PureTech Health Notes Positive Phase 1 Driving Trial Results for GlyphAllo in Major Depressive Disorder
PureTech Health plc (LSE: PRTC), a biotherapeutics company operating through a hub-and-spoke model to translate scientific innovation into potentially transformative medicines, has highlighted positive topline results from a Phase 1 Driving Simulation Trial of GlyphAllo™ (SPT-300 or Glyph Allopregnanolone), an investigational oral therapy being developed by its Founded Entity, Seaport Therapeutics.
The Phase 1 study evaluated whether evening administration of GlyphAllo could affect next-morning driving performance in healthy volunteers. The trial achieved its primary endpoint, demonstrating that an evening dose of 375 mg GlyphAllo did not impair next-morning driving performance compared with placebo on Day 5 after multiple days of dosing.
The findings provide an important safety and tolerability data point for GlyphAllo as Seaport advances the candidate through clinical development for major depressive disorder (MDD). The 375 mg dose evaluated in the study represents the highest dose currently being investigated in Seaport’s ongoing Phase 2b BUOY-1 trial.
In addition to the primary endpoint, the study met a key secondary endpoint. A single evening dose of 250 mg GlyphAllo also did not impair next-morning driving performance compared with placebo on Day 2.
Seaport plans to submit the Phase 1 driving study results to the U.S. Food and Drug Administration (FDA) as part of the continuing development program for GlyphAllo. The company also intends to present additional analyses from the study at upcoming scientific meetings.
Driving Performance Assessment Addresses Important Treatment Consideration
GlyphAllo is a novel Glyphed oral prodrug of allopregnanolone being developed as a potential treatment for MDD. Seaport is evaluating the candidate with the goal of providing the therapeutic effects associated with allopregnanolone while maintaining a profile that may be suitable for evening administration without unwanted effects the following morning.
The Phase 1 Driving Simulation Trial was specifically designed to evaluate next-morning driving performance following evening dosing. This assessment is relevant to the intended clinical use of GlyphAllo because patients taking a neuropsychiatric medicine in the evening may still need to perform activities requiring alertness and coordination the following day.
The study evaluated two doses of GlyphAllo. Participants received the 375 mg dose, which corresponds to the highest dose currently being studied in the Phase 2b BUOY-1 program, as well as a 250 mg dose.
The primary endpoint focused on the effect of repeated evening dosing of 375 mg GlyphAllo on next-morning driving performance on Day 5. The study met this endpoint, with no impairment observed compared with placebo.
The key secondary endpoint evaluated the effect of a single 250 mg evening dose on next-morning driving performance on Day 2. This endpoint was also met, with the 250 mg dose showing no impairment compared with placebo.
Together, the results provide additional evidence regarding the functional effects of GlyphAllo under dosing conditions aligned with its ongoing clinical development.
Positive Control Demonstrated Trial Sensitivity
The Phase 1 trial also incorporated a positive control designed to confirm that the study’s driving-performance assessment could detect impairment when such an effect was present.
Participants received a 7.5 mg dose of zopiclone as the positive control. Zopiclone produced statistically significant impairment compared with both GlyphAllo and placebo on Day 2 and Day 5.
The positive-control findings are important because they demonstrate that the validated driving simulator and study design were capable of detecting changes in driving performance. In other words, the absence of observed impairment with GlyphAllo was not simply the result of an assay or study design that could not identify an effect.
The inclusion of zopiclone therefore provided evidence of assay sensitivity and strengthened the interpretation of the GlyphAllo findings.
Seaport said the trial used a validated driving simulator and an evening dosing regimen consistent with the regimen planned for the Phase 2b BUOY-1 study and GlyphAllo’s intended clinical use.
GlyphAllo Well-Tolerated in Phase 1 Trial
In addition to the driving-performance findings, GlyphAllo was reported to be well-tolerated across all doses evaluated in the study.
Most adverse events were described as mild and transient, and no serious adverse events were reported. These findings add to the clinical and preclinical safety information generated for the program to date.
Safety and tolerability remain important considerations in the development of medicines for major depressive disorder, particularly for treatments that are intended for repeated use. A favorable safety profile could potentially support longer-term treatment if efficacy is demonstrated in later-stage studies.
Seaport said the driving study findings, together with previously generated clinical and preclinical data, provide additional support for the overall profile of GlyphAllo as the company advances the program.
Daphne Zohar, Co-founder and Chief Executive Officer of Seaport Therapeutics, said the company was encouraged by the results showing no next-morning driving impairment at either dose evaluated.
According to Zohar, the study design incorporated a validated driving simulator and an evening dosing regimen that was consistent with the Phase 2b BUOY-1 trial. She said Seaport believes GlyphAllo may have the potential to provide the benefits of allopregnanolone without producing next-morning driving effects.
The company views these findings as further evidence of potential differentiation for GlyphAllo as it advances the candidate toward becoming a potential first-in-class treatment for MDD.
Developing GlyphAllo for Major Depressive Disorder
GlyphAllo is being developed as a potential treatment for major depressive disorder, a common and serious neuropsychiatric condition. Seaport’s development strategy is focused on evaluating the candidate’s safety and efficacy in patients with MDD, including those with or without anxious distress.
The lead clinical program is BUOY-1, a global, randomized, double-blind, placebo-controlled Phase 2b study. The potentially registration-enabling trial uses a two-arm design and is actively enrolling patients.
BUOY-1 is intended to provide clinical efficacy and safety data that could help determine the next steps in the development of GlyphAllo. Seaport expects to report topline results from the trial during the first half of 2027.
The study represents a major milestone in the development program because it is designed to evaluate GlyphAllo in the patient population for which the therapy is ultimately intended. While the Phase 1 driving simulation trial was conducted in healthy volunteers and focused on functional safety, BUOY-1 is evaluating the candidate’s therapeutic potential in people with MDD.
Potential Differentiation Through Oral Allopregnanolone Prodrug
GlyphAllo is described by Seaport as a Glyphed oral prodrug of allopregnanolone. The candidate forms part of the company’s broader effort to develop novel neuropsychiatric medicines.
The current driving-performance results are particularly relevant to the candidate’s overall development profile because the study directly examined an important potential treatment consideration: whether evening administration could result in impairment the next morning.
The absence of statistically significant next-morning driving impairment at both evaluated GlyphAllo doses, alongside the demonstrated impairment produced by the positive control, provides a specific data point supporting continued investigation.
The 375 mg result is particularly notable for the ongoing Phase 2b program because it corresponds to the highest dose currently being evaluated in BUOY-1. Demonstrating no next-morning driving impairment at that dose in the Phase 1 setting provides information that can be incorporated into the broader clinical development package.
However, the driving study is not designed to establish the efficacy of GlyphAllo in MDD. That question will be addressed through the ongoing patient studies, including BUOY-1.
Results to Be Submitted to FDA
Following the positive topline findings, Seaport plans to submit the results to the FDA as part of the ongoing GlyphAllo development program. The company also expects to share additional analyses at future scientific meetings.
Regulatory engagement will be an important component of the program as Seaport continues to evaluate GlyphAllo and prepares for later-stage development. The driving simulation results will form part of the broader evidence package alongside clinical efficacy, safety, tolerability, pharmacology and previously generated preclinical findings.
The company’s immediate focus remains the ongoing BUOY-1 Phase 2b trial. The study is enrolling patients globally and is designed to assess the safety and efficacy of GlyphAllo in MDD patients with or without anxious distress.
PureTech’s Founded Entity Model
PureTech Health’s announcement reflects its hub-and-spoke model, under which the company creates and advances Founded Entities around potentially important scientific discoveries and therapeutic opportunities.
Seaport Therapeutics is one such Founded Entity, and GlyphAllo represents one of the programs being advanced through the company.
The positive Phase 1 driving simulation results represent another development milestone for Seaport as it builds the clinical evidence base around GlyphAllo. With the candidate now being evaluated in a potentially registration-enabling Phase 2b study, the program is moving toward a stage where efficacy results in patients will become increasingly important to determining its future development path.
The BUOY-1 topline readout, expected in the first half of 2027, will therefore be a significant upcoming milestone for both Seaport and PureTech.
For now, the Phase 1 findings provide supportive information on next-morning functional performance following evening administration. The study met its primary endpoint with 375 mg GlyphAllo following multiple-day dosing and also met its key secondary endpoint with a single 250 mg dose. The absence of serious adverse events and the generally mild and transient nature of reported adverse events further contribute to the safety and tolerability profile observed to date.
As Seaport continues enrollment in BUOY-1, the company will seek to determine whether the favorable characteristics observed in early clinical development can translate into meaningful therapeutic benefits for people living with major depressive disorder. The combination of continued clinical evaluation, planned FDA submission of the driving-study findings and forthcoming Phase 2b data will shape the next stage of GlyphAllo’s development as a potential new treatment option in neuropsychiatric medicine.
About the Phase 1 Driving Simulation Trial
The randomized, double-blind, placebo- and active-controlled, three-way, crossover Phase 1 trial was designed to investigate the effects of evening doses of GlyphAllo on next-morning simulated driving performance in 33 healthy volunteers. Participants received GlyphAllo at bedtime and underwent driving performance assessments the following morning, approximately nine hours following GlyphAllo administration, consistent with established driving simulation trial methodologies.
Driving performance was assessed using the Cognitive Research Corporation Driving Simulator-MiniSim, a widely accepted and validated tool used in clinical development. The primary endpoint was Standard Deviation of Lateral Position (SDLP), a gold standard measure of lane weaving commonly used in clinical trials to evaluate driving impairment. SDLP was assessed on Day 2 following a single 250 mg dose and then on Day 5 following multiple-day dosing of GlyphAllo at 375 mg.
The trial also included a 7.5 mg dose of zopiclone as a positive control. GlyphAllo, including the 375 mg dose, the highest dose being evaluated in the ongoing Phase 2b BUOY-1 trial, has previously demonstrated desirable pharmacokinetics and pharmacodynamics, and a favorable safety and tolerability profile in Phase 1 and Phase 2a clinical trials.
About GlyphAllo (SPT-300 or Glyph Allopregnanolone)
GlyphAllo (SPT-300 or Glyph Allopregnanolone) is a novel, Glyphed oral prodrug of allopregnanolone, an endogenous molecule that has been clinically validated in third-party trials for the treatment of postpartum depression, or PPD, a form of major depressive disorder (MDD), that shares symptomatology with MDD, as a rapidly acting antidepressant with anxiolytic and sleep-promoting effects.
GlyphAllo is designed to overcome bioavailability limitations of allopregnanolone and deliver rapid and durable efficacy in MDD. Seaport has demonstrated in a Phase 1 clinical trial that GlyphAllo reaches therapeutically relevant exposures with oral dosing, and in a Phase 2a clinical trial, GlyphAllo demonstrated initial proof-of-concept with an objective biomarker of stress in healthy volunteers and a favorable tolerability profile.
Seaport is actively enrolling patients in BUOY-1, a two-arm, global, randomized, double-blind, placebo-controlled, potentially registration-enabling Phase 2b trial investigating the safety and efficacy of GlyphAllo in patients with MDD with or without anxious distress. Topline data from the BUOY-1 trial are expected in the first half of 2027.
About Seaport Therapeutics
Seaport Therapeutics (Nasdaq: SPTX) is a clinical-stage therapeutics company focused on inventing and developing new medicines for patients with depression, anxiety, and other debilitating neuropsychiatric disorders. Through its differentiated approach, the Company identifies clinically validated mechanisms with established efficacy and safety which had historically been limited by high first-pass metabolism, low bioavailability, and/or side effects.
Seaport applies its proprietary Glyph™ platform to overcome those limitations and invent innovative oral therapies. With an experienced team of industry leaders, Seaport has a proven track record in neuropsychiatry drug discovery and development and delivering successful business outcomes. Seaport aims to develop novel, leading treatment options that will make a significant impact for patients and their families. For more information, please visit www.seaporttx.com.