Glyph Allopregnanolone for Major Depressive Disorder Meets Phase 1 Endpoints

Positive results from a phase 1 driving simulation trial of GlyphAllo (SPT-300), a prodrug of allopregnanolone for major depressive disorder, show that evening dosing did not impair next-morning driving performance compared with placebo.¹

GlyphAllo is designed to deliver allopregnanolone, an endogenous neurosteroid with rapid-acting antidepressant, anxiolytic, and sleep-promoting properties, while overcoming the bioavailability limitations that have historically restricted oral use of the molecule. Allopregnanolone-based treatment has previously been validated in postpartum depression, with GlyphAllo now being developed specifically for MDD.²

Trial Design

The randomized, double-blind, placebo- and active-controlled, 3-way crossover phase 1 trial enrolled 33 healthy volunteers, who received GlyphAllo at bedtime and underwent driving assessments the following morning, approximately 9 hours after dosing. Driving performance was measured using the Cognitive Research Corporation Driving Simulator-MiniSim, with Standard Deviation of Lateral Position (SDLP, a widely used measure of lane weaving) as the primary endpoint.

The trial evaluated a 375 mg dose, the highest dose currently under investigation in the phase 2b BUOY-1 trial, and a 250 mg dose. The primary endpoint was met: evening dosing of GlyphAllo at 375 mg did not impair next-morning SDLP compared with placebo on day 5, following multiple-day dosing. The key secondary endpoint was also met, with a single 250 mg dose showing no next-morning driving impairment versus placebo on day 2. A 7.5 mg dose of zopiclone served as a positive control and produced statistically significant driving impairment relative to both GlyphAllo and placebo on both assessment days, confirming the trial's ability to detect an impairment effect. GlyphAllo was well tolerated at all doses, with most adverse events mild and transient and no serious adverse events reported.

"We are very pleased by the results, which showed no next-morning driving impairment at either dose evaluated," said Daphne Zohar, cofounder and chief executive officer of Seaport Therapeutics. "We believe that GlyphAllo has the potential to deliver the benefits of allopregnanolone without next-morning effects on driving."

Seaport plans to submit the driving simulation results to the US Food and Drug Administration (FDA) as part of the ongoing GlyphAllo development program and to present additional analyses at upcoming scientific meetings. The company continues to enroll patients in BUOY-1, a 2-arm, global, randomized, double-blind, placebo-controlled, potentially registration-enabling phase 2b trial evaluating GlyphAllo in patients with MDD, with or without anxious distress. Drug developers plan to submit the results to the FDA and continuenenrolling its phase 2b BUOY-1 trial in MDD, with topline data expected in the first half of 2027.

References

1. Seaport Therapeutics reports positive topline results from phase 1 driving simulation trial of GlyphAllo in healthy volunteers. Press release. September 9, 2026. Accessed September 9, 2026. https://www.businesswire.com/news/home/20260909055068/en/Seaport-Therapeutics-Reports-Positive-Topline-Results-from-Phase-1-Driving-Simulation-Trial-of-GlyphAllo-in-Healthy-Volunteers

2. Pinna G, Almeida FB, Davis JM. Allopregnanolone in postpartum depression. Front Glob Womens Health. 2022;3:823616.