PureTech Founded Entity Seaport Therapeutics Publishes First-in-Human Data on GlyphAllo™ (SPT-300) in Science Translational Medicine
PureTech Health plc a biotherapeutics company focused on advancing innovative science into impactful medicines, announced that its Founded Entity, Seaport Therapeutics, has published significant clinical and preclinical findings for GlyphAllo™ (SPT-300) in the peer-reviewed journal Science Translational Medicine. This publication marks an important milestone, presenting the first comprehensive disclosure of GlyphAllo’s development journey—from early discovery through initial human clinical validation.
GlyphAllo™ is a novel oral prodrug of allopregnanolone, developed using Seaport’s proprietary Glyph™ platform. The platform, originally incubated and advanced within PureTech, is designed to overcome pharmacokinetic challenges associated with certain therapeutic molecules. After its initial development at PureTech, the Glyph platform and associated programs were transferred to Seaport Therapeutics, where they continue to be actively advanced.
The published research highlights the potential of GlyphAllo as the first triglyceride-mimetic (TG-mimetic) prodrug to achieve therapeutically meaningful drug levels in humans through oral administration. This is particularly notable because allopregnanolone, a naturally occurring neurosteroid, has historically faced challenges related to poor oral bioavailability due to extensive first-pass metabolism in the liver.
The paper, titled “An oral allopregnanolone prodrug bypasses liver metabolism via lymphatic transport enabling bioavailability in animals and humans,” details how the Glyph platform enables drug molecules to bypass liver metabolism by utilizing lymphatic transport pathways. This mechanism significantly enhances systemic exposure and allows for effective oral dosing, which could represent a major advancement in drug delivery for compounds with similar limitations.
Allopregnanolone itself is an endogenous molecule known for its rapid onset of action and clinically validated therapeutic effects. It has demonstrated antidepressant, anxiolytic, and sleep-promoting properties in prior third-party clinical studies, particularly in postpartum depression. Given that postpartum depression shares several clinical features with major depressive disorder (MDD), researchers have long been interested in exploring its broader therapeutic potential.
According to Steven Paul, M.D., Co-Founder and Board Chair of Seaport Therapeutics and a contributing author to the publication, GlyphAllo has been specifically designed to address the bioavailability challenges of allopregnanolone. By optimizing its pharmaceutical properties, the program aims to deliver both rapid and sustained clinical effects through a convenient oral formulation. This advancement opens the possibility of evaluating allopregnanolone-based therapies for MDD in a more practical and scalable manner.
The publication provides detailed insights into the discovery and optimization process of GlyphAllo. Researchers synthesized and evaluated multiple TG-mimetic prodrug candidates by conjugating allopregnanolone with lipophilic moieties. These candidates were tested across various preclinical models, where several demonstrated strong lymphatic transport and favorable plasma release profiles. These findings indicated the ability to achieve therapeutically relevant exposure levels following oral dosing.
Further preclinical work confirmed that the Glyph platform could effectively enhance the oral delivery of molecules typically hindered by high first-pass metabolism. Through iterative optimization, GlyphAllo emerged as the lead candidate, showing improved bioavailability and consistent systemic exposure. These results supported its progression into clinical development, including Phase 1 and Phase 2a studies.
Clinical translation of these findings has been encouraging. In Phase 1 trials, GlyphAllo demonstrated dose-dependent pharmacokinetics, achieving therapeutically relevant plasma concentrations of allopregnanolone in healthy volunteers. The drug was generally well tolerated across a range of single and multiple ascending oral doses, spanning from 70 mg to 1000 mg.
In addition to safety and pharmacokinetics, early signs of pharmacodynamic activity were observed. In a Phase 2a proof-of-concept study utilizing the Trier Social Stress Test (TSST)—a well-established model for inducing acute psychological stress—GlyphAllo showed a significant reduction in salivary cortisol levels compared to placebo. A single 375 mg dose resulted in a statistically significant attenuation of the stress response (p=0.0001), suggesting potential anxiolytic effects and reinforcing its therapeutic promise.
Michael Chen, Ph.D., Co-Founder and Chief Scientific Officer of Seaport Therapeutics and senior author of the publication, emphasized the broader implications of these findings. He noted that the successful demonstration of the Glyph platform not only supports GlyphAllo as a compelling drug candidate but also validates the platform’s ability to transform other small molecules with pharmacokinetic limitations into viable oral therapies.
The cumulative data from preclinical and clinical studies support the continued development of GlyphAllo as a differentiated treatment option for major depressive disorder. Building on these results, Seaport initiated the BUOY-1 trial in July 2025. This global Phase 2b study is a randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy, safety, and tolerability of GlyphAllo in adults with MDD, including those with or without anxious distress.
Beyond its application in neuropsychiatric disorders, the Glyph platform holds broader potential across multiple therapeutic areas. The publication highlights its adaptability and scalability, suggesting that it could be applied to address pharmacokinetic challenges in fields such as oncology, immunology, inflammation, metabolic diseases, and obesity. By enabling efficient and repeatable prodrug design, the platform could significantly expand the range of molecules that can be successfully developed into oral therapies.
The research described in the publication represents a collaborative effort involving multiple scientists and institutions. Lead author Jamie Simpson, Ph.D., who is also Head of Chemistry at Seaport and an original co-inventor of the Glyph technology, played a central role in driving the work. Additional contributions came from Daniel Bonner, Ph.D., Co-Founder and Senior Vice President of Platform at Seaport, as well as collaborators at Monash University.
At Monash, the research was conducted under the direction of Christopher Porter, Ph.D., Director of the Monash Institute of Pharmaceutical Sciences and another original co-inventor of the Glyph technology. This collaboration underscores the importance of interdisciplinary partnerships in advancing innovative drug development strategies.
Overall, the publication of GlyphAllo’s data in Science Translational Medicine represents a significant scientific and clinical milestone. It not only demonstrates the feasibility of delivering allopregnanolone orally at therapeutically relevant levels but also validates a novel platform that could reshape how challenging drug molecules are developed and administered.
As Seaport continues to advance GlyphAllo through later-stage clinical trials, the findings provide a strong foundation for its potential role in treating major depressive disorder and related conditions. At the same time, the broader implications of the Glyph platform suggest that its impact could extend well beyond a single therapy, offering new possibilities for innovation across the pharmaceutical landscape.
About the Glyph™ Platform
Glyph is Seaport’s proprietary technology platform which uses the lymphatic system to enable and enhance the oral administration of drugs. With the Glyph platform, drugs are absorbed like dietary fats through the intestinal lymphatic system and transported into circulation. The Glyph platform has the potential to be widely applied to many therapeutic molecules that have high first-pass metabolism otherwise leading to low bioavailability and/or side effects, including liver enzyme elevations or hepatotoxicity. For each program, Seaport leverages its Glyph platform to create unique sets of prodrugs with differentiated profiles, including lymphatic transport and conversion characteristics, as potential candidates to advance into preclinical and clinical proof-of-concept studies. Seaport exclusively licensed this technology from Monash University based on the pioneering research of the Porter Research Group. Advanced initially at PureTech Health and now at Seaport, Glyph has been applied to create therapeutic candidates for the Company’s pipeline resulting in new intellectual property, including composition of matter. The group and its collaborators have published research in supporting the Glyph platform’s capabilities. See Glyph in action here.
About PureTech Health
PureTech Health is a hub-and-spoke biotherapeutics company dedicated to giving life to science and transforming innovation into value. We do this through a proven, capital-efficient R&D model focused on opportunities with validated pharmacology and untapped potential to address significant patient needs. This strategy has produced dozens of therapeutic candidates, including three that have received U.S. FDA approval. By identifying, shaping, and de-risking these high-conviction assets, and scaling them through dedicated structures backed by external capital, we accelerate their path to patients while creating sustainable value for shareholders.
