Gilgamesh Pharmaceuticals Announces Positive Topline Phase 2a Results for GM-2505 in Major Depressive Disorder (MDD)

GM-2505, a novel 5-HT2A receptor agonist and 5-HT releaser, demonstrated rapid, robust, and durable antidepressant effect in MDD

• Demonstrated robust antidepressant effect with a -21.6 point change from baseline in MADRS total score at Day 14, a 9.6 point greater reduction than a low-dose psychoactive comparator
• Rapid antidepressant effect observed at 24 hours, with a -18.5 point change from baseline in MADRS
• Durable efficacy with a -28.0 point change from baseline in MADRS at Day 29 and sustained efficacy to Day 74 without further treatment
• MADRS remission rate of 70% at Day 14 and 94% at Day 29
• GM-2505 was safe and well tolerated with most side effects self-resolving within two hours of dosing
• Data to be presented at the American Society of Clinical Psychopharmacology Annual Meeting in Scottsdale, Arizona, May 27 – May 29, 2025

NEW YORK, May 27, 2025 /PRNewswire/ -- Gilgamesh Pharmaceuticals, a clinical-stage neuroscience company developing innovative, best-in-class new chemical entities (NCEs) that transform the treatment paradigm for psychiatric diseases, today announced Phase 2a results for GM-2505, a novel, rapid-acting 5-HT2A receptor agonist and 5-HT releaser in development for the treatment of patients with moderate-to-severe MDD.

The Phase 2a trial was a randomized, double-blind study evaluating the efficacy, safety, and durability of GM-2505 in MDD patients (n=40). Patients were randomized to receive either 10 mg GM-2505 or a low-dose psychoactive comparator of 1 mg GM-2505 via intravenous (IV) infusion on Day 1. All patients were then administered a second dose of 15 mg GM-2505 on Day 15.

GM-2505 demonstrated a clinically impactful and statistically significant reduction in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score as compared to the low-dose psychoactive comparator. In the MMRM analysis, on Day 14, a single 10 mg dose resulted in a -21.6 point change from baseline in MADRS score compared to a -12.1 point change from baseline for the 1 mg low dose (p=0.003), for an estimated effect size of 1.0. On Day 14, 70% of patients receiving 10 mg achieved MADRS remission, defined as a total score of ≤10. On Day 29, following a 15 mg dose, the high dose group (10 mg + 15 mg) demonstrated a -28.0 point change from baseline, with 94% of patients achieving remission. A rapid antidepressant effect was observed within 24 hours, with a -18.5 point change from baseline. A durable MADRS reduction was observed out to Day 74 without any additional treatment.

^{Change from baseline values reported are least squares mean estimates from MMRM analysis
Remission is defined as MADRS total score ≤10}

GM-2505 was well tolerated with no serious adverse events. The majority of adverse events were mild and typically resolved within two hours following administration.

"The clinical response and remission rates highlight the potential for GM-2505 to be a groundbreaking therapy for patients with MDD. These compelling results are the culmination of five years of research focused on designing and developing truly novel and optimized treatments." said Jonathan Sporn, MD, Founder and CEO of Gilgamesh Pharmaceuticals. "GM-2505's rapid and sustained antidepressant effect fits seamlessly into the existing two-hour in-clinic treatment model."

"The data from this Phase 2a trial are impressive, in particular the large and sustained remission rates. The robust effect size is compelling given the use of a truly psychoactive comparator in this study. Given the modest efficacy of standard antidepressants, it is exciting to see the clinical results of a novel agent targeting the 5-HT2A receptor," said Maurizio Fava, MD, Chair of the Mass General Brigham Academic Medical Centers Psychiatry Department, Harvard Medical School.

"The magnitude of symptom improvement observed through the MADRS score reductions is truly impressive. The treatment fits nicely in the two-hour in-clinic framework established by esketamine, but with the potential for significantly fewer annual visits. The use of a psychoactive control dose helps to manage the confound of functional unblinding, which is an issue with this class of investigational medicines," said Gerard Sanacora, MD, PhD, Professor of Psychiatry at Yale University and the Director of the Yale Depression Research Program.

Gerard Marek, MD, PhD, the Chief Medical Officer of Gilgamesh Pharmaceuticals, will deliver an oral presentation of the results during the American Society of Clinical Psychopharmacology's annual meeting in Scottsdale, Arizona:

• Robust antidepressant efficacy of the novel 5-HT2A receptor agonist GM-2505 in a double-blind, randomized, controlled Phase 2a trial in patients with MDD
  • Oral Presentation: Tue, May 27, 2025 at 2:30PM MST
  • Poster Presentation: Time: Wed, May 28 from 11:15AM – 1PM MST; Thu, May 29, 2025 from 11:30AM – 1PM MST

About GM-2505: GM-2505 is a novel, best-in-class 5-HT2A receptor agonist designed to provide rapid, robust, and durable antidepressant effects within a short, in-clinic treatment session. It is administered via IV infusion, with an intramuscular formulation planned for future studies. In addition to its primary receptor target, GM-2505 exhibits activity as a 5-HT releaser, which may enhance serotonergic activity and contribute to its therapeutic benefits. GM-2505 is an NCE with issued composition of matter IP.

About Major Depressive Disorder: More than 20 million people in the U.S. suffer from MDD. Up to two-thirds of patients do not achieve remission after multiple antidepressants, each of which can take weeks to show efficacy and often cause significant side effects including weight gain, sexual dysfunction, and flattened affect. There is an urgent need for rapid-acting, durable, effective, and well-tolerated treatments.

About Gilgamesh Pharmaceuticals: Gilgamesh Pharmaceuticals is a clinical-stage neuroscience biotech developing innovative, best-in-class new chemical entities that transform the treatment paradigm of psychiatric diseases, moving away from symptom management towards rapid-acting and durable therapies. The company designs therapies acting through precedented mechanisms, which are optimized for safety, efficacy, and patient access. Gilgamesh is advancing a diverse portfolio of programs, including two lead clinical programs: GM-2505, which will be moving into late-stage development, and GM-1020 (oral NMDAR antagonist), which is completing a Phase 2a study in Major Depressive Disorder in 2025. Learn more about the company's therapeutic pipeline at https://www.gilgameshpharmaceutical.com/.

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SOURCE Gilgamesh Pharmaceuticals