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Background Analysis: US FDA Committees to Review Proposed Treatment for Major Depressive Disorder by Alkermes

– NOV 1, 2018 (PDAC-DSRM)


The US FDA has scheduled a joint meeting of the Psychopharmacologic Drugs Advisory Committee (PDAC) and the Drug Safety and Risk Management (DSRM) Advisory Committee for Thursday, November 1, 2018.  The Committees will discuss the efficacy, safety, and risk-benefit profile of new drug application (NDA) for ALKS 5461 (buprenorphine and samidorphan sublingual tablets), submitted by Alkermes, Inc. (Alkermes), for adjunctive treatment of major depressive disorder.

Indication Background

Description of Indication

According to the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition), major depressive disorder (MDD) is a condition in which patients exhibit depressive symptoms, such as a depressed mood or a loss of interest or pleasure in daily activities, consistently for at least a two-week period, and demonstrate impaired social, occupational, educational, or other important functioning. An estimated 16.2 million people in the US suffered from MDD in 2016.

Product Background

Description of Product

ALKS 5461 is an investigational, once-daily oral medicine designed to act as a balanced neuromodulator in the brain. It represents a novel mechanism of action for the adjunctive treatment of MDD.

ALKS 5461 consists of samidorphan and buprenorphine. Samidorphan is a μ-opioid receptor (MOR) antagonist. Buprenorphine is an opioid partial agonist: a mixed MOR weak partial agonist and κ-opioid receptor (KOR) antagonist. The combination is designed to rebalance brain function that is dysregulated in the state of depression.

Clinical Trials of Proposed Indication

Alkermes says the NDA filing for ALKS 5461 is based on results from a clinical efficacy and safety package with data from more than 30 clinical trials and more than 1,500 patients with MDD. Comprehensive data from the clinical development program for ALK 5461, including detailed analyses by the Company and by the FDA, will be presented in briefing materials that will be posted by the FDA ahead of the meeting. These briefing materials will be summarized on the day they are posted, in our subsequent report, the Briefing Summary. Presented below are top-line results from three pivotal phase three trials (named FORWARD-3, FORWARD-4, AND FORWARD-5), based on press releases made by Alkermes and supplemented with information obtained from the ClinicalTrials.Gov database.

FORWARD-4 tested two dose levels of ALKS 5461 (2 mg buprenorphine/2 mg samidorphan, and 0.5 mg/0.5 mg) compared to placebo. 385 patients entered the study. There was a trend toward efficacy with the 2 mg/2 mg dose of ALKS 5461 on the primary endpoint, and post hoc analyses achieved statistical significance for the entire 2 mg/2 mg dose group on the MADRS (Montgomery–Åsberg Depression Rating Scale) endpoint.

FORWARD-3 tested ALKS 5461 (2 mg/2 mg) compared to placebo. 429 patients entered the study. Placebo response was greater than that observed in FORWARD-4 and no treatment effect of ALKS 5461 was observed. Alkermes notes that negative trials due to significant placebo effect are not uncommon in the study of MDD.

FORWARD 5 tested ALKS 5461 (2 mg/2 mg). 407 patients entered the study. The study met the prespecified primary endpoint of significantly reducing depression scores compared to placebo, as measured by the 6-item MADRS (p=0.018). ALKS 5461 2 mg/2 mg also demonstrated statistically significant reductions in 10-item MADRS compared to placebo (p=0.026). The 1 mg/1 mg dose of ALKS 5461 showed improvement in depressive symptoms in the study, but did not separate significantly from placebo. The most commonly reported adverse events (AEs) for ALKS 5461 in the FORWARD-5 study were nausea, dizziness and fatigue, which the company says is consistent with AEs seen in other trials.

Regulatory Background

US Regulatory Background

January 31, 2019 - PDUFA date

April 16, 2018 – Alkermes announced that the FDA rescinded the Refusal to File (RTF) letter that was announced on April 2, 2018. The company stated “FDA's acceptance of the ALKS 5461 NDA and rescission of the Refusal to File letter issued March 30, 2018 follows productive interactions with the Agency in which Alkermes clarified certain aspects of the NDA submission. No additional data or analyses were submitted by Alkermes to FDA.”

April 2, 2018 – Alkermes announced receipt of an RTF letter from the FDA. The company stated, “Upon its preliminary review, the FDA has taken the position that it is unable to complete a substantive review of the regulatory package, based on insufficient evidence of overall effectiveness for the proposed indication, and that additional well-controlled clinical trials are needed prior to the resubmission of the NDA for ALKS 5461. In addition, FDA has requested the conduct of a bioavailability study to generate additional bridging data between ALKS 5461 and the reference listed drug, buprenorphine.”

January 31, 2018 – Alkermes announced the completion of the NDA submission.

August 21, 2017 – Alkermes announced their initiation of a rolling NDA submission (NDA 210417).

Fast Track designation

Ex-US Regulatory Background

Tarius has not found any publicly-available information regarding ex-US regulatory filings.

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Alkermes, Inc., Drug Name: buprenorphine, samidorphan Drug Class: opioid agonist/antagonist Indication: major depressive disorder

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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.