Alkermes plc (NASDAQ:ALKS) sank $12.73 (22%) to $45.23 on Monday after it said FDA issued a refusal-to-file letter for its NDA for ALKS 5461 as an adjunctive treatment for major depressive disorder (MDD) in patients with an inadequate response to standard antidepressants. The company plans to appeal the decision, and hopes to meet with FDA to discuss a resubmission.
Alkermes said FDA believes it cannot complete a review of the NDA "based on insufficient evidence of overall effectiveness" in the indication, and will require additional controlled clinical trials before a resubmission. The agency also has requested a bioavailability study to generate bridging data between ALKS 5461 and buprenorphine, Alkermes said. ALKS 5462 combines samidorphan (ALKS 33), which is a mu opioid receptor (OPRM1; MOR) antagonist, with buprenorphine.
ALKS 5461 met the primary endpoint of only one of Alkermes' three Phase III studies of the candidate. In January 2016, Alkermes said that in two of the studies, FORWARD-3 and FORWARD-4, ALKS 5461 failed to significantly improve Montgomery-Asberg Rating Scale (MADRS) scores vs. placebo. Alkermes then modified the primary endpoint of FORWARD-5, a third Phase III trial that was then ongoing, to measure MADRS-6, a subscale of the 10-item MADRS designed to be more sensitive. The company also began averaging results from different time points in the trial to account for week-to-week fluctuations in depression scores. In October 2016, the company said the higher of two doses of ALKS 5461 met FORWARD-5's primary endpoint (see BioCentury, Nov. 4, 2016).
The NDA also included data from Study 202, a Phase II trial that met the primary endpoint of Hamilton Depression Rating Scale (HAM-D17) in 2013. ALKS 5461 has Fast Track designation as adjunctive therapy in refractory MDD.
Alkermes said any change in its 2018 guidance would be provided with 1Q18 earnings.
Alkermes’ news dragged down shares of Intra-Cellular Therapies Inc. (NASDAQ:ITCI), which slipped $1.67 to $19.38 on Monday. The company is planning to complete a rolling NDA submission in mid-2018 for lumateperone (ITI-007) to treat schizophrenia. The therapy failed one of two Phase III trials, which the company attributed to an unusually high placebo response. Intra-Cellular said last month that FDA agreed with the company on the proposed content and timing of the rolling NDA. Lumateperone, a dual serotonin (5-HT2A) receptor antagonist and dopamine receptor phosphoprotein modulator (DPPM), has Fast Track designation in the indication.
With Monday's stock move, Alkermes shed about $2 billion in market cap.