Developing Anti-Obesity Drugs - UK
Anti-Obesity Drugs UK
With the exception of the bulking agent methylcellulose, all drugs that
were available for the treatment of obesity when I started in industry
27 years ago have been withdrawn in the UK. The pancreatic lipase inhibitor
orlistat, and the 5-HT and noradrenaline reuptake inhibitor sibutramine,
the anti-obesity effect of which was discovered by chance, have been introduced
recently, but drug discovery scientists have not had the satisfaction
of designing a successful drug that acts at a target discovered by the
'new biology'; nor is such a drug in phase III clinical trials (though
CNTF, which caused weight loss in a trial for motor neurone disease, is).
There are grounds for optimism, however. There is no shortage of potential
drug targets. The problem is rather in choosing between targets and meeting
the various expectations of regulatory authorities, doctors and patients.
Expected Weight Loss with Anti-Obesity
Drugs
What expectations are realistic? Thermogenic drugs are unlikely to increase
daily energy expenditure by more than 10 percent and would therefore take
about 6 months to produce 5kg more weight loss than placebo if thermogenesis
is their sole mechanism. (It is therefore pointless to try to demonstrate
significant weight loss in a 4 week study.) Anorectic drugs might, in
theory, have a greater impact on energy balance, though in practice no
monotherapy has consistently achieved more than 5kg weight loss relative
to placebo in 6-month studies. Compared to anorectic drugs, thermogenic
drugs are likely to be more selective for fat rather than protein loss,
have a greater insulin sensitising effect and possibly elicit weight loss
for a longer period before body weight plateaus. It is important that
anti-obesity drugs improve metabolic status as effectively as the same
weight loss produced by diet. The insulin sensitising effect of thermogenic
drugs, such as b3-adrenoceptor agonists, may be due to enhanced oxidation
of long chain fatty acyl CoA, resulting in lowering of diacylglycerol
concentrations and deactivation of protein kinase C isozymes that inhibit
enzymes in the insulin signalling pathway.
Types of Anti-Obesity Drugs
Central targets for anti-obesity drugs may be categorised in various ways:
those that alter the defended body weight versus those that defend the
defended weight (eg sex hormones vs. neuropeptide Y?); those that interact
with tonic versus those that interact with episodic systems of weight
control (eg leptin vs. cholecystokinin); physiological versus unphysiological
mechanisms. There are pros and cons for targets of each type. Unphysiological
mechanisms might have most potential for rapid and sustained weight loss,
but they also carry greatest risk. It might be argued that since leptin
is already high in most obese subjects, interfering with leptin and downstream
neurotransmitter targets is likely to have limited effect.
In contrast to obese humans, the most convenient rodent models for evaluating
anti-obesity agents are those with a dysfunctional leptin system. These
may give a false impression of the likely efficacy in humans of drugs
that interact with receptors for leptin or its downstream neurotransmitters.
Moreover, all rodent models, but especially those with defective thermogenic
mechanisms, like the leptin dysfunction models, may overestimate the likely
efficacy in humans of thermogenic compared to anorectic drugs. Obesity
and its metabolic complications presents an enormous and increasing unmet
medical need. This is a tantalising
therapeutic area for the pharmaceutical industry.
Source: Professor Jonathan R S Arch, University of Buckingham, Buckingham,
UK (2002)
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