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28/07/2023 - Press release

Nature Medicine Publishes Discovery of New Pharmacological Class by Aelis Farma, Phase 2a Study of First Drug Candidate for Cannabis Use Disorder

Aelis Farma, a clinical-stage biopharmaceutical company focused on developing treatments for brain diseases, announced publication of a series of studies describing a new pharmacological class, cannabinoid receptor 1 signaling-specific inhibitors (CB1-SSi), and its first drug candidate, AEF0117, for the treatment of cannabis use disorder (CUD).

The report, Signaling-specific inhibition of the CB1 receptor for cannabis use disorder: phase 1 and phase 2a randomized trials,?was published online by the journal Nature Medicine.

The study involves the participation of numerous international research centers, including the research group in Cell-type mechanisms in normal and pathological behavior?group of the Hospital del Mar Research Institute and the Neuropharmacology group of the Department of Medicine and Life Sciences (MELIS) of the Pompeu Fabra University.

AEF0117 is the first compound that selectively inhibits the CB1 receptor signaling pathway responsible for the addictive effects of cannabis, without interfering with the receptor's fundamental physiological and behavioral functions. This breakthrough approach differs from previous CB1 receptor antagonists that, due to their broad blockade of all CB1 receptor activity, caused significant adverse effects preventing their clinical use.

AEF0117, discovered and developed by Aelis Farma, is the first of the new pharmacologic class, CB1-SSi, which is based on a natural brain mechanism that combats CB1 receptor hyperactivity. This mechanism was discovered by the research group of Aelis Farma Chief Executive Officer Pier Vincenzo Piazza, MD, PhD, when he was the director of the Neurocentre Magendie of the French National Institute of Health and Medical Research (INSERM) in Bordeaux. This unique mechanism of action enables CB1-SSi to inhibit only the cellular signals involved in CUD - without disrupting the receptor's physiological activity. The CB1-SSi class and AEF0117 represent a breakthrough in CB1 pharmacology.

"This landmark article culminates more than a decade of research, from discovery of this natural brain mechanism to our proof-of-concept clinical trial", said Dr. Piazza. "We are delighted to contribute to the field of neuropharmacology with a class of drugs never tested in humans before. Now, we at Aelis are sponsoring a large, placebo-controlled phase 2b study in collaboration with Columbia University Irving Medical Center, enrolling 330 participants with CUD to evaluate three dose levels of AEF0117 in treating cannabis addiction. Results should be available by mid-2024."

Because of its unique mechanism of action, AEF0117 significantly reduced phase 2a study participants' self-reported ratings of the positive subjective effects of cannabis, the primary outcome measure, by a mean of 38% (p<0.04), while also reducing cannabis use as measured by self-administration (p<0.05), the key secondary endpoint. AEF0117 produced no treatment-related serious adverse events or treatment-emergent adverse events distinct from placebo. These reductions in cannabis effects occurred without precipitating cannabis withdrawal, even for volunteers who smoked several grams of cannabis per day.

"No other medication has been shown to safely reduce the direct effects of smoked cannabis in daily cannabis smokers," said Margaret (Meg) Haney, PhD, supervisor of the phase 1 studies and principal investigator of the 2a proof-of-concept study, and Professor of Neurobiology in the Department of Psychiatry at Columbia University Irving Medical Center, where she is the Director of the Cannabis Research Laboratory and Co-Director of the Substance Use Research Center. "These novel findings clearly suggest that AEF0117 may be an effective approach for patients seeking treatment for CUD."

According to Rafael Maldonado and Elena Martín-García, investigators at UPF who had participated in the study "in our group we have demonstrated the efficacy of the new compound AEF0117 in an animal model of cannabinoid addiction in mice, using sophisticated behavioral techniques. These positive results in the preclinical model have been significant to the decision to move forward AEF0117 along the development pipeline".

Dr Arnau Busquets-Garcia

Dr. Arnau Busquets-Garcia, lead investigator at?also contributed to the preclinical proof of concept AEF0117 by "providing among the first in vivo evidences in mice that this compound is able to block different behavioral deficits induced by cannabinoid drugs and in particular the ones related to the psychotic symptomatology that can be observed in cannabis users."

Aelis Farma thanks the volunteer study participants, Dr. Haney and her team at Columbia, the National Institute of Drug Abuse, and all the participating study centers and staff for their assistance.

About Cannabis Use Disorder

Cannabis use is widespread and often leads to CUD, the current definition of problematic cannabis use, which encompasses addiction. CUD affects about 14.2 million individuals in the U.S, and its prevalence is increasing worldwide. Currently, CUD is treated using evidence-based behavioral treatments, which often have poor adherence and limited success. No medications are approved by the FDA to treat CUD.

About AEF0117

AEF0117 is the first drug candidate of the new pharmacological class of CB1-SSi, a rationally designed analog of pregnenolone, the naturally occurring steroid hormone that binds to a specific site on the CB1 receptor. Pregnenolone and AEF0117 do not modify the binding of agonists to the CB1 but only block certain signaling pathways activated by cannabinoid agonists, such as THC, on the CB1. Through this selective mechanism of action, AEF0117 potently inhibits THC's behavioral effects without altering normal behavior. Unlike pregnenolone, AEF0117, is highly bioavailable when taken orally, exhibits favorable pharmacokinetic properties for once-daily administration, and is not converted into other steroids. AEF0117 has a 13,000-fold therapeutic index (i.e., the ratio between the toxic and active dose).

The clinical investigation of AEF0117 to date consists of two phase 1 safety studies (NCT03325595, NCT03443895) and one phase 2a proof-of-concept study (NCT03717272). The phase 1 single ascending dose and multiple ascending dose studies, performed in healthy volunteers, demonstrate that AEF0117 is safe, well tolerated and produces no behavioral changes relative to placebo. AEF0117 has favorable pharmacokinetic characteristics, allowing for once daily dosing, which facilitates medication compliance. The phase 2a study, conducted in 29 randomized participants with CUD who smoked cannabis daily (averaging 2-3 grams/day), demonstrated that AEF0117 significantly decreased both the positive subjective effects of cannabis (the main study endpoint) and the frequency of cannabis use (key secondary objective) without precipitating withdrawal, which has tended to limit the acceptability of inhibitors for addiction treatment.

The development of AEF0117 was made possible by a broad multinational collaboration with the Aelis Farma team. Several research groups of the Neurocentre Magendie of INSERM in Bordeaux contributed to the early preclinical development of AEF0117. The U.S. intramural program of the National Institute of Drug Abuse (NIDA) performed some of the preclinical experiments. Columbia University Irving Medical Center played a seminal role in the coordination and execution of the clinical studies. AEF0117 development has been supported by two NIDA grants, a first grant of $3.3 million and a second one of $4.5 million. AEF0117, is protected by a patent owned by INSERM and University of Bordeaux. Aelis Farma holds an exclusive worldwide license to AEF0117.

Development of AEF0117 as a treatment for cannabis addiction is currently ongoing. A phase 2b U.S. multi-center study, sponsored by Aelis Farma and coordinated by Professor Frances Levin of Columbia University, which will include 330 participants with CUD, is comparing the efficacy of three AEF0117 doses with placebo. Initial results are expected mid-2024. Aelis Farma and Columbia University are also conducting a complementary series of clinical pharmacokinetic studies and nonclinical regulatory studies to prepare AEF0117 for the Phase 3 program.

In summary, AEF0117 is the first drug candidate in the new pharmacological class of CB1-SSi, which exhibits high specificity, signaling selectivity, and affinity for the CB1 receptor at a distinct site from where cannabinoid agonists such as THC bind. Because of this selective molecular mechanism of action, AEF0117 potently inhibits the intoxicating effects produced by cannabis and reduces cannabis use without the behavioral side effects of the past generation of CB1 receptor antagonists that prevented their use in humans. This profile suggests that AEF0117 has the potential to be a safe and novel treatment for CUD, supporting continued confirmatory investigations in phase 2b and phase 3 clinical trials.

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