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Seaport Therapeutics initiates a pivotal study for GlyphAllo, a potential breakthrough treatment for major depressive disorder, with or without anxious stress.
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Seaport Therapeutics today announced that the first patient has been dosed in the phase 2b BUOY-1 study of GlyphAllo (Glyph Allopregnanolone, or SPT-300) in major depressive disorder (MDD) with or without anxious distress. If successful, GlyphAllo could be a first-in-class treatment for patients with MDD, with or without anxious distress.1
GlyphAllo is a novel, “glyphed” oral prodrug of allopregnanolone. Allopregnanolone has been clinically validated in third-party trials as a rapidly acting antidepressant with anxiolytic effects, but its scope of clinical use was previously constrained by limitations that the Glyph platform is specifically designed to solve.
In the global, randomized, double-blind, placebo-controlled BUOY-1 study, investigators will evaluate the efficacy, safety, and tolerability of GlyphAllo in adults with MDD, with or without anxious distress. The study is expected to enroll up to approximately 360 participants, 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.”1
This 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. Investigators have thus determined that the overall safety data, pharmacokinetics, and pharmacodynamic findings support 6-week dosing of GlyphAllo in BUOY-1.
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. GlyphAllo was generally well-tolerated. Adverse events were mostly mild and transient.
“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.”1
Reference
1. Seaport Therapeutics announces first patient dosed in phase 2b BUOY-1 study of GlyphAllo (SPT-300) in major depressive disorder (MDD), with or without anxious distress. News release. July 17, 2025. Accessed July 17, 2025. https://seaporttx.com/press-release/seaport-therapeutics-announces-first-patient-dosed-in-phase-2b-buoy-1-study-of-glyphallotm-spt-300-in-major-depressive-disorder-mdd-with-or-without-anxious-distress/
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