Background Analysis: US FDA Advisory Committees to Review Brexanolone to Treat Postpartum Depression – NOV 2, 2018 (PDAC-DSRM)

Announcement

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 Friday, November 2, 2018, to discuss the efficacy, safety, and benefit-risk profile of a new drug application (NDA) for brexanolone 5 mg/mL intravenous injection, submitted by Sage Therapeutics (Sage), for the proposed indication of postpartum depression.

Indication Background

Description of Indication

Postpartum depression, also called PPD, is a mood disorder or depression that can affect some women after childbirth. Mothers with postpartum depression experience feelings of extreme sadness, anxiety, and exhaustion that may make it difficult for them to complete daily care activities for themselves or for others. Symptoms vary, but may include anxiety or panic attacks, racing thoughts, guilt, agitation, sadness, fear of being left alone with the baby, inability to sleep, tiredness, and disinterest in the baby, family, and friends.

PPD can happen any time after childbirth. It often starts within 1 to 3 weeks of having a baby and typically does not go away without treatment. It differs from “baby blues”, which is feelings of sadness or moodiness within two to three days of having a baby. “Baby blues typically does not last longer than two weeks and usually requires no treatment. Common treatments for PPD are psychotherapy or medication, including antidepressants, or both.

The cause of PPD is not well-known, but likely results from a combination of physical and emotional factors. One cause may be a drop in the levels of estrogen and progesterone hormones after childbirth, which may trigger mood swings. In addition, sleep deprivation can lead to physical discomfort and exhaustion, which can contribute to the symptoms of postpartum depression.

Up to 15% of women develop PPD after giving birth, making it the most common complication childbirth complication. About half of women with PPD experience symptoms of the disorder during pregnancy.

Product Background

Brexanolone, also referred to as SAGE-547, is an allosteric modulator of GABA-A receptors

Brexanolone is a proprietary formulation of allopregnanolone, which is synthesized from progesterone, a hormone released by the corpus luteum in the ovary. Allopregnanolone possesses a wide variety of effects, including antidepressant, anti-anxiety, stress-reducing, and sedative. Fluctuations in the levels of allopregnanolone and the other neurosteroids are important in the pathophysiology of mood, anxiety, and other neuropsychiatric conditions. If approved by the FDA, brexanolone would be the first pharmacotherapy specifically for postpartum depression.

Clinical Trials of Proposed Indication

In its clinical development program, Sage Therapeutics focused on two phase 3 randomized, placebo-controlled trials to evaluate the efficacy, safety, tolerability, and pharmacokinetics of brexanolone for treating moderate and severe PPD.

In the first trial, Study 202B or Hummingbird 202B (ClinicalTrials.gov Identifier: NCT02942004), 122 women aged 18 to 45 years with severe PPD for 6 months or less were randomly assigned (1:1:1) to receive brexanolone intravenous (IV) 90 grams/kilogram/hour, brexanolone IV 60 g/kg/hour, or placebo, each administered as a continuous inpatient infusion for 60 hours. The primary outcome measure was change in total depression score, using the Hamilton Rating Scale for Depression (HAM-D), from baseline at 60 hours. Efficacy and safety measures were analyzed for 30 days. Participants who received brexanolone IV 90 g/kg/hour had a greater mean reduction in HAM-D score compared with placebo (17.7 points vs. 14 points; p=.0252) after 60 hours, as did those who received 60 g/kg/hour brexanolone (19.9 points; p=.0013). The effect was maintained at the 30-day follow-up. Reductions in total depression scores were seen at 48 hours in patients receiving 90 g/kg/hour or 60 g/kg/hour brexanolone. Sage says that brexanolone IV was generally well-tolerated, with common adverse events of headache, dizziness and somnolence.

The second phase 3 trial was Study 202C or Hummingbird 202C (ClinicalTrials.gov Identifier: NCT02942017). In this trial, 108 women with moderate PPD, based on a major depressive episode no earlier than the third trimester and no later than the first month following delivery, were enrolled in the study. They were randomly assigned (1:1) to receive brexanolone IV 90 g/kg/hour or placebo as a 60-hour inpatient infusion. The researchers measured the change in HAM-D score from baseline to hour 60, and efficacy and safety through day 30. Sage reported that Study 202C’s data replicated the effects of brexanolone IV observed in Hummingbird 202B. From baseline, there was a greater drop in HAM-D total score among participants treated with brexanolone IV at 60 hours (14.2 points) compared with placebo (12 points; p=.016). As in the first study, the investigators first noticed statistical significance at hour 48. The mean reduction in depression score observed in the group receiving brexanolone IV at hour 60 remained at day 30. Brexanolone was well-tolerated overall, and the most common adverse events were headache, dizziness and somnolence.

Comprehensive data from the NDA, including detailed analyses by the company and by the FDA, as well as specific FDA questions for the Committee, will be presented in briefing materials that will be posted ahead of the meeting. The briefing materials for the meeting will be summarized on the day they are posted, in our subsequent report, the Briefing Summary.

Regulatory Background

US Regulatory Background

December 19, 2018 – PDUFA date

May 30, 2018 – Sage announced the FDA acceptance of the brexanolone NDA for PPD

Priority Review, Breakthrough Therapy Designation

Ex-US Regulatory Background

Brexanolone has received a PRIority MEdicines (PRIME) designation from the European Medicines Agency (EMA) for PPD. Sage has announced that it plans to submit a Marketing Authorisation Application (MAA) to the EMA, but there is, currently, no public record of a submission.

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: Sage Therapeutics Drug Name: brexanolone Drug Class: allosteric modulator of GABA-A receptors Indication: postpartum depressio

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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.