Seaport Therapeutics has announced the dosing of the first patient in its phase 2b BUOY-1 study of GlyphAllo (Glyph Allopregnanolone, or SPT-300), marking a significant milestone in the development of what could become a first-in-class treatment for major depressive disorder (MDD) with or without anxious distress.
GlyphAllo represents a novel approach to depression treatment as a "glyphed" oral prodrug of allopregnanolone. While allopregnanolone has been clinically validated in third-party trials as a rapidly acting antidepressant with anxiolytic effects, its clinical use has been previously constrained by limitations that the Glyph platform is specifically designed to address.
Study Design and Objectives
The global, randomized, double-blind, placebo-controlled BUOY-1 study will evaluate the efficacy, safety, and tolerability of GlyphAllo in adults with MDD, with or without anxious distress. The trial is expected to enroll up to approximately 360 participants, who will be randomly assigned 1:1 to receive either GlyphAllo or placebo once-daily over a 6-week treatment period.
The primary endpoint is change from baseline at 6 weeks in the Hamilton Depression Rating Scale-17 (HAM-D-17). Following the initial treatment period, eligible participants may enter an open-label extension phase, during which all participants will receive GlyphAllo for up to an additional 6 weeks.
"CNS clinical trials are inherently complex, and we are applying our team's extensive expertise to implement a high-quality study," said Antony Loebel, MD, chief medical officer and president of Clinical Development at Seaport Therapeutics. "We are confident that our rigorous clinical trial execution, including an emphasis on the quality of patient enrollment, will build on a proven mechanism and established clinical efficacy, to increase our likelihood of success in developing an effective treatment for patients with depression."
Strong Preclinical Foundation
The BUOY-1 study builds on a foundation of positive clinical data from phase 1 and phase 2a studies of GlyphAllo in healthy volunteers. In phase 1, GlyphAllo demonstrated approximately 9 times greater allopregnanolone exposure than oral dosing of allopregnanolone and reached similar exposures to the efficacious doses of intravenous-infused allopregnanolone.
Both EEG beta frequency power and reduction in saccadic eye velocity confirmed that GlyphAllo engaged with its target in a dose-dependent manner. The overall safety data, pharmacokinetics, and pharmacodynamic findings support 6-week dosing of GlyphAllo in the current phase 2b trial.
Promising Phase 2a Results
In a phase 2a proof-of-concept study in healthy volunteers using the Trier Social Stress Test (TSST), GlyphAllo significantly reduced the stress hormone salivary cortisol at all post-TSST timepoints compared with placebo. GlyphAllo met the primary endpoint with a P-value of 0.0001, demonstrating that GlyphAllo regulates hypothalamic-pituitary-adrenal axis reactivity to acute stress.
The treatment was generally well-tolerated, with adverse events that were mostly mild and transient.
Addressing a Global Health Challenge
"The initiation of BUOY-1 marks a significant milestone for Seaport's pipeline, bringing us closer to a potential new treatment for major depression, which impacts around 280 million people globally—nearly 60% of whom also experience anxious distress," said Daphne Zohar, cofounder and chief executive officer at Seaport Therapeutics. "This is an important step on our journey to deliver new treatments for patients living with depression, anxiety, and other neuropsychiatric conditions."
The trial represents a critical step in validating GlyphAllo as a potential breakthrough therapy for patients with depression and anxiety, offering hope for improved treatment options in an area of significant unmet medical need.
