Firm was unable to persuade FDA that the required cardiovascular trial could be conducted post approval of Contrave in a subset of patients.

Orexigen Therapeutics is putting on hold development of its obesity programs in the U.S. after a meeting with the FDA regarding the complete response letter (CRL) it received for Contrave did not go as planned. The company has lost almost 31.5% of its value in early morning trading and opened the day at $2.21.

The agency disagreed with the company’s suggestions that approval could be given for a subset of obese patients and that the clinical trial the CRL asked for could be conducted post-approval. On January 31, FDA issued a CRL that raised concerned about the cardiovascular safety profile when used long term.

The agency asked for 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 Contrave would not adversely affect the drug’s benefit-risk profile.

Contrave is an investigational combination therapy of naltrexone HCl and bupropion HCl. It is being developed as extended-release tablets for the treatment of obesity including weight loss and maintenance of weight loss.

Besides Contrave, Orexigen was also developing Empatic as a fixed-dose combination of zonisamide sustained release (SR) and bupropion SR. Zonisamide in an immediate-release formulation was approved in the U.S. in 2000 for the adjunctive treatment of partial seizures. Given alone the drug has reportedly shown modest weight loss in clinical trials conducted at Duke University.

Bupropion got the FDA go-ahead in 1985 for depression and in 1997 for smoking cessation. The compound is thought to increase the level of dopamine activity at specific receptors in the brain, which appears to lead to a reduction in appetite and increase in energy metabolism.

Orexigen recently met with the FDA’s Division of Metabolic and Endocrinologic Products (DMEP) to discuss the CRL for Contrave. The company proposed that the drug should be sanctioned for patients with lower cardiovascular risk and that it would conduct the additional trial post approval to determine approval for all patients.

The company suggest a trial design with 12,000 to 15,000 patients, which would have produced interim results in 2013, report Joshua Schimmer, M.D., and Steve Y. Yoo, biotech analysts at Leerink Swann. “The FDA wanted the trial to show hazard ratio near 1 for both ITT and per-protocol population, which would have required 60,000 to 100,000 patients at the time of the interim analysis.”

The DMEP advised Orexigen that the proposed cardiovascular outcomes trial would not adequately address the approval deficiency. It restated the need for the trial to be conducted pre-approval. It also stated that it would not consider approving Contrave for a narrowed population without first reviewing data from this cardiovascular outcomes trial. 

Additionally, DMEP noted that it intends to hold a general advisory committee early next year to discuss cardiovascular assessment for obesity therapeutics. It said that any agreement reached on the design of a cardiovascular outcomes trial would be subject to change following DMEP’s interpretation of the input received at this meeting.

Orexigen believes the need for a pre-approval clinical study is unprecedented and would generate significantly more information than is necessary or feasible.Dr. Schimmer and Yoo agree, saying, “Considering that bupropion is still on the market, we believe such pre-approval requirement is excessive.”

Orexigen plans on appealing DMEP’s responses through the formal dispute resolution process. The company will not continue developing its obesity programs until “a clear and feasible path to regulatory approval is identified,” it says.

“The Orexigen team has been working for the last several months with leading experts in the field of cardiovascular outcome trials to develop and submit a proposal to DMEP that we believe would more than adequately address the question of theoretical CV risk,” says Michael Narachi, CEO of Orexigen.

“We remain very disappointed in the stance of DMEP and the outcome of the recent meeting. We have serious concerns about the broader implications these actions may have on innovation in the obesity space and the availability of much-needed treatment options for obese patients in the U.S.”

Contrave was submitted for U.S. regulatory approval in March 2010 based on clinical trials conducted in more than 4,500 patients. The day after it received the CRL, on February 1, the firm’s stock dropped 70%. By February 10, Orexigen decided to cut about 40% of its staff, or 23 employees.

Takeda Pharmaceuticals, which became Orexigen’s North America partner in September 2010 with a $50 million up-front payment, does not assist in pre-approval study costs. As of March 31, Orexigen had $39.6 million in cash and cash equivalents and an additional $36.9 million in marketable securities, for a total of approximately $76.6 million. Dr. Schimmer and Yoo expect this money to carry Orexigen 2012.

FDA has also issued CRLs 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; and Vivus was was asked for clinical, labeling, REMS, safety-update, and drug-scheduling data, but no request was made for further clinical studies on Qnexa.

Regarding Vivus, Dr. Schimmer and Yoo, say, “We heard from the company this morning, and they indicated that the FDA has not discussed the potential cardiovascular advisory panel with them yet. The company still expects to resubmit the NDA in 4Q11, but we believe that the panel introduces a potential for delay in submission until mid-12 or later.”

And for Arena, they note, “Lorcaserin lowered both heart rate and blood pressure (though not to statistical significance). We do not believe the cardiovascular panel will delay the timelines for Arena.”

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