Sage tweaks primary endpoint for zuranolone depression trial, leaving key durability question unanswered

Sage Therapeutics has slightly tweaked the primary endpoint for a phase 3 trial of the Biogen-partnered depression drug zuranolone, a move analysts say is likely designed to avoid a miss on the original goal and one that could complicate the drug's real-world use.

The company disclosed the change in its third-quarter earnings report Tuesday. RBC Capital Markets said the move is not necessarily a surprise, as Sage had signaled the likely change in previous communications. Still, it may not inspire confidence for the doctors who would ultimately prescribe the therapy for major depressive disorder (MDD) if it wins an FDA approval.

Let’s unpack what’s happened to the CORAL study. Sage was hoping to show a rapid onset of depression relief when zuranolone is added to standard antidepressant therapy, according to an October release. The study is fully enrolled, with top-line data expected in early 2022. CORAL is one of a handful of trials in a program called LANDSCAPE that are being used to submit a new drug application to the FDA.

The actual goal, improving symptoms of depression, will stay the same, but Sage will now evaluate the effect at Day 3 rather than Day 15 as before. RBC said this shift will increase the likelihood of success in the late-stage study but will not help provide evidence of zuranolone’s durability of effect.

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The Day 3 symptom check matches earlier results from the phase 3 studies WATERFALL and MOUNTAIN that showed zuranolone had a rapid effect. Once the standard antidepressants kick in, the added therapy’s effect wanes, RBC said.

“We see this as a wise move from a regulatory standpoint, as it should lessen the potential for a study miss to confound the MDD regulatory filing, even if statistical significance on this study is not explicitly required,” RBC said.

But this now leaves the durability question unanswered, which RBC suspects may be important to physicians.

“It does not convey high confidence in the drug's durability of effect—which we believe remains the key commercial (and potentially regulatory) question," the firm said in a note. After the change, the results "may have limited translatability towards informing real-world usage, in which physicians are likely looking not only for acute relief for their patients but also some longer-term response/remission advantages over [selective serotonin reuptake inhibitors] alone,” the analysts added.

A readout from the late-stage WATERFALL trial issued in June showed an improvement in depression symptoms but raised concerns about how long the treatment can last. Zuranolone also failed on a couple secondary measures in the study, with the results sending Sage’s shares tumbling.

RELATED: Biogen, Sage plot 2022 filing for zuranolone approval, furthering turnaround of depression drug

At the time, Bernstein analysts predicted the therapy would still be approved based on the Waterfall data but that it would likely be limited as an adjunct therapy to boost an early effect for severe depression patients.

Sage and Biogen are trying to provide a new depression treatment to beat the standard of care daily monoamine-based oral therapies that must be taken long-term. These treatments take weeks to kick in and often come with side effects.

Zuranolone is administered once a day for two weeks and is meant to provide rapid, sustainable relief. The companies believe the therapy could treat depressive episodes on a short-term basis rather than having a patient take it over the long term.

Top-line data from the CORAL study are still due in early 2022. Sage had originally planned to have data ready by the end of this year, but the timeline slipped in the October update. 

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Sage overhauled the clinical development program for zuranolone back in 2019 after the drug failed a phase 3 trial in MDD. The new strategy called for three short-term studies that could quickly build a case for regulatory filings in multiple indications. The small biotech then brought Biogen on board through a $1.5 billion upfront stake to get some stronger Big Pharma backing.

In October, Sage reported a successful round of talks with the FDA on the submissions and said it has the safety and efficacy data needed to seek approval. The submission package will include four studies, with MDD up for consideration first. CORAL will fold into the package Sage expects to file in the second half of 2022, according to RBC. Sage will then submit for postpartum depression in 2023.