PureTech’s Seaport Therapeutics Doses First Patient in Phase 2a Trial of GlyphAgo for Generalized Anxiety Disorder
PureTech Health plc (LSE: PRTC) announced that its Founded Entity, Seaport Therapeutics (Nasdaq: SPTX), has dosed the first patient in a Phase 2a clinical trial evaluating GlyphAgo™ (SPT-320 or Glyph Agomelatine) in adults with generalized anxiety disorder (GAD) and sleep disturbance. The six-week study, being conducted in Australia, is designed to establish proof-of-pharmacology by assessing the effects of GlyphAgo on sleep and anxiety-related symptoms.
The clinical program represents an important development for Seaport’s effort to advance novel neuropsychiatric medicines using its Glyph™ platform. GlyphAgo is an oral prodrug of agomelatine designed to address some of the pharmacokinetic and hepatic limitations associated with unmodified agomelatine. The company is evaluating whether the modified formulation can achieve therapeutically relevant exposure to agomelatine at substantially lower doses while reducing exposure to the liver.
Seaport expects to report topline results from the Phase 2a trial in early 2028. The company is also planning a larger global Phase 2/3 clinical trial in patients with generalized anxiety disorder, with initiation expected during the first half of 2027 and topline data anticipated by the end of 2028.
The development program is targeting a significant unmet need in neuropsychiatric medicine. Generalized anxiety disorder is a common condition characterized by persistent and excessive anxiety that can interfere with everyday activities, relationships, work and overall quality of life. Sleep disturbance is also frequently associated with GAD and can further contribute to the burden experienced by patients.
“Anxiety disorders affect more than 300 million people globally, and place a substantial burden on patients, families, and healthcare systems,” said Daphne Zohar, Co-Founder 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 two 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.”
Phase 2a Trial Targets Anxiety and Sleep Disturbance
The Phase 2a study is a six-week, double-blind clinical trial enrolling adults with GAD and co-morbid sleep disturbance. Participants are being randomized to receive one of two daily doses of GlyphAgo.
The trial is evaluating a 16 mg/day dose, corresponding to approximately 5 mg of agomelatine, or a 32 mg/day dose, corresponding to approximately 10 mg of agomelatine.
The primary objective of the study is to establish proof-of-pharmacology by evaluating the impact of GlyphAgo on sleep. This is an important component of the development program because sleep disruption is a frequent and clinically relevant feature of generalized anxiety disorder.
Patient-reported sleep outcomes will include the Insomnia Severity Index (ISI), a validated measure used to assess the severity of insomnia symptoms. The study will also incorporate electroencephalography (EEG)-based assessments of sleep architecture, providing an objective measure of changes in sleep patterns.
In addition to sleep-related endpoints, investigators will assess anxiety severity using the Hamilton Anxiety Scale (HAM-A). The trial will also evaluate overall illness severity using the Clinical Global Impression-Severity (CGI-S) scale.
Safety, tolerability and pharmacokinetic parameters will be assessed throughout the study to provide additional information about how GlyphAgo is absorbed and processed in patients.
The combination of subjective and objective sleep measures with established anxiety assessments is intended to provide a broad evaluation of the drug’s pharmacological effects.
GlyphAgo Builds on Agomelatine
GlyphAgo is designed as a novel oral prodrug of agomelatine, an established compound that acts as an MT1/MT2 melatonin receptor agonist and serotonin 2C (5-HT2C) receptor antagonist.
Agomelatine has previously demonstrated statistically significant separation from placebo in four third-party placebo-controlled studies evaluating its use in generalized anxiety disorder.
According to published meta-analyses based on indirect comparisons across placebo-controlled studies, agomelatine has also ranked favorably for efficacy and tolerability compared with benzodiazepines and selective serotonin-reuptake inhibitors (SSRIs), which are commonly used treatments for GAD.
Seaport’s development strategy is not based simply on introducing another formulation of agomelatine. Instead, the company is attempting to modify the drug’s delivery characteristics through its Glyph platform.
The objective is to address the pharmacokinetic limitations of unmodified agomelatine, particularly its extensive first-pass metabolism in the liver. By modifying how the active compound is absorbed, Seaport believes GlyphAgo may allow clinically relevant concentrations of agomelatine to be achieved using substantially lower doses.
Daniel Bonner, Ph.D., Co-Founder and Senior Vice President, Platform, at Seaport Therapeutics, said the sleep-related properties of agomelatine make it a compelling candidate for patients with GAD and sleep disturbance.
“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,” Bonner said. “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.”
Phase 1 Data Support Dose Selection
The doses selected for the Phase 2a study are supported by pharmacokinetic data generated in an earlier Phase 1 study.
According to Seaport, the Phase 1 findings demonstrated that GlyphAgo was capable of producing clinically relevant agomelatine exposure at substantially lower doses than the approved 25 mg dose of unmodified agomelatine.
In Australia, a 25 mg dose of agomelatine is approved for the treatment of GAD, while agomelatine is also approved for major depressive disorder in Australia and the European Union.
At GlyphAgo doses corresponding to approximately 5 mg and 10 mg of agomelatine, geometric mean agomelatine exposure, measured by AUC0-24, was at or above the exposure observed following administration of the approved 25 mg dose of unmodified agomelatine.
This finding provides an important pharmacokinetic rationale for the dose levels being investigated in the Phase 2a study. Rather than administering the same amount of active compound used in conventional agomelatine treatment, GlyphAgo is designed to improve delivery so that therapeutically relevant exposure can potentially be achieved with less drug.
The Phase 1 study also showed markedly lower variability between participants. The geometric coefficient of variation for agomelatine AUC0-24 was approximately 10-fold lower with GlyphAgo than with the 25 mg dose of unmodified agomelatine.
Reduced inter-subject variability could potentially provide more predictable drug exposure across patients, although this will need to be evaluated further in larger patient populations.
Glyph Platform Designed to Bypass First-Pass Metabolism
The technology underlying GlyphAgo is based on Seaport’s Glyph platform, which is designed to use the intestinal lymphatic system for absorption.
Conventional oral drugs can undergo significant first-pass metabolism in the liver after being absorbed from the gastrointestinal tract. For compounds such as agomelatine, this process can affect systemic exposure and contribute to pharmacokinetic limitations.
GlyphAgo is designed to alter this process by facilitating absorption through the intestinal lymphatic system. The intended result is to bypass a portion of first-pass hepatic metabolism and deliver therapeutically relevant levels of agomelatine using a substantially lower dose.
Seaport believes this mechanism could also reduce liver exposure to the active drug and potentially address concerns associated with liver enzyme elevations.
The company says this approach could potentially reduce the need for routine liver function monitoring that has historically limited the clinical use of agomelatine in some settings. However, whether GlyphAgo can provide this benefit in patients with GAD will require confirmation through ongoing clinical studies.
The Phase 2a trial is therefore an important next step because it moves the technology from pharmacokinetic evaluation in healthy volunteers into a patient population with the targeted disorder.
Positive Phase 1 Safety Findings
The Phase 1 trial enrolled healthy volunteers and evaluated GlyphAgo following once-daily administration.
Seaport reported that GlyphAgo demonstrated a statistically significant 6.8-fold increase in bioavailability compared with unmodified agomelatine. This exceeded the program’s pre-specified target of a two-fold increase in bioavailability.
After seven days of once-daily treatment, both the 16 mg and 32 mg doses of GlyphAgo achieved therapeutically relevant agomelatine exposure. The doses corresponded to approximately 5 mg and 10 mg of agomelatine, respectively.
The treatment was also reported to be well tolerated in the Phase 1 study. Seaport reported no serious or severe adverse events, no liver-related adverse events and no clinically significant changes in liver-related laboratory measures, including alanine aminotransferase (ALT), aspartate aminotransferase (AST) or bilirubin.
These findings provided an initial safety and pharmacokinetic foundation for advancing GlyphAgo into clinical testing in people with GAD.
However, results from healthy volunteers cannot establish whether the drug will be safe and effective in patients with generalized anxiety disorder. The Phase 2a study is intended to provide the next level of evidence by examining pharmacology, sleep outcomes, anxiety symptoms, safety and tolerability in the target population.
Addressing Unmet Need in Generalized Anxiety Disorder
GAD affects hundreds of millions of people globally and can have a substantial impact on daily functioning. Patients may experience persistent worry, difficulty concentrating, physical symptoms associated with anxiety and sleep disruption.
While existing medications can be effective for some patients, treatment response and tolerability can vary. Benzodiazepines, for example, can raise concerns related to sedation and other risks, while SSRIs may take time to produce therapeutic effects and can cause adverse effects that lead some patients to discontinue treatment.
Seaport is therefore seeking to develop a treatment that could address both anxiety and associated sleep disturbance while offering a potentially differentiated tolerability and pharmacokinetic profile.
The company’s focus on sleep is particularly relevant because sleep disturbance is frequently intertwined with anxiety disorders. Improving sleep could potentially provide an additional benefit for patients beyond reducing anxiety symptoms alone.
The Phase 2a trial will help determine whether the pharmacological characteristics observed in earlier studies translate into measurable changes in sleep and anxiety among people with GAD.
Planned Global Phase 2/3 Study
Beyond the current Phase 2a program, Seaport plans to advance GlyphAgo into a larger global Phase 2/3 clinical trial.
The randomized, double-blind, placebo-controlled study is expected to begin in the first half of 2027 and will evaluate the efficacy and safety of GlyphAgo in patients with generalized anxiety disorder.
Topline results from the global Phase 2/3 study are expected by the end of 2028.
The planned trial represents a significant expansion of the development program and is expected to provide broader clinical evidence regarding the efficacy and safety of GlyphAgo in the intended patient population.
Data from the ongoing Phase 2a trial are expected to help inform the broader development strategy before the Phase 2/3 program advances.
PureTech’s Hub-and-Spoke Development Model
The GlyphAgo program also illustrates PureTech Health’s hub-and-spoke model for developing biotherapeutic innovations.
PureTech describes itself as a biotherapeutics company focused on translating scientific discoveries into potential medicines and creating value through its Founded Entities. Seaport Therapeutics represents one of these Founded Entities and is focused on developing novel therapies for neuropsychiatric conditions.
Through Seaport, PureTech is advancing the Glyph platform and programs designed to address limitations associated with existing therapeutic molecules.
The development of GlyphAgo demonstrates how the platform can potentially be applied to an established pharmacological mechanism while modifying the way the active compound reaches systemic circulation.
For PureTech, progress in the GlyphAgo program adds another clinical development milestone to its portfolio of therapeutic programs and provides an opportunity to validate the platform in neuropsychiatric disease.
The initiation of the Phase 2a trial marks an important transition for GlyphAgo as Seaport moves from early pharmacokinetic and safety studies into clinical evaluation among patients with generalized anxiety disorder and sleep disturbance.
The study will assess whether GlyphAgo can produce measurable effects on sleep, while also examining anxiety symptoms, overall disease severity, pharmacokinetics and safety. Results are expected in early 2028.
Meanwhile, the planned global Phase 2/3 study is expected to begin in the first half of 2027, with topline results anticipated by the end of 2028.
If future clinical studies confirm the pharmacological, efficacy and safety findings observed to date, GlyphAgo could potentially offer a differentiated approach to treating GAD by combining the established biological activity of agomelatine with Seaport’s drug-delivery technology.
For now, the first patient dosing in the Phase 2a study represents a significant milestone in the program. The trial will provide the first opportunity to assess the effects of GlyphAgo directly in people with GAD and co-morbid sleep disturbance and will help determine whether the compound’s improved bioavailability and reduced hepatic exposure translate into meaningful clinical benefits.
With generalized anxiety disorder continuing to affect a large global population and treatment options remaining limited for some patients, Seaport is positioning GlyphAgo as a potential next-generation neuropsychiatric therapy. The coming clinical readouts will be important in determining whether the company’s Glyph platform can successfully transform the pharmacological profile of agomelatine into a more effective, predictable and potentially better-tolerated treatment option for patients with GAD.
About GlyphAgo™ (SPT-320 or Glyph Agomelatine)
GlyphAgo is a novel, “Glyphed” oral prodrug of agomelatine, a clinically validated anti-anxiety and antidepressant that is approved for the treatment of GAD in Australia and Major Depressive Disorder in Australia and the European Union. Using Seaport’s proprietary Glyph™ platform, GlyphAgo is designed to enhance lymphatic absorption and avoid first-pass liver metabolism, thereby enhancing oral bioavailability and reducing side effects.
By leveraging an alternative absorption pathway via the intestinal lymphatic system used by dietary fats, GlyphAgo is designed to increase systemic exposure of agomelatine, enabling exposure levels within the range observed to be effective in prior third-party placebo-controlled studies in GAD at a lower dose that is designed to reduce liver exposure. Based on the data generated to date, Seaport believes GlyphAgo has the potential to become a leading treatment for GAD.
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.