ITI-007 · program

Lumateperone (ITI-007) for Bipolar depression

ApprovedApprovedJohnson & Johnson (JNJ)

Indications for ITI-007: Schizophrenia · Approved Bipolar depression · Approved Bipolar disorder · Phase 3 Autism spectrum disorder · Phase 3 Major depressive disorder · Approved

FDA approved Caplyta (lumateperone) 42 mg once daily on 20 Dec 2021 for the treatment of depressive episodes associated with bipolar I or bipolar II disorder in adults, both as MONOTHERAPY and as ADJUNCTIVE therapy with lithium or valproate. At the time it was the first and only FDA-approved treatment for both bipolar I and bipolar II depression as monotherapy and adjunctive therapy. Approval was supported by two positive Phase 3 placebo-controlled studies: the monotherapy Study 404 (NCT03249376), which met its MADRS Week-6 primary (LSMD vs placebo -4.6; ES -0.56; p<0.0001) and CGI-BP-S key secondary, and the adjunctive Study 402 (NCT02600507), in which lumateperone 42 mg added to lithium or valproate met its MADRS Week-6 primary (LSMD -2.4; p=0.02) and the CGI-BP-S depression key secondary (LSMD -0.3; p=0.01). An earlier US-only monotherapy trial (Study 401, NCT02600494) had missed its primary endpoint. is_lead_indication=false because schizophrenia was the original (lead) approved indication. Originated by Intra-Cellular Therapies; Caplyta is now marketed by Johnson & Johnson Innovative Medicine following the ITCI acquisition (closed 2 Apr 2025).

Data current as of

Development timeline

ApprovedDec 2021 – Feb 2023
  1. metStudy 402 positive (42 mg): lumateperone adjunctive to lithium/valproate met the MADRS Week-6 primary in bipolar depression (LSMD -2.4, p=0.02).↗
  2. metFDA approved Caplyta (lumateperone) for bipolar I and II depression in adults, as monotherapy and as adjunctive therapy with lithium or valproate.↗
Phase 3Jan 2019 – Sept 2021
  1. metStudy 404 positive: lumateperone 42 mg monotherapy met the MADRS Week-6 primary in bipolar I/II depression (LSMD -4.6, ES -0.56, p<0.0001).↗
  2. Study 402 (NCT02600507), the adjunctive-to-lithium/valproate Phase 3, completed and MET its primary at 42 mg: MADRS LSMD -2.4 vs placebo at Week 6 (p=0.02) and CGI-BP-S depression key secondary (LSMD -0.3, p=0.01). Primary completion 2020-07-02.↗
  3. Study 404 (NCT03249376), a global monotherapy Phase 3, completed and MET its primary endpoint: MADRS LSMD -4.6 vs placebo at Week 6 (95% CI -6.34 to -2.83; ES -0.56; p<0.0001), plus CGI-BP-S key secondary. The positive monotherapy pivotal study. Primary completion 2019-03-01.↗
  4. Study 401 (NCT02600494), the first US-only monotherapy Phase 3 in bipolar depression, completed but MISSED its MADRS primary endpoint (attributed to high placebo response). Primary completion 2019-01-28.

Readouts

  • 2023-02-13ReportedFull resultsmetNCT02600507

    Study 402 positive (42 mg): lumateperone adjunctive to lithium/valproate met the MADRS Week-6 primary in bipolar depression (LSMD -2.4, p=0.02). ↗

  • 2021-12-20ReportedRegulatorymet

    FDA approved Caplyta (lumateperone) for bipolar I and II depression in adults, as monotherapy and as adjunctive therapy with lithium or valproate. ↗

  • 2021-09-23ReportedFull resultsmetNCT03249376

    Study 404 positive: lumateperone 42 mg monotherapy met the MADRS Week-6 primary in bipolar I/II depression (LSMD -4.6, ES -0.56, p<0.0001). ↗

Clinical trials in Bipolar depression

NCT03249376ITI-007-404Phase 3Completedn=381

Study 404: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Assess the Efficacy and Safety of Lumateperone Monotherapy in the Treatment of Patients With Major Depressive Episodes Associated With Bipolar I or Bipolar II Disorder (Bipolar Depression) Conducted Globally

Started Nov 2017· Primary completion Mar 2019· 📍 47 sites across 6 countries (United States, Bulgaria, Ukraine, Russia)

metprimaryMADRS total score change from baseline to Day 43 (Week 6), lumateperone 42 mg monotherapy vs placebo — LSMD -4.6 (95% CI -6.34 to -2.83); ES -0.56 (<0.0001)

Primary MADRS endpoint met: lumateperone 42 mg monotherapy produced a statistically significant, clinically meaningful improvement vs placebo at Week 6 in adults with bipolar I or II depression. The positive monotherapy pivotal study supporting the 2021 bipolar-depression approval.

metsecondaryCGI-BP-S (Clinical Global Impression-Bipolar-Severity) total score change at Week 6 — ES -0.46 (<0.001)

Key secondary CGI-BP-S endpoint met with statistical significance; CGI-BP-S depression subscale also significantly improved.

NCT02600507ITI-007-402Phase 3Completedn=529

Study 402: Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Assess the Efficacy and Safety of ITI-007 (Lumateperone) Adjunctive to Lithium or Valproate in the Treatment of Patients With Major Depressive Episodes Associated With Bipolar I or Bipolar II Disorder

Started Mar 2016· Primary completion Jul 2020· 📍 71 sites across 5 countries (United States, Bulgaria, Ukraine, Russia)

metsecondaryCGI-BP-S depression subscore change at Week 6 (lumateperone 42 mg adjunctive) — LSMD -0.3 (0.01)

Key secondary CGI-BP-S depression subscore endpoint met with statistical significance for the 42 mg arm.

metprimaryMADRS total score change from baseline to Week 6, lumateperone 42 mg adjunctive to lithium/valproate vs placebo — LSMD -2.4 (0.02)

Primary MADRS endpoint met for the 42 mg arm: statistically significant improvement over placebo when added to lithium or valproate at Week 6. The 28 mg arm showed only numerical improvement (LSMD -1.7, p=0.10, not significant). The positive adjunctive pivotal study supporting the 2021 bipolar-depression approval.

NCT02600494ITI-007-401Phase 3Completedn=554

Study 401: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study With an Open-Label Extension to Assess the Efficacy and Safety of ITI-007 (Lumateperone) Monotherapy in the Treatment of Patients With Major Depressive Episodes Associated With Bipolar I or Bipolar II Disorder

Started Dec 2015· Primary completion Jan 2019· 📍 55 sites across 1 country (United States)

missedprimaryMADRS total score change from baseline at Week 6, lumateperone monotherapy vs placebo (US-only study)

First, US-only monotherapy Phase 3 in bipolar depression; the MADRS primary endpoint was NOT met, attributed to an unusually high placebo response. Negative result captured deliberately. The later global Study 404 was the positive monotherapy trial used for approval.

Formulations

FormulationRouteRegimenPharmacokinetics
Lumateperone oral capsule (Caplyta)immediate-release capsule (crystalline tosylate salt)
Capsules of 42 mg, 21 mg, and 10.5 mg lumateperone (equivalent to 60/30/15 mg lumateperone tosylate); recommended dose 42 mg once daily, with or without food.
OralOnce dailyt½ 18 h · Tmax 1.5 h · F 4.4%

Mechanism of action (compound-wide)

Multi-target small molecule. High-affinity serotonin 5-HT2A receptor antagonist (human pKi 9.3, Ki ~0.50 nM) with comparatively lower affinity at dopamine D2 receptors (pKi 7.5, Ki ~32 nM) where it acts as a presynaptic partial agonist / postsynaptic antagonist (the developer's 'dopamine receptor phosphoprotein modulator' framing), and inhibition of the serotonin transporter (SERT; pKi 7.2, Ki ~63 nM). Also modulates dopamine D1-receptor-dependent glutamatergic signaling. The combined 5-HT2A antagonism plus low/region-selective D2 occupancy and SERT inhibition underlies its low metabolic/EPS burden and proposed antidepressant activity.

TargetActionAffinity
5-HT2AprimaryHTR2AAntagonistKi 0.5 nMⓘ
D2DRD2AntagonistKi 32 nMⓘ
SERTSLC6A4InhibitorKi 63 nMⓘ

← Full ITI-007 compound page (identity, identifiers, all indications)

Sources

  1. Adjunctive lumateperone (ITI-007) in the treatment of bipolar depression: results from a randomized placebo-controlled clinical trial (Study 402) — Bipolar Disorders (Yatham et al. 2023; PMID 36779257)
  2. CAPLYTA (lumateperone) capsules - Prescribing Information — DailyMed / NIH (FDA label)
  3. Efficacy and Safety of Lumateperone for Major Depressive Episodes Associated With Bipolar I or Bipolar II Disorder: A Phase 3 Randomized Placebo-Controlled Trial (Study 404) — American Journal of Psychiatry (Calabrese et al. 2021)
  4. Intra-Cellular Therapies announces U.S. FDA approval of Caplyta (lumateperone) for the treatment of bipolar depression in adults — Intra-Cellular Therapies, Inc. (GlobeNewswire)
  5. Lumateperone — Wikipedia
  6. Lumateperone (ligand 9099) - binding data at 5-HT2A, D2, and SERT — IUPHAR/BPS Guide to Pharmacology
  7. Study 401 (ITI-007-401): ITI-007 monotherapy for bipolar depression (NCT02600494) — ClinicalTrials.gov
  8. Study 402 (ITI-007-402): ITI-007 adjunctive to lithium or valproate for bipolar depression (NCT02600507) — ClinicalTrials.gov
  9. Study 404 (ITI-007-404): Lumateperone monotherapy for bipolar depression, conducted globally (NCT03249376) — ClinicalTrials.gov