The Challenges in Getting Obesity Drugs Approved

The obesity problem in America is constantly in the news these days.  Recommendations from all sorts of people, from Dr. Oz to the First Lady, Michelle Obama, are appearing on eating healthier, getting more exercise, trying the latest new diet, etc.  And these efforts are very well justified.  It is scary to see data on the growth of America’s girth.  As shown on the Center of Disease Control’s website (http://www.cdc.gov), 34% of US adults are obese as defined as having a body mass index  (BMI) of >30.  To put this in perspective, a man who is 5’9” would have to weigh 205 pounds to have a BMI of 30.  For a woman of 5’6”, she’d have to weigh at least 186 pounds.  People with this type of physique are headed for diabetes and heart disease.

Those who have heard me speak on this topic know that diet and exercise should always be the primary method for losing weight, lowering blood pressure and controlling LDL cholesterol.  However, this doesn’t work for everyone.  Having a safe and effective drug to treat this growing problem should be a major priority of the biopharmaceutical industry as well as the FDA.  One would think that the industry’s pipeline would be full of exciting new compounds that can help people lose weight and that the FDA would be granting priority review status for such agents.  Actually, that’s not the case.

Here’s the problem.  The FDA is well aware that any drug that they approve for obesity would be immediately used by millions of people.  Such a medicine would not be used for just the morbidly obese.  People anxious to lose a few pounds for cosmetic reasons would clamor for it.  The FDA is acutely aware of this and so is wary of unleashing such a drug without EXTENSIVE safety and efficacy data.

It is hard to criticize the FDA for taking such a position.  Diet drugs have a history of having modest efficacy but significant side effects.  Most notorious was a drug known as fen-phen which was pulled from the market in 1997 as a result of valvular heart disease.  Thus, the FDA has taken the following stance.  Any drug for obesity must not only show efficacy, but it must be studied in patients over the course of 2 – 3 years to: 1) demonstrate long term efficacy in weight loss; 2) show long term safety in patients who will take this drug over the course of many years.  On this latter point, the FDA wants to see outcome studies – studies in which patients on drug are followed for multiple years to see what the impact of the drug is on heart attacks and strokes.  Such a request is not unreasonable.  After all, a drug that causes weight loss should, at the very least, not increase heart attacks and, in theory, should cause a reduction of heart disease.

The requirement of such an outcomes study has caused the biopharmaceutical industry to shy away from this disease area.  The reason is simple: you can invest between $500 million to $1 billion dollars in an obesity R&D program over 10 or more years only to learn at the last step, the outcome study, that your drug is not approvable.  That is a level of risk that is not acceptable to many investors.

This whole topic has been recently revisited with a new drug for obesity called Contrave.  This drug is being developed by a small biotech company, Orexigen.  Contrave is actually a combination of two drugs that have been on the market for decades: naltrexone (used to treat alcohol addiction) and bupropion (a smoking cessation medication).  The scientific rationale for using this combination is as follows.  Naltrexone blocks opioid receptors in the brain, reduces the reinforcing aspects of addictive substances, and negatively alters the taste of many foods, including sweets.  Bupropion increase dopamine activity in the brain and this appears to lead to appetite suppression and increased energy expenditure.

This sounds pretty exciting.  Orexigen is utilizing two marketed agents and combining them into a single pill that dulls your appetite, reduces your craving for sweets, and causes your body to expend more energy.  More importantly, clinical trials show that Contrave actually works.  Patients on the drug for 56 weeks lose an average of 6% of body fat.  This is not dramatic weight loss but it can help in one’s overall weight loss program.

Nevertheless, the FDA initially rejected this drug.  Despite the fact that Contave is the combination of two known drugs, the FDA wants to see the results of a long term cardiovascular outcomes study before approval.  Orexigen recently published the results of their meetings with the FDA which outlined the final regulatory requirements for Contrave approval.  Essentially, the FDA has asked for a trial comparing Contrave to placebo in a population of overweight and obese patients who have an estimated background rate of 1 – 1.5% annual risk of major cardiovascular events.  The length of this study is dependent upon seeing a specific number of cardiovascular events (heart attacks, strokes, revascularizations, etc.) for the FDA to be able to judge whether Contrave poses no risk in this population.

Thus, the road to approval is clear for Orexigen.  However, it is not without risk.  First of all, this study may require as many as 10,000 patients and generally at a cost of $10,000 per patient.  This will require an investment of at least $100,000,000 and Orexigen will need to go out and raise this money from investors in order to be able to pay for this study.  Second, while the FDA might approve this drug if the study finds that patients lose 6% of body fat with no increase in cardiovascular effects, will such a modest decrease in weight result in insurance companies paying for it?  Payers might take the stance that this is a “bikini drug” – it causes you to lose some weight, but there is no long term health benefit from such weight loss.  They could deem Contrave to be a “cosmetic drug” and not a real medicine.  Thus, patients who want Contrave would have to pay for it themselves – which they might do.

Of course, Orexigen could hit a home run with the following result: significant weight loss is seen, the drug is well tolerated and, most importantly, a significant drop in adverse cardiovascular results is seen as a result of this medicine.  Such is the nature of pharmaceutical R&D – high risk, but the potential for high rewards for the patient and the drug company.  And one further point – we are unlikely to have the answer until 2014.  You may, therefore, want to focus on diet and exercise as a way to control your weight.