Seaport Therapeutics a clinical-stage biopharmaceutical company developing next-generation neuropsychiatric medicines, announced that the first participant has been dosed in its Phase 1 clinical study of GlyphAgo™ (SPT-320 or Glyph Agomelatine). GlyphAgo is a novel “Glyphed” oral prodrug of agomelatine designed to overcome key limitations of the parent molecule and is being developed as a potential treatment for generalized anxiety disorder (GAD). This milestone marks the advancement of Seaport’s second therapeutic candidate into clinical development, underscoring the company’s momentum in building a differentiated neuropsychiatric pipeline.
Addressing Unmet Needs in GAD
Generalized anxiety disorder is among the most common psychiatric conditions, affecting roughly 100 million adults worldwide. Anxiety disorders broadly impact nearly 30% of adults at some point in their lives, making them the most prevalent neuropsychiatric illnesses. Yet despite this burden, treatment innovation has lagged. In the United States, no new drug classes or mechanisms have been approved for GAD in decades. Existing options, such as selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines, are often associated with suboptimal efficacy, delayed onset of action, and adverse effects including weight gain, sexual dysfunction, or risk of dependence.
Agomelatine, the parent compound of GlyphAgo, is a melatonin receptor agonist and serotonin 2C receptor antagonist with both anxiolytic and antidepressant properties. It is currently approved for the treatment of GAD in Australia and for major depressive disorder (MDD) in the European Union and Australia. Across four placebo-controlled trials conducted by independent investigators, agomelatine has consistently demonstrated statistically significant benefits over placebo in GAD, while offering favorable tolerability compared with standard-of-care drugs.
However, the clinical utility of agomelatine has been limited by first-pass liver metabolism, which results in the loss of more than 90% of the active drug before it reaches systemic circulation. At higher doses, this metabolism is associated with elevations in liver enzymes, necessitating regular monitoring and limiting the drug’s widespread adoption.
The Glyph™ Platform and GlyphAgo
Seaport’s proprietary Glyph™ platform is designed to address challenges like these by rerouting absorption away from the liver. By shifting uptake toward the intestinal lymphatics, the platform enables higher systemic exposure at lower doses while reducing liver-related side effects.
GlyphAgo applies this approach to agomelatine, with the goal of maintaining its proven efficacy while improving its safety and tolerability profile. Preclinical studies have already shown that GlyphAgo can increase plasma exposure of agomelatine by more than tenfold compared with the parent drug alone. In these studies, more than 50% of orally administered GlyphAgo was absorbed through the mesenteric lymphatics, compared with less than 1% for standard oral agomelatine.
These findings, presented at the Society of Biological Psychiatry (SOBP) Annual Meeting 2025, suggest that GlyphAgo may deliver therapeutic exposure levels of agomelatine at lower doses, without triggering the dose-dependent liver enzyme elevations that have constrained its clinical use.
Clinical Development Plan
The ongoing Phase 1 trial is a multi-part study designed to evaluate the safety, tolerability, and pharmacokinetics of GlyphAgo in healthy adult volunteers. The program includes:
- Single-ascending dose (SAD) cohorts to assess safety and dose proportionality.
- Multiple-ascending dose (MAD) cohorts to evaluate tolerability and pharmacokinetics over repeated administration.
- A food-effect crossover study, which will help determine whether meals influence absorption or systemic exposure.
The trial also includes direct comparisons between GlyphAgo and agomelatine to confirm the pharmacokinetic advantages observed in preclinical models. The combination of open-label and placebo-controlled designs provides a comprehensive early assessment of the candidate’s potential.
Expert Perspective
Dr. Antony Loebel, Chief Medical Officer and President of Clinical Development at Seaport Therapeutics, emphasized the significance of this milestone:
“Anxiety disorders are the most prevalent neuropsychiatric disorders, impacting nearly 30 percent of adults at some point in their lives, with GAD alone affecting approximately 100 million adults worldwide. Despite this, in the U.S., no new drugs or mechanisms have been approved for GAD in decades. Our Phase 1 proof-of-concept study could be highly derisking for the GlyphAgo program, as agomelatine’s efficacy in GAD is already well established. The key question is whether we can achieve effective exposure at a lower dose, which would demonstrate GlyphAgo’s ability to avoid agomelatine’s dose-dependent liver issues. We believe GlyphAgo has the potential to redefine the treatment landscape for GAD and represents an important clinical advancement for patients.”
Looking Ahead
With two candidates now in clinical development, Seaport continues to advance its mission of transforming neuropsychiatric treatment through innovative science and a proven development strategy. The GlyphAgo program exemplifies this approach by building on a validated therapeutic mechanism and applying proprietary technology to enhance safety and effectiveness.
If successful, GlyphAgo could provide millions of patients worldwide with a new option for managing generalized anxiety disorder—one that combines the efficacy of a validated therapy with a significantly improved safety profile.All the therapeutic candidates in its pipeline of first and best-in-class medicines are based on the Glyph platform, which is uniquely designed to enable oral bioavailability, bypass first-pass metabolism and reduce liver enzyme elevations or hepatotoxicity and other side effects. Seaport is led by an experienced team that invented and advanced important neuropsychiatric medicines and is guided by an extensive network of renowned scientists, clinicians, and key opinion leaders. For more information, please visit www.seaporttx.com.
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 Nature Metabolism, Frontiers in Pharmacology, Journal of Controlled ReleaseandMolecular Pharmaceutics supporting the Glyph platform’s capabilities. See Glyph in action here.
About GlyphAgo™ (SPT-320 or Glyph Agomelatine)
GlyphAgo (SPT-320 or Glyph Agomelatine), an oral prodrug of agomelatine, is in clinical stage development with the potential to be the first new treatment for generalized anxiety disorder (GAD) in decades. Using the Glyph™ platform, GlyphAgo was designed to bypass first-pass liver metabolism in order to lower the dose, reduce liver exposure, and reduce or eliminate the need for liver enzyme monitoring.
Agomelatine is a clinically validated anxiolytic and antidepressant approved for GAD in Australia and major depressive disorder (MDD) in Australia and the European Union (EU). The use of agomelatine has been limited by high first-pass liver metabolism resulting in liver enzyme elevations in some patients and frequent, burdensome liver enzyme monitoring requirements. GlyphAgo is currently in a Phase 1 proof-of-concept study to evaluate the safety, tolerability, and pharmacokinetics in healthy adult volunteers.
About Seaport Therapeutics
Seaport Therapeutics is a clinical-stage biopharmaceutical company advancing the development of novel neuropsychiatric medicines in areas of high unmet patient needs. The Company has a proven strategy of advancing clinically validated mechanisms previously held back by limitations that are overcome with its proprietary Glyph technology platform.
