The Midstage Crop

The most exciting drugs in development, Wong believes, are those in Phase II, even though preliminary revenue forecasts currently lag behind the projections for Phase III candidates. Wong identifies three compounds that are showing the double-digit weight-loss percentage that prescribers want.

Tesofensine, by Neurosearch, a Danish biotech, is a dopamine, serotonin, and norepinephrine re-uptake inhibitor originally in development for Alzheimer's and Parkinson's diseases. The drug boasts weight-loss efficacy data of 29 to 33 pounds. Patients in typical obesity studies average 220 pounds, according to Wong. Tesofensine's performance rivals the efficacy of Fen-phen, and outstrips the weight losses achieved by either rimonabant or sibutramine. The triple mechanism of action, however, may present serious side-effect issues in large-scale trials.

Wong's pick of the litter is Amylin Pharmaceuticals' combination of pramlintide, a glycemic control drug for insulin-dependent diabetics, and metreleptin, recombinant human leptin. Leptin is a messenger molecule produced naturally by a fat cell that tells the brain how much energy is stored inside the cell. When the brain perceives leptin, it believes it has sufficient energy stores and shuts down the appetite. Amgen began to develop a leptin drug in the 1990s; although the drug worked well in mice, it was ineffective in obese humans. The problem, Wong explains, was leptin resistance: Obesity appears to desensitize the brain to leptin, even when it is circulating in high quantities. Enter pramlintide, which apparently restores the brain's response to leptin. "And if you administer this combination with extra leptin, you can actually decrease appetite," Wong says. In a 28-week Phase II dosing study, patients with a starting BMI less than 35 who were treated with the highest dose lost 11 percent of their baseline weight, compared to 1.8 percent for placebo. InThought sees a 2013 launch with revenues reaching $389 million by 2016. Sagient sees a 2014 launch with $102 million in revenues by 2016.

The Tough Take-Home

It's far from certain which, if any, of these six drugs FDA will ultimately approve. All face unique safety hurdles, and it is unclear how high agency standards will be in the coming years. Big Pharma companies are not rushing to partner with any of the small companies that have drugs in Phases II and III, though all will likely need to make deals to fund further large-scale clinical trials or to access sales and marketing forces at launch time.

This situation is no surprise, says Cuttler. In the years when rimonabant looked like the next great blockbuster, most big companies were working on competing obesity agents, and had little incentive to acquire new ones, especially combinations based on compounds that would go generic sooner than their own candidates. Now, with CB1 receptor blockers out of the clinic (a handful remain in preclinical development), the smaller companies with viable candidates are in the driver's seat. They may choose to wait until their Phase III data is out before signing a licensing agreement, if only to push for a better deal.

If these modestly effective drugs do reach the market, the challenge for drugmakers will be targeting them to the populations where they'll do the most good and the least damage, according to Datamonitor, whose analysts also project the lowest revenues for today's late-stage drug candidates.

In the absence of effective drug therapies—and ignoring bariatric surgery, which is recommended for only the most obese patients—behavioral changes around diet and exercise offer the best chance for countering obesity. But lifestyle improvements, Datamonitor's Angell notes, have generally shown poor results in adult populations. Wong's research shows that most patients fail to stick to diet and exercise routines for more than two or three months at a time.

Yet such lifestyle interventions may prevent young people from becoming obese in the first place. In government-run health systems like that of the UK, the vast majority of money is being put into preventing obesity, not treating it. Regulators in the EU are currently debating tougher food advertising and labeling restrictions, as well as pushing the food and retailing industries to reformulate recipes, cutting back on salt and fat. Advocates in the US are mobilizing around similar goals.

Even if behavioral changes were to take root widely, rates of obesity would likely be slow to change—shrinking only as older obese people die and are replaced by fewer younger ones. A similar process is reducing the number of tobacco smokers, at least in countries with anti-smoking campaigns. This gradual process means that the present obese population—and the giant potential market for new drugs—is almost certain to remain underserved for another generation.