After Orexigen Gaffe, What Role for Drugs Amid Obesity Crisis?

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or morbidly obese: people with a body mass index of 40 or more, or 35 or more with related health problems. For these folks, especially, weight loss through diet and exercise is tough to do. The most extreme solution, stomach surgeries, can show dramatic improvement but carry risks, both from surgical complications and post-surgical effects, like hormonal changes that are part of the mysterious relationship between our guts and our brains.

They are, however, becoming less invasive and of shorter duration (one to two hours, depending on the procedure), says Stanley Rogers, director of UCSF’s bariatric surgery center. (When the surgeries succeed, patients can lose up to three-quarters of their excess body weight. That means a 360-pound person whose ideal weight is 160 could get down to 185.)

One reason there aren’t many drugs now is that pharma practically abandoned the field ten years ago. The science is tangled: Researchers are learning more about the body’s hardwired resistance to losing weight, the possible damage wrought by obesity in the hypothalamus—the brain’s appetite center—as well as inflammation around the body that makes fighting it even tougher.

“Once people gain weight, physical changes in the brain makes it difficult to lose weight,” says Louis Aronne, director of the Comprehensive Weight Control Center at Weill Cornell Medical College in New York City. “There are problems in the signaling pathways, and the brain can’t sense how much fat is stored or how much food has come in.”

Sorting out the biology and attacking it will take a long time. Investment will be risky. Just ask the partners of Third Rock Ventures, a successful biotech venture group that doesn’t shy away from pouring tens of millions of dollars into emerging science. Four years ago, the firm committed $34 million to a new idea, that the body could be coaxed into burning off excess energy—energy expenditure—instead of storing it.

That effort, named Ember Therapeutics, was shut down and folded into an arthritis company earlier this year. Former Third Rock partner Lou Tartaglia was Ember’s first CEO. “Energy expenditure is early, it’s daring, and I think there’s a lot of potential,” says Tartaglia, who declined to comment specifically about Ember. (He is currently CEO of Solstice Biologics in San Diego and no longer affiliated with Third Rock or Ember.)

At the other end of the drug development cycle is regulation. The huge populations, combined with obesity itself not being deadly, make for an abundance of regulatory caution. “It’s not classified by itself as a disease that causes death,” says Grove. “Obesity is a chronic disease that leads to other complications that lead to death.”

The American Medical Association reclassified obesity as a disease two years ago, a move that got a lot of press but has had little effect on day-to-day treatment, or even attitudes toward obesity, which some people feel are dismissive.

“We really need wake up as a society and a community, we need to understand the problem better,” says Tom Hughes, CEO of Zafgen (NASDAQ: ZFGN), a Cambridge, MA-based biotech whose weight-loss drug beloranib is in Phase 3 tests for two rare conditions that lead to unquenchable hunger, extreme obesity, and early death. “If it were 17 percent of American children developing tumors, there would be a war on the problem that would reach into the military.”

Beloranib is also being tested for a more general population with severe obesity, and Zafgen wants to position the drug as an alternative to bariatric surgery. In earlier studies, patients had an average of 11 percent weight loss after 12 weeks on beloranib. If that average can be sustained in the current larger trials with acceptable safety risks, it would be a big step forward. “Some people see a 15 percent loss as game-changing,” says Hughes.

That’s not to say a lower amount of weight loss is negligible. It’s accepted that five percent weight loss can significantly reduce the risk of diabetes and other complications from obesity. But even that five-percent target is hard to hit. Aronne of Weill Cornell says diet and exercise and other behavior modifications alone frequently fall short because the body’s resistance mechanisms are hard to overcome.

Omada Health of San Francisco thinks it has cracked that code. The four-year-old startup has built a program on top of longstanding national guidelines known as the Diabetes Prevention Program (DPP). It includes a digital app, social network connections, a wireless scale for weight monitoring, and coaches who check in with participants. When I spoke with Omada CEO Sean Duffy last fall, he said behavior modification has to be comprehensive. “It’s so hard to build a program that’s high enough ‘touch’,” he said, meaning the personal contact required to keep participants motivated. “For every person, you need to metaphorically drop in the paratroopers.”

Omada recently reported that users of its “Prevent” program averaged 4.9 percent weight loss after one year and 4.3 percent after two years. Medical director Cameron Sepah says some groups, such as seniors, have seen six to seven percent weight loss. Omada keeps adding features, “so we do think we’ll continue to innovate and improve outcomes,” Sepah says.

Two-year data aside, the big question is how long those losses can be sustained. The same caveat applies to the newer drugs, too. And many would like to see more than roughly 5 percent weight loss—Tartaglia calls that bar set by the appetite suppressant drugs “wimpy.”

One way to aim for more dramatic and longer lasting effects is to match … Next Page »

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2 responses to “After Orexigen Gaffe, What Role for Drugs Amid Obesity Crisis?”

  1. Regie Tayaben says:

    *All* are combinations or reformulations of older drugs?? You talk about 4 major drugs and you didn’t even mention Belviq, the one novel drug. Do a little research the next time.