GlyphAllo Shows No Next-Morning Driving Impairment at 375 mg

Seaport Therapeutics’ oral allopregnanolone prodrug GlyphAllo showed no impairment of next-morning simulated driving performance at 375 mg after multiple evening doses, supporting continued development of the investigational therapy for major depressive disorder (MDD).

Phase 1 Trial Supports Driving Safety Profile

The randomized Phase 1 driving simulation trial evaluated GlyphAllo (SPT-300, Glyph Allopregnanolone) in 33 healthy volunteers. The primary endpoint was met, with evening dosing of 375 mg showing no impairment of next-morning driving performance versus placebo on Day 5 following multiple-day dosing.

The key secondary endpoint was also met. A single 250 mg evening dose did not impair next-morning simulated driving performance compared with placebo on Day 2.

These findings are particularly relevant to GlyphAllo’s intended evening dosing regimen. The 375 mg dose is also the highest dose currently being evaluated in the Phase 2b BUOY-1 trial in patients with MDD.

Validated Driving Assessment

The randomized, double-blind, placebo- and active-controlled, three-way crossover trial assessed driving performance approximately nine hours after bedtime dosing. Investigators used the Cognitive Research Corporation Driving Simulator-MiniSim, a validated tool used in clinical drug-development studies.

The primary endpoint was Standard Deviation of Lateral Position (SDLP), a standard measure of lane weaving used to detect drug-related driving impairment.

The study included 7.5 mg zopiclone as an active positive control. Zopiclone produced statistically significant impairment compared with both GlyphAllo and placebo on Days 2 and 5, confirming that the assay could detect drug-related driving impairment.

GlyphAllo was well tolerated across the evaluated doses. Most adverse events were mild and transient, and no serious adverse events were reported.

Glyphed Oral Prodrug of Allopregnanolone

GlyphAllo is a “Glyphed” oral prodrug of allopregnanolone developed using Seaport’s proprietary Glyph™ platform. The platform uses the intestinal lymphatic system to enhance oral drug administration, with prodrugs absorbed through pathways involved in dietary fat transport before entering systemic circulation.

Allopregnanolone is an endogenous neuroactive steroid that modulates GABA-A receptors and has demonstrated rapidly acting antidepressant, anxiolytic, and sleep-promoting effects. However, its low oral bioavailability has limited conventional oral administration. GlyphAllo uses the prodrug approach to generate therapeutically relevant allopregnanolone exposure following oral dosing.

Earlier Phase 1 and Phase 2a studies established dose-dependent systemic exposure and provided initial pharmacodynamic evidence, while also showing a favorable tolerability profile.

BUOY-1 Data Expected in 2027

Seaport is evaluating GlyphAllo in BUOY-1, a global, randomized, double-blind, placebo-controlled Phase 2b trial in patients with MDD, with or without anxious distress. The potentially registration-enabling study is assessing the therapy’s safety and efficacy, with 375 mg representing the highest dose under investigation.

The company plans to submit the Phase 1 driving-simulation results to the U.S. Food and Drug Administration as part of GlyphAllo’s ongoing development program and expects to present additional analyses at upcoming scientific meetings.

Topline BUOY-1 results are expected in the first half of 2027. The driving-simulation findings add supportive functional safety data as GlyphAllo advances toward a later-stage efficacy readout in MDD, where the effects of evening treatment on next-morning functioning could be clinically relevant.

 Reference

Seaport Therapeutics Reports Positive Topline Results from Phase 1 Driving Simulation Trial of GlyphAllo™ in Healthy Volunteers, Seaport Therapeutics, 09 September 2026