related,
cardiovascular risk factors produced by Contrave were commensurate with the degree of reduction of bodyweight (Table 2). In
obese diabetics, Contrave reduced plasma HbA1c by almost 0.5%
(Contrave NDA, 2010). The major problem for Contrave was blood
pressure did not decrease in-line with weight-loss and compared
with equivalent weight-loss on placebo, Contrave produced small
mean increases in both systolic blood pressure (SBP) and diastolic
blood pressure (DBP) (Table 2). In addition to having a propensity
to increase blood pressure, Contrave slightly increased the incidence of hypertension and palpitations. The most frequent sideeffects of this drug were gastrointestinal that are likely to be
linked to the opiate antagonist actions of naltrexone (Contrave
NDA, 2010) http://www.fda.gov/downloads/advisorycommittees/
committeesmeetingmaterials/drugs/endocrinologicandmetabolic
drugsadvisorycommittee/ucm235671.pdf). Other adverse events
included headache, dizziness, insomnia, and dry mouth (Contrave
NDA, 2010) that probably derive from bupropion’s pharmacology
as a catecholamine reuptake inhibitor. Although the FDA’s Advisory Committee voted to recommend approval of Contrave, the
FDA declined the application in Feb, 2011 because of the safety risk
to patients from increases in blood pressure. The agency has said
that it wishes to see acceptable data for Contrave from a long-term
cardiovascular outcome trial before it would grant approval of this
anti-obesity medication. In the light of the recent withdrawal of
sibutramine, which had similar effects on blood pressure, because
of an increased incidence of non-fatal cardiovascular events, the
decision by FDA looks reasonable and fair. Orexigen recently
announced that it has reached a tentative agreement with the FDA
over the design of the cardiovascular outcome trial and will
conduct it with a view to resubmitting the NDA in 2013 or 2014
(Orexigen Therapeutics Press Release, 2011).
3.4. Summary
None of the recent NDA submissions has received approval by
the FDA though each of these CNS anti-obesity drug candidates has
a path to reach this goal. Broadening the discussion to include
Europe, the EMA’s guideline for the efficacy of weight-loss drugs,
i.e., 10% reductions from baseline maintained at 1-year that is also
(2012), doi:10.1016/j.neuropharm.2012.01.017
5% greater than achieved on placebo (EMA, 2007), is very different
from the criterion employed by the FDA, i.e., 5% placebosubtracted reduction in bodyweight (FDA, 2007). Although these
criteria are the primary efficacy endpoints, both agencies will
consider results from categorical analyses in their decision-making.
On the basis of the information included in the NDAs, Qnexa is the
only medication that would appear unequivocally to satisfy the
EMA guidelines.
Even assuming that one or more of these new medications
receives regulatory approval, in the real world, their contribution to
combating the obesity epidemic will be determined by a number of
factors that are briefly discussed here. It is now generally accepted
that because anti-obesity drugs are treatments, not cures, they will
need to be taken long-term, and as a consequence, maintenance of
pharmacological effect is essential. In the case of Qnexa, there is
good evidence to demonstrate that its weight-loss effect is maintained out to 2 years with no evidence of tachyphylaxis, i.e., the
percentages of subjects (placebo-subtracted) who achieved 10%
weight-loss on the high dose of Qnexa were 54.6% at Week-56 and
42% at Week-108 (Qnexa NDA, 2010). In contrast, the Year-2 results
from the BLOOM trial revealed the worrying emergence of tolerance to lorcaserin in the drug-responder group (Smith et al., 2010).
Consistent with this conclusion, the difference between the
percentage of patients who achieved 5% weight-loss on lorcaserin
versus placebo decreased from 27.2% at Week-52 to 17.6% at Week104. In the absence of indisputable evidence that pharmacotherapy
in obesity reduces the long-term burden of illness or enhances life
expectancy, the use of new anti-obesity drugs will be highly
restricted by healthcare providers and/or patients will have to
fund all or part of the costs of their treatments. In the latter
5
situation, most patients equate efficacy with sustained, progressive
weight-loss, and for many, the weight maintenance phase of
treatment is considered to be a signal that the drug is no longer
working. Since the majority of subjects are unlikely to achieve the
high degree of weight-loss that they are seeking, it is questionable
how willing they will be to pay for drugs that do not satisfy their
expectations. These new medications could therefore follow the
same marketing path as sibutramine and orlistat with a very high
initial uptake of treatment that is followed by a quite rapid decline
in prescription numbers.
4. New CNS approaches for treatment of obesity
In the CNS field, the major sources for potential anti-obesity
compounds have been novel hypothalamic neuropeptide regulators and various monoaminergic targets. A list of current CNS
targets with drug candidates in late-stage preclinical or early clinical development is shown in Table 3.
When assessing the potential of these new pharmacological
targets and drug candidates, the translational validity of results
from animal experiments to the human situation is critical to
pharmaceutical R&D. In the case of obesity and related metabolic
diseases, we are in the fortunate position that rodents are particularly well suited to the study of these disorders. Rodents are
omnivorous and when fed a nutritionally well-balanced diet under
laboratory conditions, they will maintain a reasonably healthy
weight and body composition during adolescence and early
adulthood. However, rodents find unhealthy, calorie-dense, sweet
and/or high-fat foods irresistible and when given free access to
such foods, they will overeat and gradually become grossly obese.
Table 3
Centrally-acting anti-obesity drug-candidates in research and development.
Drug
Trade name
Mode of action
Company
Clinical development
phase
Obinepitide (TM30338)
TM30339
Velneperit (S2367)
Tesofensine (NS2330)
PRX00933
MK-0493
Symlin þ metreleptin
Betahistine
ALB127158
Synthetic peptide YY (PYY)3e36
S234462
GSK1521498
ZYO1
MK5046
OAP189
PF2575799
TKS1225
HPP404
P120107
MCH1 antagonists
PT15
PYY336 EMISPHERE
GEMS-PYY
BMS193885
LY448100
5-HT2C agonists
AMR-SIX-1
Not stated
AEZS123
AMX808 with VRS859
AC164209
AOD9604
PSN602
_
_
_
_
_
_
_
Histalaen
_
_
_
_
_
_
_
_
_
_
_
NPY Y2/Y4 agonist
Y4 agonist
Y5 antagonist
Triple monoamine reuptake inhibitor
5-HT2C agonist
MC4 agonist
Amylin agonist þ leptin agonist
H1 agonist/H3 antagonist
MCH1 antagonist
Y2 agonist
Y5 antagonist
m-opioid inverse agonist
CB1 antagonist
Not revealed
Not revealed
Not revealed
Not revealed
Not revealed
Not revealed
MCH1 receptor antagonists
MC4 receptor agonist
Y2 agonist
Y2 agonist
Y1 antagonist
5-HT2C receptor agonist
5-HT2C agonists
5-HT6 antagonist
Ghrelin antagonist
Ghrelin receptor antagonist
AMX808 (glucagon receptor agonist) þ VRS859 (exenatide)
GLP-1 receptor agonist
Growth hormone receptor Agonist
NA þ 5-HT reuptake inhibitor/5-HT1A agonist
7-TM
7-TM
Shinogi
Neurosearch
Proximagen
Merck
Amylin/Takeda
Obecure
Albany
Amylin
Shinogi
GSK
Zydus
Merk
Pfizer
Pfizer
Pfizer
TransTech
Piramal/Lilly
Albany
AstraZeneca
Emisphere
enGene
BMS
Eli Lilly
Athersys
Albany
Elixir
AEterna Zentaris
Amunix Inc/Versartis
Amylin
Calcoza
OSI Pharmaceuticals
Phase 2
Phase 2
Phase 2
Phase 2
Phase 2
Phase 2
Phase 2
Phase 2
Phase 1
Phase 1
Phase 1
Phase 1
Phase 1
Phase 1
Phase 1
Phase 1
Phase 1
Phase 1
Phase 1
Research
Research
Research
Research
Research
Research
Research
Research
Research
Research
Research
Research
Research
Discontinued
_
Sources: MedTrackÒ and information posted by companies on official websites.
(2012), doi:10.1016/j.neuropharm.2012.01.017
6
As described in a series of articles (Dickinson et al., 2001; Heal and
Jagger, 2005; Heal et al., 2009, 2011), we have demonstrated that
the cafeteria-fed, dietary-induced obese (DIO) female rat has
exceptionally good predictive validity with 95% correlation
between the magnitude of weight change produced by various
anti-obesity and anti-diabetic drugs in clinical trials and their rank
order for inducing weight-loss in this model. In addition to the DIO
female rat, there are a number of other well validated rodent
models of human obesity including the high fat-fed, obese,
growing, male rat and the DIO mouse and we will also discuss
results obtained from these various paradigms.
4.1. Monoaminergic targets
4.1.1. Tesofensine
Tesofensine (NeuroSearch) is a potent, non-selective reuptake
inhibitor of dopamine, noradrenaline and 5-HT, but there is relatively little information in the public domain describing its in vitro
pharmacological profile. Tesofensine inhibits [3H]dopamine, [3H]
noradrenaline and [3H]5-HT transport into synaptosomes with IC50
values of 6.5 hM, 1.7 hM and 11.0 hM, respectively (Lehr et al.,
2008).
In a recently published article using a variant of the DIO rat
model, tesofensine (0.5e3 mg/kg sc) dose-dependently reduced
nocturnal food intake with an ED50 of 1.3 mg/kg (Axel et al., 2010).
Pharmacological characterisation with selective monoaminergic
receptor antagonists demonstrated roles for a1-adrenergic and
dopamine D1 receptor-mediated neurotransmission in its hypophagic effect with no involvement of D2, D3, 5-HT2A/C or
a2-adrenergic receptor pathways. The selective catecholaminergic
mode of action of tesofensine differentiates it from the mixed
noradrenergic/serotonergic mechanism of sibutramine or the
5-HT2C receptor-mediated mechanism of lorcaserin and D-fenfluramine. When tesofensine (1 or 2 mg/kg po) was administered to
DIO rats for 28 days, it reduced the bodyweight of these animals by
5.7% and 9.9%, respectively (Hansen et al., 2010). Sibutramine
(7.5 mg/kg po), which was the reference comparator in this
experiment, produced 7.6% weight-loss. If these results translate
into clinical outcomes, tesofensine would have the potential to have
equal or perhaps greater efficacy than sibutramine. Weight-loss
induced by tesofensine in DIO rats was accompanied by improvements in metabolic status that included reductions in abdominal
and subcutaneous fat mass, reductions in plasma lipids and
increased insulin sensitivity (Hansen et al., 2010). Together this
combination of an ability to decrease obesity and improve various
cardiometabolic risk factors in a DIO rat model provided evidence
to support its clinical development as a novel anti-obesity drug.
Tesofensine was initially taken into clinical development for
treatment of Parkinson’s or Alzheimer’s disease. Although clinically
significant efficacy was not observed in either neurological condition, a meta-analysis of the results revealed that tesofensine
(0.125e1.0 mg once daily) produced dose-dependent weight-loss in
the combined patient group with w32% of obese subjects on the
highest dose of drug achieving 5% weight reduction after 14
weeks of treatment (Astrup et al., 2008a). The efficacy and tolerability of tesofensine was subsequently evaluated in a 24-week,
randomised, double-blind, placebo-controlled Phase 2 trial in
medically-uncomplicated obesity (BMI 30e40 kg/m2). Tesofensine
was impressively effective in this trial producing mean placebosubtracted decreases in bodyweight of 4.5 kg (2.5%), 9.1 kg (7.2%)
and 10.6 kg (8.6%) with once daily doses of 0.25 mg, 0.5 mg and
1.0 mg, respectively (Astrup et al., 2008b). These reductions were
accompanied by decreases in body fat and waist circumference and
also modest improvements in plasma lipids. Dose-dependent
increases in diastolic blood pressure and heart rate were noted on
tesofensine treatment with placebo-subtracted mean increases of
1.5 mmHg and 7.4 bpm at the suggested clinical dose of 0.5 mg
(Astrup et al., 2008b). Psychiatric adverse events were also
a potential cause for concern with 6.1% of subjects reporting
depressed mood on the highest dose of tesofensine compared with
0% on placebo. Moreover, these adverse events occurred in a patient
group that had been pre-selected to exclude those with known
psychiatric disorders. Overall, tesofensine is impressively effective
in terms of weight reduction. However, bearing in mind that
rimonabant was withdrawn for the emergence of psychiatric
adverse events and sibutramine was withdrawn for cardiovascular
safety concerns, the challenge for this drug-candidate will be to
convince regulatory agencies and prescribers that its safety profile
is acceptable for approval and use as an anti-obesity drug.
4.1.2. 5-HT6 receptor ligands
The 5-HT6 receptor-null mouse was discovered to be resistant to
dietary-induced obesity (Caldirola, 2003) stimulating research into
this receptor as a potential target for the development of new antiobesity drugs. More recently, Frassetto et al. (2008) confirmed
these findings. When fed a high-fat diet, 5-HT6 receptor knockout
mice consumed approximately 8% less food than their wild-type
counterparts, but gained about 35% less weight over an 11 week
period. Body composition analysis of the mice showed that the
reduced weight gain in the knockout mice was mostly due to
decreased fat accumulation (Frassetto et al., 2008).
BVT-5182, synthesised by Biovitrum, was the first 5-HT6 antagonist to have been extensively evaluated as a potential anti-obesity
drug candidate. This compound was shown to decrease food
intake when given acutely and chronically, to produce sustained
weight-loss in dietary-induced obese (DIO) rats and mice and
improve obesity-related cardiometabolic risk factors, eg visceral
adiposity as well as blood leptin and insulin levels (Svartengren et al.,
2003, 2004). Since those initial investigations, various other 5-HT6
ligands, e.g., BVT-71346, MEM68753 (Memory), SUVN-504 and
SUVN-51005 (Suven) have also been demonstrated to produce
improved cardiometabolic profiles in DIO rodents (Sastry et al.,
2007; Svartengren et al., 2007; Shanmuganathan et al., 2008;
Callahan et al., 2009).
In our laboratory, we have investigated the profiles of a number
of 5-HT6 ligands in rodent models of obesity, the DIO female rat and
the high-fat fed male rat models. They include the antagonists,
PRX-07034 (Epix), MEM68626 (Memory), SB-742457 (GSK) and the
partial agonist, E-6837 (Esteve). In these two models, substantial
weight-loss was observed (Fig. 1) after repeated treatment with the
5-HT6 antagonists, PRX-07034 (Gannon et al., 2006a,b; Shacham
et al., 2006), MEM68626 (Murray et al., 2008) and SB-742457
(Sargent, 2007), and also with the partial agonist, E-6837 (Fisas
et al., 2006).
In the cafeteria-fed DIO rats, the 5-HT6 antagonist, PRX-07034
caused a sustained, progressive decrease in body weight (Fig. 1)
when given chronically resulting in a 12.7% reduction after 6 weeks
of administration (Gannon et al., 2006a,b; Shacham et al., 2006).
The highest dose of PRX-07034 administered (10 mg/kg, ip, bid)
produced a significant reduction of food intake in the animals for
virtually all of the 6 week treatment period. A body composition
analysis revealed that the reduction in bodyweight produced by
PRX-07034 dosing was the result of a highly selective reduction in
fat mass with minimal effects on either body water or protein
content (Gannon et al., 2006b; Shacham et al., 2006). Consistent
with a marked decrease in white adipocyte fat mass, plasma
leptin concentrations in the PRX-07034-treated group of rats
were decreased by more than 75% compared with the vehicletreated controls. The reduced adiposity produced by administration of PRX-07034 improved glycaemic control in obese rats with
(2012), doi:10.1016/j.neuropharm.2012.01.017
7
E-6837 and sibutramine – DIO females
PRX-07034 – DIO females
420
490
-1.3%
400
Body weight (g)
Body weight (g)
410
390
380
370
*** -12.7%
360
470
450
350
390
340
370
-5
-3
-1
1
9
11 13 15 17 19 21 23 25 27 29 31 33 35 37 39
41 43
*** -11.0%
430
410
*** -15.7%
-5
-3
-1
1
3
5
7
9
Day
Vehicle ip bid
11
13 15
17
19
21
23
25
27
29
Day
PRX-07034 3 mg/kg ip bid
SB-742457 – high fat fed, obese males
E-6837 30 mg/kg po bid
Vehicle po bid
PRX-07034 10 mg/kg ip bid
Sibutramine 5 mg/kg po qd/Vehicle po qd
MEM68626 and sibutramine – high fat fed,
obese males
570
480
* -2.3%
460
450
** -2.8%
440
430
*** -9.8%
Body weight (g)
Body weight (g)
470
* -5.6%
520
***-10.3%
470
***-11.6%
420
420
*** -10.4%
410
370
***-24.7%
400
320
-2
-1
0
1
2
3
4
5
6
7
8
-1
1
3
5
7
Vehicle
(3 ml/kg po bid)
Vehicle1%
pomethylcellulose
bid
SB-742457 1 mg/kg po bid
9
11
13
15
17
19
21
23
25
27
29
Day
Day
Vehicle po bid
MEM 68626 10 mg/kg po bid
Sibutramine
po po qd/ Vehicle qd
Sibutramine(7.5
7.5mg/kg
mg/kg
Sibutramine 7.5 mg/kg po qd/vehicle po qd
Fig. 1. Effects of various 5-HT6 receptor ligands on body weight in the mature DIO females and high fat-fed, growing male rats e models of human obesity and related
co-morbidities. Results are adjusted mean body weight SEM (n ¼ 9e10). Figures in the graphs represent percentage reductions of bodyweight compared with the appropriate
vehicle-treated controls at the end of treatment. *p < 0.05, **p < 0.01, ***p < 0.001 versus controls. Data taken from: Gannon et al. (2006a,b), Murray et al. (2008), Sargent (2007),
Fisas et al. (2006).
statistically significant reductions of plasma glucose and insulin
concentrations.
When assessed in the high-fat fed male rat model, PRX-07034
(100 mg/kg, po, bid) produced a reduction in body weight of
11.8% after 4 weeks. This was comparable to the weight-loss caused
by sibutramine and better than rimonabant, which produced
reductions of 10.4% and 6.5%, respectively (Gannon et al., 2006b;
Shacham et al., 2006). PRX-07034 treatment also resulted in
significant reductions of plasma leptin, glucose and insulin in these
animals (Gannon et al., 2006b; Shacham et al., 2006).
One of the enigmas in the 5-HT6 field is that antagonists and
agonists of this receptor subtype produce the same pharmacological effect on a number of CNS responses. Thus, it has been
reported that cognitive function in the novel object recognition
rest is improved by both antagonists (Murray et al., 2008; Woolley
et al., 2003; King et al., 2004; Vickers et al., 2004) and agonists
(Kendall et al., 2010) and similarly, antidepressant-like effects
in the mouse tail suspension test have been reported with the
5-HT6 receptor antagonist, SB 271046 (Svenningsson et al., 2007)
and the agonist, EMDT (Wesolowska and Nikiforuk, 2007).
An identical situation applies in the obesity field where a similar pattern of weight loss to that produced by PRX-07034 was
evoked in the cafeteria-fed DIO rat by repeated treatment with the
5-HT6 receptor agonist, E-6837 (Fisas et al., 2006; Fig. 1). This
compound also significantly reduced food intake of the rats (Fisas
et al., 2006) in the first week of the 29 day treatment period
(Fig. 1).
SB-742457 and MEM68626 have both been evaluated in the
high fat-fed, obese, male rat where they produced dose-dependent
reductions in body weight (Fig. 1). When MEM68626 was administered bi-daily to high fat-fed, obese male rats for 29 days, it
produced a weight loss of 11.6% at the highest dose (Murray et al.,
2008). SB-742457 produced a comparable weight loss in this
model after only 8 days of oral dosing (Sargent, 2007).
The effects of MEM68626, SB-742457 and E-6837 (Murray et al.,
2008; Sargent, 2007; Fisas et al., 2006) on weight loss in these rat
models were compared with the anti-obesity drug, sibutramine
(now withdrawn in Europe and the USA). The weight-loss effects of
these three compounds were either comparable to, or in the case of
E-6837, greater than sibutramine (15.7% weight-loss compared to
11% respectively) after 29 days of bi-daily dosing (Fig. 1).
Proof of principle for the obesity indication has been only obtained for the 5-HT6 antagonist, PRX-07034. In a randomised,
double-blind, placebo-controlled Phase Ib trial in healthy obese
adults, a placebo-subtracted weight-loss of 1.82 kg was observed
after 28 days of treatment on 600 mg compound, twice-daily (Epix
Press Release, 2007).
4.1.3. Compounds with monoamine reuptake inhibition and 5-HT1A
agonist properties
5-HT1A agonists were first developed as centrally-acting
hypertensive agents, but interest in the concept diminished when
it was observed that tolerance rapidly developed to their beneficial
effects. It was postulated that although 5-HT1A agonists were
(2012), doi:10.1016/j.neuropharm.2012.01.017
8
4.2. Hypothalamic peptides
not suitable for development as novel antihypertensive drugs,
they may be sufficiently effective to prevent the increases in
blood pressure and heart rate produced by sibutramine (Heal and
Cheetham, 2001). This concept was proven by demonstrating that
sibutramine-induced increases in blood pressure and heart rate in
conscious, telemetered rats were abolished by co-administration of
the selective 5-HT1A agonist, flesinoxan. These findings formed the
basis for a patent filing on this pharmacological combination (Heal
and Cheetham, 2001). Prosidion also developed PSN-1 and PSN-2,
which combined potent noradrenaline reuptake inhibition and
5-HT1A agonism in the same molecule (Thomas et al., 2006). These
compounds decreased food intake and produced weight-loss in
both DIO female (Fig. 2) and high fat-fed male obese rats
(Thomas et al., 2006). The effects of PSN S1 (Fig. 2) and PSN S2 on
bodyweight and food intake were similar in magnitude to those of
sibutramine (Thomas et al., 2006). The weight-losses were mediated by a selective reduction in adiposity together with increased
insulin sensitivity, but plasma lipid profiles were not altered
(Thomas et al., 2006). PSN S1 was subsequently taken into clinical
development, but the programme has now been discontinued.
In the last twenty years, there has been an enormous expansion
in the number of hypothalamic peptides that have been reported to
play a role in the regulation of food intake and energy expenditure
(Woods and Seeley, 2005; Hofmann and Tschöp, 2005). Although
many of these hypothalamic peptides have been proposed as
targets for the development of novel anti-obesity drugs, currently,
there are very few candidates in clinical development and some
very favoured approaches have failed to live up to expectations.
Neuropeptide Y (NPY) is a 36-amino acid peptide that is one of
the most powerfully orexigenic hypothalamic peptides (Beck,
2006; Kamiji and Inui, 2007). For this reason, the development of
novel, brain-penetrative, small molecule, compounds to block its
actions was a scientifically logical approach to anti-obesity drug
therapy that has been explored both preclinically and clinically
(Kamiji and Inui, 2007). However, the pharmacology of NPY is
complex and it exerts its actions in mammalian species via 6
distinct receptor subtypes (Y1eY6) (Beck, 2006; Kamiji and Inui,
2007). Moreover, there has been some disagreement about which
Body weight
Baseline
440
Treatment
Body weight (g)
420
*
400
*
-6.5%
-9.6%
-10.9%
380
*
360
-6
-4
-2
0
2
4
6
10
8
12
14
16
18
20
22
24
26
28
Day
Food intake
Baseline
1400
Treatment
Daily food intake (kJ/kg)
*
*
1200
*
*
1000
*
*
**
* *
**
*
** *
*
*
*
*
*
* *
*
800
600
400
200
0
-6
-4
-2
0
2
4
6
**
*
8
10
12
14
16
18
20
22
24
26
28
Day
Vehicle 5 ml/kg po
PSN S1 5.6 mg/kg po
PSN S1 11.2 mg/kg po
Sibutramine 5 mg/kg po
Fig. 2. Effect of the novel 5-HT1A agonist and noradrenaline reuptake inhibitor, PSN S1, on body weight and food intake in the DIO female rat model of human obesity. Results are
adjusted means SEM (n ¼ 9e10). Figures in the upper graph represent percentage reductions of bodyweight compared with the vehicle-treated control group at Day 29. *p < 0.05
versus vehicle control group. Data taken from: Thomas et al. (2006).
(2012), doi:10.1016/j.neuropharm.2012.01.017
NPY receptor is the most appropriate candidate for the development of novel antagonists with Y1 and Y5 subtypes being the most
favoured (Beck, 2006). A number of pharmaceutical companies
initiated programmes to synthesise novel Y5 antagonists and
although several were shown to attenuate feeding behaviour and
the development of diet-induced obesity in rodents, not all of the
studies demonstrated their positive potential as anti-obesity drug
candidates (Beck, 2006; Kamiji and Inui, 2007). In contrast to the
positive findings obtained in some rodent studies, in a 52-week
randomised, placebo-controlled, double-blind trial in obese
adults, the Y5 receptor antagonist, MK-0557, produced weight loss
that was statistically greater than placebo, but not clinically
meaningful (Erondu et al., 2006). MK-0557 was found to be ineffective at preventing weight regain in obese subjects who had lost
6% of the baseline bodyweight after 6 weeks on a very low calorie
diet (Erondu et al., 2007a) and it also failed to augment the weightloss produced in obese subjects by sibutramine or orlistat (Erondu
et al., 2007b). Based on this evidence, it appears that the sceptical
view about the viability of the Y5 receptor as an anti-obesity drug
target was correct. The Y1 receptor was thought to be a more
relevant target for development and various potent Y1 receptor
antagonists have been reported to inhibit food intake (Kamiji and
Inui, 2007). However, many of these compounds suffer from poor
bioavailability and pharmacokinetics making them unsuitable for
development. Although several new chemical series have been
exploited in the search for better drug candidates (Kamiji and Inui,
2007), to the best of our knowledge, none of these compounds has
entered clinical development.
Agonists of NPY Y2 and Y4 receptor subtypes have also been
evaluated after it was discovered that the gut hormone, peptide YY
(PYY), decreased food intake by stimulating hypothalamic Y2
receptors. Several groups have reported that infusion of PYY3e36
decreased food intake in lean and obese subjects when administered acutely (Kamiji and Inui, 2007). However, because this
molecule is a polypeptide, finding a dosing formulation suitable for
repeated administration posed a significant problem. PYY3e36 was
found to have reasonable bioavailability when given in a nasal
spray formulation, but in a 12-week, randomised, double-blind,
placebo-controlled, clinical trial in healthy obese subjects, nasal
administration of the lower dose produced only nominally greater
weight-loss than placebo. The higher dose was not well tolerated
mainly due to nausea and vomiting (Gantz et al., 2007). 7-TM
Pharma, a biotech company specialising in the development of
small molecule GPCR agonists and antagonists, has been actively
working to discover novel ligands for various NPY receptors.
TM30335 is a potent, highly selective, small molecule Y2 receptor
agonist. In the DIO mouse model of human obesity, our laboratory
has shown that repeated subcutaneous administration of TM30335
produced weight loss indistinguishable from that caused by
PYY3e36 together with reductions in adiposity and plasma cholesterol concentrations (Elling et al., 2006, Fig. 3). Although, TM30335
may be much better suited to clinical development than a peptide,
this compound is no longer listed on the company’s website. In the
same scientific communication, Elling et al. (2006) reported that
TM30339, which is a small molecule Y4 receptor agonist, produced
profound weight loss in DIO mice that was greater than the effects
of the Y2 agonists, PYY3e36 and TM30335 (Fig. 3). This compound
also provided the metabolic benefits of reduced adiposity and
plasma concentrations of cholesterol (Fig. 3). TM30339’s development status is listed as Phase 1/2 on 7-TM’s website. Finally, obinepitide (TM30338) is a dual Y2eY4 receptor agonist that produces
very substantial weight reduction in the DIO mouse model; in fact,
its effect was considerably greater than that produced by the
selective Y2 agonists, PYY3e36 and TM30335 (Elling et al., 2006,
Fig. 3). In a clinical trial, obinepitide has been shown to be well
9
tolerated and to suppress food intake for up to 9 h when administered to healthy obese individuals by subcutaneous injection
(Elling et al., 2006). In December, 2011, obinepitide’s development
status on 7-TM’s website was also listed as Phase 1/2.
Melanin concentrating hormone (MCH) is a 19-amino acid cyclic
peptide and, in the CNS of mammals, this molecule is exclusively
expressed in the lateral hypothalamus (Pissios, 2009). MCH has
orexigenic effects and soon after the synthesis of the first MCH1
receptor antagonists, T-226296 (Takeda) and SNAP-7491 (Synaptic),
these compounds were reported have powerful actions to reduce
food intake and body weight in rodents (Pissios, 2009). There was
also tentative evidence to suggest that MCH1 receptor antagonists
modestly enhance energy expenditure by increasing resting
metabolic rate (Ito et al., 2009). In DIO mice, AMR-MCH-1 (30 and
60 mg/kg po) was shown to produce profound and progressive
weight-loss over 28 days (Sargent et al., 2008; Fig. 4). In contrast to
sibutramine that was used as a positive control, not only was the
reduction in body weight greater (AMR-MCH-1 ¼ 11.1% and 13.9% at
30 and 60 mg/kg, respectively, versus sibutramine ¼ 5.8%), but
there was also continuous weight loss throughout the dosing of
AMR-MCH-1 (Sargent et al., 2008; Fig. 4). Marked reductions in
visceral adiposity were also observed after treatment with AMRMCH-1 and sibutramine (Sargent et al., 2008; Fig. 5). More
recently, another more potent MCH1 antagonist, AMR-MCH-14
(5 and 15 mg/kg po bid), has been reported to induce doserelated weight-loss in the DIO mouse that resulted in a 21.8% fall
with the higher dose; an effect that was 3 times greater than that
observed with sibutramine (Surman et al., 2009; Fig. 4). Fig. 5
shows that AMR-MCH-14 markedly decreased the plasma
concentration of leptin indicating a substantial reduction in fat
mass and this was accompanied by reductions in atherogenic
plasma lipids (Surman et al., 2009; Fig. 5). A major setback to
exploiting this drug target was an inability to synthesise potent,
selective MCH1 antagonists that lack affinity for the hERG (human
ether-a-go go related gene) ion channel (Berglund et al., 2009).
Albany Molecular appear to have overcome this problem and have
recently reported on several chemical series that contain potent
selective MCH1 receptor antagonists with reduced hERG affinity
(Surman et al., 2010; Hadden et al., 2010; Henderson et al., 2010).
We have shown that examples of compounds from each of these
series produced marked weight reductions when administered
repeatedly to DIO mice (Surman et al., 2010; Hadden et al., 2010;
Henderson et al., 2010).
The melanocortin 4 (MC4) receptor subtype is present not only
on the hypothalamus, but it is also widely distributed across other
regions of the mammalian brain. Signalling via MC4 receptors in
the hypothalamus is tonically regulated by the actions of the
endogenous agonists, aMSH, bMSH and gMSH, and antagonist,
agouti-related protein (AgRP) (Adan et al., 2006). Intracerebral
administration of the natural agonist, aMSH, or the synthetic
agonist, melanotan-II (MTII), was found to decrease food intake
and body weight in wild-type mice, but not in MC4 knockouts
(Adan et al., 2006) suggesting that agonists of this receptor may
have utility in the treatment of obesity. Designing and synthesising small molecule agonists for GPCRs where the endogenous
ligand is a large peptide poses a much greater challenge than
discovering peptide receptor antagonists. Nevertheless, several
pharmaceutical companies, including Merck, have succeeded in
this objective. MK-0493 is a potent selective MC4 receptor agonist
with orally bioavailability (Krishna et al., 2009). In human
volunteers, MK-0493 produced a significant reduction in calorie
intake, but the effect was much smaller than that of the reference
comparator anti-obesity drug, sibutramine (Krishna et al., 2009).
In placebo-controlled clinical trials in overweight and obese
subjects, a fixed dose of MK-0493 produced a small reduction
(2012), doi:10.1016/j.neuropharm.2012.01.017
10
Body weight
40.00
Vehicle
TM30338 1 mg/kg BD
39.00
Vehicle
TM30339 1 mg/kg OD (1mg/kg BD from Day 17)
TM30335 1 mg/kg BD (2mg/kg BD from Day 17)
Body Weight adjusted means (g)
38.00
PYY3-36 1 mg/kg BD
37.00
Amended dosing began on Day 17
36.00
Y4-selective
-7.1%**
35.00
34.00
-8.4%**
33.00
-11.5%**
32.00
31.00
Y4-selective
-14.7**
Dual Y2/Y4-selective
30.00
Day 1 Day 3 Day 5 Day 7 Day 9 Day 11 Day 13 Day 15 Day 17 Day19 Day21 Day23 Day25 Day27 Day29 Day31 Day33 Day 35 Day 37 Day 39
Fat content
Plasma cholesterol
250
20
**
***
***
***
10
Plasma cholesterol
(mg/dl)
Fat content (%)
30
200
***
150
***
***
100
50
0
0
A
B
D
E
F
A
B
D
E
F
Group
Group
A: Vehicle sc bid
B: TM30338 1mg/kg sc bid
D: TM30339 1mg/kg sc bid
E: TM30335 2mg/kg sc bid
F: PYY3-36 1mg/kg sc bid
Fig. 3. Effect of Y2 and Y4 receptor subtypes on the body weight, plasma cholesterol and fat content of male DIO mice. Data are adjusted means þ SEM that have been calculated
from the residuals of the statistical model. First day of dosing was Day 1. Significantly different from appropriate vehicle-treated control group: *p < 0.05, **p < 0.01, ***p < 0.001
Dunnett’s test. Data taken from Elling et al. (2006).
from baseline body weight at 12 weeks, but the effect was not
significantly different from placebo. In an 18-week trial employing
a stepped titration dosing protocol for MK-0493, the same
outcome was observed (Krishna et al., 2009). On this basis, the
authors concluded that MC4 receptor agonism would not be
a viable approach for developing novel drugs to treat human
obesity.
In summary, research into hypothalamic peptides has exponentially increased our knowledge about the multiplicity of
systems within the CNS that regulate energy intake and expenditure. Many of these potential drug targets have yet to be tested
within a clinical setting. Although there have been some disappointing failures in the clinic, NPY Y2, Y4, and dual Y2eY4 receptor
agonists, and MCH1 antagonists appear to show promise as
potential new CNS approaches to obesity treatment.
4.3. Fixed-dose combinations
4.3.1. Empatic (bupropion SR þ zonisamide SR)
EmpaticÒ (bupropion SR þ zonisamide SR) is the second fixeddose combination medication being developed by Orexigen.
Empatic has completed its Phase 2 proof-of-concept evaluation.
The pharmacology of the catecholamine reuptake inhibitor,
bupropion, has been described in the section on Contrave. Zonisamide (ZonegranÒ) is an anti-convulsant drug with an unresolved pharmacological mechanism of action. Weight-loss is
a known side-effect associated with the use of zonisamide in
epilepsy and this property prompted a preliminary evaluation of
its value as an obesity treatment. Gadde et al. (2003) conducted
a small, double-blind, placebo-controlled trial of zonisamide in
moderately obese, healthy subjects and reported a mean 5.0 kg
(2012), doi:10.1016/j.neuropharm.2012.01.017
11
AMR-MCH-1
42
41
Body weight (g) - adjusted means
40
39
38
**
37
36
***
35
34
33
Vehicle (po bid)
32
AMR-MCH-1 (30 mg/kg po bid) -11.1%
31
30
Sibutramine (20 mg/kg po qd) -5.8%
***
29
-13
-11
-9
-7
-5
-3
-1
1
3
5
7
9
11
13
15
17
19
21
23
25
27
Day
AMR-MCH-14
42
41
Body weight (g) - adjusted means
40
39
38
**
37
36
35
34
***
33
Vehicle (po bid)
32
31
30
Sibutramine (20 mg/kg po qd) -5.8%
***
29
-13
-11
-9
-7
-5
-3
-1
1
3
5
7
9
11
13
15
17
19
21
23
25
27
Day
Fig. 4. Effect of repeated administration of the MCH 1 antagonists, AMR-MCH-1 and AMR-MCH-14 on body weight in male C57BL/6J DIO mice. Data are adjusted means SEM
(n ¼ 8e9) that have been calculated from the residuals of the statistical model. Data analysed by ANCOVA with body weight on Day 1 as covariate followed by Williams’ test.
Significantly different from appropriate vehicle-treated control group: **p < 0.01, ***p < 0.001. Figures in legend are percentage difference from control on Day 28 (i.e., after 27 days
dosing). Data taken from Sargent et al. (2008) and Surman et al. (2009).
(5.0%) placebo-subtracted reduction in body weight at the end of
16 weeks of treatment indicating its potential usefulness as an
anti-obesity drug. Zonisamide, like topiramate, is a potent inhibitor of carbonic anhydrase isoenzymes and this pharmacological
mechanism has been proposed to mediate its metabolic effects
(De Simone et al., 2008). Orexigen employs a novel sustained
release formulation of zonisamide that they have stated reduces
its potential to cause adverse events. A 7-arm, 24-week, doseranging, proof-of-concept trial revealed that the high dose of
Empatic (bupropion 360 mg þ zonisamide 360 mg) produced
a substantial, placebo-subtracted, weight-loss of 7.5% at the end of
treatment (Orexigen Therapeutics Press Release, 2007). Importantly, the weight reduction observed with the fixed-dose
combination was approximately equivalent to the sum of
the effects of each component drug given alone (Orexigen
Therapeutics Press Release, 2007). More recently, Orexigen reported results from a second Phase 2 trial evaluating high
(bupropion 360 mg þ zonisamide 360 mg) and medium (bupropion 360 mg þ zonisamide 120 mg) doses of Empatic showing
placebo-subtracted weight-losses of 6.1% and 4.7%, respectively, at
24 weeks (Orexigen Therapeutics Press Release, 2009). When
these results are viewed as a categorical analysis, 20.7% and 28.3%
of subjects achieved >10% reduction of their baseline weight on
the medium and high doses of Empatic (Orexigen Therapeutics
Press Release, 2009). Common adverse events reported for
Empatic were headache, insomnia and nausea which are consistent with the known properties of the constituent drugs (Orexigen
Therapeutics Press Release, 2009). In the light of the FDA’s negative opinion on the cardiovascular profile of Contrave and the fact
that bupropion comprises one of the active moieties in both
(2012), doi:10.1016/j.neuropharm.2012.01.017
12
Fig. 5. Effect of repeated administration of the MCH 1 antagonists, AMR-MCH-1 and AMR-MCH-14, on adiposity and plasma lipids in male DIO mice C57Bl/6. Data are shown as
adjusted means SEM (n ¼ 8e9) that have been calculated from the residuals of the statistical models. Multiple comparisons against vehicle were by Williams’ test. Significances
are denoted by *p < 0.05, **p < 0.01, ***p < 0.001. Data taken from Sargent et al. (2008) and Surman et al. (2009).
combination products, a key piece of information that is not yet in
the public domain is what effect Empatic had on blood pressure in
these clinical trials. Overall, the clinical evidence indicates that
Empatic and Contrave are approximately equivalent in terms of
efficacy, but a more critical point is whether Empatic has less
adverse influence on blood pressure than Contrave. Development
of Empatic is currently on hold while Orexigen concentrates its
resources on agreeing and conducting the cardiovascular outcome
trial that is the key to the US approval of Contrave.
4.3.2. Pramlintide þ metreleptin
Amylin Pharmaceuticals successfully developed pramlintide
(SymlinÒ), which is a synthetic analogue of the pancreatic peptide,
amylin, for the management of Type 2 diabetes. In obese human
volunteers, injections of pramlintide three times daily prior to
meals resulted in significant reductions in meal size with reduced
cravings for food (Smith et al., 2007). After 43 days on this regime,
pramlintide-treated subjects experienced a w2.0 kg decrease in
bodyweight (Smith et al., 2007). Because pramlintide delays gastric
emptying, nausea is a common side-effect that could have
contributed to reduced food intake; however, although the severity
of nausea was higher with pramlintide treatment than placebo, this
adverse event was not responsible for the reduction in calorie
intake (Smith et al., 2007). In a 16-week, Phase 2 trial in obese
subjects with or without Type 2 diabetes, pramlintide (240 mg tid)
produced placebo-subtracted weight-losses of 2.4% (w2.4 kg) in
diabetic subjects and 2.8% (w2.8 kg) in non-diabetics (Aronne
et al., 2007). The authors also showed that the overall reduction
in body weight was similar in subjects with and without persistent
nausea confirming that weight-loss was not mediated by this sideeffect (Aronne et al., 2007). In a 4-month, Phase 2B trial in nondiabetic, obese subjects that also included a single-blind 8 month
extension period, twice daily dosing of pramlintide (240 mg) was
found to be as efficacious as the three times daily regime (Smith
et al., 2008). The conservative, ITT-LOCF analysis recorded
a placebo-subtracted weight-loss of w4.0 kg that realistically was
(2012), doi:10.1016/j.neuropharm.2012.01.017
not sufficient to support clinical development as a monotherapy.
Amylin subsequently explored its anti-diabetic drug, pramlintide,
combined with metreleptin (recombinant human methyl leptin)
for the treatment of obesity. The former neuro-hormone is a hindbrain satiety signal and the latter is a hypothalamic regulator of
long-term energy homeostasis. Leptin is a regulatory hormone that
is released into the bloodstream by adipocytes, which regulates
food intake and energy expenditure by activating leptin receptors
in the hypothalamus. Deficiencies in leptin signalling underpin the
profound genetic obesity present in the Zucker fa/fa rat and ob/ob
mouse. Initial enthusiasm about leptin’s potential as a wonder
treatment for obesity was dashed by disappointing efficacy in
clinical trials (Heymsfield et al., 1999); a finding that fitted with the
observation that rather than having low levels of leptin, obese
subjects had very high circulating levels of this hormone indicating
that polygenic human obesity is associated with leptin resistance
rather than leptin deficiency (Toornvliet et al., 1997; Bennett et al.,
1997). Experiments performed in obese rodents revealed complex
metabolic interactions between pramlintide and metreleptin with
the former restoring impaired leptin signalling in the hypothalamus and the combination having a synergistic action to reduce
body weight and adiposity (Trevaskis et al., 2008; Roth et al., 2008).
Ravussin et al. (2009) reported results from a 24-week, Phase 2 trial
in obese subjects where the efficacy of the pramlintide (360 mg
bid) þ metreleptin (5.0 mg bid) was compared against the individual treatments. Because no placebo arm was included in the
trial, the results were reported as reduction of weight compared
with baseline. The w12.0 kg reduction observed with the fixeddose combination was greater than the w8.0 kg recorded in the
subjects receiving either pramlintide or metreleptin alone, but
less than the sum of their effects. Amylin conducted a second Phase
2 trial using a placebo-controlled, multi-dose, multi-arm design,
and showed that after 28 weeks, the pramlintide (360 mg
bid) þ metreleptin (5.0 mg bid) combination produced a placebosubtracted 8.2 kg reduction in the weight of moderately obese
subjects (Amylin Pharmaceuticals Press Release, 2009). This result
was the less conservative completers’ analysis and the ITT-LOCF
data were not provided in the press release. In all of these trials,
the most commonly reported adverse events were nausea
and injection site reactions. Although the results show that the
pramlintide/metreleptin combination delivered efficacy that was
equivalent to many other centrally-acting drugs and better
than some, the requirement for twice-daily injections remained
a significant barrier to patient acceptance. Following the report of
an antibody-related safety issue, Amylin suspended its clinical trial
and discontinued development of the pramlintide/metreleptin
combination in 2011 (Amylin Pharmaceuticals Press Release, 2011)
5. Conclusions
The treatment of obesity with powerful centrally-acting drugs is
an area where the question of whether the benefits justify the risks
is debatable based on past experiences of poor safety with many of
these agents. Furthermore, no clinical outcome study has yet been
performed which demonstrates that long-term treatment with antiobesity drugs has a positive effect to reduce rates of morbidity and
mortality in obese subjects. The modest efficacy of current antiobesity drugs causes prescribers and patients to question the
value of drug treatment, and based on the available clinical data, this
hurdle does not appear to have been overcome by either lorcaserin
or Contrave. The uncertainty that still surrounds the US approvals of
lorcaserin, Qnexa and Contrave is unsettling because it feeds the
belief that the current safety barriers are so high and the appetite for
new pharmacological treatments so low, it is impossible to get
a new drug registered for the obesity indication. This assessment is
13
incorrect and unfair to the regulatory agencies that have provided
very balanced reviews of the latest drug candidates and appear very
willing to work with the Sponsors to address their concerns. As
demonstrated by the other reviews and original articles contained in
this issue, a wealth of preclinical research has been undertaken that
has provided a far greater understanding of the complex nature of
the hypothalamic regulation of food intake, and in turn, it has
generated a wide range of new molecular targets for the development of drug candidates to treat obesity. Although many of these
approaches are still at a very early stage of development, several of
these clinical candidates, e.g., 5-HT6 antagonists and partial agonists,
MCH1 antagonists and various NPY agonists, have yielded results in
preclinical models of obesity that predict they have the potential to
deliver greater weight-loss than existing drugs. The discontinuation
of several drug candidates in clinical development demonstrates the
careful balance that needs to be drawn between efficacy versus
tolerability and/or safety in order to achieve an acceptable benefit/
risk profile in the indication of obesity. With the rates of obesity
showing no signs of slowing, it has to be hoped that some of the
drug candidates that are currently in development will form part of
a new generation of anti-obesity drugs with increased efficacy and
safety that is so urgently needed.
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