Feeling guilty about all that Valentine's Day chocolate you polished off last weekend?

Chances are you're not the only one who overindulged. The Centers for Disease Control and Prevention estimates that more than a third of Americans - about 72 million people - are obese, and another third are overweight. Globally, the World Health Organization projects that 400 million adults are obese and 1.6 billion are overweight. Those figures are expected to grow to 700 million and 2.3 billion, respectively, by 2015.

But most folks don't need convincing that obesity is a problem; one trip to a local shopping mall, airport or restaurant is usually enough to do the trick. The question is why the pharmaceutical industry hasn't found a way to successfully tap this market.

The demand is certainly there. According to a recent report from JPMorgan Securities Inc., the overall U.S. market for weight-loss remedies and diet products was more than $50 billion in 2006. Yet prescription pharmaceutical products accounted for just $200 million in 2007 - less than one percent of the total market.

JPMorgan analyst Cory Kasimov said the explanation is "really quite simple: there are no safe and effective drugs."

In the U.S., prescription drug options for obesity include the generic drug phentermine, F. Hoffmann-La Roche Ltd.'s Xenical (orlistat) and Abbott's Meridia (sibutramine HCl monohydrate capsules C-IV).

Phentermine is the most prescribed obesity drug, but its placebo-adjusted weight loss is only 3 percent to 5 percent, and its amphetamine-like action and abuse potential limit it to short-term usage.

Xenical works in the gut, inhibiting gastric and pancreatic lipases to decrease the absorption of dietary fat. A meta-analysis of clinical trial data showed that Xenical's average placebo-adjusted weight loss was 2.9 percent, with a drop-out rate of 30 percent.

Meridia didn't fare much better, with a 4.2 percent weight loss and 31 percent drop-out rate. The drug works in the brain to signal a sense of fullness by inhibiting the reuptake of norepinephrine, serotonin and dopamine.

And then there's Sanofi-Aventis Group's Acomplia (rimonabant), which is approved in Europe but was withdrawn from the FDA registration process last year after a negative advisory committee panel. The drug blocks cannabinoid-1 (CB1) receptors in the brain, liver and gastrointestinal tract to regulate glucose and fat absorption and suppress appetite. Data from the meta-analysis showed a placebo-adjusted weight loss of 4.7 percent and a 40 percent drop-out rate.

The FDA said in a guidance document that it wants to see at least a 5 percent placebo-adjusted weight loss from obesity drugs. Although weight loss of 5 to 10 percent has been shown to significantly decrease health issues associated with obesity, Kasimov said in his report that "meaningful weight loss for patients and physicians in the 'real world' is between 10 and 20 percent."

Double-Size Drugs to Battle the Bulge

Building a better obesity drug is no easy task. Obesity involves a host of genetic, behavioral, emotional and socio-cultural factors. And any successful drug will be taken by millions of patients, resulting in a safety hurdle that will "probably be greater than for any other drug out there," Kasimov said.

Several obesity drugs are now in late stage development, and many have similar mechanisms to the approved drugs. Merck & Co. Inc. and Pfizer Inc. are conducting Phase III trials with the CB1 blockers MK-0364 (taranabant) and CP-945598, respectively. Arena Pharmaceuticals Inc. is in Phase III with lorcaserin, which agonizes the 5-HT2c serotonin receptor. And Alizyme Therapeutics Ltd. is in the process of getting special protocol assessments approved and finding a partner for Phase III trials of gastrointestinal lipase inhibitor, cetilistat.

But the physician consultants JPMorgan spoke with believe single agents will have "limited benefit because they can only target one pathway effectively, which is likely insufficient to produce long-term, sustained weight loss." The doctors believe that "the combination approach will become standard of care," Kasimov wrote.

As evidence, Kasimov points out that the only prescription drug ever to produce significant weight loss and take the obesity market by storm was, in fact, a combination drug. The infamous Fen-Phen, prior to being recalled for safety issues, demonstrated 15 percent weight loss and generated more than 20 million prescriptions annually.

Today's combination drugs for obesity are built from generics, which Kasimov said allows their safety profiles to be well understood. The most advanced are Orexigen Therapeutics Inc.'s Contrave and Vivus Inc.'s Qnexa, both in Phase III.

Orexigen's Contrave combines long-acting versions of naltrexone, an opioid blocker approved for opioid and alcohol addiction, and bupropion, a dopamine stimulator approved for depression and smoking cessation. Orexigen President and CEO Gary Tollefson explained that the two drugs affect the reward pathways associated with food addictions, both on the involuntary level that regulates hunger and energy burn, and on the voluntary level that causes excessive eating.

Additionally, bupropion enhances weight loss by increasing energy burn, a normally short-lived benefit that naltrexone helps to extend. And bupropion has anti-depressive effects, addressing a frequent co-morbidity of obesity.

Data from combined clinical trials show an average weight loss of 4.6 percent after 24 weeks on Contrave, similar to what the existing drugs produce over a year. Yet while other drugs hit a plateau, Contrave provides a "slow, steady, progressive reduction in weight," Tollefson said, and patients completing a year of treatment achieved 8 percent to 10 percent reductions.

Even more dramatic weight loss may come from Orexigen's second product candidate, Empatic, a combination of long-acting bupropion and long-acting zonisamide, a seizure drug believed to modulate sodium channels and enhance dopamine and serotonin activity. The zonisamide inhibits neurons that contribute to the weight loss plateau by promoting energy storage and hunger when weight starts to drop off. This ability to prevent weight gain synergizes with bupropion's ability to promote weight loss.

Pooled trial data show Empatic offers average weight loss of 7.5 percent after 24 weeks, which increased to 14 percent after a year according to Phase IIb data presented last month. The drug also has a drop-out rate of just 9 to 21 percent, which Tollefson said was due to the company's reformulation of zonisamide to limit side effects.

Empatic is slated for one more Phase II trial, which could produce data later this year, before moving on to Phase III in 2009. Meanwhile Contrave is already being studied in four Phase III trials, and data from the first trial are expected in December. The remaining trials should produce results in the first half of 2009, supporting a new drug application filing by the end of 2009.

Vivus's Qnexa also seeks to create a synergistic effect by combining the generic diet drug phentermine with topiramate, a drug approved for epilepsy and for migraine prevention. Phentermine decreases appetite and increase energy usage, while topiramate increases feelings of fullness. Separately, the two drugs have only mild weight loss effects, but together they produce "true synergy" due to the fact that they target different areas in the brain, said Vivus Director of Clinical Development Barbara Troupin.

Troupin added that the two drugs also mitigate each other's side effects, since topiramate tends to dull the senses while phentermine stimulates them. Qnexa also uses low doses of both drugs to decrease the incidence of side effects.

So far, the synergy appears to be working. In a Phase II trial, Qnexa produced average placebo-adjusted weight loss of 8.6 percent in 24 weeks, with a drop-out rate of just 8 percent. JPMorgan 's physician consultants said they believe the product "may potentially have a best-in-class clinical profile."

But analysts have expressed concern about the fact that the Phase II trial was conducted at a single trial site. Data expected next quarter from a multi-center Phase II trial in diabetes could assuage those fears, since the study will evaluate weight loss as a secondary endpoint. Kasimov called the data the most exciting event in the obesity space in 2008.

Vivus has also launched a broad pivotal program for Qnexa consisting of three Phase III trials that will enroll more than 3,750 patients altogether. The first trial is expected to deliver data by the end of the year, with the other two following around the middle of 2009.

In the end, Kasimov predicts that Contrave, Empatic and Qnexa will hit their endpoints, but that the risk associated with the drugs will come from regulatory and commercial issues. That's where the expertise of a big pharma partner will come in handy, he said, adding that it's "a question of when, not if" the three drugs will eventually be partnered.

Once they are, he expects all three to find a place in the obesity market, which he said has "room for multiple players."

Kasimov projected that as these and other new products gain approval, the market for prescription obesity drugs will grow from $200 million in 2007 to $1.5 billion in 2012 and more than $4.6 billion in 2017.