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Amylin, Dark Horse of the Obesity Drug Battle, Follows Fast Behind Arena, Orexigen

Xconomy San Diego — 

The competition to create new obesity drugs is usually portrayed as a three-way battle royal among San Diego’s Arena Pharmaceuticals, crosstown rival Orexigen Therapeutics, and Mountain View, CA-based Vivus. Yet there’s one more San Diego biotech company with a drug in an earlier phase of development, Amylin Pharmaceuticals, which may just have the most effective weight loss drug of the bunch.

This is the story of Amylin’s effort to resurrect one of the biotech industry’s notorious flame-outs of the 1990s—leptin. We first told the tale back in October of how Amylin plucked this drug from Amgen’s scrap heap, reimagined it in tandem with its diabetes drug pramlintide (Symlin), and took another shot to see if leptin would ever live up to all that misplaced hype from years ago.

Obesity is one of the nation’s biggest public health problems, and drug companies know the winner in this category might dominate the biggest pharmaceutical market ever. In this couch-loving, junk-food eating culture, health officials now say two-thirds of U.S. adults have become overweight or obese. Yet Big Pharma has been gun shy about this market opportunity since Wyeth was burned by the multi-billion legal payments related to heart damage patients suffered from the fen-phen drug combo in the 1990s, and Sanofi-Aventis failed to win approval two years ago for a drug that was linked to rare cases of suicidal thoughts. If any of the new contenders can assure the FDA their drugs are truly safe, obesity drugs will again become a popular culture tsunami, and will be pitched as a catch-all for illnesses related to obesity—like diabetes, high blood pressure, high cholesterol, and depression.

Leptin was once hailed as the magic bullet for obesity based on rat studies in the 1990s. Amylin (NASDAQ: AMLN) isn’t ready to make any breathless claims yet, but its combination of pramlintide and a genetically modified form called metreleptin has shown far more convincing evidence from human trials that it has discovered something potentially big. It’s also an injection designed to melt away fat in a different way than the others, which mainly hit receptors in the brain that control the body’s feeling of fullness.

“This is a big deal,” says Amylin’s Christian Weyer, the company’s vice president of corporate development for diabetes and obesity.

Data on the Amylin drug combo is still preliminary, but they are encouraging. The company looked at a variety of doses in a study of 608 overweight or obese patients, and has reported preliminary results after a little more than six months of observation. Patients on the highest doses, and who had body-mass indexes of less than 35, lost 11 percent of their body weight on the Amylin drug combo, compared with 1.8 percent average body weight loss in the placebo group.

There are caveats in the data. Patients who are more severely overweight, with a body-mass index of greater than 35, saw some benefit on the Amylin combo, but not as much as less-obese patients. The full one-year results aren’t in yet, and haven’t been presented at a medical meeting or in a peer-reviewed journal. And the Amylin combination still has to be injected twice daily, while other drugs can be taken as oral pills, so it remains to be seen how many injections obese patients will be willing to put up with.

How well does the Amylin drug combo stack up against competitors? That’s hard to answer because none of the clinical trials results released this year have directly compared new drugs head-to-head. But all compared themselves to a placebo, and measured the percentage of body weight lost in the drug and the placebo groups. The FDA has said it wants to see at least 5 percentage points of greater weight loss with a drug than with placebo, meaning that if people lose 1 percent of their body weight on a placebo, they should lose at least 6 percent on the drug.

This spread between the drug and placebo is called “placebo-adjusted weight loss.” So based on the high-doses in the moderately overweight population Amylin had a 9.2 score on placebo-adjusted weight loss—easily clearing the FDA’s standard.

Vivus (NASDAQ: VVUS) made national headlines last week when it offered what it called “unprecedented” effectiveness. Its best reported clinical trial produced a 9.4 percentage points of greater weight loss on average than placebo. In separate studies, Orexigen’s biggest advantage over placebo was 5.2 percentage points, and Arena Pharmaceuticals showed a 3.6 percentage point advantage earlier this year.

To be fair, weight loss isn’t the only thing being measured in these studies, and the FDA has other criteria for determining whether an obesity drug is effective enough for the market. All the above companies point to other measurements of effectiveness, like their drugs’ ability to help reduce the risk of diabetes, high blood pressure, high cholesterol, and depression—all ailments related to obesity.

Amylin’s game plan is unlike other companies, which are developing small-molecule drugs, taken as oral pills, that hit receptors on brain cells that control whether people feel full. The problem with those medicines is that they tend to hit other cells in the brain that control moods, leading to side effects, Weyer has said.

The Amylin approach is to use pramlintide, a genetically modified version of a hormone that’s secreted from the pancreas to slow down stomach emptying. It’s combined with metreleptin, a genetically modified version of the leptin hormone that’s secreted from fat cells, which sends a signal to the brain that it’s time to stop eating, Weyer says. The company’s scientists believe the drugs have complementary action, which is greater than either individual part, Weyer says. Since they are relatively large molecules, they are too big to cross the blood-brain barrier, and shouldn’t cause mood-altering side effects, he says.

What are the next steps for Amylin? Weyer wasn’t ready to make many announcements when we talked. The company wants to see the full one-year results which should come out by the end of 2009 and get presented at a major medical meeting in 2010. It will need to carefully look over the data from the Phase II trial to determine the Phase III clinical trial design, which will go a long way toward finding a market niche for the Amylin drug combo.

Amylin is currently working on a device that would allow pramlintide and metreleptin to be given in a single shot, instead of in two shots a day, although Weyer said it’s too early to comment on how that might be incorporated into Amylin’s development plans. But he made it sound like the drug will be positioned in the market as the big gun for weight loss, and won’t try to hang its hat entirely on some secondary measurements of effectiveness.

“If I had the choice between having mediocre weight loss across the board for patients, versus having marked weight loss in 70-75 percent of patients, I’d take the latter,” Weyer says.