Phase 2b Randomized, Double-Blind, Placebo-Controlled Trial Evaluating Mebufotenin (GH001) Efficacy and Safety in Treatment-Resistant Depression Patients

The primary objective of this Phase 2b trial is to determine the **efficacy** of a single day individualized dosing regimen (IDR) of GH001 compared with placebo in improving depressive symptoms as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS) in patients with **treatment-resistant depression** (TRD) at the end of the 7-day double-blind (DB) Part 1. This is clinically relevant as it aims to address the unmet need for effective treatments in patients who do not respond to conventional antidepressant therapies.

Secondary objectives include:

• To determine the effect of a single day IDR of GH001 compared with placebo on depressive symptoms as assessed by MADRS, global disease severity as assessed by the Clinical Global Impression-Severity (CGI-S), anxiety as assessed by the Hamilton Anxiety Rating Scale (HAM-A), and quality of life as assessed by the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) in patients with TRD at the end of the 7-day DB Part 1.
• To determine the effect of GH001 IDR as needed on depressive symptoms as assessed by MADRS, global disease severity as assessed by CGI-S, anxiety as assessed by HAM-A, and quality of life as assessed by Q-LES-Q-SF in patients with TRD during the 6-month open-label extension (OLE) Part 2.

The clinical trial focuses on individuals diagnosed with **treatment-resistant depression (TRD)**, aiming to evaluate the efficacy of a single-day individualized dosing regimen of GH001 compared to a placebo. The study population includes both male and female participants, aged between 18 and 64 years, who meet the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) criteria for single-episode or recurrent major depressive disorder (MDD) without psychotic features. Participants are required to have a current major depressive episode (MDE) lasting no more than two years and must have shown nonresponse to at least two but no more than four oral antidepressant treatments during the current episode. The trial includes a vulnerable population, although specific lifestyle considerations such as diet or physical activity are not detailed. The sponsor has not provided information regarding the total number of participants involved in the study.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** Phase 2b study with an open-label extension. The primary objective is to evaluate the efficacy of a single-day individualized dosing regimen of **GH001** in improving depressive symptoms in patients with **treatment-resistant depression** (TRD), as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS) at the end of a 7-day double-blind period. The trial is expected to commence recruitment on May 24, 2023, and conclude by March 30, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including age between 18 and 64 years and a diagnosis of major depressive disorder (MDD) without psychotic features. The trial will include multiple follow-up visits to monitor safety and efficacy, with the primary endpoint being the mean change in MADRS from baseline to Day 7. The end-of-study visit will assess the overall outcomes and any adverse events.

The expected duration of participant involvement is approximately 6 weeks, with the possibility of early termination if significant adverse effects occur or if the participant withdraws consent. The trial will utilize **Mebufotenin** in the form of an inhalation powder, administered using a vaporization device, with a maximum daily dose of 18 mg and a total dose not exceeding 108 mg over the treatment period. The study is not classified as a low-intervention trial and does not involve pediatric formulations or orphan drug status.

The clinical trial involves the administration of **Mebufotenin**, an experimental medication formulated as an **inhalation powder**. The active substance, also known as **5-MeO-DMT** or **5-methoxy-N,N-dimethyltryptamine**, is of chemical origin. The pharmaceutical form is designed for **inhalation use**. The trial includes three different dosing regimens of Mebufotenin. The first regimen involves a maximum daily dose of 12 mg, with a total maximum dose of 72 mg over a treatment period of 6 days. The second regimen allows for a maximum daily dose of 6 mg, with a total maximum dose of 36 mg over the same period. The third regimen permits a maximum daily dose of 18 mg, with a total maximum dose of 108 mg, also over 6 days. The administration of the inhalation powder is facilitated by the **Volcano Medic 2**, a vaporization device that has received CE marking, ensuring compliance with European safety standards.

In addition to the experimental treatment, the study employs a **placebo** as a comparator to evaluate the efficacy of Mebufotenin. The placebo is administered in a similar manner to the active treatment, ensuring blinding and maintaining the integrity of the trial design. The placebo is also delivered using the Volcano Medic 2 device, ensuring consistency in the method of administration across all study arms.

Participant compliance with the dosing schedule is monitored throughout the trial. The study design includes a double-blind phase, followed by an open-label extension, allowing for comprehensive assessment of both the safety and efficacy of the treatment in patients with treatment-resistant depression. The trial aims to determine the efficacy of a single-day individualized dosing regimen of GH001, the sponsor product code for Mebufotenin, in improving depressive symptoms as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS).

The efficacy of the investigational product **Mebufotenin** will be assessed in a randomized, double-blind, placebo-controlled, Phase 2b clinical trial with an open-label extension. The primary objective is to evaluate the efficacy of a single-day individualized dosing regimen of GH001 compared to placebo in improving depressive symptoms in patients with treatment-resistant depression. Efficacy will be measured using the Montgomery-Åsberg Depression Rating Scale (MADRS), a validated scale for assessing depressive symptoms. The primary endpoint is the mean change in MADRS score from baseline to Day 7 of the double-blind part of the trial.

Data collection will occur at specified timepoints, with the primary assessment at the end of the 7-day double-blind period. The trial will utilize the Volcano Medic 2 vaporization device for the administration of the inhalation powder form of **Mebufotenin**. The trial is designed to ensure rigorous evaluation of the treatment's impact on depressive symptoms, with the MADRS serving as the primary tool for efficacy assessment. The trial is expected to conclude by March 2025, with recruitment having commenced in May 2023.