Woman with depression with head in hands
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It’s the first FDA-approved pill for postpartum depression (PPD), and thus a breakthrough treatment for the most common complication of childbirth. But the lack of an approval for major depressive disorder (MMD) put a big damper on Sage Therapeutics’ news about Zurzuva (zuranolone)’s pending launch.

In February of this year, Sage and their collaborator Biogen announced the FDA had granted priority review of zuranolone for both PPD and MMD. Last week they learned the drug has only nabbed approval in PPD.

“While we were very disappointed by the recent Complete Response Letter (CRL) we received from the FDA regarding zuranolone in the treatment of MDD, we are reviewing the feedback from the FDA and evaluating next steps,” said Barry Greene, CEO at Sage Therapeutics.

The only other approved PPD treatment is Sage’s GABA-A modulator Zulresso (brexanolone), which is administered by IV. PPD is estimated to affect 10–15% of mothers annually. The world market for PPD was estimated to be worth more than $5B in 2021. The market for MMD is more than five times that size.

There are few drugs in trial for PPD, with many of the interventions being testing involving psychological support. The pipeline for MMD is also sparse. A recent review found nine drugs currently in Phase II or III that act by means other than the traditional monoaminergic hypothesis. These include psychedelic drugs such as psilocybin and ayahuasca.

Zuranolone is a next-generation positive allosteric modulator (PAM) of GABAA receptors. The major advantages of the drug are that it’s a pill and it works quickly, often in as little as three days. That’s much faster than general antidepressants, which can take two weeks or longer to have an effect. It also only needs to be used for a couple of weeks, and since it is specific for PPD, it is thought that more people will be willing to take it.

Sage is focused on novel chemical entities for brain health by targeting the GABA and NMDA receptor systems. Dysfunction in these systems is thought to be at the core of numerous neurological and neuropsychiatric disorders. Zyranolone is Sage’s lead candidate drug. It is being developed with Biogen for PPD, MDD, treatment-resistant depression, generalized anxiety, and bipolar depression.

The setback in MMD may force changes at Sage.

“While we believe we are well capitalized, given the impact of the CRL for zuranolone in MDD on our plans, we are currently evaluating resource allocation, including pipeline prioritization and a workforce reorganization with a goal of extending our cash runway. With a right-sized organization and portfolio, we believe we have an opportunity to emerge as an even stronger company. We plan to provide greater detail and next steps before the end of the third quarter,” Green said, in a press release.

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