Small Molecule · AEF0117

AEF0117 (lixosicone)

Phase 2Aelis Farma S.A. (AELIS)

Oral, once-daily, first-in-class signaling-specific inhibitor of the CB1 cannabinoid receptor (CB1-SSi), a pregnenolone-derived biased negative allosteric modulator. Unlike orthosteric CB1 antagonists/inverse agonists (e.g., rimonabant), AEF0117 does not modify agonist binding at CB1; instead it restricts the agonist-induced receptor conformations, selectively inhibiting a subset of CB1 signaling (notably MAPK/ERK phosphorylation) while leaving other pathways intact. This blunts the effects of THC without precipitating cannabinoid withdrawal or the anxiety/depression/suicidality liabilities of CB1 antagonists. Developed by Aelis Farma as a treatment for cannabis use disorder; the Phase 2b SICA2 study missed its primary responder endpoint in 2024.

Also known as: AEF0117, AEF-0117, lixosicone, 3beta-(4-methoxybenzyloxy)pregn-5-en-20-one, 1610878-71-1

Data current as of

Key facts

Modality
Small molecule
Chemical class
pregnane steroid, benzyl ether, pregnenolone derivative
Chemistry
Single enantiomer
Mechanism
CB1 NAM
Highest phase
Phase 2
Lead indication
Cannabis use disorder
Developer
Aelis Farma S.A. (AELIS)
Trials
2 tracked · 12 sites

Mechanism of action#

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—ⓘ

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

Development timeline#

2022202320242025Phase 226 Mar 2025 — readout (missed) — 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).4 Sept 2024 — phase change — 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 Sept 2024 — readout (missed) — Phase 2b SICA2 missed its primary responder endpoint (cannabis use <=1 day/week) and key secondary abstinence endpoints.6 May 2022 — phase change — Phase 2b SICA2 (NCT05322941) initiated; first patient dosed reported June 2022.8 Jun 2021 — Option exercise — Aelis Farma grants Indivior an exclusive option-license for AEF0117 in cannabis-related disordersPhase 122 Jun 2023 — phase change — 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.
Phase change Readout Event UpcomingHover a marker for details.
Phase 2Jun 2021 – 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.
  5. Option exerciseAelis Farma grants Indivior an exclusive option-license for AEF0117 in cannabis-related disorders↗
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.↗

AEF0117 (lixosicone) for Cannabis use disorder#

Phase 2ActiveCannabis use disorder indication →

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).

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#

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

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.

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

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

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.

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.

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.

Sources#

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