Boston Globe
February 19, 2006

There's still no magic pill for weight loss (but that's not stopping drug companies from looking)
By Diedtra Henderson, Globe Staff

Dr. Barbara Corkey, a Boston University professor of medicine and biochemistry, started AdipoGenix Inc. with a simple fat-busting strategy: ''Let's ask the fat cell to tell us what works. What decreases the amount of fat in a fat cell?"

Simply put, not all fat cells are created equal. Some are merely fat. Others are really fat. That realization led the Boston company to develop a short list of molecules it will test in obese rodents this spring. Each molecule has the potential to become a drug that can shrink fat cells and, in the process, shrink belly fat.

Despite the sliding sales of diet pills and the spectacular failure of fen-phen, drug makers have built up an appetite for finding a weight-loss treatment that works. About 162 experimental diet pills are in company pipelines, nearly three times the number in 1999, according to Adis R&D Insight. But with history as a guide, nine of 10 will fail before reaching a pharmacy shelf.

The incentive? Two-thirds of American adults — roughly 130 million people — are overweight or obese, representing a market worth billions of dollars. Analysts estimate the right diet pill could quickly attain blockbuster status. That includes Sanofi-Aventis's Acomplia, which the Food and Drug Administration could approve this month, and which Sanofi expects to sell by the middle of this year.

The overall prescription diet-pill market, which includes Meridia and Xenical, has steadily shrunk to $243.2 million in sales in 2005, down from $431 million in 2001, according to IMS Health, a healthcare information company.

Some say the field remains shaken by the FDA's decision to pull fenfluramine and dexfenfluramine from the market in 1997. The combination known as fen-phen had been used as an obesity treatment until Mayo Clinic researchers linked fenfluramine, the ''fen" part of the drug combination, to heart-valve damage. Phentermine, the other drug in the fen-phen combination, remains on the market as a weight-loss treatment.

The right treatment, however, could spur diet-pill sales.

MedMarket Diligence, a California market research company, projects that out-of-pocket spending on prescription diet pills could jump to $600 per consumer by 2009 from the current $400, if new, more expensive diet pills take off. That would make annual diet-pill sales in the United States and Canada reach $2.7 billion by 2013, up from $378 million annually, according to the firm.

That spending trend could reverse a sales decline of such diet pills as Xenical, which lost popularity as dieters and their doctors realized how few pounds patients on the drugs lost, how quickly weight returned, and how dreadful side effects could be.

Dr. Frank Sacks' overweight and obese patients at Brigham and Women's Hospital were among many disappointed by Xenical. Because their bodies produce too much ''bad" cholesterol, diet and exercise alone were not shaving enough excess pounds. But shedding the weight with Xenical wasn't worth side effects that included oily stools, greasy flatulence, and uncontrolled bowel movements.

''It's kind of nasty," said Sacks, a Harvard Medical School professor of medicine. ''I basically gave up on it."

Indeed, Xenical sales dropped to $86.6 million in 2005, a dip of 15 percent from the previous year, and down significantly from $202 million in 2000, according to IMS Health.

Xenical is a good example of why drug makers continue to amass a string of diet-pill failures, despite decades of trying.

The GlaxoSmithKline drug blocks the body from absorbing dietary fat, then ferries the fat out of the body in the stool, shaving roughly 200 calories per day. But the 5 percent to 10 percent total weight loss in six months happens only if the dieters stick to a low-fat diet and exercise, said Steve Burton, GlaxoSmithKline's vice president of weight control.

While the body's strategies for stashing calories to stave off starvation are complex, drug maker's approaches to diet pills, such as blocking some of the body's absorption of dietary fat, have been simplistic.

''Turns out that the regulation of body weight is infinitely more complicated and infinitely more important to life than we have realized," said Dr. Lee M. Kaplan, director of the Obesity Research Center at Massachusetts General Hospital.

Add to that the challenges of modern life: sedentary behavior compounded by stress, disrupted sleep, the abundance of highly processed, calorie-rich foods, and little time for exercise.

''We have an environment that conspires in at least a dozen ways to interfere with the normal weight-regulation system," Kaplan said.

AdipoGenix seeks to short-circuit the body's cues that make fat cells in the center of the body balloon into bigger fat cells. Amassing too much central body fat — such as belly fat — raises the risk of developing such ailments as diabetes and cardiovascular disease.

''If you have 'small' fat cells, you're much healthier than if you have 'big' fat cells," said Ed Cannon, the Boston company's chief executive. ''Shrinking them is good."

The next few months will be crucial for the company, Cannon says, as three dozen molecules that shrink human fat cells in test tubes are tried in rodents that model human obesity and diabetes. The super-sized rodents will shed weight, he predicts.

''We think it will be a significant drop, not just a little 5 or even 10 percent drop," Cannon said.

Sanofi-Aventis's Acomplia also trims abdominal obesity, but by blocking certain haywire brain receptors that encourage overeating. Analysts and the company expect Acomplia to quickly ramp up to $3 billion in annual sales.

Sho Matsubara, a Standard & Poor's analyst, forecasts that annual sales of Acomplia could reach about $1.78 billion by 2010. The figure could be higher or lower, depending on the drug's safety. Nearly 90 percent of patients taking Acomplia in a recent clinical trial suffered side effects, including nausea, dizziness, bronchitis, and depression, Matsubara said.

Julissa Viana, a Sanofi spokeswoman, described the bulk of the adverse events as ''mild to moderate intensity."

In the face of such competition, GlaxoSmithKline wants to push its diet pill Xenical off doctor's prescription pads and into the over-the-counter realm. The company seeks to sell Xenical at a lower dose under the name Alli. Federal advisers whose votes guide FDA decisions agreed that Alli should be sold over-the-counter. If drug regulators agree, Alli would become the first over-the-counter diet pill to carry FDA approval.

''There are people out there right now in the OTC world who are desperate for a real solution," George Quesnelle, president of Glaxo's North American consumer healthcare division, said recently. ''Alli is a real solution."

Diedtra Henderson can be reached at