Sage and Biogen’s depression drug quickly relieved symptoms of depression in a phase 3 trial, but the readout did little to quell concerns about the med’s durability of effect, an issue that investors and analysts have been concerned about.
In the phase 3 trial called Coral, zuranolone met the primary endpoint, which was depression symptom improvement at day 3, and the drug was administered along with standard-of-care medications. Sage is positioning the drug as a fast-acting option for patients who begin depression treatment, as the usual medications can take up to a month to become active.
Sage tweaked the endpoint for the Coral study in November 2021 to look at day 3 rather than day 15. RBC Capital Markets analysts at the time said the change could help the company avoid a miss on the original goal and therefore prevent confusion once the FDA gets hold of an application for the therapy in major depressive disorder (MDD). But the change would not reveal anything about zuranolone’s durability.
Now, with the results in hand, RBC said the change was “indeed prudent.” But overall, the firm called the data mixed. On the one hand, the topline results showed zuranolone's rapid-acting effect and that it could play a role in higher-risk patients, particularly those at risk of suicide.
But the durability question is still unanswered after Coral.
“If anything, we believe today's results continue to highlight this issue,” RBC wrote.
Sage did report results for a secondary endpoint measuring blended response over the first 15 days, saying that it reached statistical significance. But RBC notes that the results from the two arms of the trial on this endpoint got closer and closer as the days went on, and “by day 42, there were no differences between the arms.”
“We believe most investors had assumed the day 3 endpoint would hit, but some suggestion of near-term durability would be key to broaden commercial uptake of the agent (and perhaps ensure FDA comfort with the consistency of effects across the studies),” RBC said.
Sage plans to submit data from the larger Landscape program, which Coral is a part of, to the FDA for the MDD indication. The program has so far determined that zuranolone benefited patients with MDD who also had elevated anxiety.
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“We believe the Coral study is clinically meaningful, and with the addition of this data, the Landscape program now demonstrates zuranolone has three potential real-world uses for the treatment of MDD,” said Sage CEO Barry Greene.
Sage plans to begin the rolling submission for a new drug application with the FDA in MDD early this year, as planned, according to Greene.
Zuranolone will be reserved to a “niche market” and will likely not reach the $1 billion blockbuster sales that were originally expected, RBC predicts. But the therapy could find some uptake given its clean safety profile and novel mechanism in an area of high unmet need.
RBC previously called the Coral trial a “high-risk study,” because zuranolone was being administered along with standard-of-care medicines and because Sage continued it through the COVID-19 pandemic. Last month, RBC noted that depression can look very different during a pandemic and companies have had to adjust to using strict criteria for which patients to actually include in their trials to ensure a consistent population.
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Sage experienced delays in the Coral study for zuranolone during the pandemic but stuck it out to completion. RBC said that previously reported data variability may have been due to a lower effect size for the therapy.
With the omicron wave cresting and a reopening potentially on the way, Sage could see a smoother path for future trials of zuranolone in postpartum depression and for other meds like SAGE-718, which is under investigation for Parkinson’s and Alzheimer’s disease.