At the Day 3 primary endpoint, zuranolone 50 mg co-initiated with a standard of care antidepressant showed a statistically significant reduction in depressive symptoms
Key secondary endpoint demonstrates zuranolone co-initiated with an antidepressant was statistically significant in reducing depressive symptoms compared to an antidepressant co-initiated with placebo over the 2-week treatment period
Zuranolone 50 mg co-initiated with a standard of care antidepressant was generally well-tolerated with most TEAEs reported as mild or moderate and no new safety signals identified
CAMBRIDGE, MA, USA I February 16, 2022 I Sage Therapeutics, Inc. (Nasdaq: SAGE), and Biogen Inc. (Nasdaq: BIIB) today announced the CORAL Study in people with major depressive disorder (MDD) met the trial objectives, demonstrating a rapid and statistically significant reduction in depressive symptoms at Day 3 and over the 2-week treatment period, achieving the primary and key secondary endpoints. This significance was demonstrated at the first measured time point, Day 3, with zuranolone 50 mg co-initiated with an open-label standard of care antidepressant (ADT) as assessed by change from baseline in the 17-item Hamilton Rating Scale for Depression (HAMD-17). The CORAL Study also met its key secondary endpoint, with zuranolone co-initiated with a standard of care ADT demonstrating a statistically significant improvement in depressive symptoms compared to ADT co-initiated with placebo, over the 2-week treatment period. Zuranolone was generally well-tolerated, and no new safety signals attributable to zuranolone were identified. In meeting its pre-defined objectives, the CORAL Study supports the potential of zuranolone, when co-initiated with standard of care, to accelerate the benefit of depression treatment compared to treatment with ADTs alone.
The CORAL Study was an active comparator trial comparing the combination of zuranolone 50 mg co-initiated with an active standard of care ADT to standard of care ADT co-initiated with placebo in people with MDD blinded to receipt of zuranolone or placebo. The trial demonstrated a mean change from baseline in HAMD-17 total score of -8.9 ± 0.39 (n=210) at Day 3 for people in the zuranolone co-initiated with ADT arm compared with -7.0 ± 0.38 (n=215) mean change from baseline for people in the ADT co-initiated with placebo arm. The key secondary endpoint measured the treatment effect over the 2-week treatment period at all scheduled visits (measured using equal weighted means for Days 3, 8, 12 and 15 of the study). The mean change over the treatment period for people who received zuranolone co-initiated with an ADT was -11.7 ±0.40 (n=210) compared with -10.1 ±0.39 (n=215) for people who received ADT co-initiated with placebo. Other secondary endpoints demonstrated a statistically significant reduction in HAMD-17 score in the zuranolone co-initiated with ADT arm compared to the ADT arm at Days 8 and 12, while Day 15 demonstrated numerical superiority and Day 42 showed equivalence.
Based on consistent findings suggesting a benefit of zuranolone in people with MDD with elevated anxiety across the LANDSCAPE program, the CORAL Study prospectively examined this population. In this CORAL Study subgroup (n=218 of 425 people (51.3%) with HAM-A total score ≥20 at baseline) zuranolone co-initiated with an ADT was nominally statistically significant to ADT with placebo in reducing depressive symptoms as measured by the primary endpoint (-9.3 compared to -6.0; HAMD-17 total score change from baseline) and key secondary endpoint (-11.7 compared to -9.4; HAMD-17 total score change from baseline) demonstrating the potential to address the unmet need for this population, which has been historically less responsive to chronically administered ADTs.
“We believe the CORAL Study is clinically meaningful and with the addition of this data the LANDSCAPE program now demonstrates zuranolone has three potential real world uses for the treatment of MDD. The LANDSCAPE data support zuranolone as a monotherapy, and since many people in the previously completed studies were already on maintenance ADTs, we believe our data also support zuranolone as additive therapy. The CORAL Study further supports the use of zuranolone to accelerate the benefit of conventional ADTs in treating MDD with a well-tolerated safety profile,” said Barry Greene, Chief Executive Officer at Sage. “Including the CORAL Study, zuranolone now has six positive clinical studies, and we remain on track to start the rolling submission for a New Drug Application in MDD early this year with completion targeted for the second half of 2022.”
“These positive results from the CORAL Study indicate that zuranolone co-initiated with standard of care may offer more rapid relief from depressive symptoms than current standard of care taken alone,” said Priya Singhal, M.D., M.P.H., Head of Global Safety and Regulatory Sciences and Interim Head of R&D at Biogen. “Based on the collective results observed across the LANDSCAPE clinical development program, we believe that zuranolone has the potential to offer a new clinically meaningful treatment option for people with major depressive disorder.”
In the CORAL Study, zuranolone 50 mg co-initiated with a standard of care ADT was generally well-tolerated with no new safety signals identified. The majority of people in the study experienced treatment emergent adverse events (TEAEs) that were mild or moderate in severity, consistent with previous data in the LANDSCAPE program. The adverse events occurring 10% or higher in the zuranolone plus ADT arm were somnolence (18.4%), dizziness (13.2%) and headache (11.8%). In the ADT plus placebo arm the AEs occurring 10% or greater were headache (14.7%) and nausea (23.4%). The CORAL Study safety data support the known safety profile of zuranolone based on clinical trials to date.
“The CORAL Study results were particularly interesting because the data demonstrated that zuranolone worked within days to provide rapid reduction in depressive symptoms as compared to current ADTs, which in clinical practice can take weeks or months to work,” said Sagar Parikh, MD, Professor of Depression and Clinical Neuroscience, and Psychiatry Sciences, University of Michigan. “In my experience, people with MDD deserve to feel better as soon as possible with a treatment with tolerable side effects. These data suggest that zuranolone has the potential to offer this option and to provide physicians the opportunity to think differently about treating MDD.”
The Phase 3 CORAL Study builds on the foundational data assembled within the LANDSCAPE clinical program to date. Data from this program has been presented at numerous medical and scientific conferences, and the companies plan to present additional data from the CORAL Study in future scientific forums.
CORAL Study Summary Results
The CORAL Study was a Phase 3, randomized, double-blind, placebo-controlled trial, which enrolled 440 people with MDD (n=220 per treatment arm). People in the study received zuranolone 50 mg co-initiated with an open-label standard of care ADT or open-label standard of care ADT co-initiated with placebo once nightly for 14 days. Results for the primary and key secondary efficacy endpoints during the treatment period are outlined in the following table and all favor zuranolone.
- The mean (SD) baseline HAMD-17 score at entry into the study was 26.8 (2.5) in the zuranolone co-initiated with ADT arm and 26.6 (2.6) in the ADT co-initiated with placebo arm.
- 180 (84.9%) people in the study who received zuranolone co-initiated with ADT, and 177 (81.2%) people who received ADT co-initiated with placebo, completed the study.
| Zuranolone 50 mg co-initiated with an ADT | ADT co-initiated with placebo | ||
| LS Mean HAMD-17 Total Score CFB (n= 210) | LS Mean HAMD-17 Total Score CFB (n=215) |
p value | |
| Day 3 Primary Endpoint | -8.9 | -7.0 | 0.0004 |
| Key Secondary Endpoint LS Mean Change in HAMD-17 total score using equal weights for Days 3, 8, 12, and 15 (over the blinded treatment period) |
-11.7 | -10.1 | 0.0054 |
ADT = antidepressant; CFB = change from baseline; HAMD-17 = 17-item Hamilton Depression Rating Scale; LS Mean = Least Squares Mean
| Mean CFB in HAMD-17 Total Score at Each Time Point in the Blinded Treatment Period (Applied to Calculate the Key Secondary Endpoint) | |||
| Zuranolone 50 mg co-initiated with an ADT |
ADT co-initiated with placebo |
||
| LS Mean HAMD-17 Total Score CFB | LS Mean HAMD-17 Total Score CFB | p value | |
| Day 3 Primary Endpoint | -8.9 | -7.0 | 0.0004 |
| Day 8 | -11.3 | -9.2 | 0.0012 |
| Day 12 | -12.8 | -11.4 | 0.0381 |
| Day 15 | -13.7 | -12.9 | 0.2477 |
ADT = antidepressant; CFB = change from baseline; HAMD-17 = 17-item Hamilton Depression Rating Scale; LS Mean = Least Squares Mean
Safety and tolerability of zuranolone 50 mg co-initiated with an ADT:
- Over the study period, the AEs 10% or higher in either treatment arm (zuranolone with an ADT vs. ADT with placebo) were: somnolence (18.4% vs 8.3%), dizziness (13.2% vs 7.3%), headache (11.8% vs 14.7%), and nausea (9.0% vs 23.4%).
- The percentage of people reporting TEAEs leading to discontinuation of study drug were 6.6% in the zuranolone co-initiated with an ADT arm, and 3.7% in the ADT co-initiated placebo arm, respectively. Similarly, the percentage of people reporting TEAEs leading to discontinuation of ADT were 7.5% in the zuranolone co-initiated with an ADT arm, and 5.5% in the ADT co-initiated placebo arm, respectively.
- No evidence of increased suicidal ideation/behavior was identified with zuranolone when co-initiated with an ADT compared with ADT co-initiated with placebo as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS), and systematic evaluations revealed no evidence of withdrawal symptoms in either study arm.
About the CORAL Study
The CORAL Study (217-MDD-305) was a Phase 3, randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of zuranolone 50 mg co-initiated with an open-label standard of care antidepressant (ADT) compared to a standard of care ADT co-initiated with placebo in adults with MDD. In the study, 440 people were enrolled. People in the study were randomized to receive zuranolone 50 mg with a standard of care ADT or a standard of care ADT co-initiated with placebo once nightly for two weeks. People in the study were then followed for four weeks during which they continued their ADT. The study included five ADTs across different SSRI and SNRIs (sertraline, escitalopram, citalopram, duloxetine, desvenlafaxine) that represent the most commonly used ADTs. The choice of ADT was made by the clinician. The primary endpoint was the change in baseline 17-item Hamilton Rating Scale for Depression (HAMD-17) total score at Day 3.
About Major Depressive Disorder (MDD)
Major depressive disorder (MDD) 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 more than 19 million adults in the U.S. and more than 260 million people worldwide suffer from depression. While antidepressants are widely used to treat MDD, large-scale studies have demonstrated the need for additional therapies with a differentiated profile.
About Zuranolone
Zuranolone (SAGE-217/BIIB125) is a once-daily, two-week, investigational 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 to regulating brain function.
Zuranolone is being evaluated in the LANDSCAPE and NEST clinical trial programs. The two development programs include multiple studies examining use of zuranolone in several thousand people with a variety of dosing, clinical endpoints, and treatment paradigms. The LANDSCAPE program includes five studies of zuranolone in people with MDD (MDD-201B, MOUNTAIN, SHORELINE, WATERFALL, and CORAL Studies). The NEST program includes two placebo-controlled studies of zuranolone in people with PPD (ROBIN and SKYLARK Studies). Additionally, Shionogi recently completed a Phase 2 study of zuranolone in Japan in people with MDD.
About Sage Therapeutics
Sage Therapeutics is a biopharmaceutical company fearlessly leading the way to create a world with better brain health. Our mission is to pioneer solutions to deliver life-changing brain health medicines, so every person can thrive. For more information, please visit. www.sagerx.com.
About Biogen
As pioneers in neuroscience, Biogen discovers, develops, and delivers worldwide innovative therapies for people living with serious neurological diseases as well as related therapeutic adjacencies. One of the world’s first global biotechnology companies, Biogen was founded in 1978 by Charles Weissmann, Heinz Schaller, Sir Kenneth Murray, and Nobel Prize winners Walter Gilbert and Phillip Sharp. Today, Biogen has a leading portfolio of medicines to treat multiple sclerosis, has introduced the first approved treatment for spinal muscular atrophy, and is providing the first and only approved treatment to address a defining pathology of Alzheimer’s disease. Biogen is also commercializing biosimilars and focusing on advancing the industry’s most diversified pipeline in neuroscience that will transform the standard of care for patients in several areas of high unmet need.
In 2020, Biogen launched a bold 20-year, $250 million initiative to address the deeply interrelated issues of climate, health, and equity. Healthy Climate, Healthy Lives™ aims to eliminate fossil fuels across the company’s operations, build collaborations with renowned institutions to advance the science to improve human health outcomes, and support underserved communities.
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SOURCE: Biogen
