Durability, safety questions linger despite Biogen, Sage's zuranolone hitting main goal of depression study

Biogen and Sage Therapeutics said Tuesday that a Phase III study of zuranolone in patients with major depressive disorder achieved its primary endpoint, with the experimental drug significantly improving depressive symptoms compared with placebo at day 15 based on the 17-item Hamilton Rating Scale for Depression (HAMD-17). However, shares in Sage fell as much as 19% on the news over concerns about the durability and safety of the next-generation GABAA receptor positive allosteric modulator.

The WATERFALL study randomised 543 adults with major depressive disorder to receive zuranolone or placebo, once-nightly for two weeks. Along with the trial's main goal of change from baseline in the HAMD-17 total score at day 15, secondary endpoints included change from baseline in the Clinical Global Impression-Severity of Illness (CGI-S), Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A) total score.

Treatment effect wanes

Top-line results showed that zuranolone was associated with a 1.7-point difference compared to placebo in the HAMD-17 total score at day 15, with Biogen and Sage noting that responders retained on average 86.1% of their improvement at day 42, which was four weeks after dosing ended. However, detailed data revealed a 3-point difference on HAMD-17 between the zuranolone and placebo groups at day three that subsequently narrowed over the two-week course of treatment to 1.7 points. (see table below).

Meanwhile, zuranolone was associated with a 0.2-point difference compared to placebo on the CGI-S scale at day 15, which was not significant. Biogen and Sage added that, using the MADRS scale, people who responded to zuranolone at day 15 maintained 87.6% of that response at day 42. The companies noted that while not statistically significant, a numerical advantage in favour of zuranolone was demonstrated at day 42.

"The stock reaction may be mixed as investor expectations on key day 15/day 42 endpoints were a little higher, but we'd reiterate the results are fundamentally positive," commented Jefferies analyst Andrew Tsai.

Somnolence, dizziness lead side effects

Biogen and Sage indicated that the rate of treatment-emergent adverse events (TEAEs) in the zuranolone group was 60.1% versus 44.6% in the placebo group. Specifically, somnolence occurred in 15.3% of patients in the zuranolone arm, compared to 3% for placebo, while dizziness was seen at rates of 13.8% and 2.2%, respectively, and sedation at rates of 7.5% and 0.4%, respectively. The companies added that 8.6% of patients on zuranolone reduced their dose due to TEAEs, compared to 0.4% in the placebo group.

Last year, Biogen agreed to pay Sage $875 million in cash upfront under a deal to develop zuranolone for major depressive disorder and postpartum depression (PDD), as well as SAGE-324 for essential tremor. The companies said Tuesday that following the results of the WATERFALL study, which are expected to be presented in full at a future medical meeting, they plan to discuss next steps with the FDA.

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