Last week’s news about Orexigen’s Contrave obesity drug and its struggles with the FDA’s Division of Metabolic and Endocrinologic Products has left me puzzled. Obesity is such an enormous epidemic, one has to wonder why the FDA is taking such a hardline approach.
Ignoring the advice of their own Advisory Committee last December, which voted for approval, they have now rejected what seems on the surface to be a robust proposal by Orexigen to do one of the largest Phase 3 clinical trials ever to bring Contrave to market. In an attempt to address the cardiovascular risk questions posed by the FDA’s Complete Response earlier this year, Orexigen proposed a very rational REMS approach to safe use of the drug and doing a monster 12-15,000 patient study. That’s a huge trial. But apparently not big enough. Using the FDA’s statistical powering methods implied that the trial size they wanted would need to include 50,000-100,000 patients. That’s an absolutely untenable, multi-year, many billions of dollars study.
How is Orexigen, a small cap biotech, supposed to fund that? It’s not. The FDA doesn’t want Contrave to see the light of day.
Where’s the FDA’s consideration of the benefit part of the “risk-benefit” calculation? Even modest weight loss has been shown to have big health benefits, , particularly related to prevention of diabetes. Contrave showed in multiple studies it could consistently deliver placebo-adjusted weight loss of almost 5%. Would the FDA have approved it if it were 7.5%? 10%? I’m not sure. We’ll find out with Qnexa, Vivus’ obesity drug, that appears to deliver weight loss near 10%, but its hard to be enthusiastic today.
Fundamentally, the only interpretation of Contrave’s struggles, and that of the other Phase 3 anti-obesity agents, is that the FDA does not believe obesity is a disease. For a group supposedly focused on science and data, I think that’s astounding.
Sadly, a lot of people don’t believe obesity is a disease. Many believe its simply a lifestyle choice, and that changes to diet and exercise are the only “right” ways to treat obesity. But the data certainly don’t support that notion. There’s an important role for lifestyle modifications for sure, but the molecular physiology of chronic obese patients suggest there’s a lot more going on than just too many calories and too little exercise. There’s a growing scientific literature around altered molecular pathways in obese patients, genetic parameters, epigenetic changes, serious metabolic and mitochondrial dysfunction, impaired ability to burn fat and an exaggerated storage of fat, common viruses causing fat deposition, etc… Once these changes are in place at the molecular, cell, and organ level, they don’t just switch back to normal with diet and exercise. Furthermore, we all know the lean person that eats a ton and never exercises, and vice versa. We simply don’t fully understand the drivers of obesity today. But its clearly more than just a lifestyle issue. Some contend, convincingly, that dietary imbalances are an important driver of the disease (and not overeating or sedentary lifestyles). But once you’re obese, however, you are stuck there without a serious intervention.
Take one of Contrave’s Phase 3 studies: the drug was given on top of “intensive lifestyle interventions” that included counseling, diet, and exercise. This “placebo” treatment led to a respectable 5.1% weight loss after 52 weeks. A whole year’s worth of lifestyle changes led to an average loss of 5%. This means that many (if not most) patients in the study failed to achieve even 5% weight loss after a full year of intensive lifestyle modification. When Contrave was added to this, patients lost 9.3% – more than 80% greater weight loss than lifestyle changes alone. This just underscores for me that both approaches are important to get to the goal of reducing obesity, and that neither alone represents a solution to the problem.
The advocates of lifestyle-only intervention seem to be religious in their approach: driven by beliefs rather than data. Diet and exercise don’t typically work on their own, and don’t lead to long term outcomes in most patients. Even the celebrated community- and school-based programs for reducing childhood obesity, like the Shape Up program in Somerville MA that involved intensive lifestyle and diet changes for eight year olds, have achieved only modest weight reductions at best (i.e., Shape Up reduced the weight of the top quartile of kids by less than 1.5% after 8 months of aggressive intervention). Don’t get me wrong: I’m all for these preventative strategies, eating better foods, reducing sugary drinks in the diet, encouraging more exercise for both kids and adults, etc… These all feel like the right things to do. But I don’t think they will by themselves solve the obesity crises, especially for those adults that are already obese. We should be careful not to confuse these useful programs with treatments for obesity. They simply do not, and cannot drive weight loss in the population of high risk patients with established obesity.
I think the lack of advocacy within the FDA in support of medical interventions for obesity, especially in light of the 10s of millions of adults with obesity and more critically morbid obesity, is a travesty of our current healthcare and regulatory system, and we’ll pay the price for this in the future. The FDA approves poorly tolerated and incredibly expensive medicines that provide only glancing benefits to many diseases (like a few weeks survival benefit in cancer), and supports devices for surgical treatment of obesity despite significant rates of death and serious comorbidities. The playing field is simply not level, and our healthcare system will one day pick up the tab in higher costs for treatment of obesity-derived diabetes, arthritis, cancer, and heart disease.
Harvard Medical School Dean Jeffrey Flier summed it up well in his closing of a Cell piece on the Obesity Wars in 2004:
“However much the image of people being medicated to reduce the obesity epidemic may discomfort those who seek a behavioral or public policy remedy, to cease the search for safe and effective medications would be to abandon a major segment of the population to an unhealthy fate”
Furthermore, by putting up seemingly insurmountable roadblocks to getting new medicines approved for obesity, the FDA’s actions are driving scarce R&D and venture capital funding out of the field which will have long term negative consequences to patients and society – no new funding, no new research, no new drugs, and no new levers to pull in the battle against obesity.
