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PureTech Health plc, a hub-and-spoke biotherapeutics company dedicated to giving life to science and transforming innovation into value, announced that its founded entity, Seaport Therapeutics (Seaport), a clinical-stage biopharmaceutical company that is advancing novel neuropsychiatric medicines with a proven strategy and team, announced that the first participant has been dosed in the phase 1 study of GlyphAgo (SPT-320 or Glyph Agomelatine).
GlyphAgo is being developed to treat generalized anxiety disorder (GAD), one of the most common mental health conditions worldwide. It is a “Glyphed” oral prodrug of agomelatine, a medicine that has already shown clinical benefit in multiple third-party studies of GAD, but whose use has been limited by liver-related side effects. Using Seaport’s proprietary Glyph platform, GlyphAgo is designed to improve how the drug is absorbed in the body so that people living with GAD may potentially achieve a therapeutic benefit at lower doses with reduced liver exposure.
The study marks the second therapeutic candidate from Seaport’s pipeline to advance into clinical-stage development.
GlyphAgo is an oral prodrug of agomelatine, a medicine with established clinical efficacy in four out of four previous third-party randomized, placebo-controlled studies in generalized anxiety disorder.
Building on agomelatine’s proven clinical efficacy, GlyphAgo is designed to overcome a key limitation of agomelatine by shifting absorption toward the intestinal lymphatics, avoiding first-pass liver metabolism, and increasing systemic exposure of the drug.
Phase 1 proof-of-concept study will evaluate the safety, tolerability, and pharmacokinetics of GlyphAgo and is designed to demonstrate therapeutic levels of agomelatine at lower doses that reduce liver exposure.
Agomelatine, a clinically validated melatonin receptor agonist and serotonin 2C receptor antagonist, is an effective anxiolytic and antidepressant approved for the treatment of GAD in Australia and major depressive disorder in Australia and the European Union. In generalized anxiety disorder, agomelatine has demonstrated statistically significant separation from placebo in four out of four third-party placebo-controlled studies and has better efficacy and tolerability – including reduced risk of abuse potential, sexual dysfunction, and weight gain – than standard of care drugs, like selective serotonin reuptake inhibitors (SSRIs) or benzodiazepines. However, over 90 per cent of unmodified agomelatine is lost to first-pass liver metabolism and its use has been limited by dose-dependent liver enzyme elevations and the need for frequent liver monitoring.
Using Seaport’s proprietary Glyph platform, GlyphAgo is designed to overcome this limitation by shifting absorption toward the intestinal lymphatics, avoiding first-pass liver metabolism, and increasing systemic exposure of agomelatine. As a result, GlyphAgo has the potential to achieve exposure levels that have demonstrated efficacy in generalized anxiety disorder. At a lower dose that does not cause an increase in liver enzymes and reduces or eliminates the need for liver function testing.
“Anxiety disorders are the most prevalent neuropsychiatric disorders, impacting nearly 30 per cent of adults at some point in their lives, with GAD alone affecting approximately 100 million adults worldwide. Despite this, in the US, no new drugs or mechanisms have been approved for generalized anxiety disorder in decades,” said Antony Loebel, Chief Medical Officer, President of Clinical Development at Seaport Therapeutics. “Our Phase 1 proof-of-concept study could be highly derisking for the GlyphAgo program, as agomelatine’s efficacy in generalized anxiety disorder 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 generalized anxiety disorder and represents an important clinical advancement for patients.”
The phase 1 study will be conducted in multiple parts to evaluate the safety, tolerability, and pharmacokinetics of GlyphAgo compared to agomelatine. It will include single- and multiple-ascending dose phases, as well as a food-effect crossover portion, using both open-label and placebo-controlled designs.
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