GlyphAgo for Treatment of Anxiety Shows Positive Phase 1 Topline Results

GlyphAgo (SPT-320), a modified form of agomelatine, showed proof-of-concept in topline phase 1 results. The drug attained therapeutic levels of agomelatine at lower doses than unmodified agomelatine, reducing potentially harmful liver exposure and the need for liver testing.

“In GAD, agomelatine has demonstrated robust and statistically significant separation from placebo in 4 third-party placebo-controlled studies and has been observed in meta-analysis to have better efficacy and tolerability than selective serotonin-reuptake inhibitors or benzodiazepines,” said Steven Paul, MD, cofounder and board chair at Seaport Therapeutics, in a press release.² “Despite this positive profile, over 90 percent of unmodified agomelatine is lost to first-pass metabolism and its use has been limited by dose-dependent liver enzyme elevations. The enhanced pharmaceutical properties of GlyphAgo and resulting markedly reduced interindividual variability in systemic exposure to agomelatine support our clinical development of GlyphAgo in GAD,” he added.

The phase 1 trial is a multi-part study evaluating the safety, tolerability, and pharmacokinetics of GlyphAgo as well as compare it to agomelatine alone. The trial includes both single and multiple ascending-dose cohorts and a crossover portion. In the single-ascending dose portion, participants received a sngle administration of ascending doses of GlyphAgo or a 25 mg dose of agomelatine. These patients had no evidence of liver impairment and no other medications or supplements known to alter pharmacokinetics of agomelatine. The crossover portion randomized participants to 1 of 2 sequences intended to assess food effect on a single dose of GlyphAgo compared with a 25 mg dose of agomelatine.

The novel, modified form of GlyphAgo showed over a 2-fold increase in bioavailability of agomelatine, compared with unmodified agomelatine, in the proof-of-concept results. In the head-to-head crossover, GlyphAgo showed a 6.8-fold increase (90% CI: 4.7-10) in agomelatine bioavailability and a 10-fold lower (P < 0.0001) pharmacokinetic variability compared with unmodified agomelatine. The trial included some patients who were taking oral contraceptives containing estrogen, but GlyphAgo exposure was shown to be unaffected by the contraceptives; this result supports the ability of GlyphAgo to bypass first-pass liver metabolism. GlyphAgo showed a 9.6 to 14.5-fold increase in dose-normalized exposure compared with agomelatine in a single-ascending dose portion of the trial. The medication was well tolerated with no observed adverse events related to the liver.

GlyphAgo is a novel, glyphed oral prodrug of agomelatine currently being developed for treatment of generalized anxiety disorder. Agomelatine is an MT1/MT2 melatonin receptor agonist and 5-HT2C receptor agonist intended to function as an anxiolytic and antidepressant. This form of agomelatine is designed to improve lymphatic absorption and avoid first-pass liver metabolism, enhancing bioavailability and reducing adverse effects. Because of its alternative absorption pathway via the intestinal lymphatic system, the drug can increase systemic exposure of agomelatine at lower doses to reduce liver exposure and potentially eliminate the need for liver function testing.

Agomelatine is approved for treatment of anxiety in Australia, and approved for depression in Australia and the European Union. In both regions, the drug’s label requires liver function testing before and during treatment, as well as with increased doses. Agomelatine is not currently approved for any indication in the United States.

“These topline data, from a well-powered Phase 1 trial, strengthen our conviction in GlyphAgo’s potential and provide further clinical validation for the Glyph platform,” said Daphne Zohar, cofounder and chief executive officer at Seaport Therapeutics. “Based on these data, we plan to advance GlyphAgo into 2 parallel trials, a Phase 2a proof-of-pharmacology trial to evaluate the potential sleep benefit of GlyphAgo in patients with GAD, and a Phase 2b trial in GAD, that is a randomized placebo-controlled trial designed to be registration-enabling. We believe that GlyphAgo has the potential to bring patients with generalized anxiety disorder what could be the first new therapy in decades in the US for this underserved and debilitating disorder.”

The completed portion of the trial showed the pharmacokinetic proof-of-concept, and the ongoing multiple ascending dose portion is intended to further characterize the safety profile and pharmacokinetics of repeat dosing with GlyphAgo. Seaport Therapeutics, the developing company, announced plans to continue with a phase 2a proof-of-pharmacology trial evaluating potential sleep benefits, and a phase 2b trial intended to be registration-enabling.

References

1. PureTech founded entity Seaport Therapeutics announces positive proof of concept topline results from ongoing phase 1 trial of GlyphAgo in healthy volunteers. Press release. April 2, 2026. Accessed April 2, 2026. https://www.businesswire.com/news/home/20260401820161/en/PureTech-Founded-Entity-Seaport-Therapeutics-Announces-Positive-Proof-of-Concept-Topline-Results-from-Ongoing-Phase-1-Trial-of-GlyphAgo-in-Healthy-Volunteers

2. Stein DJ, Ahokas A, Márquez MS, et al. Agomelatine in generalized anxiety disorder: an active comparator and placebo-controlled study. J Clin Psychiatry. 2014;75(4):362-8.