Alkermes acknowledged today that the FDA sent the company a “Refuse to File” letter in response to its New Drug Application (NDA) for the once-daily major depressive disorder candidate ALKS 5461—all but torpedoing the company’s plans to shepherd the drug toward approval this year and a commercial launch in 2019.

ALKS 5461 is a once-daily, oral investigational medicine with a novel mechanism of action for the adjunctive treatment of major depressive disorder in patients with an inadequate response to standard antidepressant therapies.

ALKS 5461 consists of samidorphan and buprenorphine, and is designed to rebalance brain function that is dysregulated in people with depression. Had it been approved, ALKS 5461 would have established a new category of depression medicines based on modulation of the brain's endogenous opioid system, a key regulator of human emotion and mood.

After ALKS 5461 missed primary endpoints in two Phase III trials, the depression drug fared better in a third late-stage study. In October 2016, Alkermes trumpeted positive topline results from the 407-patient FORWARD-5 trial, showing statistically significant changes from baseline compared with placebo on the 6-item and 10-item versions of the Montgomery-Åsberg Depression Rating Scale (MADRS-6 and MADRS-10) for the 2 mg/2 mg dose.

Alkermes responded by quickly starting a rolling application to the FDA, reasoning that combined data from the successful trial data from more than 30 clinical trials would persuade the agency to approve the drug. The company noted that of the two other Phase III studies, the 385-patient FORWARD-4 trial showed statistical efficacy for the 2 mg/2 mg dose and missed its primary endpoint at a single time point, while asserting that the 329-patient FORWARD-3 study failed due to high placebo response.

“We strongly believe that the clinical development program, including data from more than 1500 patients with MDD, provides substantial evidence of ALKS 5461's consistent antidepressant activity and a favorable benefit–risk profile,” Alkermes CEO Richard Pops said in a statement. “We are extremely disappointed with this decision and the implications for patients in the U.S. suffering from major depressive disorder, a serious disease where there is a clear and urgent need for new treatment options for patients and their families.”

“A Potential Blockbuster”

In releasing fourth-quarter and full-year 2017 results on February 14, Alkermes said it expected the FDA to accept the NDA and assign a Prescription Drug User Fee Act (PDUFA) target decision date in the second quarter, then approve the drug during the second half of this year, potentially after an advisory committee meeting.

“We see ALKS 5461 as a potential blockbuster and are investing appropriately in its launch,” Alkermes CFO Jim Frates told analysts on a February 14 conference call following the release of fourth-quarter and full-year 2017 results, according to a transcript published by Seeking Alpha. “Our expectations for SG&A [selling, general, and administrative] expense in the range of $555 million to $585 million reflect our plans to expand our field sales team by approximately 200 sales representatives in mid-2018 as we prepare for the potential launch of ALKS 5461 in early 2019.”

Today, Alkermes said it is assessing the effect of the FDA refusal on its previously issued financial guidance to investors for 2018.

The company has projected for this year total revenues ranging from $975 million to $1.025 billion—as well as a GAAP net loss ranging from $250 million to $280 million, adjusted down to a non-GAAP loss ranging from $5 million to $35 million after excluding expenses due to share-based compensation, depreciation, amortization, and noncash net interest, though the income tax expense is projected to increase up to $10 million.

“Our financial expectations for 2018 reflect important investments that will drive future value as we advance our late-stage pipeline and prepare for the anticipated launch of ALKS 5461, with the planned expansion of our commercial organization midyear,” Frates said in February.

ALKS 5461 is one of two pipeline candidates for which applications have been submitted to the FDA. The other is Aripiprazole Lauroxil NanoCrystal® Dispersion (ALNCD), designed for initiation onto Alkermes’ already-marketed schizophrenia drug Aristada® (aripiprazole lauroxil), for which a PDUFA target action date of June 30, 2018, has been assigned.

Two other Alkermes candidates are in Phase III trials—the schizophrenia treatment ALKS 3831 and the multiple sclerosis treatment BIIB098 (monomethyl fumarate prodrug, formerly ALKS 8700), which Biogen has licensed from Alkermes and is developing and commercializing under an up-to-$228 million-plus collaboration announced in November 2017.

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