The drug’s developers respond to the FDA’s decision to deny approval and consider future directions for this indication.
Information about the US Food & Drug Administration (FDA)’s Complete Response Letter (CRL) for Zurzuvae’s (zuranolone’s) New Drug Application (NDA) for treating major depressive disorder (MDD) may provide some clarity about next steps for the agent. The FDA announced in August that (zuranolone) was approved as a treatment for postpartum depression (PPD) in adults, but not approved for its other proposed indication of MDD.1
Reports note that the FDA cited concerns about safety due to the drug’s adverse effects, a lack of evidence of the drug’s effectiveness, and the need for more studies in order to support approval for the MDD indication.2,3
“The FDA approved zuranolone for the indication of PPD but did not approve it for the second indication of unipolar major depression in women and men,” John J. Miller, MD, told Psychiatric Times®. “…Sage [Therapeutics] and Biogen, collaborators in the zuranolone development project, will need to review the reasons why the FDA denied approval for unipolar major depression in women and men, and determine how to proceed.”1
Miller is Editor in Chief of Psychiatric Times; medical director at Brain Health; a staff psychiatrist at Seacoast Mental Health Center; and a consulting psychiatrist at Exeter Hospital and Insight Meditation Society.
In response to the decision, Sage and Biogen have been reviewing the FDA’s feedback in detail in order to determine next steps.3 Sage has also announced that it is cutting around 40% of its workforce following reports that its shares had dropped almost 54% by August 7.4
“In regard to the CRL for MDD, we are highly disappointed for patients, particularly amid the current mental health crisis and millions of people with MDD struggling to find symptom relief,” said Barry Greene, chief executive officer at Sage, in a press release. “We remain committed to our mission to deliver life-changing brain health medicines.”2
Some specific issues in the MDD research cited by the FDA include a patient who was unresponsive to stimuli for 50 minutes following administration of a high dose of zuranolone, and a small number of patients who reported having suicidal thoughts after either starting or stopping zuranolone treatment. It has also been reported that a couple of patients had seizures. 3,4 In the CRL, however, the FDA stated that other factors, such as comorbid conditions and consumption of another drug that lists seizures as a possible adverse effect, may have been the actual cause(s) of the seizures in these patients.5
There have also been positive findings about zuranolone for the treatment of MDD throughout the road to approval. When the rolling NDA submission for zuranolone was completed in December 2022, data from the LANDSCAPE and NEST development programs showed that zuranolone demonstrated rapid and sustained improvement of depressive symptoms, largely good tolerability, and a consistent safety profile.6
Representatives from Sage and other entities have also offered differing views about the MDD research and the FDA’s conclusions. According to Matthew Henson, spokesman for Sage, the patients referenced above had received a double-sized dose of zuranolone.4 And Brian Abrahams, analyst for RBC Capital Markets, has been quoted as saying that the FDA’s conclusions about the overall safety profile of zuranolone “does not appear completely aligned with Sage’s historical interpretations.”3
In addition to determining next steps for MDD, Sage has announced that it is currently focusing on PPD, which it plans to launch in the fourth quarter of 2023. Zuranolone for the treatment of PPD is expected to be commercially available in fourth-quarter 2023 and to potentially draw $240 million in eventual sales.2,4
Follow the progress of zuranolone as a treatment for PPD and MDD at psychiatrictimes.com.
1. O’Brien E. FDA approves first oral treatment for postpartum depression in adults. Psychiatric Times. August 4, 2023. Accessed September 5, 2023. https://www.psychiatrictimes.com/view/fda-approves-first-oral-treatment-for-postpartum-depression-in-adults
2. FDA approves ZURZUVAE™ (zuranolone), the first and only oral treatment approved for women with postpartum depression, and issues a Complete Response Letter for major depressive disorder. Biogen. News release. August 4, 2023. Accessed September 5, 2023. https://investors.biogen.com/news-releases/news-release-details/fda-approves-zurzuvaetm-zuranolone-first-and-only-oral-treatment
3. Bell J. FDA documents hint at ‘uphill battle’ for broad approval of Sage’s depression drug. BioPharma Dive. September 1, 2023. Accessed September 5, 2023. https://www.biopharmadive.com/news/sage-depression-drug-fda-review-documents-zurzuvae-safety/692625/
4. Gatlin A. FDA documents suggest Sage’s battle in depression drugs will be trickier than expected. Investor’s Business Daily. September 1, 2023. Accessed September 5, 2023. https://www.investors.com/news/technology/sage-stock-could-a-workforce-cut-lift-its-depression/
5. Integrated review. Application number: 217369Orig2s000. US Food & Drug Administration Center for Drug Evaluation and Research.
6. O’Brien E. Rolling NDA submission of zuranolone for MDD, PPD is completed. Psychiatric Times. December 7, 2022. Accessed September 5, 2023. https://www.psychiatrictimes.com/view/rolling-nda-submission-of-zuranolone-for-mdd-ppd-is-completed