FDA to Evaluate Zuranolone for Major Depressive Disorder, Postpartum Depression


Zuranolone is a rapid-acting, once-daily, 14-day oral short course therapy for adult patients with major depressive disorder and postpartum depression.

Biogen Inc and Sage Therapeutics have completed a rolling submission to the FDA of a New Drug Application for zuranolone for the treatment of major depressive disorder (MDD) and postpartum depression (PPD). The investigational drug is being evaluated as a rapid-acting, once-daily, 14-day oral short course therapy for adult patients with MDD and PPD.

The NDA submission for zuranolone includes data from the LANDSCAPE and NEST clinical development programs. The LANDSCAPE program includes 5 studies (MDD-201B, MOUNTAIN, SHORELINE, WATERFALL, and CORAL) of zuranolone conducted in adult patients with MDD. The NEST program includes 2 studies (ROBIN and SKYLARK) of zuranolone in adult women with PPD.

“Based on the data in the LANDSCAPE and NEST programs, we believe that zuranolone has the potential to be a meaningful new therapy for depression,” Priya Singhal, MD, MPH, head of Global Safety and Regulatory Sciences and interim head of R&D at Biogen, said in a press release. “We look forward to working with the FDA as this filing progresses.”

Zuranolone is a neuroactive steroid with a novel mechanism of action as a positive allosteric modulator of GABA-A receptors. In patients with depression, zuranolone may help to rapidly rebalance dysregulated neuronal networks to help improve brain function. The drug targets brain networks that are responsible for functions such as mood, arousal, behavior, and cognition.

Thus far, zuranolone has shown rapid and sustained improvement of depressive symptoms and has been found generally well-tolerated with a consistent safety profile. The FDA granted zuranolone with Fast Track Designation in 2017 and Breakthrough Therapy Designation in 2018 for MDD. The FDA granted Fast Track Designation to zuranolone for PPD in 2022.

At the 2022 Psych Congress in September, 11 new analyses showed the potential of the medication to improve the symptoms of depression. The ongoing open-label, longitudinal SHORELINE study in patients with MDD (30 mg cohort, 50 mg cohort) found the median time to the first repeat treatment course for patients who responded to the initial 14-day treatment course was 135 days for the completed 30 mg cohort and 249 days for the ongoing 50 mg cohort.

The research further supports zuranolone as a potential episodic treatment for people with MDD, according to the study authors. Some of the key findings from the completed 30 mg cohort of the SHORELINE study, other clinical data and health economics and outcomes research, and patient survey, included:

  • In the 30 mg cohort of the SHORELINE study of patients with elevated anxiety and without elevated anxiety, there was a mean reduction in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score from baseline to day 15. Among patients with an HAMD-17 response at day 15 and who continued in the study beyond day 28, scores remained below baseline through day 70 independent of the presence of elevated anxiety at baseline.
  • Among patients with and without elevated anxiety in the 30 mg cohort of the SHORELINE study who responded to the initial 14-day treatment at day 15, approximately 70% received 1 or 2 total treatment courses through their time in the study.
  • In patients who accomplished 1 year of follow-up in both cohorts of the SHORELINE study, most had minimal or mild depressive symptoms at the end of the study, as assessed by the Clinical Global Impressions-Severity scale.
  • Zuranolone was generally well-tolerated with a safety profile consistent with prior clinical studies, with the most common adverse events (AEs) associated with zuranolone including headache, somnolence, dizziness, and sedation.
  • Data from a post-hoc analysis of 4 studies in the LANDSCAPE program demonstrated that enhancements in depressive symptoms with zuranolone at day 15 were sustained beyond the end of treatment.
  • A post-hoc analysis of the WATERFALL study in MDD evaluated the statistically significant reduction in depressive symptoms as measured by HAMD-17 at day 15, as well as rapid onset observed at day 3 and day 8 with zuranolone 50 mg versus placebo. This suggested that the differences were clinically meaningful by estimates of minimal important difference, according to the study authors.
  • Results from a cross-sectional survey of US adults with depression found unmet needs in the treatment of MDD. The characteristics most respondents rated as very or extremely important were preventing recurrence of depression symptoms, fewer AEs, a treatment supported by a body of research on safety and efficacy, being able to discontinue a drug without withdrawal symptoms, fast-acting, and can be repeated if symptoms recur.
  • The health economics data showed that patients with MDD given a prescription for anxiety medication incurred more than double the annual all-cause health care costs than those without an anxiety prescription medication.

“Mental health is a highly underserved area with an urgent unmet need for innovative therapies. We need to rethink how MDD and PPD are treated. Existing treatments often take weeks to months to provide symptom relief, and patients may need to cycle through multiple treatment options to fully address their symptoms. People with MDD and PPD deserve better,” Laura Gault, MD, PhD, chief medical officer at Sage, said in a press release. “We believe that zuranolone, if approved, could evolve the way depression is treated and this submission brings us one step closer to that goal.”


Biogen and Sage Therapeutics Complete Rolling Submission of New Drug Application for Zuranolone in the Treatment of Major Depressive Disorder and Postpartum Depression. Biogen Inc. News release. December 6, 2022. http://media.biogen.com/news-releases/news-release-details/biogen-and-sage-therapeutics-complete-rolling-submission-new

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