Sage Therapeutics: Positive Results for Postpartum Depression Drug

December 07, 2017

Sage Therapeutics has reported positive top-line results from the Phase 2, double-blind, placebo-controlled clinical trial of SAGE-217 in the treatment of 89 adult patients with moderate to severe major depressive disorder (MDD). In the trial, treatment for 14 days with SAGE-217 was associated with a statistically significant mean reduction in the Hamilton Rating Scale for Depression (HAM-D) 17-Item total score from baseline to Day 15 (the time of the primary endpoint) of 17.6 points for SAGE-217, compared to 10.7 for placebo (p<0.0001). Statistically significant improvements were observed in the HAM-D compared to placebo by the morning following the first dose through Week 4 and the effects of SAGE-217 remained numerically greater than placebo through the end of follow-up at Week 6. At Day 15, 64 percent of patients who received SAGE-217 achieved remission, defined as a score of 7 or less on the HAM-D scale, compared with 23 percent of patients who received placebo (p=0.0005). Other secondary endpoints were all similarly highly significant at Day 15 (p≤0.002).

SAGE-217 was generally well-tolerated with no serious or severe adverse events; the most common adverse events (AEs) in the SAGE-217 group were headache, dizziness, nausea, and somnolence. A low rate of discontinuations due to AEs was reported; overall reports of AEs were similar between drug (53%) and placebo (46%), with a safety profile consistent with that seen in earlier trials. SAGE-217 was granted Fast Track Designation by the U.S. Food and Drug Administration (FDA) in May 2017.

“These very encouraging data suggest the potential of SAGE-217 in the treatment of MDD as well as other mood-related disorders that we may pursue,” said Jeff Jonas M.D., chief executive officer of Sage Therapeutics. “There has been little innovation in the discovery and development of treatments for depression in the last two decades. Coupled with our recent positive Phase 3 data read-out evaluating brexanolone for the treatment of postpartum depression, the findings in this study suggest our pipeline of proprietary GABAA modulators may impact novel and fundamental brain mechanisms, offering potential development opportunities in a variety of indications. The positive activity and safety findings of SAGE-217 in MDD support advancing the program into later stage clinical development and we will work with the FDA to determine next steps in the further development of SAGE-217.”

The GABA system is the major inhibitory signaling pathway of the central nervous system (CNS), and contributes significantly to regulating CNS function. SAGE-217 is a novel, highly potent and selective, next generation GABAA receptor positive allosteric modulator that is being developed as a once-daily, oral therapy for the treatment of various CNS disorders. SAGE-217 was discovered by Sage, and the Company maintains worldwide rights to the compound.

“There are currently significant gaps in the disease management of depression and our development goal at Sage is to change patients’ expectations by transforming the treatment landscape for MDD,” said Steve Kanes, M.D., Ph.D., chief medical officer of Sage Therapeutics. “If successfully developed, SAGE-217 has the potential to offer the first truly new mechanism of action in the pharmacologic treatment of depression in more than 20 years. If the results from this trial are replicated in Phase 3 trials, SAGE-217 may meet the needs of patients with MDD for a once-daily oral treatment that potentially provides a rapid, well-tolerated and durable response with a high rate of remission.”

Summary of Top-line Results from the Placebo-Controlled Phase 2 Trial
Effect on Depressive Symptoms through end of Treatment (Day 15):

  • Treatment with SAGE-217 was associated with a statistically significant mean reduction from baseline in the Hamilton Rating Scale for Depression (HAM-D) total score at Day 15 of 17.6 points compared with a 10.7 point mean reduction associated with placebo (p<0.0001).
  • The majority of patients (64%) who received SAGE-217 achieved remission at Day 15 as determined by a HAM-D total score less than or equal to 7 (compared with 23% of patients who received placebo, p=0.0005).
  • Other secondary endpoints (e.g., MADRS, CGI-I) were similarly highly significant at Day 15 (p≤0.002).

Effect on Depressive Symptoms over Time:

  • Statistically significant mean reductions from baseline in the Hamilton Rating Scale for Depression (HAM-D) total score were observed following the first dose (Day 2) and maintained through Week 4, two weeks after end of treatment (p<0.0318).
  • At Week 4, the mean reduction from baseline in HAM-D total score was 15.6 for the SAGE-217 group and 11.9 for the placebo group (p=0.0243).
  • At Week 6, the mean reduction in HAM-D total score for the SAGE-217 group was 15.0 and numerically, but not statistically improved compared to the placebo group reduction of 13.0.
  • Rates of remission at Week 4 and Week 6 for patients treated with SAGE-217 were 52 percent and 45 percent compared to 28 percent and 33 percent for placebo, with statistical significance maintained at Week 4 (p=0.0221) but not Week 6.

Safety and Tolerability:

  • SAGE-217 was generally well tolerated in the trial. The overall incidence of patients who experienced adverse events was 53 percent for the SAGE-217 treatment group and 46 percent for the placebo group.
  • There were no deaths, serious or severe adverse events.
  • Rates of discontinuation from dosing of study drug due to adverse events were low; two patients (4.4%) treated with SAGE-217 and none treated with placebo.
  • The most common adverse events in the SAGE-217 group were headache, dizziness, nausea and somnolence.
  • There was no signal for increased risk for patients treated with SAGE-217 as measured by structured assessments of suicidality and sedation.

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