Sage Therapeutics' experimental drug SAGE-217 fails to hit main goal of late-stage major depressive disorder trial

Shares in Sage Therapeutics sunk as much as 64% on Thursday after the company reported that a Phase III study of the experimental drug SAGE-217 in adults with major depressive disorder (MDD) failed to meet its main goal. Still, CEO Jeff Jonas said that "notwithstanding the finding on the primary endpoint, the drug displays good activity on most measures," noting that statistical significance was achieved "at the majority of timepoints, and in relevant populations."

The MOUNTAIN trial involved 581 patients with MDD who were randomised to receive one of two doses of SAGE-217 or placebo once-nightly for a fixed course of two weeks. The study's primary endpoint was change from baseline on the 17-item Hamilton Rating Scale for Depression (HAM-D) total score at the 15-day mark. Meanwhile, secondary objectives include change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A) total score, among others.

Top-line results demonstrated that the higher dose of SAGE-217, also known as zuranolone, was associated with a mean reduction of 12.6 in HAM-D total score compared to 11.2 for placebo, which was not statistically significant. However, Sage Therapeutics indicated that patients in the higher-dose group did achieve significant reductions in the HAM-D total score at days three, eight and 12.

According to the company, a post-hoc analysis revealed that approximately 9% of patients in the SAGE-217 group had no measurable drug concentration, suggesting that they were not taking the medicine as directed. "Excluding these patients from the primary analysis set resulted in statistical significance at all timepoints through, and including, day 15," it noted.

Sage Therapeutics also said "improvements in depressive symptoms were sustained in all treatment groups through day 42," with HAM-D total score reductions of 11.9 for the higher dose of SAGE-217 and 11.7 for placebo. "Preliminary data suggest maintenance of improvement in depressive symptoms in those patients who have completed long-term follow-up up to six months," the company remarked, adding these data will continue to be collected in the coming months.

In regards to safety, the drugmaker said two patients in the higher-dose SAGE-217 arm experienced serious adverse events during treatment, including one suicide attempt in a subject with a longstanding history of MDD and a past suicide attempt, and one report of a bile duct stone requiring removal in a participant with a prior bile duct repair. Further, three patients, one in each of the study arms, reported serious adverse events during follow-up, all occurring at least one week following cessation of treatment.

Jonas indicated that Sage Therapeutics' plans "are going to remain the same… We're encouraged by the maintenance of the data we've seen here." Meanwhile, chief medical officer Steve Kanes said "we are evaluating the path forward to more fully inform a potentially expedited pathway to approval, and any amendments we might consider to the ongoing SAGE-217 pivotal programme."

Commenting on the news, analyst Cory Kasimov of JP Morgan said "expectations were so high for a positive outcome…this is going to be a painful setback for many." In January, Sage Therapeutics announced that the Phase III ROBIN study of SAGE-217 in women with postpartum depression met its primary endpoint, while the company later expanded development of the experimental drug to include use in patients with treatment-resistant depression.

Meanwhile, Stifel's Paul Matteis suggested the MOUNTAIN data "will inevitably take the 'halo effect' off SAGE-217 in the eyes of investors." Still, he pointed to the drug achieving statistical significance at days three, eight and 12, adding that "the failure is a surprise in one sense, but in another sense, not at all unprecedented...even Prozac (fluoxetine) failed in a number of efficacy studies."

The FDA cleared Sage Therapeutics' Zulresso (brexanolone) earlier this year as the first treatment approved in the US for post-partum depression.  

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