Small Molecule · Icalcaprant

Icalcaprant

Phase 2Cerevel Therapeutics Holdings, Inc.

Icalcaprant (development codes CVL-354, ABBV-1354; originator code PF-06874354) is an orally administered, brain-penetrant, selective kappa opioid receptor (KOR) antagonist with weaker mu opioid receptor (MOR) antagonism. Originated by Pfizer and developed by Cerevel Therapeutics (an AbbVie subsidiary), it is in Phase 2 development for major depressive disorder; a separate Phase 2 program is ongoing in bipolar depression.

Also known as: Icalcaprant, CVL-354, ABBV-1354, PF-06874354, 2227384-17-8, 4-[4-[[(2S)-2-(3-methoxy-1-methylpyrazol-4-yl)pyrrolidin-1-yl]methyl]phenoxy]benzamide

Data current as of

Modality
Small molecule
Chemical class
benzamide, pyrazole, pyrrolidine
Chemistry
Single enantiomer
Mechanism
KOR antagonist
Highest phase
Phase 2
Lead indication
Major depressive disorder
Developer
Cerevel Therapeutics Holdings, Inc.
Trials
1 tracked · 1 recruiting · 33 sites
Next catalyst
2H 2027 — Topline data (Major depressive disorder)

Mechanism of action

Selective antagonist of the kappa opioid receptor (KOR / OPRK1), a class A GPCR. It is also a weaker antagonist of the mu opioid receptor (MOR / OPRM1), with approximately 31-fold lower affinity and approximately 27-fold lower inhibitory potency at MOR relative to KOR. KOR antagonism is the proposed antidepressant mechanism (blockade of dynorphin/KOR signaling implicated in dysphoria and anhedonia).

TargetActionAffinity
KORprimaryOPRK1Antagonist—ⓘ
MOROPRM1Antagonist—ⓘ

Formulations

FormulationRouteRegimenPharmacokinetics
Icalcaprant oral capsule
Oral capsule dosed once daily; multiple-ascending-dose Phase 1 tested 10, 25, 50, and 85 mg QD for up to 14 days; Phase 2 MDD tests two once-daily oral doses over 6 weeks
OralOnce daily—

Development timeline

Phase 2Dec 2025 – Sept 2027
  1. UpcomingAnticipated Phase 2 topline (MADRS change from baseline at week 6) for icalcaprant in major depressive disorder
  2. Phase 2 MDD efficacy/safety trial (NCT07276997) initiated; actual study start 2025-12-18.
Phase 1Nov 2021
  1. First-in-human Phase 1 single/multiple ascending dose trial of CVL-354 in healthy participants (NCT05138653) under Cerevel Therapeutics; supportive PET target-occupancy (NCT05547542) and PK trials followed.

Icalcaprant for Major depressive disorder

Phase 2RecruitingMajor depressive disorder indication →

Phase 2, multicenter, 6-week, double-blind, placebo-controlled study of icalcaprant in adults with major depressive disorder (NCT07276997), evaluating two oral once-daily doses versus placebo on change from baseline in MADRS total score. Approximately 195 participants across ~35 North American sites; recruiting as of 2026. No designations identified.

Readouts

  • 2H 2027AnticipatedTopline dataNCT07276997

    Anticipated Phase 2 topline (MADRS change from baseline at week 6) for icalcaprant in major depressive disorder

Clinical trials

NCT07276997Phase 2Recruitingn=195

A Phase 2, Multicenter, 6-Week, Double Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Icalcaprant in Subjects With Major Depressive Disorder

Started Dec 2025· Primary completion Sept 2027· 📍 33 sites across 1 country (United States)

Related compounds

Other KOR compounds

More from Cerevel Therapeutics Holdings, Inc.

Identifiers

Sources

  1. A Phase 2 Study to Evaluate the Efficacy and Safety of Icalcaprant in Subjects With Major Depressive Disorder — ClinicalTrials.gov
  2. A Single and Multiple Ascending Dose Trial of CVL-354 in Healthy Participants — ClinicalTrials.gov
  3. Icalcaprant — Wikipedia