Array Withdraws Binimetinib's US Filing On Heels Of Late-Cycle Meeting With FDA

Company explored ‘a number of paths to approval’ with agency, but modest progression-free survival benefit in monotherapy treatment of NRAS-mutant melanoma appears to have doomed the new drug application, which was pulled less than two weeks before advisory committee review.

The late-cycle meeting required by the US FDA user fee review program cemented Array BioPharma Inc.’s decision to withdraw its new drug application (NDA) for the oncologic binimetinib (MEK162) ahead of an advisory committee review.

On March 17, Array withdrew the NDA for binimetinib, a MEK inhibitor, for monotherapy treatment of NRAS-mutant melanoma. The withdrawal followed a late-cycle meeting with FDA’s Division of Oncology Products 2 that occurred the same day.

“This action was based on thorough discussions and communications with the FDA, including exploration of various paths to approval, and followed the late-cycle review meeting held with the FDA,” Array said in a March 19 press release announcing the withdrawal.

Array’s announcement may mark the first time that a company has cited a late-cycle meeting as the proverbial straw that broke the camel’s back when it came to withdrawing an NDA.

“Based on feedback from the agency, Array concluded that the clinical benefit demonstrated in the Phase III NEMO clinical trial would not be found sufficient to support approval of the NRAS-mutant melanoma NDA,” the company said.

In the NEMO study, binimetinib demonstrated a 1.3-month median benefit in progression-free survival over a comparator drug.

In response to questions from the Pink Sheet about the nature of FDA’s concerns with the application, Array said: “Clinical benefit observed in the overall NEMO study was modest.”

Late-Announced ODAC Meeting

Binimetinib was undergoing a standard review with a June 30 user fee goal date. The NDA withdrawal came less than two weeks before the application was to be considered by the Oncologic Drugs Advisory Committee at a March 29 meeting.

Although Array has previously said an advisory committee meeting was planned, FDA did not officially announce the meeting until March 15, when a notice was published in the Federal Register.

It’s unclear whether uncertainties about the status of the binimetinib application may have contributed to FDA’s delayed meeting announcement.

When asked about the late meeting notice, FDA said it “makes every attempt and intends to issue the FR Notice for advisory committee meetings no less than 15 days in advance of a meeting, but that is not always possible for a variety of reasons. FDA regrets that it was unable to publish this notice 15 days prior to the March 29” meeting.

Binimetinib was one of two products to be reviewed by the oncology panel on March 29. The committee is still set to consider Genentech Inc.’s application for a new subcutaneous formulation of the anti-CD20 monoclonal antibody Rituxan (rituximab), co-formulated with Halozyme Therapeutics Inc.’s Enhanze recombinant human hyaluronidase enzyme platform, for treatment of lymphoma and leukemia. (Also see "Recent And Upcoming FDA Advisory Committee Meetings" - Pink Sheet, 17 Mar, 2017.)

It is uncommon, although not unheard of, for a sponsor to withdraw an NDA ahead of an anticipated negative advisory committee review. Such withdrawal decisions usually follow the sponsor’s receipt of the agency’s briefing book, which is sent to advisory committee members two to three weeks ahead of the meeting.

In the oncology space, CTI BioPharma Corp. withdrew the NDA for Pixuvri (pixantrone) less than two weeks ahead of what would have been the second advisory committee review for the lymphoma drug. (Also see "Saving Face? Cell Therapeutics Withdraws Pixantrone NDA Ahead Of Advisory Committee Review" - Pink Sheet, 30 Jan, 2012.)

More recently, Endo Pharmaceuticals Inc. withdrew an sNDA requesting abuse-deterrent labeling for the long-acting opioid Opana ER (oxymorphone extended-release) in August 2016, ahead of a planned advisory committee review, in anticipation of additional postmarketing epidemiology data coming available. Although FDA cancelled the initially planned advisory committee, it convened its external experts for a March 13-14 session to consider whether the product’s reformulation has led to an increase in intravenous abuse. (Also see "Opana ER Looking At REMS – Or Worse – After US FDA Panel Weighs Intravenous Abuse Risk" - Pink Sheet, 14 Mar, 2017.)

Array’s announcement may mark the first time that a company has cited a late-cycle meeting as the proverbial straw that broke the camel’s back when it came to deciding to withdraw an NDA.

Culmination In Talks On ‘Paths To Approval’

The late-cycle meeting for new molecular entities and novel biologics was established in the current iteration of the Prescription Drug User Fee Act (PDUFA), beginning with applications submitted on or after Oct. 1, 2012.

Under the PDUFA V “program,” total review target dates were extended by two months for novel products in exchange for increased transparency into FDA’s review and more opportunities for formal communication with the agency before and during the review process. These opportunities include a mid-cycle communication, which is usually a teleconference, and a late-cycle meeting, which may be a face-to-face meeting or a teleconference.

Potential topics for discussion at late-cycle meetings include major deficiencies identified to date, information requests from the review team, matters to be brought before an advisory committee and risk management issues.

For those applications headed to an advisory committee, late-cycle meeting are to occur not less than 12 calendar days before the date of the panel meeting. Array’s meeting with FDA pushed this timeline to its limit, with the late-cycle meeting occurring exactly 12 days before the scheduled panel review.

FDA’s briefing package for the late-cycle meeting must include its background package for the advisory committee meeting, which will be sent to the sponsor not less than 20 calendar days before the advisory committee meeting.

Review issues discussed at the late-cycle meeting usually do not come out of the blue. Rather, clinical efficacy and safety issues to be discussed generally are flagged by FDA as issues of potential concern at the mid-cycle communication, if not earlier.

When asked whether there were any review issues raised by FDA at the late-cycle meeting that the company had not previously been made aware of, Array said: “We had worked with the FDA throughout the review period to explore a number of paths to approval, but based on correspondence and discussion leading up to and during the late-cycle review meeting, we concluded the clinical benefit demonstrated in the Phase III NEMO clinical trial would not be found sufficient to support approval of the NRAS-mutant melanoma NDA.”

Modest PFS Impact, No Survival Benefit

FDA likely questioned the clinical magnitude of the 1.3-month median PFS benefit seen with binimetinib in NEMO.

NEMO evaluated the safety and efficacy of binimetinib compared to dacarbazine. Prior immunotherapy treatment was allowed, and patients underwent radiographic assessment of disease status every six weeks, with progression assessment determined by blinded central review. The study was conducted at more than 100 sites across North America, Europe, South America, Asia and Australia.

NEMO met its primary endpoint, demonstrating a statistically significant 38% reduced risk of progression or death with binimetinib. Median PFS was 2.8 months in the binimetinib group compared to 1.5 months with dacarbazine.

Binimetinib looked more impressive in a pre-specified subset of patients who received prior immunotherapy. In this group, patients who received binimetinib experienced a median PFS of 5.5 months compared with 1.6 months in the dacarbazine group.

Despite the strong results in the immunotherapy subgroup, Array seemed to be preparing investors for the regulatory challenge facing the NDA.

Public disclosure of FDA’s briefing document on the monotherapy NDA, and a potential negative review by the panel, could dampen enthusiasm for binimetinib’s regulatory and commercial prospects in combination therapy.

In statements about the NEMO study results, Array noted that while the results in the pre-specified sub-group of prior immunotherapy-treated patients were “of interest, interpretation beyond overall consistency with the primary result should be made with care. Array anticipates that the primary consideration for marketing approval will be the results for the primary endpoint of the trial.”

A key consideration for FDA was likely the modest improvement in median PFS coupled with the neutral finding on overall survival. Median overall survival was estimated at 11.0 months in patients receiving binimetinib versus 10.1 months for patients treated with dacarbazine, a finding that did not reach statistical significance.

Array reported that binimetinib “was generally well-tolerated and the adverse events reported were consistent with previous results in NRAS-mutant melanoma patients.”

While some sponsors are willing to gamble with proceeding to an advisory committee review despite a negative FDA briefing document, Array may have been unwilling to take this risk because public disclosure of FDA’s advisory committee briefing document on the monotherapy NDA, and a potential negative review by the panel, could dampen enthusiasm for binimetinib’s regulatory and commercial prospects in combination therapy.

The company expects an NDA submission in mid-2017 for binimetinib in combination with the BRAF inhibitor encorafenib in the larger indication of BRAF-mutant melanoma based on results from the Phase III COLUMBUS trial.

Withdrawal of the NDA for NRAS-mutant melanoma takes away Array’s ability to establish the indication as a launching pad for broader commercialization efforts around the binimetinib/encorafenib combination.

Although ongoing trials of binimetinib will continue, the company said it would evaluate options going forward with regard to the NRAS-mutant melanoma monotherapy indication.