Appetite downer drug

[Guest guest]

Hi All,

A safe appetite downer drug is in the works, it seems. See the pdf-available

article below.

Business

Nature 437, 618-619 (29 September 2005) | doi: 10.1038/437618a

Appetite downer awaits approval

Meredith Wadman

A pill that works by putting the hunger induced by cannabis into reverse could

jump-start a languishing market for obesity drugs, reports Meredith Wadman.

A French drug company could be within months of winning regulatory approval for

rimonabant, a drug widely tipped as the first 'blockbuster' weight-loss pill.

After decades of false starts, the prospect will raise a sceptical eyebrow or

two.

Previous weight-loss therapies have left in their wake a trail of disappointed

dieters and dangerous or unpleasant side effects — not to mention an obesity

epidemic that is veering out of control.

But Paris-based Sanofi & #8722;Aventis said in June that the US Food and Drug

Administration (FDA) is considering its new-drug application for rimonabant,

which

would go on sale in the United States as Acomplia. A decision could come as soon

as

next spring. The company, which was formed in a merger last year and is the

world's

third-largest drugmaker, has also applied for approval in Europe and elsewhere.

The drug works by blocking one of the receptors where the active ingredient in

cannabis docks. Dubbed the CB1 receptor, it is widely dispersed in the brain and

other organs. The receptor helps to regulate energy balance, fat and sugar

metabolism, and appetite, and is stimulated by the body's own cannabis-like

neurotransmitters. In what smokers of the weed might recognize as a 'reverse

munchie' effect, the blocking of the receptor makes people feel sated, so they

eat

less.

Impressive results

In one completed clinical trial, investigators reported in April that 363 obese

Europeans who took 20 milligrams of the drug daily for a year lost an average of

8.6

kilograms (Lancet 365, 1389 & #8722;1397; 2005). Their waistlines shrank by an

average

of more than 8 centimetres. And this wasn't just a cosmetic improvement: excess

abdominal fat is a significant risk factor for heart disease.

The subjects also showed healthy changes in blood levels of important

heart-disease-related substances: levels of HDL, the so-called 'good'

cholesterol,

rose significantly, and those of triglycerides — fat transport and storage

molecules

— fell. The most common side effects included nausea (12.9%), dizziness (8.7%)

and

diarrhoea (7.2%). But investigators said that these were " mild to moderate and

considered to be transient, based on the occurrence mainly during the first

months

of the study " .

Over the past 18 months, researchers have reported other findings from a total

of

seven phase III clinical trials involving over 13,000 subjects. These indicate

that

the drug is effective not just for weight loss but also in controlling diabetes

and

even in quitting smoking.

These results make Sanofi far and away the leader of the pack of drug companies

chasing the potentially vast obesity market. Scientists in company laboratories

at

Montpellier in France began their hunt for the drug soon after the brain

receptor

for cannabis was identified in 1990 (see Nature 346, 561 & #8722;564; 1990). Their

reasoning was that if marijuana creates the munchies, a compound that blocks its

effects could decrease appetite. That early insight has left more recent

entrants to

the field, such as Merck, Pfizer and Bristol & #8722;Myers Squibb, scrambling to

recover lost ground.

Not for dieters

But the French company has been at pains to portray rimonabant as anything but a

pill for cosmetic dieters. " There have been a whole host of positive impacts

we've

seen with this product in overweight, obese and diabetic patients, " says company

spokeswoman Julissa Viana. " It's not for someone who just wants to lose five or

ten

pounds. " That being said, physicians in the United States can prescribe an

approved

drug to anyone for any purpose.

Sanofi's market timing could hardly be better. Last week, the World Health

Organization declared that more than 1 billion people worldwide are overweight,

a

number expected to grow to 1.5 billion by 2015. Yet in the United States, only

three

key weight-loss drugs are currently approved; their annual sales totalled $224

million last year, according to IMS Health, a Pennsylvania-based pharmaceutical

information and tracking company.

" As a business, this is just terrible, " says Caro, an endocrinologist who

is in

charge of obesity drug research at Eli Lilly, based in Indianapolis. He says his

company has five anti-obesity compounds of its own in early clinical

development.

According to Decision Resources, a market-research firm based in Waltham,

Massachusetts, only one in twenty-five obese people in the United States have

prescriptions for drug treatment.

Existing weight-loss drugs have well-known side effects, including faecal

incontinence and high blood pressure. They are only mildly effective; none

produces

an average weight loss of more than 4.5 kilograms. So many insurance plans will

not

reimburse patients for them, and many patients discard them after a few months.

Thousands are turning instead to surgery to lose weight (see graph, below).

Bernice Welles, an endocrinologist and vice-president at DiObex, a San

Francisco-based biotechnology company, told an obesity meeting in Washington DC

earlier this month that, if it lives up to its promise, rimonabant will

transform

this picture.

" Sanofi & #8722;Aventis definitely has a blockbuster drug on its hands, " says

Donny

Wong, a biochemist and analyst at Decision Resources. Wong's firm is predicting

an

annual obesity drug market of $2.3 billion by 2013, with rimonabant accounting

for

some 60% of those sales. Other analysts have suggested that sales could go

higher

than that — but the drug's prospects are dampened by concerns that insurers may

refuse to pay for it.

And safety concerns will lurk in the background until the drug is tried and

tested

in the market. In a letter to The Lancet in July, Bernard Hirschel, an

infectious

disease specialist at Geneva University Hospital, suggested that

Sanofi & #8722;Aventis test its drug candidate in high-risk groups before it goes

on

sale (Lancet 366, 369; 2005).

Bland, a biochemist and president of Metagenics, a maker of nutritional

products based in San Clemente, California, says that diet drugs that act on the

brain have had a troubled history. A case in point is the

fenfluramine & #8722;phentermine combination popularly called 'fen & #8722;phen',

made

by Wyeth of Madison, New Jersey. Its fenfluramine component suppressed appetite

by

boosting serotonin levels in the brain. But it was found to cause serious damage

to

heart valves and was withdrawn in 1997. " In central nervous system-mediated

medication, we almost always learn something once those products are released

that

we didn't know before, " Bland says.

Others, like Lilly's Caro, predict that in the long term, pharmacological

approaches

to obesity are unlikely to hinge on any single drug, however effective. They

will

probably involve several, deployed in combinations devised for each patient. In

the

short term, however, rimonabant could soon have the obesity medicine chest

largely

to itself.

Al Pater, PhD; email: old542000@...

__________________________________

- PC Magazine Editors' Choice 2005

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