Although Orexigen Therapeutics Inc. failed in its latest bid to persuade FDA’s Center for Drug Evaluation and Research to consider approving Contrave (naltrexone/bupropion) before results come in from a dedicated cardiovascular outcomes study, the company believes the response received from the agency puts it on a path to a speedier NDA resubmission for the obesity agent.

Orexigen acknowledges that procedural details for an earlier resubmission need to be worked out with the agency. Nevertheless, the company expects it will be able to resubmit the NDA in advance of a planned interim analysis of the ongoing CV outcomes trial, known as the Light Study, with the idea that the interim data would be “dropped in” during the course of the agency’s review.

Orexigen’s appeal to the CDER director’s office resulted in a response with which the company can live.

This approach, coupled with faster-than-expected enrollment in the Light trial, could enable an approval as early as third quarter 2013, one analyst predicts.

Speedier Enrollment …

Contrave is positioned to become the third new obesity drug on the market, following the approval of Arena Pharmaceuticals Inc.’s Belviq (lorcaserin) and Vivus Inc.’s Qsymia (phentermine/topiramate) on June 27 and July 17, respectively.

Belviq is awaiting a Drug Enforcement Administration determination on controlled substance scheduling and has not yet launched. Qsymia launched in mid-September, and more than 2,000 patients took the drug during its first month on the market, Cowen and Company analyst Simos Simeonidis said in an Oct. 22 note, citing data from IMS Health and Wolters Kluwer.

Although Contrave, Qysmia and Belviq all were the subject of FDA “complete response” letters, the agency’s January 2011 first-cycle rejection of Contrave was unique among the three in that the agency required Orexigen to conduct a pre-approval cardiovascular outcomes study, which threatened to scuttle the drug’s development Also see "Losing The Battle Of The Bulge: FDA Holds Up Orexigen's Contrave" - Pink Sheet, 1 February, 2011..

The company pursued dispute resolution of the review division’s demand for a pre-approval CV outcomes study. In September 2011, Orexigen received written correspondence detailing the Office of New Drugs’ design requirements for a CV outcomes trial, requirements that the company believed were feasible. Under this approach, FDA said it would reconsider approval of Contrave if the company could rule out an unacceptable cardiovascular risk in the interim analysis of a pre-approval outcomes study, with the final analysis to be submitted post-approval Also see "Orexigen Agreement On Contrave CV Trial Hints At FDA’s Thinking On Obesity" - Pink Sheet, 26 September, 2011..

A Special Protocol Assessment for the study was finalized in February 2012 Also see "With SPA Finalized, Orexigen To Begin CV Outcomes Study For Contrave In Second Quarter" - Pink Sheet, 6 February, 2012.. Orexigen plans to enroll 10,000 patients in the study. An interim analysis will be performed after 87 major adverse cardiovascular events have taken place, a number which Orexigen said is expected to require enrollment of about 7,000 patients. The trial must exclude a doubling in the relative risk of major adverse CV events with Contrave at the interim analysis.

The company initiated the Light Study in June; in August, it announced that enrollment was proceeding faster than expected, allowing the company to shorten its projected timeline for re-filing and potential approval. At the time, Orexigen said it expected to reach the interim analysis in the second half of 2013, potentially leading to FDA approval in 2014 Also see "Orexigen On Quicker-Than-Expected Pace To Obtain Data Needed To Re-File NDA For Contrave" - Pink Sheet, 7 August, 2012..

This timetable was further accelerated in Orexigen’s Oct. 22 update on the status of the Light Study and the company’s recent interactions with FDA.

The study has already enrolled more than 7,000 patients and is expected to reach the 9,000-patient mark by the end of 2012, the company said. “With the resulting increase in observation time in the study, the time to accrual of the 87 major adverse cardiovascular events needed to conduct the interim analysis should occur up to two months sooner, potentially as soon as the second quarter of 2013,” a company press release states.

… And Another Appeal To FDA

Thanks to its most recent appeal to FDA, the company also now thinks it will be able to resubmit the NDA without having the result of the interim analysis in hand.

Orexigen recently filed a dispute resolution request to the CDER director’s office asking that Contrave be considered for approval on the basis of existing data, with the interim CV outcomes data to be submitted shortly after approval.

In making this request, the company pointed to the approvals of Belviq and Qsymia, as well as the Endocrinologic and Metabolic Drugs Advisory Committee’s March meeting on CV safety assessments for obesity drugs. At that meeting, a majority of panelists said that sponsors must rule out a certain degree of excess CV risk, although this may be accomplished through a meta-analysis rather than a dedicated outcomes trial Also see "CV Risk Assessment For All Obesity Drugs Seems Inevitable Pre-Approval Requirement" - Pink Sheet, 30 March, 2012..

“Given the recent regulatory progress with obesity therapeutics in the U.S., such as the general obesity AdComm this March and two recent approvals of obesity therapeutics, Orexigen requested that Contrave be considered for approval on the basis of existing data together with a post-marketing requirement to supply the interim cardiovascular outcomes data soon after approval,” CEO Michael Narachi said during an Oct. 22 analysts call.

In seeking dispute resolution, Orexigen has followed a path taken by an increasing number of sponsors in recent years that are unhappy with review division demands for additional pre-approval data Also see "Emerging Sponsors And FDA: Will Better Communication Under PDUFA V Ease Inherent Tensions?" - Pink Sheet, 2 January, 2012.. Office of New Drugs Director John Jenkins has previously noted that few such appeals are successful in overturning a review division’s decision.

Although Orexigen may not have gotten exactly what it wanted from its formal dispute resolution request – specifically, conversion of the requirement for a pre-marketing CV study into a post-approval requirement – the response that came from the CDER director’s office appears to be one it can live with.

“CDER denied this request reaffirming that cardiovascular outcomes data from the interim analysis of the Light Study is required prior to approval,” Narachi said. “However, CDER indicated that it was highly supportive of the exploration of a faster path to resubmission of the Contrave NDA. The procedural details have yet to be worked out, and we plan to engage with the agency as soon as possible to more fully define how this might be implemented.”

During the call, Narachi quoted from what he described as the relevant section of CDER’s response “that makes us optimistic that there may be a faster path to resubmission” (see box). The agency’s letter was signed by CDER Deputy Director for Regulatory Programs Douglas Throckmorton, the company said.

CDER Letter To Orexigen

“In the absence of an acceptable pathway to approval utilizing labeling, you have suggested another pathway for the review of Contrave in lieu of waiting for the interim results from the cardiovascular outcomes study to resubmit your application. You and OND have already begun important work to most efficiently use the data collected as part of the ongoing CVOT [cardiovascular outcomes trial]. The additional step you suggest, to plan for a submission to be under review at the time of the interim analysis in order to be as prepared as possible to act soon afterwards, represents a further refinement of that work. While there are procedural issues to be addressed, I am highly supportive of discussions with CDER about this approach in this critical area of public health need.”

“With today’s recommendation from the FDA, Orexigen will work with CDER to define a path to expedite resubmission in advance of an anticipated completion of the interim analysis, in order to enable a potentially earlier PDUFA date for the Contrave application,” the company said.

Narachi told analysts during the call that the idea behind such a proposal would be to resubmit the NDA with the knowledge that the interim data analysis would be forthcoming soon thereafter and “dropped in” to the application in the midst of the review.

It is unlikely the NDA would be resubmitted before early 2013, Narachi said.

“The spirit of this is that the resubmission would occur prior to the day that the data would be added. So the first thing that we need to – other than working out those details assuming that paradigm is ratified in a full detailed agreement with the agency – we need to know when we’re going to have that interim analysis. We wouldn’t want to submit and then have the interim analysis seven months later.” He said the company expects the resubmission will be subject to a six-month review.

In an Oct. 22 note, J.P. Morgan analyst Corey Kasimov said that with more than 7,000 patients already enrolled in the Light Study and the possibility of an earlier resubmission, “we assume approval of Contrave could now occur by 3Q13.”

“What If” Scenario Not Addressed

Orexigen execs were not asked during the analysts’ call what would happen if the NDA were resubmitted ahead of the interim analysis, but the interim look at the data failed to rule out a doubling in the risk of major adverse CV events with Contrave.

Kasimov, however, views this as unlikely.

“We remain highly confident in Contrave’s ultimate approvability as we see it as highly unlikely that the product increases the risk of major adverse CV events (bupropion, a component of Contrave, has been on the market for many years, and we assume we would know by now if it were cardiotoxic).”

Orexigen Eyes Earlier Resubmission Of Contrave NDA

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