With SPA Finalized, Orexigen To Begin CV Outcomes Study For Contrave In Second Quarter

The company expects to be able to re-file the NDA for its obesity candidate by 2014, after 87 major adverse events were recorded in the 10,000-patient, placebo-controlled safety trial.

Having finalized a Special Protocol Assessment (SPA) with FDA that charts the course for a 10,000-patient cardiovascular safety outcomes trial, Orexigen Therapeutics Inc. says it can see a path forward to eventual approval of Contrave to combat obesity. Orexigen is competing with Vivus Inc. and Arena Pharmaceuticals Inc. to bring the first new obesity drug to market in over a decade.

San Diego-based Orexigen filed an NDA for Contrave (naltrexone/bupropion) in 2010 but received an FDA “complete response” letter in January 2011 citing a need for more data on cardiovascular safety, despite an FDA advisory committee having voted one month earlier 13-7 in favor of the drug’s approval (Also see "Orexigen Resurrects Contrave With New Trial Agreement With FDA" - Pink Sheet, 20 Sep, 2011.).

Vivus’ Qnexa (topiramate/phentermine) and Arena’s Lorqess (lorcaserin) also were the subject of “complete response” letters, but those applications were resubmitted to FDA last year (Also see "Obesity Drugs Go Back To The Drawing Board; FDA To Hold Advisory Cmte On CV Risk" - Pink Sheet, 3 Jun, 2011.). The PDUFA date for Qnexa is April 17, while Lorqess has an anticipated action date in late June, based on it being re-filed on Dec. 27. Meanwhile, FDA will convene an advisory committee specifically to review Qnexa on Feb. 22. The agency also is planning a separate panel to review the cardiovascular safety risks of obesity drugs – the date is not yet set, but is expected for late March.

Orexigen announced Feb. 6 that it intends to begin the Contrave outcomes trial late in the second quarter. The double-blind, placebo-controlled trial is slated to enroll 10,000 patients, but the company expects to have enrolled about 7,000 by the time it reaches the barrier for an interim analysis that will determine whether it can re-file its NDA. The interim analysis will hinge on 87 major adverse cardiovascular events (MACE) occurring. If Contrave is approved following the interim analysis, Orexigen will complete the study through the 10,000-patient goal.

Under terms negotiated under FDA’s formal dispute resolution process with the Division of Metabolic and Endocrinologic Products, approval of Contrave will be reconsidered if an unacceptable cardiovascular risk can be ruled out after the interim analysis; it is expected to take two years to reach that point (Also see "Orexigen Agreement On Contrave CV Trial Hints At FDA’s Thinking On Obesity" - Pink Sheet, 26 Sep, 2011.).

The study will be based on an intent-to-treat analysis, meaning it will take into account all patients who start the trial, regaredless whether a patient completes treatment. Orexigen has agreed that any patient who does not achieve a pre-defined weight-loss goal after 16 weeks of treatment will discontinue Contrave therapy, which will eliminate unnecessary exposure to risk for patients who are not benefiting from the drug.

The trial population is required to have an estimated background rate of a 1.0% to 1.5% annual risk of major cardiovascular events. In this population, the upper bound of the 95% confidence interval should exclude those with a relative risk of 2.0 at the interim and 1.4 at the final analysis.

10,000-Patient Trial Expected To Cost Nearly $100 Million

In an interview, Orexigen Chief Business Officer Jay Hagan estimated that conducting the trial through to re-filing and potential approval should cost the company less than $100 million. The company netted $87.3 million in a follow-on public offering this past December [See Deal].

“We announced [in January] that we ended the year with approximately $145 million on our balance sheet, so we feel confident that that should fund our business through 2014, during which time we would expect to complete the interim analysis and re-submit for approval,” Hagan said. “We’re in a good position in terms of the strength of our balance sheet right now and our projected expense for the study.”

Asked about Orexigen’s expectations for the Qnexa and cardiovascular safety advisory panels, Hagan was circumspect other than to note that his firm has been assured by FDA that the parameters for its safety trial will not be affected by any findings of the latter panel. “We feel pretty confident in our path forward now given our specific correspondence [with FDA],” he added.

The Qnexa panel should not directly affect Orexigen, as FDA’s CR letter to Vivus spelled out concerns about teratogenicity. Vivus has narrowed its proposed indication to exclude women of child-bearing age in an attempt to get around this concern. The Arena drug was cited for concerns about cancer signals in rodents – an advisory committee is not yet scheduled to review Lorqess.

What The SPA Adds

Preston Klassen, Orexigen’s senior VP and head of global development, said the SPA provides two specific benefits to Orexigen. It provides a timetable for the ongoing process, as well as clarity on exactly what Orexigen must do to address FDA’s concerns about cardiovascular risk.

“It lays out a clear timetable to provide a protocol and get comments back from the agency, so there’s a specific clock that is associated with getting comments back,” Klassen said. “That does not guarantee that you will on the first, the second, the third or even more cycles achieve that agreement with the agency but it does provide more of a structured framework for those discussions to take place.”

In addition, he said, the SPA makes it “very clear” to both the sponsor and the agency what the details of the study need to look like. The SPA does not provide any new clarification, however, beyond what Orexigen and the agency previously had worked out last fall.

“The SPA was a reaffirmation of the clarity and framework for the study that was outlined to us in the letter from the Office of New Drugs,” Klassen said. “That came out of the formal resolution process.”