331. Rapid antidepressant effects of inhaled GH001 in treatment-resistant depression: results from a phase 2b, double-blind, randomized controlled trial with 6-month follow-up

Abstract

Abstract Background Treatment-resistant depression (TRD) represents a particularly challenging form of major depressive disorder (MDD), defined by an inadequate response to at least two antidepressants given at adequate dose and duration within the current depressive episode. TRD affects nearly one-third of individuals with MDD and is consistently linked to greater psychiatric and medical comorbidity, increased rates of hospitalization, elevated suicide risk, and a significantly reduced quality of life compared to non-resistant depression. There are currently only two pharmacotherapies approved for TRD, highlighting the significant unmet need for fast-acting, effective, and safe treatments. Mebufotenin (5-methoxy-N,N-dimethyltryptamine [5-MeO-DMT]) is a highly potent naturally occurring psychoactive substance from the tryptamine class which acts as a non-selective serotonin (5-HT) agonist with the highest affinity for the 5-HT1A receptor subtype. Evidence from early-phase trials suggest that GH001, a synthetic form of mebufotenin for pulmonary inhalation, is well tolerated in healthy volunteers and patients with TRD, and may induce rapid improvements in depressive symptoms. Aims & Objectives This Phase 2b trial aimed to assess the efficacy and safety of GH001 in patients with TRD. Method This Phase 2b multicenter trial (NCT05800860) included a 7-day, randomized, double-blind, placebo-controlled phase (Part 1) where patients were randomized 1:1 to GH001 or placebo, and Part 2, a 6-month open-label extension (OLE) with up to five GH001 re-treatments based on Montgomery–Åsberg Depression Rating Scale (MADRS) scores and prior dose tolerability. All patients transitioned from Part 1 to Part 2 on Day 8. In both parts, GH001 (or placebo in Part 1) was given as an individualized dosing regimen (IDR) of up to three escalating doses (6, 12, and 18 mg) on a single day, with a 1-hour interval between doses. This trial was conducted under the supervision of qualified healthcare professionals, providing psychological support per standard-of-care, but without any planned psychotherapeutic intervention before, during, or after dosing. The primary endpoint was mean MADRS change from baseline to Day 8, assessed by an independent blinded rater. Results Eighty-one patients with TRD were enrolled in Part 1 (GH001, n=40; placebo, n=41). MADRS change from baseline to Day 8 was significantly greater with GH001 vs. placebo (least squares mean difference [SE], -15.5 [1.7]; P<0.0001; Cohen’s d=-2.0). Significant reductions were also achieved at 2 hours post-dose and on Day 2. Remission rates (MADRS ≤10) on Day 8 were 57.5% (GH001) vs. 0% (placebo; P<0.0001). Of the 63 completers in Part 2, 73% (n=46) were in remission at 6 months, after a mean of four treatments. Median duration of psychoactive effects was 11 minutes. GH001 was well tolerated and most adverse events were mild or moderate, with no treatment-related serious adverse events (SAE). There was one unrelated SAE reported in the OLE (migraine). At 99% of treatment visits, patients were discharge-ready at 1-hour post-dose. Discussion & Conclusions GH001 was well tolerated and showed rapid, significant depressive symptom improvements in TRD. Data from the OLE indicate GH001 resulted in sustained remission over 6 months with infrequent treatments.