Agency says interim analysis of proposed CVOT could be sufficient for resubmission of NDA.

Antiobesity drug developer Orexigen® Therapeutics has received from FDA the design requirements for cardiovascular outcomes trial (CVOT) that the agency said in January will be required before it can consider approving the firm’s lead obesity treatment, Contrave® (a combination of naltrexone HCL and bupropion HCL). Orexigen says the trial design requirements detailed by FDA are reasonable and feasible, and “provide the certainty required to reinitiate development of Contrave.”

FDA’s written correspondence detailing the trial design requirements also stated that positive analysis of interim data from the trial may be enough to support an NDA resubmission and approval. Orexigen now hopes to finalize design of the Contrave CVOT with FDA and initiate the study in the first half of 2012, which it says could enable approval of the drug in 2014.

The key aspects of the CVOT design outlined by FDA include both that the trial is powered based on an intent-to-treat analysis, and includes criteria for interpreting the results at interim and final analyses that are similar to those applied to diabetes drugs. In particular, the trial will need to enroll a population of overweight and obese patients with an estimate background rate of 1–1.5% annual risk of major cardiovascular events. Orexigen estimates that the entire study will require less than 10,000 patients and take less than two years from start to interim analysis.

The firm has been in veritable limbo since the end of January, when FDA issued Orexigen a complete response letter saying it couldn’t approve the submitted NDA for Contrave due to concerns about the cardiovascular safety profile of naltrexone/bupropion when used long-term in a population of overweight and obese patients. In effect, the agency’s decision went against the overall opinion of its Endocrinology and Metabolic Drugs Advisory Committee, which the previous month had agreed in a majority vote that available data on the drug adequately demonstrated that the benefits of Contrave outweighed the potential risks of the drug. The Committee did recommend that a study be carried out to examine the drug’s effects on risk for major adverse cardiac events, but suggested that this should be a postapproval study.

The receipt in January of a CRL from FDA stating that a CVOT would be required preapproval forced Orexigen to cut 40% of its workforce to save cash. The firm has been working with FDA since then to agree on a feasible path forward, including the potential to seek approval for a narrower indication in patients with lower cardiovascular risk. However, in June FDA’s Division of Metabolic and Endocrinologic Products (DMEP) said that even this would still require a CVOT to be undertaken. A further blow came in the form of DMEP’s decision to hold a general advisory committee meeting early in 2012 to discuss cardiovascular assessment for obesity therapeutics. This meant that any agreement that was reached on the design of a CVOT for Contrave in the meantime could still be subject to change dependent on the findings of the 2012 meeting.

Fortunately, Orexigen’s latest correspondence from FDA has not only detailed a workable CVOT design, but also confirmed that the design won’t be subject to change following the DMEP meeting next year. “While we still plan to convene a public advisory committee meeting to discuss topics related to obesity drug development early next year, that meeting will not impact on the advice provided in this letter and the agency will honor the advice provided,” the letter states.

Orexigen says confirmation of a clear and workable way forward means it can also now reboot discussions with firms interested in partnering the development of Contrave for ex-North American markets. In September 2010 the firm received $50 million from Takeda Pharmaceutical as part of a deal giving the latter exclusive marketing rights to the drug in the U.S., Mexico, and Canada, with Orexigen retaining a right to co-promote the drug in the U.S. Under terms of the agreement the firms are working together on development of the drug, with Orexigen heading preapproval activities and Takeda leading postapproval activities. Orexigen could receive over $1 billion in regulatory and sales-based milestones, plus tiered double-digit royalty payments on net sales by Takeda.

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