"A Study of a Deuterated Psilocin Analog (CYB003) in Humans With Major Depressive Disorder"

A Phase III, Placebo-Controlled, Randomized, Double-Blind Trial of Oral Doses of CYB003 to Assess Combined Safety and Efficacy in Humans With Major Depressive Disorder

The purpose of this study is to examine the efficacy, safety, and tolerability of CYB003 compared to matching placebo as adjunctive treatment in participants with MDD.

Inclusion Criteria:

Participants must meet all the following criteria to be included in the trial:

• Aged 18 to 85 years inclusive, at Screening
• Participant has a diagnosis of MDD (single or recurrent episode as defined by DSM-5 TR [if single episode, duration of ≥4 weeks and ≤24 months] and established as per evaluation by the Investigator. The first MDD episode must have occurred prior to age 60.
• Depression is of moderate to severe degree at Screening and Baseline, independently confirmed by additional clinical assessments
• Participant has been on a stable dose of a single antidepressant medication at an adequate dose (label specified) for an adequate duration in the last month prior to Screening and has had an inadequate response (less than 50% improvement), as judged by the Investigator.
• Participant has a body mass index (BMI) of 40 kg/m2 or less (BMI ≤ 40 kg/m2), inclusive, at Screening.
• Participant is able to refrain from nicotine use during the dosing session (up to 8 hours)
• Registered with a healthcare professional who can confirm the diagnosis and previous treatments received by the participant.
• Participants capable of producing sperm must use a condom plus spermicide during the trial and for 12 weeks after their final dose of trial medication, if their partner is a person of childbearing potential.
• Participants of childbearing potential who have a partner capable of producing sperm must agree to use a highly effective method of contraception (i.e., failure rate less than 1% when used consistently and correctly) in combination with the use of a condom plus spermicide during the trial and for 12 weeks after their final dose of trial medication. Such participants must have a negative pregnancy test at Screening and Day 1 prior to dosing.
• Female participants who were capable of producing eggs (ova) must agree that the only exclusion from the requirement for contraception during the trial is to be postmenopausal or permanently sterile following hysterectomy, bilateral salpingectomy, or bilateral oophorectomy. Postmenopausal is defined as spontaneous amenorrhea for at least 12 months, and a serum follicle-stimulating hormone level in the menopausal range, unless the participant is taking hormone replacement therapy or is using hormonal contraception.
• Participant has provided written informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form.

Exclusion Criteria:

Participants with any of the following characteristics/conditions will be excluded from trial participation:

• Current or previously diagnosed schizophrenia spectrum or other psychotic disorders, including schizophrenia, schizoaffective disorder, schizotypal disorder, schizophreniform disorder, brief psychotic disorder, current or previous history of bipolar disorder, or current borderline personality disorder.
• Participants with a medical diagnosis of attention deficit hyperactivity disorder (ADHD) will be excluded if currently taking medication for ADHD
• Family history of schizophrenia, schizoaffective disorder, or bipolar disorder type 1 (first degree relatives).
• Significant suicide risk within the past 6 months, during the Screening Period, or at Baseline; or (b) suicidal behaviors within 12 months of Screening; or (c) clinical assessment of significant suicidal risk during clinical interview; or (d) non-suicidal self-injury within 12 months of Screening.
• Current or previous diagnosis of treatment-resistant MDD, defined as failure to respond to 2 or more antidepressant treatments of 2 different classes given at an adequate dose (label specified) for an adequate duration as judged by the Investigator and clinical interview.
• Has had electroconvulsive treatment, transcranial magnetic stimulation, deep brain stimulation, or vagal nerve stimulation for any episode of MDD in the last 6 months.
• Currently receiving a monoamine oxidase inhibitor, tricyclic antidepressant, mirtazapine, trazodone, moclobemide, buspirone, ketamine or S-ketamine, or an antipsychotic or mood stabilizer for MDD. Note: if receiving these medications for another indication, they must be discontinued ≥ 14 days or 5 half-lives, whichever is longer, prior to Day 1.
• Participant report of (or if available in medical record) exposure to psilocin, or 5-HT2a receptor agonists, or any other psychedelics, such as ayahuasca, mescaline, lysergic acid diethylamide, peyote, or 3,4-methylenedioxymethamphetamine, more than 10 times over the participant's lifetime or any psychedelic use within 12 months prior to Screening.
• Participant report of (or if available in medical record) treatment with ketamine or S-ketamine use within 6 months prior to Screening.
• Clinically relevant history of abnormal physical health interfering with the trial as determined by medical history and physical examinations obtained during Screening as judged by the Investigator (including but not limited to, neurological, cardiovascular, respiratory, gastrointestinal [including dyspepsia or gastroesophageal reflux disease], hepatic, or renal disorder).
• Participants with renal insufficiency.
• Has hypothyroidism or hyperthyroidism, unless controlled on appropriate medication.
• Current diagnosis of uncontrolled hypertension or an arrhythmia, or clinically relevant abnormal results for heart rate or blood pressure
• History or clinical evidence of any disease and/or existence of any surgical or medical condition which might interfere with the absorption, distribution, metabolism, or excretion of the trial medication.
• Participant has a presence or relevant history of organic brain disorders (e.g., epilepsy, seizure, intracranial hypertension, intracranial bleed and aneurysmal disease, brain tumor or other medical conditions associated with seizures or convulsions).
• Known sensitivity to psilocin and/or any excipients present in the formulation.
• Participant is taking or has taken OTC doses of 5-HTP or St John's Wort within 14 days prior to trial medication administration.
• The participant has participated in a clinical trial and has received a medication or a new chemical entity within 12 weeks prior to dosing with the current trial medication. Participants who have completed observational or non-interventional studies will be allowed.
• Participants capable of producing sperm who will not abstain from sperm donation between first dosing and 12 weeks after final dosing.
• Participants of childbearing potential who are pregnant, breastfeeding, planning to conceive or unwilling to abstain from egg (ova) donation between first dosing and 12 weeks after final dosing.
• History of serotonin syndrome.
• Unwilling to consent to audio and video recording of psychological support and dosing sessions.
• Staff and family members of Cybin IRL Limited, investigator sites, contract research organization or other vendors.