Therapy Areas: Central Nervous System
Sage Therapeutics, Biogen Post Positive Pivotal Phase 3 Results for Zuranolone, an Investigational Two-Week, Once-Daily Therapeutic Being Evaluated for Major Depressive Disorder
17 June 2021 - - 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, US-based Sage Therapeutics, Inc. (NASDAQ: SAGE) and Biogen Inc. (NASDAQ: BIIB) said.

LS means change from baseline in HAMD-17 total score at Day 15 for patients who received zuranolone 50 mg was -14.1 compared with -12.3 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.

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 reported serious adverse events 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.

Zuranolone has been granted Breakthrough Therapy Designation by the US Food and Drug Administration, and the Companies intend to discuss next steps with the Agency.

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.

Zuranolone (SAGE-217/BIIB125) is a once-daily, two-week drug in development for the treatment of major depressive disorder and postpartum depression. Zuranolone is an investigational oral neuroactive steroid GABA-A receptor positive allosteric modulator.

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 US Food and Drug Administration.

Zuranolone is being evaluated as a potential rapid-acting, two-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 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.

Major depressive disorder is a common but serious mood disorder in which people experience depressive symptoms that impair their social, occupational, educational or other important functioning, such as a depressed mood or loss of interest or pleasure in daily activities, consistently for at least a two-week period.

It is estimated that approximately 17m people in the US and more than 250 m people worldwide suffer from MDD each year.

While antidepressants are widely used to treat MDD, large-scale studies have demonstrated the need for additional therapies with a differentiated profile.

Sage Therapeutics is a biopharmaceutical company committed to developing novel therapies with the potential to transform the lives of people with debilitating disorders of the brain.

Biogen discovers and develops innovative therapies for people living with serious neurological and neurodegenerative diseases as well as related therapeutic adjacencies.
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