Advancement of AEF0117 as a potential treatment for Cannabis Use Disorder: Preclinical toxicity and Clinical pharmacokinetic studies

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Project Summary: Cannabis use disorder (CUD) is a significant and escalating problem in the United States, and the development of an efficacious medication is a public health priority. The goal of this proposal is to conduct the complementary development and pharmacokinetic studies necessary to support Phase 3 trials of AEF0117, a novel medication developed by Aelis Farma specifically for the treatment of CUD.

In addition to highly positive preclinical and Phase 1 safety data, a recent human laboratory study showed that AEF0117 decreased cannabis self-administration and its abuse-related effects (‘good drug effect’) in daily cannabis smokers without producing physical discomfort or disrupting mood or sleep. AEF0117’s favorable pharmacokinetic and safety profile combined with the preclinical and human laboratory data make this compound a highly promising approach for the treatment of CUD.

Prior to large-scale clinical trials to test AEF0117 in patients with CUD, it is necessary to conduct non-clinical toxicology studies in parallel with safety and pharmacokinetic studies in human volunteers: (1) Non-Clinical AEF0117 Development (following FDA and ICH guidelines): Toxicity. We will conduct a 6-month rodent (rats) and 9-month non-rodent (dogs) oral toxicity studies including immunotoxicity evaluation.

The drug will be administered to animals at three doses that are multiples in excess of the anticipated human dose. Phototoxicity. Rats will receive three daily administrations of AEF0117 at three doses.

The highest dose will also be administered without UVR exposure. Reproductive toxicity. The toxicity of AEF0117 will be tested at three doses in non-pregnant female rabbits during a 7-day maximum-tolerated dose study.

A subsequent dose range-finding study will test three doses of AEF0117 in pregnant rats and rabbits, and embryo-fetal development will be tested in an additional set of pregnant females rats and rabbits. Clinical Studies: A single dose parallel group pharmacokinetic study in two parts will be conducted to investigate a) the effect of food on oral bioavailability of AEF0117 and 2) a potential pharmacokinetic interaction between smoked cannabis and oral administration of AEF0117.

Specifically, the pharmacokinetics of AEF0117 (1 mg PO) will be assessed over 14 days under 10-hour fasting (n=24) and non-fasting conditions (n= 24). In addition, the pharmacokinetics of AEF0117 and/or cannabis will be compared over 14 days across 3 groups of cannabis smokers (n=15/group) who will receive either (a) AEF0117 (1 mg) alone, (b) AEF0117 (1 mg) and cannabis (7.0%), (c) cannabis (7.0%) alone.

To conclude, a substantial strength of this proposal is in pairing Aelis Farma, a company dedicated to the development of a treatment for CUD, with leading academic investigators in the field of CUD treatment. With this partnership, we will conduct FDA-required studies to ready AEF0117 for Phase 3 trials. This project has the potential for high impact, yielding the necessary results to advance AEF0117 closer to FDA approval as the first medication to treat CUD.