Sage Therapeutics (SAGE), Biogen (BIIB) Phase 3 for Zuranolone for Major Depressive Disorder Shows Statistically Significant Improvement

(Updated - June 15, 2021 6:32 AM EDT)

Sage Therapeutics, Inc. (Nasdaq: SAGE) and Biogen Inc. (Nasdaq: BIIB) today announced that the WATERFALL Study in patients with MDD met its primary endpoint with zuranolone (SAGE-217/BIIB125) 50 mg showing statistically significant improvement in depressive symptoms compared with placebo at Day 15 as assessed by the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score. LS means (SE) change from baseline in HAMD-17 total score at Day 15 for patients who received zuranolone 50 mg was -14.1 (0.51) compared with -12.3 (0.50) for patients who received placebo (LS mean difference -1.7 points; p=0.0141).

Monoamine-based antidepressants have been the standard of care for chronic treatment of MDD for the past 60 years. They are treatments administered daily, which require sufficient exposure and continuous use to maintain effect. Zuranolone is a two-week, once-daily oral drug under investigation for the treatment of MDD. It is a molecule that is designed to potentially provide a rapid-acting, sustainable treatment option, and could represent a breakthrough in the current management of depression.

The WATERFALL Study was a pivotal, Phase 3, double-blind, randomized, placebo-controlled study evaluating the efficacy and safety of zuranolone 50 mg in adults 18 to 64 years with MDD (N=543). The WATERFALL Study enrolled patients who had MDD with a HAMD-17 total score ≥24 at screening and Day 1 prior to dosing.

“Sage’s expertise in the modulation of the GABA receptor pathway in the brain, coupled with insights on the treatment wants and needs of clinicians and patients, has resulted in our targeting a unique benefit/risk profile with the development of zuranolone supported to date by the data generated in the WATERFALL Study and the broader Landscape and NEST programs,” said Barry Greene, Chief Executive Officer at Sage Therapeutics. “We dared to imagine a different future for the treatment of MDD where patients have the potential to experience a rapid response that is well-tolerated and that may enable them to stay better with long periods free from depression symptoms, and free from daily chronic treatments and related side effects. In doing so, we aspire to help eliminate stigma associated with brain health disorders so that we can move beyond brain health awareness to brain health action.”

“Together with our collaboration partners at Sage, we are proud to announce highly encouraging results from the Phase 3 WATERFALL Study of zuranolone in major depressive disorder. These results represent hope and positive progress for the more than 250 million patients worldwide who are estimated to live with depression,” said Alfred Sandrock, Jr., M.D., Ph.D., Head of Research and Development at Biogen. “Major depressive disorder is a common co-morbidity of many diseases represented in Biogen’s neuroscience portfolio. We believe zuranolone has the potential to offer a unique, first-in-class therapeutic for depression with a distinct benefit-risk profile to people living with this common but serious mental health condition.”

Zuranolone was generally well-tolerated in the WATERFALL Study and demonstrated a safety profile consistent with previous clinical studies. The rate of treatment emergent adverse events (TEAEs) in the zuranolone group was 60.1% (161/268) vs the placebo group at 44.6% (120/269). The majority of the TEAEs were mild to moderate. The most common TEAEs that were ≥ 5% in patients treated with zuranolone (rates vs placebo) included somnolence 15.3% (vs 3.0%), dizziness 13.8% (vs 2.2%), headache 10.8% (vs 7.8%), and sedation 7.5% (vs 0.4%); these events predominantly occurred during the 14-day treatment period. Throughout the study, a total of two patients each (0.7%) reported serious adverse events (SAEs) in the zuranolone and placebo groups; no death occurred in the study. The percent of patients reporting TEAEs leading to drug discontinuation was 3.4% (9/268) and 1.5% (4/269), in the zuranolone and placebo groups, respectively. No signal for withdrawal symptoms as assessed by the 20-item Physician Withdrawal Checklist (PWC-20), or for increased suicidal ideation or behavior as per the Columbia-Suicide Severity Rating Scale (C-SSRS) were identified.

“I’m really excited about these breakthrough data: we know MDD is episodic and zuranolone has the potential to treat episodically. The LANDSCAPE clinical studies are all helpful taken together because they provide data on both short- and long-term use of zuranolone,” said Anita H. Clayton, M.D., Chair of Psychiatry and Neurobehavioral Sciences, University of Virginia School of Medicine. “These data suggest that this treatment, if approved, has the potential to work fast with a short-course of therapy that is well-tolerated, with the effect maintained over the long-term. This will empower my patients to think differently about their depression and treatment, and to rapidly return to their life. Depression is not an identity, it’s an episodic disorder that we hope in the future to be able to treat quickly with treatments that are well-tolerated and with benefits that last.”

“MDD is a pressing mental health concern and, unlike physical health concerns where innovation is commonplace, many of the treatments for MDD were first approved more than two decades ago,” said Paul Gionfriddo, President and CEO of Mental Health America (MHA). “We welcome today’s news, and the potential for a new and innovative treatment that could change the way we treat depression.”

Zuranolone has been granted Breakthrough Therapy Designation by the U.S. Food & Drug Administration, and the Companies intend to discuss next steps with the Agency. Full data from the WATERFALL Study will be shared at future scientific forums.

Detailed Topline Results from the WATERFALL Study

• The WATERFALL Study enrolled 543 patients with MDD. The patients were treated with zuranolone 50 mg or placebo once nightly for 14 days.
• The primary endpoint of the study was the change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) total score at Day 15; the first secondary endpoint was the change from baseline in the Clinical Global Impression-Severity of Illness (CGI-S) at Day 15
• The mean (SD) baseline HAMD-17 score at entry into the study was 26.8 (2.60) in the zuranolone 50 mg treatment group (n=268) and 26.9 (2.67) in the placebo group (n=269).
• 90.3% of patients who received zuranolone, and 87.4% of patients who received placebo, completed the study
• Results for the primary endpoint and several topline secondary efficacy endpoints during the treatment period are outlined in the following table and all favor zuranolone:

Except for HAMD-17 at Day 15 (primary) which was statistically significant and CGI-S (first secondary endpoint) which was not significant at Day 15, all p-values in the table are nominal and not adjusted for multiple comparisons. *Pre-specified primary endpoint^Pre-specified key secondary endpointsLS = least squares; LS mean difference = difference in LS means of change from baseline between zuranolone and placebo groups

Patients with a response at Day 15 in the zuranolone group retained on average 86.1% of their HAMD-17 improvement at Day 42 (4 weeks after dosing ended). A similar maintenance of response was also observed with the MADRS scale, where people who responded to zuranolone at Day 15 maintained 87.6% of that response at Day 42. While not statistically significant, a numerical advantage in favor of zuranolone was demonstrated at Day 42.

Safety and tolerability:

• Adverse events were consistent with the safety profile of zuranolone seen to date in clinical studies.
• The incidence of treatment emergent adverse events (TEAEs) in the zuranolone group was 60.1% (161/268) vs the placebo group at 44.6% (120/269).
• The majority of the TEAEs were mild to moderate, with 8 (3.0%) and 3 (1.1%) being severe in the zuranolone and placebo groups respectively.
• The most common TEAEs observed in ≥5% of patients in either treatment group are listed below and occurred predominantly during the 14-day treatment period. These events were non-serious, and most were mild to moderate.

• Discontinuation rates of the study drug due to AEs in patients receiving zuranolone were 3.4% (9/268) compared to 1.5% (4/269) in those receiving placebo.
• Throughout the study, a total number of 4 patients reported serious adverse events (SAEs), 2 (0.7%) each in the zuranolone and placebo groups.
• No deaths occurred in the study.
• No signal in increased suicidal ideation or behavior, as assessed by the C-SSRS, was observed throughout the study in patients receiving zuranolone 50 mg or placebo.
• No signal in withdrawal effects, as assessed by the PWC-20, was observed after discontinuation of zuranolone.
• No loss of consciousness, or adverse effects such as weight gain, sexual dysfunction, or euphoria were reported.

About the WATERFALL Study The WATERFALL Study was a double-blind, placebo-controlled pivotal Phase 3 study evaluating the efficacy and safety of zuranolone in adults with major depressive disorder. In the study, 543 patients were enrolled. Patients were randomized to receive zuranolone 50 mg, or placebo, once-nightly for two weeks. The primary endpoint of the study was the change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) total score at Day 15. Secondary endpoints included the change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A) total score, among others.

About ZuranoloneZuranolone (SAGE-217/BIIB125) is a once-daily, two-week drug in development for the treatment of major depressive disorder (MDD) and postpartum depression (PPD). Zuranolone is an investigational oral neuroactive steroid (NAS) GABA-A receptor positive allosteric modulator (PAM). The GABA system is the major inhibitory signaling pathway of the brain and central nervous system and contributes significantly to regulating brain function. Zuranolone has been granted Breakthrough Therapy Designation by the U.S. Food & Drug Administration.

Zuranolone is being evaluated as a potential rapid-acting, 2-week treatment for PPD and MDD in the NEST and LANDSCAPE clinical trial programs. The programs are designed to generate data to support a potential NDA filing as efficiently as possible. If successful, LANDSCAPE and NEST may support paths to approval with three distinct opportunities to address patient needs: PPD, acute rapid response therapy (RRT) in MDD when co-initiated with a new standard antidepressant, and as-needed treatment of MDD.

Zuranolone is being evaluated as a potential rapid-acting, 2-week treatment for PPD and MDD in the NEST and LANDSCAPE clinical trial programs. The two development programs include multiple studies examining use of zuranolone in several thousand patients with a variety of dosing, clinical endpoints, and treatment paradigms. The LANDSCAPE Program includes six studies of zuranolone in patients with MDD. Data have been reported from three studies of zuranolone 30 mg in patients with MDD (MDD-201, MOUNTAIN Study and the 30 mg cohort from the ongoing SHORELINE Study), and one study of zuranolone 50 mg in patients with MDD (WATERFALL Study). Two additional studies evaluating zuranolone 50 mg in patients with MDD are expected to read out by the end of 2021 (CORAL Study and a 50mg cohort of the SHORELINE Study).

The NEST Program includes two placebo-controlled studies of zuranolone in patients with PPD. Positive data from the ROBIN Study (zuranolone 30 mg) have been previously reported. The SKYLARK Study (zuranolone 50 mg) is anticipated to readout by the end of 2021.

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