First Patient Dosed in Phase 2a Trial of GlyphAgo for Generalized Anxiety Disorder and Sleep Disturbance

The first patient has been dosed in Seaport Therapeutics’ Australian phase 2a clinical trial evaluating GlyphAgo (SPT-320 or Glyph Agomelatine), in adults with generalized anxiety disorder (GAD) and sleep disturbance.¹

“Anxiety disorders affect more than 300 million people globally, and place a substantial burden on patients, families, and health care systems,” said Daphne Zohar, the cofounder and chief executive officer at Seaport Therapeutics. “Patients with generalized anxiety disorder experience persistent anxiety symptoms that can make it difficult to carry out normal activities, and sleep disturbances are among the most frequently reported debilitating symptoms. Despite the widespread impact of GAD, there have been no new approved therapies in almost 2 decades, and many patients continue to experience inadequate symptom relief or tolerability issues that limit treatment. The initiation of this trial is an important step in bringing this potential new medicine to patients and their families.”

About GlyphAgo

GlyphAgo is a novel, “glyphed” oral prodrug of agomelatine, which is a clinically validated MT1/MT2 melatonin receptor agonist and serotonin 2C (5-HT2C) receptor antagonist. Agomelatine has demonstrated statistically significant separation from placebo in 4 third-party placebo-controlled studies in GAD.^2-5 According to data from meta-analyses using indirect comparisons across placebo-controlled trials, agomelatine ranked highest for efficacy and tolerability compared with benzodiazepines and selective serotonin-reuptake inhibitors (SSRIs),^6,7 which are considered standard drugs for GAD.

Investigators designed GlyphAgo for absorption via the intestinal lymphatic system, which bypasses first-pass hepatic metabolism and achieves therapeutically relevant agomelatine exposure at substantially lower doses and with reduced liver exposure. Seaport believes this approach has the potential to reduce the risk of liver enzyme elevations.

More About the Phase 2a Trial

In the 6-week phase 2a clinical trial, patients with GAD and comorbid sleep disturbance will be randomly assigned in a double-blind manner to 1 of 2 dose levels of GlyphAgo, 16 mg/day (containing approximately 5 mg agomelatine) or 32 mg/day (containing approximately 10 mg agomelatine). The trial is designed to establish proof-of-pharmacology by evaluating the effects of GlyphAgo on sleep, assessed by patient-reported sleep outcomes, such as the Insomnia Severity Index and EEG-based measures of sleep architecture. Additional endpoints include anxiety severity as measured by the Hamilton Anxiety Scale, overall illness severity (Clinical Global Impression-Severity), and safety, tolerability, and pharmacokinetics.

Seaport expects to report topline data from the trial in early 2028.

“Agomelatine has been shown to improve sleep quality and sleep architecture without the daytime sleepiness seen with other therapies, making it a compelling candidate for patients with GAD and sleep disturbance,” said Daniel Bonner, PhD, the cofounder and senior vice president, Platform, at Seaport Therapeutics. “We designed GlyphAgo with our Glyph platform to bypass first-pass liver metabolism and address the bioavailability and hepatic limitations of unmodified agomelatine. We believe that GlyphAgo represents a potentially important treatment advance for people with GAD.”

Previous Phase 1 Data

Investigators selected the 2 GlyphAgo dose levels for the phase 2a trial based on previous phase 1 data, which showed that GlyphAgo achieves clinically relevant agomelatine exposures while delivering substantially less drug than a 25 mg dose of agomelatine. The 25 mg dose is currently approved for the treatment of GAD in Australia and major depressive disorder in Australia and the European Union. At GlyphAgo doses delivering approximately 5 mg or 10 mg agomelatine, geometric mean agomelatine AUC_0-24 was at or above that observed with the approved 25 mg dose of unmodified agomelatine. GlyphAgo also showed markedly lower inter-subject variability, with a geometric CV% for agomelatine AUC_0-24 approximately 10-fold lower than that of agomelatine 25 mg.

GlyphAgo demonstrated a statistically significant 6.8-fold increase in bioavailability compared to unmodified agomelatine, exceeding the program’s prespecified 2-fold target. After 7 days of once-daily dosing, the 16 mg and 32 mg doses (5 mg and 10 mg agomelatine equivalent) of GlyphAgo achieved therapeutically relevant exposures of agomelatine and were well tolerated, with no serious or severe adverse events (AEs), no liver-related AEs, and no clinically significant changes in liver-related laboratory parameters, including ALT, AST, or bilirubin.

Next Steps

Seaport also plans to initiate a global, randomized, double-blind, placebo-controlled phase 2/3 clinical trial evaluating the efficacy and safety of GlyphAgo in patients with GAD in the first half of 2027. Topline data from the Phase 2/3 trial are expected by the end of 2028.

References

1. Seaport Therapeutics announces first patient dosed in phase 2a clinical trial evaluating GlyphAgo^TM in patients with generalized anxiety disorder and sleep disturbance. News release. October 7, 2026. Accessed October 7, 2026. https://www.businesswire.com/news/home/20261007823670/en/Seaport-Therapeutics-Announces-First-Patient-Dosed-in-Phase-2a-Clinical-Trial-Evaluating-GlyphAgoTM-in-Patients-with-Generalized-Anxiety-Disorder-and-Sleep-Disturbance

2. Stein DJ, Ahokas AA, de Bodinat C. Efficacy of agomelatine in generalized anxiety disorder: a randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol. 2008;28(5):561-566.

3. Stein DJ, Ahokas A, Albarran C, et al. Agomelatine prevents relapse in generalized anxiety disorder: a 6-month randomized, double-blind, placebo-controlled discontinuation study. J Clin Psychiatry. 2012;73(7):1002-1008.

4. Stein DJ, Ahokas A, Marquez MS, et al. Agomelatine in generalized anxiety disorder: an active comparator and placebo-controlled study. J Clin Psychiatry. 2014;75(4):362-368.

5. Stein DJ, Ahokas A, Jarema M, et al. Efficacy and safety of agomelatine (10 or 25 mg/day) in non-depressed out-patients with generalized anxiety disorder: a 12-week, double-blind. 2017;27(5):526-537.

6. Slee A, Nazareth I, Bondaronek P, et al. Pharmacological treatments for generalized anxiety disorder: a systematic review and network meta-analysis. Lancet. 2019;393(10173):768-777.

7. Hood SD, Odufowora-Sita O, Briere JB, et al. Systematic review and network meta-analysis of agomelatine for the treatment of generalized anxiety disorder in adult patients. Int Clin Psychopharmacol. 2025;40(2):62-74.