A First in Human Study of CMND-100 in Healthy and Alcohol Use Disorder (AUD) Subjects

This is a Phase I/II, four-parts study (Parts A to D) in HVs and subjects with AUD, evaluating the tolerability, safety, and pharmacokinetics/ pharmacodynamics (PK/PD) of single and repeated doses of CMND-100. Parts A and B are open-label, non-controlled parts, in which HVs and subjects with AUD respectively will be treated with single, ascending dose cohorts of CMND-100, for evaluation of tolerability, safety and PK/PD. Parts C and D are randomized, double-blind, placebo-controlled part, in which HVs and subjects with AUD respectively will be treated with repeated doses of CMND-100, for evaluation of safety, PK/PD and preliminary efficacy. Below is a short description of each part of the study.

• Part A - Single dose (~ 24) HVs: At least four consecutive ascending dose cohorts (20 mg, 40, 80 and 160mg) will be included in this part of the study in accordance with a pre-defined dose escalating scheme (see Section 5.2). In each cohort, 6 HVs will receive a single dose of investigation medicine product (CMND-100) with the first cohort starting with the lowest dose of 20 mg. Once dosed, the subjects will be sampled for PK for 24 hours following dosing and will be monitored for drug effects with a physical examination at the end of 24 hours after dosing and daily monitored for safety for a period of 1 week following dosing. Assuming no serious adverse reactions (as defined in Section 11.1) or limiting toxicity (grade 2 and higher) in up to 2 subjects, as defined in Section 5.2) are observed in this dose level, then the next 6 subjects are treated with the next escalated dose, in accordance with a pre-defined dose escalating scheme. The information gathered in this part of the study will be reviewed by the DSMB and guide the doses to be studied in Parts B, C and D of this study.
• Part B - Single dose (~12) subjects with AUD: Once Part A has been completed and data analyzed and approved by the DSMB, Part B will be initiated and will consist of enrolling subjects with AUD in at least 2 consecutive ascending single dose cohorts using the highest tolerable doses found in Part A. The first cohort will start with the lower ascending dose. Six subjects will be dosed and sampled for PK for 24 hours following dosing and will be monitored for drug effects with a physical examination at the end of 24 hours after dosing and daily monitored for safety for a period of 1 week following dosing. Assuming no serious adverse reactions (as defined in Section 11.1) or limiting toxicity (grade 2 and higher in up to 2 subjects, as defined in Section 5.2) are observed in this dose level, then the next 6 subjects are treated with the next escalated dose. For any grade 2 or higher toxicity in more of two subjects refer to Section 5.2. At the end of this part, real time PK data from the dose cohorts will be collected and analyzed and this information together with the safety information gathered in this part of the study and the data observed in Part A will be reviewed by the DSMB and will guide the dose to be studied in Part D of this study.
• Part C - Multiple dose (18) HVs: Once Part A has been completed, the data analyzed and approved by the DSMB, Part C will be initiated. This part will consist of a repeated-dose cohort based on the higher tolerable dose found in Part A. HVs will be randomized into either the treatment or the placebo arm at a ratio of 2:1 (12 subjects treated with the investigation product and 6 subjects receiving placebo) and will receive the drug/placebo at a daily basis for a total of 5 consecutive days. Each subject will be sampled for PK for 24 hours after first and last dosing and will be daily monitored for drug effects and safety throughout the study period and until 1 week after the last dosing. Real time PK data will be collected, and results analyzed (as defined in Section 5.2). The PK and safety information gathered from in this part of the study will be evaluated by the DSMB and will guide the dose to be studied in Part D of this study.
• Part D - Multiple dose (18) subjects with AUD: Once Part B and Part C has been completed, the data analyzed and approved by the DSMB, Part D will be initiated. This part will consist of a repeated-dose cohort, based on the higher tolerable dose found in Part C and considering the dose effects found in Part B. Subjects will be randomized into either the treatment or the placebo arm at a ratio of 2:1 (12 subjects treated with the investigation product and 6 subjects receiving placebo) and will receive the drug/placebo at a daily basis for a total of 5 consecutive days. Each subject will be sampled for PK for 24 hours after first and last dosing and will be daily monitored for drug effects and safety throughout the study period and until 1 week after the last dosing. The PK and safety information gathered from in this part of the study will be evaluated by the DSMB.

Inclusion criteria

All Subjects

• Signed informed consent prior to any study-related procedures,
• Subjects understand the nature and the procedures related with the study design of the trial and accept to fulfill all activities related to this trial,
• Subjects 18 to 60 years of age,
• Body mass index between 18 and 35 kg/m2, with a weight above 60 kg.
• No (history of) clinically significant conditions and/or concomitant medications which in the opinion of the investigator could endanger the safety of the subject or impact the validity of the study results,
• Male subjects who wish use condoms for the duration of the study and for a suitable time period after the last drug dose (e.g., 5 half-lives),
• Female subjects who are not pregnant or breast-feeding or who do not wish to become pregnant during the period of the clinical study and for three months later,
• Female subjects of childbearing potential (less than 24 months after the last menstrual cycle) who use adequate contraceptive methods. Adequate contraceptive methods may include any approved method of birth control such as combined estrogen and progestogen containing hormonal contraception, associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intra-uterine devices, condoms, abstinence or vasectomized partner. Contraception should be maintained until study end.

Additional Criteria for AUD Subjects

Treatment seeking subjects with AUD meeting DSM-5 criteria as assessed by SCID by qualified medical staff and:

• Consumed at least 4 binge drinking days (i.e. ≥ 5 standard drinks in a day for men or ≥ 4 standard drinks in a day for women) in the month prior to screening.
• A desire to reduce or stop drinking.
• Stable housing in the 3 months prior to screening with no foreseeable risk to lose this in the 3 months after screening,
• Agree to abstain from new/additional psychotropic medications, except for benzodiazepines as rescue medication prescribed by the PI or a stable dose of psychotropic medications in the 14 days (or 5 half-lives; whichever is longer) prior to enrollment/randomization with the intention to continue this medication during the study.

Exclusion criteria

All Subjects

• The subject has a clinically significant history of a disease or a disorder that could interfere with the interpretation of the results or could increase the risk to the subject all according to the opinion of the PI,
• Subject has a substance use disorder at time of screening (except for alcohol use in AUD subjects and nicotine use disorders),
• Subjects with cannabis or other drug use for at least 5 half-lives prior to screening, including nicotine use (i.e., subjects must abstain from nicotine use for at least five half-lives prior to screening).
• Subjects with symptoms of alcohol withdrawal or intoxication at time of screening (assessed using CIWA-Ar tool). if medically appropriate, intoxicated individuals will be provided transportation home while those experiencing alcohol withdrawal will be referred to an appropriate level of care.
• Subjects with history of seizures or epilepsy,
• Current or past history of Major Depressive Disorder (MDD) (within past 1 years), Bipolar Disorder, Schizophrenia, suicidal ideation (within past 2 years) or suicide attempts in the past 2 years,
• Uncontrolled inter-current illness (i.e., active infection),
• Clinically significant abnormal vital signs (e.g., systolic blood pressure ≥139 mmHg, diastolic blood pressure ≥90 mmHg, heart rate >90 beats per minute) at separate three measures before dosing,
• Clinically significant abnormal ECG parameters, including subjects with QTc greater than 450 msec.
• Clinically significant abnormal liver functions (ALT and AST), higher than three times the upper normal amount, clinically significant abnormal Hb, and/or clinically significant laboratory abnormalities (e.g., abnormal renal function, electrolyte derangements, etc.)
• Subjects who take, or are planning to take, any prescription or non-prescription medications, within at least 14 days (or 5 half-lives; whichever is longer) prior to enrollment/randomization, and for the entire duration of the study including: antipsychotic and mood stabilizing medications (including SSRIs such as Fluoxetine and Paroxetine, SNRIs and trazodone), OCT1 and OCT2 substrates (such as Metformin, Cisplatin, Imatinib, Procainamide, Citalopram, Cimetidine, Quinidine), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs) or lithium, serotonin-acting herbal medicines and supplements, dietary supplements (such as 5-hydroxy-trypthophan or St. John Wort), and enzyme altering agents (such as and/or grapefruit juice and/or rifampin, barbiturates, phenothiazines, cimetidine, etc.) or any other medications that may have significant interaction with the study medication,
• Received an experimental drug or used an experimental medical device within 1 month or within a period <5 times the drug's half-life for small molecules, or 3 months for biologics, whichever is longer, before the study drug is administered for the first time,
• Donated blood within 90 days or plasma within 30 days of study dosing,
• Any subject who may not be able to fulfill the study requirements per the investigator's clinical judgement.

Additional Criteria for Healthy Subjects

• Subject is unable to abstain from ingesting alcohol for 72 hours prior to dosing.