The Effect of Food on the Oral Bioavailability of AEF0117 in Healthy Volunteers

Study Overview
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Brief Summary
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Cannabis use is increasing and will only further escalate with legalization of recreational and medical cannabis use in western countries , with a prevalence greater than 30 % in the US and most European countries for individuals between 16 and 24 years of age. There are no available pharmacological treatments of cannabis use disorder (CUD). Thus, the development of safe and effective medications for the treatment of CUD is an urgent public health priority. The preclinical efficacy and available ADMET (Administration, Distribution, Metabolism, Elimination and Toxicology) in animal and human data suggest that AEF0117, an investigational new study drug, could constitute a very efficacious and safe treatment for cannabis abuse disorders. In the 3 early studies conducted with AEF0117, AEF0117 was administered orally after a light breakfast. AEF0117 showed a good bioavailability and favorable, dose-proportional pharmacokinetics . In this protocol, the effects of food on AEF0117 bioavailability in healthy volunteers will be investigated by comparing the rate and extent of AEF0117 when 1 mg AEF0117 is administered in fed state versus fasting state. The safety and tolerability of AE0117 has been demonstrated in the clinical studies conducted to date. This trial will provide data on the effect of food on the oral bioavailability of AEF0117 to support the next stage of the clinical development of the drug.

Detailed Description
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Cannabis is the most widely used illicit drug with approximately 28 million individuals reporting past-month use, and 14% of those receiving substance use disorder treatment in the US reporting cannabis as their primary drug of abuse. While psychotherapeutic approaches have some utility for treating Cannabis Use Disorder (CUD), the vast majority of patients have difficulty significantly reducing their use or achieving abstinence. Safe and effective medications to treat CUD are urgently needed. The overall goal of this clinical trial is to contribute to advancing a safe and effective pharmacotherapy for CUD along the FDA approval pipeline. When the CB1 receptors are over-activated by very high doses of THC, quite higher than the doses of THC used by cannabis abusers, the concentration of the steroid hormone pregnenolone increases in the brain. Pregnenolone then binds to a specific site on the CB1 receptors, distinct for the one of CB1 agonists and THC, and acts as an endogenous signaling specific inhibitor of the CB1 receptors. Pregnenolone cannot be used as a pharmacological treatment because it is poorly bioavailable, has a very short half-life and is converted downstream to active steroids. Aelis Farma, in collaboration with researchers from the Institut National de la Santé et de la Recherche Médicale (INSERM), has developed a new pharmacological class, the synthetic signaling specific inhibitor of the CB1 receptor (sCB1-SSi) AEF0117, by modifying pregnenolone's chemical structure to prevent conversion to active steroids, and to increase absorption and biological stability while maintaining THC antagonism. To date, 3 clinical studies have been completed with AEF0117 including 2 phase 1 studies in healthy volunteers (AEF0117-101 single ascending dose study and AEF0117 102, multiple ascending dose study), and a phase 2a trial in cannabis users (AEF0117 201). The phase 1 studies showed good safety and tolerability of AEF0117 in the dose range tested (0.2 mg as single dose and 0.6-6 mg/day as single and multiple doses) and the phase 2a trial found that the 1 mg/day dose of AEF0117 significantly reduced both the abuse-related subjective effects of cannabis and its self-administration, while the 0.06 mg dose did not. Importantly, AEF0117 was well tolerated in daily cannabis smokers, with no evidence of precipitated withdrawal, physical, or psychological discomfort. There were no SAEs and a limited number of TEAEs. These results confirm preclinical data showing that AEF0117 does not function as an orthosteric antagonist and does not produce any of the adverse effects associated with rimonabant. Thus, AEF0117 is to our knowledge the first medication to safely and robustly attenuate the positive subjective and reinforcing effects of cannabis in participants with CUD. In the 3 early studies conducted with AEF0117, AEF0117 was administered orally after a light breakfast. AEF0117 showed a good bioavailability and favorable, dose-proportional pharmacokinetics . In this protocol, the effects of food on AEF0117 bioavailability in healthy volunteers will be investigated by comparing the rate and extent of AEF0117 when 1 mg AEF0117 is administered in fed state versus fasting state. The safety and tolerability of AE0117 has been demonstrated in the clinical studies conducted to date. This trial will provide data on the effect of food on the oral bioavailability of AEF0117 to support the next stage of the clinical development of the drug.

Official Title
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The Effect of Food on the Oral Bioavailability of AEF0117 in Healthy Volunteers

Conditions
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Marijuana Abuse

Intervention / Treatment
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* Drug: 3ß-(4-methoxybenzyloxy)pregn-5-en-20-one in fed condition
* Drug: 3ß-(4-methoxybenzyloxy)pregn-5-en-20-one in fasting condition


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy, non-smoking male or female of any race, 18 to 55 years old, both inclusive. Both males and female participants must use highly effective contraception during the entire trial period. Male participants should refrain from donating sperm or planning a pregnancy throughout the trial. Male participants must agree to use double-barrier contraceptive methods: male condoms and spermicide. FHeterosexually active females are only eligible if they are documented to be surgically sterile (e.g., hysterectomy, tubal ligation) or post-menopausal (amenorrhea >1 year and follicle-stimulating hormone [FSH] >25.8 mIU/mL) and with a negative pregnancy test. Body mass index (BMI) of 22.0-35.0 kg/m2 (inclusive). Be informed of the nature of the trial and provide signed informed consent to participate in the trial prior to any trial-specific procedures. After being shown the high fat meal, understands and accepts that the entire meal should be consumed within 30 minutes. Be legally competent and able to communicate effectively (in English) with trial personnel. Exclusion Criteria: Tobacco cigarette smokers within the last 3 months prior to dosing with trial drug. Any disease or condition that might compromise the cardiovascular, hematologic, renal, hepatic, pulmonary (including chronic asthma), endocrine (e.g., diabetes), central nervous, or gastrointestinal (including an ulcer and cholecystectomy) systems, or any clinical laboratory values assessed as potentially clinically significant by the investigator . Blood pressure outside normal range (140/80 mmHg systolic/diastolic) and considered potentially clinically significant. Congenital long QT syndrome, history of prolonged QT in the 3 months prior to screening. A corrected QT interval (Fridericia's - QTcF) >450 msec (male) or >470 msec (female) or history of risk factors for Torsades de Pointes. A history of alcoholism or drug addiction within the past 2 years, recent use (in the last month) of any illicit drugs, or positive results from a urine screen for substances of abuse or from an alcohol breath test. A history of or current serious mental illness including active or recent suicidal ideation, severe psychological distress (e.g., active suicidal plans, psychosis, debilitating panic disorder) and/or an abnormal Columbia-Suicide Severity Rating Scale (C-SSRS) result. Severe learning disability, brain damage, or pervasive developmental disorder. A history of difficulty donating blood or inadequate venous access. Clinically significant anemia or low hemoglobin (levels <9 g/dL) at screening, or donation of >250 mL of blood or plasma within the 30 days prior to prior to receiving trial drug or received any blood and plasma for medical/surgical reasons within the 30 days prior to prior to receiving trial drug, or intention to donate blood or plasma within 1 month after receiving trial drug. History of or current HIV or hepatitis B or C. History of COVID-19 within 4 weeks prior to Day -1, or positive COVID 19 test, according to standard procedures at the site, at screening or Day 1. Positive serum pregnancy test (ß-hCG) at screening or positive urine pregnancy test at Day 1 confirmed by a serum pregnancy test result. Allergies to the trial drug and known allergies to pregnenolone or to corn and corn derivatives. Use of any prescription or over-the-counter drug therapy, including psychoactive and/or psychotropic medication, herbal, homeopathic, vitamins, minerals, and nutritional supplements, bodybuilding supplements unapproved by the sponsor, within 2 weeks prior to receiving the trial drug (for drugs with an elimination half-life greater than 10 days, this will be extended to 60 days). Use of a drug therapy, or diet or supplements (e.g., St. John's Wort) food and fruit juices (e.g., grapefruit juice) known to induce or inhibit hepatic drug metabolism within 30 days prior to receiving trial drug or during the trial. Legal status that would interfere with participation. Unable to follow the restrictions outlined in the protocol. Ingestion of an investigational drug or product, or participation in a drug trial within a period of 90 days prior to receiving trial drug.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a single center, randomized, parallel-group, 2-arm, open-label, single-dose trial in healthy male and female volunteers aged 18-55 years to obtain data on the effect of food on the oral bioavailability of AEF0117.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AEF0117 1.0 mg in fasted condition<br>16 participants receive 1 dose of AEF0117 1 mg in fasted condition | Drug: 3ß-(4-methoxybenzyloxy)pregn-5-en-20-one in fasting condition<br>* a single dose of 1 mg AEF0117 in fasting condition<br>|
| Experimental: AEF0117 1.0 mg once daily (QD) in fed condition<br>16 participants receive 1 dose of AEF0117 1 mg fed condition | Drug: 3ß-(4-methoxybenzyloxy)pregn-5-en-20-one in fed condition<br>* a single dose of 1 mg AEF0117 in fed condition<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bioavailibility of AEF0117 | Peak Plasma Concentration (Cmax) induced by a single dose of AEF0117 will be determined based on serial blood sample collections and plasma AEF0117 concentration after fed conditions relative to fasting conditions | up to 312 hours after dosing | 
| Bioavailibility of AEF0117 | Time to maximum plasma concentration (tmax) of a single dose of AEF0117 will be determined based on serial blood sample collections and plasma AEF0117 concentrationafter fed conditions relative to fasting conditions. | up to 312 hours after dosing | 
| Bioavailibility of AEF0117 | Time to last measurable plasma concentration (tlast) based on serial blood sample collections and plasma AEF0117 concentration after fed conditions relative to fasting conditions | up to 312 hours after dosing | 
| Bioavailibility of AEF0117 | Area under the plasma concentration versus time curve from time 0 (AUC0-t) based on serial blood sample collections and plasma AEF0117 concentration after fed conditions relative to fasting conditions. | up to 312 hours after dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC (area under curve) of AEF0117 | Area under the plasma concentration based on serial blood sample collections and plasma AEF0117 concentration after fed conditions relative to fasting conditions | up to 312 hours after dosing | 
| Lowest Peak Plasma (Cmin) of AEF0117 plasma exposure | Lowest Peak Plasma (Cmin) induced by a single dose of AEF0117 will be determined based on serial blood sample collections and plasma AEF0117 concentration after fed conditions relative to fasting conditions | up to 312 hours after dosing | 
| Terminal elimination half-life (t1/2) of AEF0117 | Terminal elimination half-life (t1/2) based on serial blood sample collections and plasma AEF0117 concentration after fed conditions relative to fasting conditions | up to 312 hours after dosing | 
| Incidence of Treatment-Emergent Adverse Events [safety and tolerability] | Collection of advserve events (AEs), blood pressure (BP), heart rate (RT) and electrocardiogramme (ECG) | up to 312 hours after dosing | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AEF0117, Cannabis-related Use Disorder, Cannabis subjective effects, Cannabis self-administration cannabis-induced analgesia, Cannabis-related cognitive disorder