AEF0117 · program

AEF0117 (lixosicone) for Cannabis use disorder

Phase 2ActiveAelis Farma S.A. (AELIS)

Lead indication. The pivotal Phase 2b SICA2 study (NCT05322941; 333 treatment-seeking patients, 84% with severe CUD; AEF0117 0.1/0.3/1.0 mg once daily vs placebo for 12 weeks across 11 US sites) reported topline results on 3 Sep 2024 and a final analysis on 26 Mar 2025: the primary endpoint (proportion of responders reducing cannabis use to <=1 day/week) was NOT met (AEF0117 1 mg 4.4% vs placebo 2.2%, not statistically significant), nor were the abstinence / <=2 days-per-week secondary responder endpoints. AEF0117 1 mg did reduce the number of cannabis-use days per week (-16% vs placebo, P=0.077, approaching significance in the final treatment month) and showed near-significant improvements in Hamilton anxiety (P=0.057), with positive signals in a pre-specified high-motivation subgroup (~24% of patients; -55% days of use, P=0.038). AEF0117 was safe and well tolerated with no CB1-antagonist-type psychiatric adverse effects. Partner Indivior, which held a 2021 option/license, announced on 4 Sep 2024 that it does not expect to exercise its option. Aelis positions the data as validating the CB1-SSi class and plans future studies of higher doses over longer treatment in highly motivated patients; the program remains active (not discontinued).

Data current as of

Development timeline

Phase 2May 2022 – Mar 2025
  1. missedFinal SICA2 analysis: primary endpoint confirmed not met; 1 mg reduced days of cannabis use (-16% vs placebo, P=0.077) with a positive high-motivation subgroup (P=0.038).↗
  2. Indivior announced it does not expect to exercise its 2021 option to license AEF0117 following the Phase 2b primary-endpoint miss; rights remain with Aelis Farma.↗
  3. missedPhase 2b SICA2 missed its primary responder endpoint (cannabis use <=1 day/week) and key secondary abstinence endpoints.↗
  4. Phase 2b SICA2 (NCT05322941) initiated; first patient dosed reported June 2022.
Phase 1Jun 2023
  1. Phase 1 SAD (NCT03325595) and MAD (NCT03443895) and Phase 2a human laboratory study (NCT03717272) reported together in Nature Medicine: AEF0117 was safe/well tolerated and reduced cannabis' positive subjective effects (19% at 0.06 mg, 38% at 1 mg vs placebo, P<0.04) and self-administration (1 mg, P<0.05), without precipitating withdrawal.↗

Readouts

  • 2025-03-26ReportedFull resultsmissedNCT05322941

    Final SICA2 analysis: primary endpoint confirmed not met; 1 mg reduced days of cannabis use (-16% vs placebo, P=0.077) with a positive high-motivation subgroup (P=0.038). ↗

  • 2024-09-03ReportedTopline datamissedNCT05322941

    Phase 2b SICA2 missed its primary responder endpoint (cannabis use <=1 day/week) and key secondary abstinence endpoints. ↗

Clinical trials in Cannabis use disorder

NCT05322941SICA2Phase 2Completedn=333

A Multicenter, Double-blind, Placebo-controlled, Randomized, Parallel-group, Phase 2b Study in Treatment-seeking Patients With Cannabis Use Disorder to Assess the Efficacy, Safety, and Tolerability of AEF0117 in Reducing Cannabis Use (SICA2)

Started May 2022· Primary completion Apr 2024· 📍 11 sites across 1 country (United States)

missedsecondaryProportion reaching complete abstinence or <=2 days/week (key secondary)

Secondary responder endpoints (complete abstinence; <=2 days/week) also not met.

missedprimaryProportion of responders reducing cannabis use to <=1 day/week (primary) — AEF0117 1 mg 4.4% vs placebo 2.2% (not significant)

Primary responder endpoint not met; AEF0117 did not significantly increase the proportion of patients reducing cannabis use to <=1 day/week vs placebo. Doses 0.1/0.3/1.0 mg vs placebo, 12 weeks.

missedsecondaryNumber of days of cannabis use per week (1 mg, final treatment month) — -16% vs placebo (0.077)

AEF0117 1 mg reduced weekly days of cannabis use, an effect that increased over time and approached significance in the final month (P=0.077); did not reach the pre-specified threshold.

missedsecondaryHamilton anxiety score (1 mg) — placebo 4.0+/-0.44 vs AEF0117 1 mg 2.8+/-0.44 (0.057)

Near-significant improvement in anxiety with AEF0117 1 mg vs placebo; contrasts with the anxiety/depression worsening seen with CB1 antagonists.

metexploratoryHigh-motivation subgroup (~24%): days of cannabis use, final month — -55% vs placebo (0.038)

In a pre-specified high-motivation subgroup, AEF0117 1 mg reduced days of cannabis use by 55% (P=0.038) and dollars spent on cannabis per day by 76% (P=0.029) vs placebo in the final treatment month.

NCT03717272Phase 2Completedn=29

A Phase 2a Human Laboratory Study to Assess the Effect of AEF0117 on the Reinforcing and Subjective Effects of Smoked Cannabis

Started Jan 2019· Primary completion Jan 2021· 📍 1 site across 1 country (United States)

metprimaryCannabis positive subjective effects ('good drug effect') vs placebo — -19% (0.06 mg); -38% (1 mg) vs placebo (<0.04)

AEF0117 significantly reduced cannabis' positive subjective effects in a human laboratory paradigm.

metsecondaryCannabis self-administration — reduced at 1 mg (<0.05)

AEF0117 1 mg reduced cannabis self-administration without precipitating withdrawal; supported advancement to Phase 2b.

Formulations

FormulationRouteRegimenPharmacokinetics
AEF0117 oralcorn oil solution (oral capsule)
0.06-6 mg once daily; 1 mg/day highest dose in Phase 2a/2b
OralOnce dailyTmax 3 h

Mechanism of action (compound-wide)

First-in-class CB1 receptor signaling-specific inhibitor (CB1-SSi), a pregnenolone-derived biased negative allosteric modulator of the CB1 cannabinoid receptor (CNR1). AEF0117 does not modify orthosteric agonist binding (it does not displace [3H]CP55,940 at CB1) but restricts the conformational changes an agonist can induce, selectively inhibiting a subset of CB1-mediated signaling — notably MAPK/ERK1/2 phosphorylation — without affecting cAMP-mediated signaling. This biased inhibition reduces the effects of THC and cannabis self-administration without precipitating CB1-antagonist-like withdrawal, anxiety, depression, or suicidality.

TargetActionAffinity
CB1primaryCNR1NAM—ⓘ

← Full AEF0117 compound page (identity, identifiers, all indications)

Sources

  1. Aelis Farma announces the final analysis of the landmark Phase 2b clinical trial in cannabis use disorder (CUD) with the CB1-SSi AEF0117 — Aelis Farma / Business Wire
  2. Aelis Farma announces the results of its clinical Phase 2b study with AEF0117 among participants with cannabis use disorder (CUD) — Aelis Farma / Business Wire
  3. Effect of AEF0117 on Treatment-seeking Patients With Cannabis Use Disorder (CUD) — SICA2, Phase 2b (NCT05322941) — ClinicalTrials.gov
  4. Indivior provides update on Aelis Farma's Phase 2b study results with AEF0117 — does not expect to exercise its option — Indivior PLC / PR Newswire
  5. Phase 2a human laboratory study of AEF0117 in cannabis use disorder (NCT03717272) — ClinicalTrials.gov
  6. Signaling-specific inhibition of the CB1 receptor for cannabis use disorder: phase 1 and phase 2a randomized trials — Nature Medicine (PMC)