FDA issues refuse-to-file letter for Alkermes' experimental antidepressant ALKS 5461

Shares in Alkermes declined as much as 22 percent on Monday after the company said it received a refuse-to-file letter from the FDA regarding its marketing application for ALKS 5461, a once-daily oral therapy for the adjunctive treatment of major depressive disorder (MDD) in patients with an inadequate response to standard antidepressants. According to Alkermes, the FDA determined that the filing contains "insufficient evidence of overall effectiveness for the proposed indication," and that additional clinical trials of ALKS 5461 are needed prior to a resubmission. 

Moreover, the FDA has requested a bioavailability study to generate additional bridging data between ALKS 5461 and the reference listed drug buprenorphine, the company said. Alkermes stated that it "strongly disagrees" with the agency's decision, which the drugmaker intends to appeal, adding that it will also seek immediate guidance in order to help determine next steps and clarify the information required by the regulator.

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Alkermes CEO Richard Pops remarked "we are extremely disappointed with this decision and the implications for patients in the US suffering from major depressive disorder." He added that "we strongly believe that the clinical development programme, including data from more than 1500 patients with MDD, provides substantial evidence of ALKS 5461's consistent antidepressant activity and a favourable benefit-risk profile." The company says ALKS 5461, a fixed-dose combination of buprenorphine and samidorphan, "acts as an opioid system modulator and represents a novel mechanism of action" for the adjunctive treatment of MDD in patients who do not respond adequately to standard antidepressant therapies.

In 2016, Alkermes reported that the Phase III FORWARD-3 and FORWARD-4 studies had failed to show that ALKS 5461 significantly improved symptoms of MDD in patients with an inadequate response to a stable dose of a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor. At the time, the company suggested the results were affected by a "significant placebo effect."Alkermes later unveiled top-line results from the Phase III FORWARD-5 trial, which demonstrated that the higher dose of ALKS 5461 significantly reduced symptoms of depression compared to placebo, as measured by 6-item Montgomery–Åsberg Depression Rating Scale (MADRS-6) scores.

Commenting on the FDA update, EvercoreISI analyst Umer Raffat said another late-stage trial was likely necessary for the drug to get approved "given how the various [Phase III studies] played out," but a need for multiple new clinical trials "is critical and clearly below expectations." Alkermes initiated the Phase IIIb Study 217 of ALKS 5461 last June in patients suffering from MDD who have had an inadequate response to commonly prescribed drugs for depression, including SSRIs or SNRIs, although Pops indicated that whether the company will be able to move ahead with that study is "entirely dependent on what the FDA feels is deficient in our current package."

Meanwhile, Alkermes indicated that it is evaluating the impact of the FDA's refuse-to-file letter on the company's previously announced financial guidance for 2018, adding that any update will be provided in its first-quarter results disclosures.

For additional analysis, see ViewPoints: FDA says one out of three won’t cut it for Alkermes’ ALKS 5461.


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