A drug to make you thin

   A drug to make you thin Pharma companies large and small are in hot pursuit of the blockbuster of all blockbusters -- a drug that lets you lose weight safely and effortlessly. A drug to make you thin! Drug marketers go glassy-eyed when they calculate the potential. At least 44 million Americans are obese -- as many as 60 million by some estimates. And for reasons that go well beyond the associated health problems, virtually everyone who is fat is desperate not to be. In a 1991 University of Florida survey of 47 formerly obese adults -- who had each lost 100 pounds or more through gastric bypass surgery -- the majority said they would rather be deaf or blind than be fat again. In a more recent study, children who were shown pictures of other children with various disabilities -- with crutches, in a wheelchair, with an amputated hand, and overweight -- picked the pudgy child as the most unlikable in the group. In a culture that so vilifies fat, it's difficult to imagine that an effective cure for the obese wouldn't quickly find its way to the merely overweight -- another 67 million customers. Moreover, an obesity medicine is not something patients would take only until they "got better." It could be consumed by tens of millions of Americans every day for years. Estimates of the annual revenue for such a market range from $25 billion to $50 billion within 10 years, depending on how many non-obese users wangle prescriptions. Even at the lower estimate, weight-loss pills would be by far the single most lucrative category in the history of pharmaceuticals. At $50 billion in annual U.S. revenue, they would outsell today's three largest drug categories -- cholesterol-lowering statins ($13.5 billion), antidepressants ($13.2 billion), and heartburn medications ($12.9 billion) -- combined. No wonder the race to create an effective thin pill gets more crowded by the day. Weight-loss meds, obviously, have been on the pharmaceutical agenda since doctors dispensed thyroid hormones to overweight patients a century ago. But in recent years, the urgency has grown exponentially, as the health-care establishment has gone from dismissing excess fat as a cosmetic misfortune to labeling it a health crisis. James Anderson, head of the Obesity Research Network at the University of Kentucky, keeps a spreadsheet of obesity drugs in development. By his count, 94 companies -- including Pfizer (PFE), Merck (MRK), Johnson & Johnson (JNJ), and GlaxoSmithKline (GSK), the biggest of big pharma -- are pushing 176 would-be blockbusters. "Every time I do the spreadsheet," he says, "the number grows." Mindful of the money at stake, competitors scour one another's scientific papers for insights while shrouding their own progress in secrecy. "We have hundreds of people working on multiple approaches," allows Mike Jirousek, a lead Pfizer researcher. "But I can't comment specifically." Mark Heiman, an Eli Lilly (LLY) scientist known for his pioneering work on ghrelin, an intestinal hormone that causes hunger, complains that at conferences "my competitors try to pick my brain." Ken Fujioka, a weight expert at San Diego's Scripps Clinic who has helped drug companies test diet drugs for years, says his clients occasionally pat him down for recording devices before admitting him to meetings. Outside the closed laboratory doors, rumors abound. Merck refuses to comment on whispers that it has created a miracle mouse that can eat all day without getting fat; another story has it that a mouse deprived of an appetite-controlling hormone stuffed itself until it nearly filled its cage. Some improbable yarns turn out to be true: Pfizer really did pour millions into a failed effort to derive a hunger suppressant from a cactus chewed by African bushmen. Amylin and Lilly are currently pinning their hopes on a compound derived from the saliva of the Gila monster, a venomous lizard found in the Arizona desert. As hospital food goes, the menu was positively four-star:chicken curry and rice, fruit salad, chocolate drops, and candy bars. For the two dozen hungry test subjects gathered for a meal at London's Hammersmith Hospital in 2002, only the appetizers were unappetizing: 90-minute blood infusions juiced with a mystery hormone called PYY3-36. Watching videos to put them at ease, diners sat by themselves behind curtains as nurses served trays of food in equal portions. Thirty minutes later, a dietitian began to record the results. Half of the test subjects were severely overweight, the other half slender, but all of those given the PYY injection downed nearly a third fewer calories than they did at another meal without the hormone. And when they went home, they continued to eat less for 12 more hours. Back at the offices of Nastech Pharmaceutical, 20 miles outside Seattle, the Hammersmith leftovers were big news. Even before the experiment in London, Nastech scientists had begun work on a PYY-based nasal spray designed to fool the brain into regarding a half-empty stomach as full. The Hammersmith result only reinforced their hope that they might have found what the company's vice president for clinical research, Gordon Brandt, called "the perfect product." Perfect, indeed. Such a drug would do what no medicine, diet, book, personal trainer, or Dr. Phil episode has yet been able to do: allow people, safely and effortlessly, to eat fewer calories than they burn. Which is, ultimately, the only way to get thin. As competitive as this race is, it's still in its early laps. Many estimate that the market is 5 to 10 years from reaching its multibillion-dollar potential, and the existence of a holy grail -- a pill that cures fatness like Tylenol cures headaches -- remains to be proven. But we're not talking about a manned Mars expedition. Two possible next-generation treatments are already in phase 3 trials; one could hit the market as early as next year. The Food and Drug Administration is considering accelerating the approval process for obesity drugs -- an accommodation it usually makes only for fatal diseases like cancer -- which could put more meds in pharmacies even sooner. Meanwhile, a gold rush mentality is taking hold. The Obesity Research Network's Anderson is currently running clinical trials for eight drug prospects and has 10 more on the docket for next year. "Companies are frantic to get in on this," he says. "Cholesterol might be the biggest thing in the market now, but within the next 10 years obesity will be. There's just that much need." In their effort to get svelte, Americans last year spent roughly $1 billion on weight-loss supplements with no proven effectiveness. Another $40 billion went into diet and exercise products and programs. It's safe to say that much of that money was wasted. The problem is, thousands of years of evolution have hardwired people's brains to keep them from starving, not to make them look good in a bathing suit. "You'd think your body would say, 'You have plenty of leftovers in the fridge. Don't order out,'" says Louis Aronne, an obesity expert at Cornell University. But no. As dieters shed pounds, the brain's myriad defenses against starvation kick into gear, sending an urge to eat that can be as intense as the craving for water in the desert. That's why it's so brutally difficult to lose more than 10 percent of body weight and keep it off. It's why dieters literally dream of food. Even exercise won't induce significant weight loss without dieting. "We are programmed to stuff our face whenever we find food," says Stephen Bloom, an expert on PYY and the lead author of the Hammersmith study. Drugs hold out the promise of disabling those starvation-prevention mechanisms. Unfortunately, the pharmaceutical record is not encouraging. The wonder drugs of the mid-1990s, fen-phen and Redux, caused heart valve damage. (As a measure of people's desperation, however, patients demanded prescriptions even after the dangers were made public.) Today's leading obesity prescriptions -- Roche Laboratories's Xenical and Abbott Labs's Meridia -- are only modestly effective and can still have serious side effects. Meridia, which helps patients feel full faster, can elevate blood pressure. Xenical, which blocks fat absorption, can cause violent diarrhea. Yet the pair's combined revenue is nearly $1 billion a year. In 1994, however, a more promising pathway opened up when scientists at Rockefeller University discovered leptin -- a hormone that signals the brain that its owner has eaten enough. "Prior to leptin, the only hypotheses about the regulation of fat mass were just ghosts," says Alex DePaoli, a lead Amgen (AMGN) scientist. "With its arrival came a whole cadre of discoveries about weight regulation." Leptin-deprived mice, scientists found, could not stop eating. The discovery set off fireworks in the industry. "We thought, 'This is the fountain of youth. We're home-free,'" Fujioka recalls. Amgen shelled out $20 million in licensing fees to develop a drug based on the hormone. Its scientists soon discovered, however, that overweight people have leptin resistance, not leptin shortage, so giving them more doesn't help. Amgen eventually abandoned the project. Other appetite-regulating hormones may someday prove more fruitful. Lilly researchers and others are pursuing ghrelin, the so-called hunger hormone. High levels of ghrelin are what make dieters so ravenous. Create a drug that can block it, the thinking goes, and you have a blockbuster. Similar logic rules Nastech's PYY nasal spray, which the firm hustled from idea to clinic in 11 months. "It goes into the bloodstream after you eat, travels to your brain, and triggers the feeling of satiety," says CEO Steven Quay. "You think you'll never have to eat again." At $8.4 billion French pharmaceutical company Sanofi-Synthelabo, scientists have been pushing ahead with a drug designed to have a similar impact on appetite. Called Rimonabant, the formula works by blocking the brain's cannabinoid receptors -- the very cells that give pot smokers their high and, more important, the munchies. According to a company spokesperson, by year's end Sanofi will have wrapped up a phase 3 trial -- the final and most expensive hurdle before FDA approval. If it passes, Rimonabant could hit the market by early 2006. While such drugs aim to keep people from eating too much, others try to make food burn up or dissolve before it turns to fat. That's the idea behind "869682," a top obesity prospect at GlaxoSmithKline. The compound acts to flush out excess levels of glucose in the bloodstream, before the liver starts converting it to fat. Taken after a meal, the drug would offer the weight-loss benefits of the Atkins regimen without depriving dieters of beloved carbs. "This is what I call the chemical Atkins diet," explained Tadataka Yamada, GSK's R&D chairman, at a conference in December. Although it has only reached phase 1 testing, 869682 joins an elite group of 22 experimental drugs that GSK claims have blockbuster potential -- $1 billion or more in yearly sales. Smaller firms are experimenting with variations on the theme. Chris Belyea, CEO of Australian startup Metabolic, says his company has spent $18 million and five years developing a compound based on a part of the human growth hormone that controls fat burning. In a phase 2 study, he says, obese users of the compound showed twice the weight loss of users of current obesity drugs. Belyea says the drug will move into phase 3 tests early next year. All these substances face years of trials, of course. But another group of obesity-market aspirants seeks a different path to the drugstore: finding hidden weight-loss functions in compounds targeted at other diseases. Regeneron, a biotech firm in Tarrytown, N.Y., stumbled accidentally onto its obesity prospect, Axokine, in the mid-'90s, when the drug failed a clinical trial for treating Lou Gehrig's disease. The chief scientific officer on the project, George Yancopoulos, remembers despondently poring over the data and noticing that some test subjects lost a lot of weight. "We made a joke about how we might have a weight-loss drug here," he recalls. The joke turned serious when Yancopoulos's team realized that the weight loss had not been accompanied by weakness or loss of muscle. In follow-up testing, it became evident that Axokine worked on the brain's hunger receptors, not unlike leptin. Unfortunately, most test subjects developed antibodies to Axokine. Still, 11 percent dropped more than 10 percent of their body weight in one year. "Eleven percent of the obese population is still more than 6 million patients," Yancopoulos points out. As Regeneron considers further phase 3 testing, it's working on a genetic test to identify in advance those who will respond positively to the drug. Exenatide, a new diabetes treatment that regulates blood glucose levels, may do double duty as an obesity drug. Amylin Pharmaceuticals, in a joint venture with Eli Lilly, showed in a phase 3 trial last year that Exenatide not only lowers glucose levels but also slows digestion and suppresses hunger, causing weight loss; most diabetes drugs do the opposite. The medicine's prime ingredient is a hormone found in the saliva of the Gila monster, a creature that intrigued Lilly researchers because it can go months between meals. Which of these ventures is best positioned to grab the brass ring? Only two, Rimonabant and Axokine, have made it to phase 3 trials, which could give them a head start in the marketplace. Both, however, are fairly blunt instruments, medically speaking, so side effects may limit their market impact. Axokine's tendency to trigger an immune response suggests that the drug affects more than just the hunger receptors it's aimed at, which worries researchers. Likewise, Rimonabant targets brain receptors that, in addition to triggering the munchies, are known to play a role in fighting anxiety. Daniele Piomelli, an expert on cannabinoids at the University of California at Irvine, notes that Rimonabant has contributed to psychotic behavior in lab animals. Sanofi officials stand by Rimonabant's potential. Yet Metabolic's Belyea and other researchers claim it would generate only the same modest weight loss as Meridia, the blood-pressure-raising diet pill now on the market. "That means your doctor can choose between making you thinner and possibly hypertensive," Belyea jibes, "or thinner and possibly psychotic." Although they have much further to go in the approval process, drugs based on naturally occurring hormones like ghrelin and PYY may prove to have fewer side effects. The bigger question is whether they actually curb appetite. Ghrelin drew enough buzz last year to be the subject of a 60 Minutes II episode, but Eli Lilly's own researchers admit that they're divided about the hormone's prospects. Be that as it may, Lilly is starting three new obesity-related clinical trials this year, targeting both hunger and the rate of calorie burn. At Nastech, there is no divided opinion about PYY. In head-to-head tests between it and other hormones, Quay says, "PYY always won, no matter what combination of hormones was given." The company has cleared preliminary tests on animals and last fall completed a study showing that its spray gets PYY into the bloodstream. Still, the drug is only in phase 1 trials; it has at least three years before the public learns whether the swagger is justified. In the end, the body's multilayered defense against starvation may mean that there will never be a single thin pill. In the short term, treatment for obesity may follow a path similar to that for AIDS or high blood pressure: drug "cocktails" that will attack the condition from different angles. The long-term hope -- not just for obesity but for many afflictions -- is that genetic testing will let doctors pinpoint the perfect remedy for each individual. That still leaves visions of greatness dancing in the heads of the Nastech crew. "Look at the market for obesity drugs right now -- already $1 billion a year," says Ed Bell, the company's new marketing chief. "Now imagine a product that's safer and actually effective. I mean, you have to believe this is going to grow." Here's another reason to believe: As Glenn Gaesser, an exercise physiology professor at the University of Virginia and author of the book Big Fat Lies, puts it, "Americans are willing to try just about anything."