Long-Term Extension Study Evaluating Safety and Efficacy of Deupsilocin Besilate (CYB003) in Major Depressive Disorder Patients

The primary objective of this Phase III long-term extension trial is to assess the **durability of response** to the investigational product (IP), CYB003, following initial randomized, double-blind treatment in participants with **Major Depressive Disorder**. This objective is clinically relevant as it evaluates the sustained efficacy of the treatment, which is crucial for long-term management of the disorder.

Secondary objectives include:

• Assessing the proportion of participants who require either 2 or 3 additional doses of the investigational product during the EXTEND trial. This key secondary objective provides insights into the potential need for dose adjustments to maintain therapeutic effects.
• Further assessing the long-term efficacy of the investigational product, which is important for understanding the extended benefits and potential for sustained symptom relief in the target population.

The clinical trial involves a total of **391 participants** diagnosed with **Major Depressive Disorder**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, indicating a broad adult demographic. Participants were selected based on their successful completion of either the APPROACH or EMBRACE trial, having received both dose administrations of the trial medication. They are required to have maintained a stable dose of antidepressant medication throughout the previous 12-week trial period. The trial population includes individuals who are part of a vulnerable population, necessitating specific ethical considerations. Participants are expected to refrain from nicotine use during dosing sessions and adhere to stringent contraceptive measures if applicable. The trial does not confirm postmenopausal status with follicle-stimulating hormone levels, thus requiring continued adherence to contraception requirements. All participants have provided written informed consent, ensuring compliance with the trial's requirements and restrictions.

The clinical trial is a **Phase III** long-term extension study designed to assess the safety and long-term efficacy of the investigational product, CYB003, in participants with **Major Depressive Disorder**. The trial employs a randomized, double-blind, controlled design to evaluate the durability of response following initial treatment. The trial is expected to commence recruitment on August 22, 2025, and conclude by September 6, 2027, with a maximum treatment period of 43 days for each participant. Participants will be administered CYB003 in capsule form, with a maximum daily dose of 16 mg, taken orally.

The study includes several key visits: an inclusion (screening) visit, multiple follow-up visits, and an end-of-study visit. The inclusion visit will confirm eligibility based on criteria such as successful completion of prior trials (APPROACH or EMBRACE), stable antidepressant medication use, and agreement to maintain consistent psychotherapeutic relationships. Follow-up visits will monitor the participants' response to treatment, adherence to the protocol, and any adverse events. The end-of-study visit will assess the primary endpoint, which is the time to first relapse from baseline in participants with a stable response in previous trials.

Participant involvement is expected to last up to 43 days, with conditions for early termination including non-compliance with the study protocol, withdrawal of consent, or the occurrence of significant adverse events. Secondary endpoints include the percentage of participants requiring additional doses of the investigational product, sustained response and remission rates, and changes in the total score of the **Montgomery-Åsberg Depression Rating Scale (MADRS)**. The trial aims to provide comprehensive data on the long-term efficacy and safety of CYB003 in treating major depressive disorder.

The clinical trial involves the administration of the experimental medication **CYB003**, which contains the active substance **deupsilocin besilate**. This investigational product is provided in the form of a **capsule** and is intended for **oral** administration. The maximum daily dose of CYB003 is 16 mg, with the same amount being the maximum total dose permissible within a 24-hour period. The treatment period for participants is capped at 43 days. The medication is developed by CYBIN IRL LIMITED and is not classified as a pediatric formulation. The chemical origin of the active substance is confirmed, and the product is not designated as an orphan drug.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of CYB003 to evaluate its safety and long-term efficacy in participants diagnosed with **Major Depressive Disorder**. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen. Participants are required to follow the dosing instructions precisely to maintain the integrity of the trial data.

The efficacy of the investigational product, CYB003, in the treatment of **Major Depressive Disorder** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the time to first relapse from the baseline of the EXTEND trial in participants who have demonstrated a stable response in either the APPROACH or EMBRACE trial. Secondary endpoints include the percentage of participants who require additional doses of the investigational product, the percentage of participants with sustained response or remission, and changes in the total score of the Montgomery-Åsberg Depression Rating Scale (MADRS).

Participants' responses will be evaluated using the MADRS, a validated scale for assessing depression severity. The schedule for measuring these efficacy parameters includes assessments at baseline and at subsequent visits throughout the trial. The analysis will focus on the percentage of participants achieving sustained response or remission, defined by specific criteria related to MADRS scores, and the change in MADRS scores from baseline to the last visit for those who did not respond in previous trials. The trial aims to provide insights into the long-term efficacy of CYB003 in maintaining response and preventing relapse in individuals with Major Depressive Disorder.