- A closely watched, experimental treatment for depression from Sage Therapeutics and partner Biogen met the main goal of a large clinical trial, as a 15-day course of the drug, called zuranolone, reduced patients' symptoms more than a placebo.
- Study results disclosed by Sage and Biogen on Tuesday, however, were mixed. While treatment with the drug showed a greater effect than placebo, the benefit appeared to wane over time. The difference between groups on an important secondary goal of the study, meanwhile, was not statistically significant. Treatment was associated with higher rates of side effects like drowsiness and sedation.
- In a statement, the companies said they would discuss their findings with the Food and Drug Administration. The trial is the most important of several studies that Sage executives previously said they hoped could support an approval of zuranolone. Investors, however, seem to have doubts, sending Sage shares down by double digits in pre-market trading Tuesday.
Zuranolone has been central to Sage's future for several years. The biotech company designed the drug to work differently than typical antidepressants and its effects are meant to kick in fast, rather than after a few weeks of treatment.
Sage has also hoped testing would show zuranolone to be safer than existing drugs for depression, some of which come with warnings about the risk of suicidal thoughts and behaviors.
But Sage has had trouble proving the drug's worth. A Phase 3 study failed in late 2019, forcing the company to change up its plans for clinical development. Such setbacks are not uncommon for psychiatric drugs; many have won approval despite mixed clinical results, and developers often struggle to deal with strong placebo responses.
Sage designed three new Phase 3 trials following the disappointing 2019 data, giving it several new paths to bring the drug through to regulators. The drug's potential attracted Biogen, which signed a multi-billion dollar deal with Sage last November to gain access to it and a treatment for essential tremor.
Tuesday's results keep at least one of those paths open, although the companies didn't say whether the data on its own would be sufficient to ask the FDA for approval.
"We'll sit down with the agency to map out next steps, and we'll share updates in the coming months," said Sage's CEO Barry Greene, who joined the company in December, on a conference call Tuesday.
Overall, the study was a success. After 15 days, treatment with a 50 mg dose of zuranolone reduced depressive symptoms as measured by a rating scale called HAMD-17 more than placebo. The difference between the two study groups was statistically significant, a benefit Greene claimed was "unlike anything on the landscape today."
But the treatment effect was greatest at Day 3 and waned at each time point measured through to Day 15. On another rating scale, called CGI-Severity, the difference between zuranolone and placebo was not statistically significant. Neither was the difference between drug and placebo in the share of study participants who maintained their response at Day 42, although Sage said there was a numerical advantage in favor of zuranolone.
The results, then, raise important questions about the size of the benefit zuranolone provides, how long its effects last, and how widely the drug would be used if approved by regulators.
Mizuho analyst Vamil Divan, for instance, noted that experts he’s spoken with had been looking for at least a 3-point difference between drug and placebo. Though patients retained most of the treatment benefits after 42 days, "that is not relevant in our opinion if initial efficacy is so limited," Divan wrote. Even if approved, "we think the commercial outlook for the product would be quite limited," he added.
But that could depend, in part, on how quickly real-world patients need additional treatment with zuranolone or another drug to deal with their depression. Greene noted that 70% of patients treated in a study called SHORELINE needed only one or two treatment courses to "maintain wellness" over a year. If so, wrote Stifel analyst Paul Matteis, "that trumps the relevance" of the durability data.
On safety, zuranolone was associated with greater side effects than placebo, particularly drowsiness, dizziness, sedation and headache. Encouragingly, there were no signs of withdrawal or suicidal ideation, Sage said. Fewer patients treated with zuranolone dropped out of the trial, an important factor for antidepressant studies.
Called WATERFALL, the trial enrolled 543 adults between 18 and 64 years old. The dose of zuranolone tested, 50 mg, was higher than the two doses studied in the clinical trial which failed in 2019.
Sage still has multiple additional Phase 3 trials underway for zuranolone, among them a study called CORAL testing the drug alongside another antidepressant. Results from that study are expected by the end of the year, and if the FDA believes they "are important in a major review," the company will wait for the data before filing an application, Greene said.