Novel 5-HT2A Agonist GM-2505 Achieves 94% Remission Rate in Phase 2a MDD Trial, With Rapid and Durable Efficacy

In a phase 2a trial of patients with moderate-to-severe major depressive disorder (MDD), the investigational compound GM-2505 demonstrated rapid, robust, and sustained antidepressant efficacy, achieving a remission rate of 94% after 29 days of treatment and -28.0 point reduction from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) score following 2 doses.¹

_{Courtesy of Gilgamesh Pharmaceuticals}

Antidepressant effect was observed in study participants treated with BM-2505 within 24 hours, according to a statement from BM-2505 developer Gilgamesh Pharmaceuticals, with a -18.5 point change from baseline in MADRS. The reduction in MADRS score was sustained to study day 74 without further treatment.¹

"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, Maurizio Fava, MD, chair of the Mass General Brigham Academic Medical Centers Psychiatry Department, Harvard Medical School, said in the statement. "Given the modest efficacy of standard antidepressants, it is exciting to see the clinical results of a novel agent targeting the 5-HT2A receptor."¹

GM-2505 is a selective 5-HT2A receptor agonist developed for rapid-onset antidepressant treatment delivered during short, supervised clinical sessions. The compound is administered intravenously, with an intramuscular formulation under development, Gilgamesh said. GM-2505 demonstrates dual mechanisms of action through 5-HT2A receptor agonism and serotonin release, potentially contributing to enhanced serotonergic signaling.

The phase 2a randomized, double-blind trial enrolled 40 participants with MDD to evaluate the safety and efficacy of GM-2505 administered via intravenous infusion. On day 1, participants received either 10 mg (active treatment) or 1 mg (active comparator) GM-2505. All participants received a second 15 mg dose on day 15. Change-from-baseline values represent least squares mean estimates from a mixed model for repeated measures (MMRM) analysis.¹

Among participants who received GM-2505, Gilgamesh reported a -21.6 point MADRS change from baseline by day 14 after a single 10 mg IV infusion, significantly outperforming a low-dose psychoactive comparator (1 mg) that produced a -12.1 point change (P= .003). As noted, the antidepressant effect emerged within 24 hours, with patients experiencing a -18.5 point MADRS reduction.

Following a second 15 mg dose on day 15 and assessed at day 29, the GM-2505 treatment arm achieved a -28.0 point MADRS reduction compared to -21.1 in the control group. The antidepressant response remained durable through day 74 without further dosing, with the high-dose group sustaining a -25.1 point MADRS reduction, according to the statement.

Remission, defined as a MADRS score of 10 or less, was reached by 70% of participants in the 10 mg group by day 14, and 94% by day 29 after the second dose. In contrast, the comparator group showed remission rates of 25% and 55% at the same time points, respectively.¹

GM-2505 was well tolerated, with no serious adverse events reported. Most side effects were mild and resolved within 2 hours of dosing, a safety profile that aligns well with the two-hour in-clinic treatment model already established by esketamine.²

"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," said Gerard Sanacora, MD, PhD, professor of psychiatry at Yale University and the director of the Yale Depression Research Program, observed in the Gilgamesh statement. 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."

GM-2505’s dual mechanism—agonism at the 5-HT2A receptor and serotonin release—differentiates it from existing antidepressants and psychedelic compounds, suggesting a novel pharmacodynamic profile that may drive both its rapid onset and durable effect.

Gilgamesh’s Chief Medical Officer, Gerard Marek, MD, PhD, will present the full dataset this week at the American Society of Clinical Psychopharmacology’s annual meeting in Scottsdale, Arizona.

With more than 20 million Americans affected by MDD—and the majority not achieving remission with first-line therapies—the findings raise the possibility that GM-2505 could become a transformative treatment option, pending further validation in larger trials.

References
1. GM-2505, a novel 5-HT2A receptor agonist and 5-HT releaser, demonstrated rapid, robust, and durable antidepressant effect in MDD. News release. Gilgamesh Pharmaceuticals. May 27, 2025. Accessed May 27, 2025. https://www.prnewswire.com/news-releases/gilgamesh-pharmaceuticals-announces-positive-topline-phase-2a-results-for-gm-2505-in-major-depressive-disorder-mdd-302465404.html
2. Halsey G. FDA approves esketamine as monotherapy for adults with treatment-resistant depression. Patient Care Online. January 21, 2025. https://www.patientcareonline.com/view/fda-approves-esketamine-as-monotherapy-for-adults-with-treatment-resistant-depression