Lessons Learned About the Outlook for New Obesity Drug Approval

7/16/10

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together in the drug. First, despite improving blood pressure and lipids, Qnexa increased heart rate by a small amount (on average, 1.6 beats per minute over 56 weeks of treatment) and increased the percentage of people experiencing rapid heart rates. This is a known function of phentermine. There was no escaping that observation, despite very positive effects observed with Qnexa treatment on blood pressure, lipids, and inflammatory markers. The committee expressed clearly that they would prefer seeing a clean profile in patient populations that would be at increased risk of cardiovascular problems. That means more studies, or perhaps a first approval of Qnexa’s lower (but still effective) doses.

Second, there is an issue with topirimate itself. The higher doses used to treat epilepsy increases rates of cleft palate, a birth defect, in topirimate-exposed pregnancies. The Qnexa protocols counseled women to avoid pregnancy by using multiple forms of birth control. Well, a few women did get pregnant during the trials and delivered babies—thankfully without any birth defects—making it pretty clear that avoiding pregnancy in clinical trials is easier planned than accomplished. To compound the matter, altered attention span and memory loss are additional side effects of topirimate. This might make it harder for women on the drug to remember to take birth control pills, or to adhere to other contraceptive procedures. More work is needed, in the opinion of the panel.

Third, another topirimate-related matter was unresolved. Topirimate inhibits an enzyme called carbonic anhydrase, which is involved in keeping our blood balanced with respect to negatively charged components like chloride, carbonate, and lactic acid. Too big of a ‘gap’ in anion-cation balance leads to bone loss and kidney stones. This needs more work too, in the opinion of the panel.

These problems, partially studied in the Vivus trials, are of real concern to the panel members and could lead to dramatic and unwanted consequences if a really effective agent were released into the U.S. obesity market—a market just seething with unmet, pent up demand for therapies. The next months will determine whether Vivus can adequately address these concerns, adjust their proposed label and risk management plan, and win approval.

So are there take-home lessons here?

I’ve been going to as many of the FDA events as I can lately, to try to learn what matters in drug approval so that plans for our own obesity treatment can be as good as possible. What is the committee looking for? What can we do with our clinical program at Zafgen to give it the best possible chance at success at gaining approval? I’m glad to say I’m encouraged. There are some steps we can take to improve our chances here.

First, we need to stop treating obesity as a single, homogeneous problem. There are important differences between different groups of obese patients. Severe obese patients with sky-high cardiovascular risk profiles may not be the same as metabolically fit obese patients. Asian patients will have different body mass index (BMI) profiles worthy of treatment than Caucasians or Hispanics or African-Americans. Women may respond differently from men. Careful profiling—and registration in a manner that targets the groups who will benefit the most from a given treatment—makes enormous sense. Patient registries may be essential to allow the community to collect the kinds of data that can sculpt use of products once they are available. Our medical records in the U.S. are behind the times, relative to other more advanced healthcare systems such as Sweden’s. We can’t readily study treatment outcomes post-market without formal registries. It’s time to fix that.

Second, we may need to carefully limit and monitor drug access in this country in a way that ensures that the correct and well-studied patient population gets the drug without leaking across to people who simply think they should have it, or who want it to their own detriment. Obesity is an area ripe for abuse. Having carefully managed access will likely need to be a part of any registration path for new drugs that would be acceptable in the right population but potentially devastating in the wrong people. Companies filing for registration of new molecules should consider these aspects early, and seek counsel of the agencies and leaders in the field.

This advisory meeting was chapter one of a three-part miniseries. There are two more advisory committee meetings planned for new obesity products this year—for Arena Pharmaceuticals’ lorcaserin in September, and for Orexigen Therapeutics’ naltrexone/bupropion (Contrave) in December. It’s going to be a long, long year.

Tom Hughes is CEO of Cambridge, MA-based Zafgen. Follow @

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  • http://www.mangiasano.org Leoluca Criscione

    Dear Tom,
    We should rather educate people!!!
    This is the lesson i learned from the 10 years obesity research experience.
    We wrote a book about the topic with the title “Eating healthy and dying obese”, (available in german, italian and soon in english).
    A chapter reads “science feeds the confusion”. Another chapter is about my own studies eating McDonald’s and loosing weight and eating healthy foods (5000 kcal like supersize me author) and gaining 3.2 kg in a week!
    I wellcome the decision of the FDA to reject ANY drug to reduce weight!