Topline results from the phase 3 MOUNTAIN trial show that the experimental drug SAGE-217 (Sage Therapeutics) did not meet its primary endpoint in patients with major depressive disorder (MDD), the manufacturer announced.

The company noted in a press release December 5 that adult patients with MDD who received the study drug did not achieve a significant reduction in baseline total scores on the 17-item Hamilton Rating Scale for Depression (HAM-D) at day 15 vs those who received placebo.

However, the participants receiving SAGE-217 at a once-daily dose of 30 mg did show significantly greater reductions on the HAM-D vs the placebo group at days 3, 8, and 12.

Various post-hoc analyses showed even better results, giving reason for cautious optimism, the manufacturer noted.

"This study did not meet the primary endpoint. With that, the data are supportive of the activity of SAGE-217 in MDD given the statistical significance at the majority of timepoints and in relevant populations," Jeff Jonas, MD, chief executive officer of Sage, said in the release.

"Notwithstanding the finding on the primary endpoint, the drug displays good activity on most measures," he added.

MOUNTAIN Top Results

SAGE-217 is an oral neuroactive steroid GABA A receptor positive allosteric modulator.

The MOUNTAIN trial was created to assess the efficacy, safety, and pharmacokinetics of the drug in patients who had a HAM-D total score at baseline of at least 22 and a Montgomery-Asberg Depression Rating Scale total score of at least 32.

All participants (n = 581) were randomly assigned to receive 14 days of treatment with the oral drug at 30-mg or 20-mg daily doses or matching placebo.

At day 15, the 30-mg group showed a greater score reduction from baseline on the HAM-D vs the placebo group but the difference was not significant (mean reduction, 12.6 vs 11.2, respectively; P = .115).

The between group differences were statistically significant in favoring SAGE-217, however, at days 3 (P = .016), 8 (P = .008), and 12 (P < .018).

The manufacturer notes that about 9% of the 30-mg group members "had no measurable drug concentration, consistent with non-compliance in taking SAGE-217." After those patients were excluded in post-hoc analysis, the rest of the 30-mg group showed a significant difference from the placebo group at all time points, including day 15 (P < .048).

The press release also notes that previous studies of the drug were comprised of patients with more severe MDD. When another post-hoc analysis only included patients with a score of 24 or greater on the HAM-D, signifying more severe MDD, those receiving 30 mg of the study drug again showed a significant difference vs placebo at each time point (P < .03).

Among the participants who had measurable concentrations of the study drug and a baseline score of at least 24 on the HAM-D, the 30-mg group showed a least-square mean difference of -2.6 vs the placebo group at day 15 (P = .017).

There were no statistically significant differences for any outcomes between the 20-mg group and the placebo group.

"Well-Tolerated"

Safety analyses showed that the drug "was generally well-tolerated and showed a similar safety profile as seen in earlier studies," Sage reported.

Adverse events (AEs) during the treatment period and 28-day follow-up were 54.2% in 30-mg group, 50% in the 20-mg group, and 48.9% in the placebo group.

Headache, dizziness, somnolence, fatigue, diarrhea, and sedation were the most common AEs reported by the active-drug groups.

"We understand that drug development is an iterative process. In this study, we've gathered new data…we believe support our hypothesis that SAGE-217 has a unique profile with the potential for rapid and robust onset with durable effect," Jonas said.

The company notes that the drug's development program "includes five other pivotal studies, two of which have reported positive data." The positive data-studies assessed MDD (MDD-201) and postpartum depression (ROBIN study). Three other studies are ongoing: REDWOOD, SHORELINE, and RAINFOREST.

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