Agency not only went against its advisory panel’s recommendation but also asked for clinical studies.

FDA has decided not to follow its advisory panel’s recommendation to approve the anti-obesity drug Contrave, which is being developed by Orexigen Therapeutics and Takeda Pharmaceutical. The agency issued the companies a complete response letter voicing concern about the cardiovascular safety profile when used long-term and asking for an additional clinical trial. Orexigen stock lost about 70% of its value in early morning trading today. It opened today at $2.57 after closing yesterday at $9.09.

The complete response letter specifies, “Before your application can be approved, you must conduct a randomized, double-blind, placebo-controlled trial of sufficient size and duration to demonstrate that the risk of major adverse cardiovascular events in overweight and obese subjects treated with naltrexone/bupropion does not adversely affect the drug’s benefit-risk profile.”

Contrave, an investigational combination therapy of naltrexone HCl and bupropion HCl, was studied for its ability to help people with obesity initiate and sustain weight loss of at least 5% of their starting body weight in one year. The NDA submission was based on clinical trials that evaluated Contrave in more than 4,500 patients, Orexigen and Takeda note.

Takeda signed on as Orexigen’s North America partner in September 2010 with $50 million up front and a deal to pay $1 billion in sales-related milestones plus tiered double-digit royalties. “In terms of cost sharing for any additional studies, the first $60 million will be borne by Orexigen,” note Adam Cutler and Manisha Narasimhan, Ph.D., analysts at Canaccord Genuity. “Further costs will be split 75:25 between Takeda and Orexigen for some studies. Overall, Orexigen expects to foot about 50% of the bill for any cardiovascular outcomes study.”

Joshua Schimmer, M.D., and Steve Y. Yoo, biotech analysts at Leerink Swann, state, “Unless Orexigen can convince the FDA that the trial can wait until postapproval, the company faces a cloudy future, particularly since Takeda does not assist in pre-approval cardiovascular (CV) study costs. The pre-approval CV outcomes trial requirement would delay approval potentially until around 2014 timeframe or beyond.

“Orexigen had $100 million in cash as of September 30, 2010, which translates to a little over $2 per share in cash. We believe that Orexigen will need to raise additional funding to operate the company and complete the outcomes trial, which will be very dilutive at the current share price.”

In December 2010, FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13 to 7 in favor of allowing Contrave on the market. They concluded that the potential benefits of Contrave outweigh the potential risks when used long-term in a population of overweight and obese individuals and support approval. To assess the risk of major adverse cardiac events, the committee voted 11 to 8 that approval be given with a REMS plan in place.

While the FDA is not mandated to follow the recommendation of its advisory panels, it is rare that it doesn’t. The decision to require Contrave to undergo another clinical trial before approval is not surprising, however, when you consider that the agency has taken an overall cautious stand with approving therapies for weight loss.

In October 2010, FDA issued complete response letters to the other two anti-obesity NDA filers. Arena and Eisai were asked to provide additional clinical and nonclinical data as well as conduct another clinical trial with their candidate, lorcaserin. Vivus was the second firm up for approval of their weight loss therapy, Qnexa. The agency asked for clinical, labeling, REMS, safety-update, and drug-scheduling data, but no request was made for further clinical studies at the time.

“The approvability of Arena’s lorcaserin remains unchanged by the FDA’s decision today as its major concern is addressing preclinical tumor risk,” Dr. Schimmer and Yoo point out. “For Vivus’ Qnexa a potential avenue of concern opens up. Currently, the company is in discussions with the FDA to identify ways to conduct a healthcare database study to clarify teratogenicity signal. However, Qnexa does raise the heart rate by about 1.4–1.7 bpm so the specter of the pre-approval CV outcomes trial re-enters the picture.”

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