Two recent happenings prompted this column. First, Orexigen Therapeutics drew fire from, well, nearly everyone earlier this month for an improper release of data related to its weight-loss drug Contrave. The second happening is Memorial Day weekend.
I’m assuming you, like me, did not spend the long weekend hunting and gathering, sharpening your arrowheads, and ranging far for firewood.
But that’s what our bodies still expect us to do, and they plan accordingly, storing as much energy as possible in our cells. “Humans are one of the few species who eat when we’re sad, happy, angry, even when we’re sick,” says Kevin Grove, an obesity expert at Oregon Health & Science University in Portland who was recently tapped to run Novo Nordisk’s obesity R&D group in Seattle. “It’s that secure feeling we get from various foods, whether it’s chocolate cake or a big steak.”
Our ancestors never knew when the next meal was coming. Now, the next meal is just a weekend barbecue or online delivery away, and it’s often filled with the fats and sugars we’ve evolved to crave but no longer have the lifestyle to burn off.
Which brings us to Contrave from San Diego-based Orexigen (NASDAQ: OREX). The drug is actually a combination of naltrexone, a substance-abuse deterrent, and buproprion, an anti-depressant, and it’s one of only four products approved for obesity in the U.S. They generally work by suppressing appetite, and all are combinations (like Contrave) or reformulations of older drugs (like Novo Nordisk’s Saxenda, a higher-dose version of Novo’s approved diabetes drug liraglutide).
In other words, faced with a full-blown epidemic—35 percent of adults and 17 percent of children in the U.S. are obese, according to the latest figures from the Centers for Disease Control—doctors don’t have a lot of pharmaceuticals to prescribe.
Now both Orexigen and Contrave are under a dark cloud. After four years of regulatory pinball, the FDA approved the drug in September 2014 under special conditions. Among other things, Orexigen has to keep testing it for long-term cardiovascular side effects. It’s that work that has the company in hot water.
“It’s the latest in a series of—I won’t exactly say ‘failures’—but certainly problems coming up with drugs to treat obesity,” says Rick Hecht, director of research at the Osher Center for Integrative Medicine at the University of California, San Francisco.
In March, Orexigen filed a patent application that disclosed 25 percent of the heart study data and touted a purportedly positive benefit of Contrave in preventing heart attacks. But that ill-timed release, against the wishes of the academics running the trial, backfired. The FDA now says the trial is tainted; Orexigen has said it will do it again from scratch; and its R&D partner, Takeda Pharmaceutical, wants Orexigen to pay the entire bill—potentially hundreds of millions of dollars. What’s more, further testing that produced another 25 percent of the data reduced the positive cardio effect to neutral, according to a statement from Steven Nissen, the Cleveland Clinic cardiologist running the trial.
The Contrave situation could exacerbate what’s already a tepid response to the latest obesity drugs. “Doctors aren’t prescribing them,” says Edmund Pezalla, national medical director, pharmacy policy and strategy of the insurance giant Aetna. “It’s been a really slow uptake.”
The latest numbers compiled by RBC Capital Markets biotech analyst Simos Simeonidis show that the four big brand-name drugs have leveled off at roughly 30,000-to-35,000 prescriptions a week recently.
That’s about double the rate from the end of 2014, and if sustained for a full year would account for up to 1.8 million prescriptions. But here’s an interesting point of comparison: One study showed that in 2011, before any of the new drugs were approved, 2.74 million Americans were prescribed anti-obesity drugs. Assuming some of those Americans received more than one prescription that year, the current crop of drugs have a lot of catching up to do. (It’s also worth noting that most of those Americans in 2011 were being prescribed phentermine, one component of the notorious “fen-phen” combination that was taken off the market in 1997 after multiple deaths. The other component, fenfluramine, not phentermine, was the culprit).
Pezalla says that although the average weight loss for each drug is different, there’s a lot of overlap among patients, and no way of knowing prior to taking the drugs how effective they’ll be. It’s not just doctors who are reticent; Pezalla also notes that 85 percent of Aetna members are in plans that don’t cover weight-loss drugs.
Drugs have done tremendous things to fight some diseases in some parts of the world: turning HIV infection in developed countries from a death sentence into practically a chronic condition, for example. But they’ve done little good in other areas, including obesity. Why should we pin our hopes on pharma to melt away our societal fat?
Losing the war on obesity means a host of other complications for millions of Americans like diabetes, heart disease, hypertension, sleep disorders, and on and on. (The CDC estimates 86 million Americans over the age of 20 are in danger of turning diabetic.) A study last fall suggested obesity rates have stabilized—a tiny glimmer of good news—presumably with little to no help from pharmaceutical interventions.
But it seems drugs will have to be at least part of the solution, especially for the severely 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 the right patients with the right therapies, whether they be drugs, surgery, or lifestyle changes. As with cancer, obesity could have genetic factors that steer patients toward the right treatments and away from those that won’t work.
For example, Aetna is working with a diagnostics company that believes it has pinpointed three genetic markers that determine which diet and exercise plans will help obese people shed pounds. Aetna’s Pezalla declined to say more; a study will be published in the next couple months.
Farther out on the frontier is the microbiome, the trillions of bacteria and other microbes living in and on our bodies. The Mayo Clinic in Rochester, MN, is building a microbiome research program and is working with biotechs, including Second Genome of South San Francisco, CA, and Enterome of Paris, France, to understand the relationship of the gut microbiome to people’s weight. But like all emerging science, those explorations will likely take years to bear fruit.
UCSF’s Hecht, who admits that some of his views are controversial, wants to see a more holistic approach, testing “environmental interventions”—steering people away from junk food—and new ideas about behavior modification like mindful eating.
“Our level of obesity now is way higher than 30 or 40 years ago,” says UCSF’s Hecht. “It’s not like our genetics changed in that time. Reversing the epidemic means getting back to where we were in the 1970s.”
Meanwhile, Americans—and a growing number of people around the world—are dangerously overweight. Whether it’s 1970-levels of less junk food and more exercise, or the quest for effective drugs, or other goals that research might point toward, we need to get there as quickly as possible.
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