335. Safety and tolerability results from a phase 2b, double-blind trial with an open-label extension of GH001 in treatment-resistant depression

Abstract Background Treatment-resistant depression (TRD) is a chronic condition affecting approximately 30% of patients with major depressive disorder, posing a significant unmet need for safe and effective treatments. GH001, an inhaled formulation of mebufotenin (5-MeO-DMT), has shown good tolerability and safety in early stage clinical trials in healthy volunteers and patients with TRD. Aims & Objectives This trial evaluated the safety and tolerability of GH001 in patients with TRD in a double-blind, placebo-controlled setting with a 6-month open-label extension (OLE).

Method: This was a two-part, Phase 2b multicenter trial (NCT05800860) assessing the safety and efficacy of GH001 in patients with TRD. In Part 1, a 7-day, double-blind, placebo-controlled part, patients were randomized 1:1 to GH001 or placebo. Patients received an individualized dosing regimen (IDR) of up to three escalating doses of GH001 (6, 12, and 18 mg) or three doses of placebo on a single day with a 1-hour interval between doses. Administration of subsequent doses in the IDR was based on patients’ subjectively reported psychoactive effects and safety and tolerability of previous dose(s). In Part 2 (a 6-month OLE with up to five GH001 IDR re-treatments) patients were assessed for re-treatment based on Montgomery-Åsberg Depression Rating Scale score and safety and tolerability of previous dose(s). 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. Safety assessments included treatment-emergent adverse events (TEAEs), vital signs, electrocardiogram (ECG), physical examinations, laboratory assessments, spirometry, and other safety assessment tools.

Results: A total of 81 patients with TRD were enrolled and randomized in Part 1 (GH001, n=40; placebo, n=41). In Part 1, TEAEs were observed in 29/40 (72.5%) patients receiving a GH001 and 3/41 (7.3%) patients receiving placebo. There were no serious TEAEs reported in either group and no TEAE resulted in study drug withdrawal or early withdrawal. All patients completed Part 1 and automatically transitioned to Part 2, of which 63 completed after receiving a mean of four treatments over 6 months. In Part 2, TEAEs were observed in 72/81 (88.9%) of patients and most were mild (72.1%) or moderate (27.5%). One mild TEAE of asthma resulted in early withdrawal from Part 2. There were no treatment-related serious AEs during the 6-month duration of the trial. The most commonly reported TEAEs in Part 2 were nausea (45.7%), paraesthesia (38.3%), and salivary hypersecretion (29.6%). There were no TEAEs of suicidal intent or behavior reported throughout the 6-month duration of the trial. In both Part 1 and Part 2, patients were deemed discharge ready at 1 hour post-dose at 99% of treatment visits. Discussion & Conclusions GH001 administered as an IDR with up to five re-treatments over 6 months was well tolerated in patients with TRD. There were no new safety or tolerability concerns in the 6-month OLE. The overall safety and tolerability profile remained consistent with previously reported trials investigating GH001, supporting its potential as a new treatment option for TRD without compromising patient safety.