Lumateperone

Lumateperone, sold under the brand name Caplyta, is a medication used for the treatment of schizophrenia and bipolar depression.[1] It is a butyrophenone atypical antipsychotic developed by Intra-Cellular Therapies, licensed from Bristol-Myers Squibb.[2]

Lumateperone
Clinical data
Pronunciation/luːməˈtɛpərɑːn/
loo-mə-TE-pə-ron
Trade namesCaplyta
Other namesITI-007; ITI-722
AHFS/Drugs.comMonograph
MedlinePlusa620014
License data
Routes of
administration		By mouth
Drug classAtypical antipsychotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability4.4%[1]
Protein binding97.4%[1]
MetabolismMultiple UGTs, CYP450s, and AKR enzymes[1]
Excretion<1% excreted unchanged in urine[1]
Identifiers
  • 1-(4-Fluorophenyl)-4-(3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-butanone
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
Chemical and physical data
FormulaC24H28FN3O
Molar mass393.506 g·mol−1
3D model (JSmol)
  • [H][C@]12CCN(CCCC(=O)C3=CC=C(F)C=C3)C[C@@]1([H])C1=CC=CC3=C1N2CCN3C

The most common side effects include sleepiness and dry mouth.[3]

Lumateperone was approved for medical use in the United States in December 2019,[3][4] and became available in February 2020.[1]

Medical uses

Schizophrenia

On December 20, 2019, the United States Food and Drug Administration (FDA) approved lumateperone for the treatment of schizophrenia in adults.[3][4][5]

Bipolar depression

In December 2021, the FDA approved lumateperone for the treatment of bipolar depression in adults as monotherapy and as adjunctive therapy with lithium or valproate.[1][6]

Pharmacology
Receptor affinities[1]
ReceptorKi (nM)
5-HT2A0
 .54
Dopamine receptor D141
Serotonin transporter33
Dopamine receptor D232
Dopamine receptor D4<100
Alpha-1A adrenergic receptor<100
Alpha-1B adrenergic receptor<100

Mechanism of action

Lumateperone acts as an antagonist of 5-HT2A receptor and antagonizes several dopamine receptor subtypes (D1, D2, and D4). It has moderate serotonin transporter reuptake inhibition. It has additional off-target antagonism at alpha-1 receptors, without appreciable antimuscarinic or antihistaminergic properties.[1]

Pharmacokinetics

After taking the medication by mouth, lumateperone reaches maximum plasma concentrations within 1–2 hours and has a terminal elimination half-life of 18 hours.[1] Lumateperone is a substrate for numerous metabolic enzymes, including various glucuronosyltransferase (UGT) isoforms (UGT1A1, 1A4, and 2B15), aldo-keto reductase (AKR) isoforms (AKR1C1, 1B10, and 1C4), and cytochrome P450 (CYP) enzymes (CYP3A4, 2C8, and 1A2).[1]

Lumateperone does not cause appreciable inhibition of any common CYP450 enzymes. It is not a substrate for p-glycoprotein.[1]

History

The FDA approved lumateperone based on evidence from three clinical trials (Trial 1/NCT01499563, Trial 2/NCT02282761 and Trial 3/NCT02469155) that enrolled 818 adult participants with schizophrenia.[3] The trials were conducted at 33 sites in the United States.[3] Trials 1 and 2 provided data on the benefits and side effects of lumateperone, and Trial 3 provided data on side effects only.[3]

Three trials provided data for the approval of lumateperone.[3] In each trial, hospitalized participants with schizophrenia were randomly assigned to receive either lumateperone or a comparison treatment (placebo or active comparator) once daily for four weeks (Trials 1 and 2) or six weeks (Trial 3).[3] Neither the participants nor the health care providers knew which treatment was being given until after the trials were completed.[3]

Trials 1 and 2 provided data for the assessment of benefits and side effects through four weeks of therapy.[3] Benefit was assessed by measuring the overall improvement in the symptoms of schizophrenia.[3] Trial 3 provided data for the assessment of side effects only during six weeks of therapy.[3]

Two Phase III lumateperone monotherapy studies were conducted and completed for the treatment of bipolar depression, those being trial Study 401 and Study 404.[7] A third trial, Study 402, aims to test lumateperone in addition to lithium or valproate,[8][9] the data pertaining this trial is due out in 2020.[10][9]

Study 401 was conducted solely in the United States while Study 404 was a global study and included patients from the US. Of the entire Study 404 population (381 patients), two-thirds were from Russia and Colombia. At the completion of the two monotherapy Phase III trials only Study 404 met its primary endpoint and one of its secondary endpoints.[11][12] In Study 404, patients received 42 mg lumateperone once daily or placebo for six weeks. Study 404 patients saw an improvement of depressive symptoms compared to placebo as documented by a change in MADRS total score of 4.6.[13]

References
  1. "Caplyta- lumateperone capsule". DailyMed. Intra-Cellular Therapies, Inc. 27 December 2019. Retrieved 3 July 2020.
  2. Celanire S, Poli S, eds. (13 October 2014). Small Molecule Therapeutics for Schizophrenia. Springer. pp. 31–. ISBN 978-3-319-11502-3.
  3. "Drug Trials Snapshots: Caplyta". U.S. Food and Drug Administration (FDA). 20 December 2019. Retrieved 2 July 2020. This article incorporates text from this source, which is in the public domain.
  4. "Drug Approval Package: Caplyta". U.S. Food and Drug Administration (FDA). 21 January 2020. Retrieved 1 July 2020.
  5. "FDA Approves Intra-Cellular Therapies' Novel Antipsychotic, Caplyta (lumateperone) for the Treatment of Schizophrenia in Adults" (Press release). Intra-Cellular Therapies Inc. 23 December 2019. Retrieved 1 July 2020 – via GlobeNewswire.
  6. "Intra-Cellular Therapies Announces U.S. FDA Approval of CAPLYTA® (Lumateperone) for the Treatment of Bipolar Depression in Adults | Intra-Cellular Therapies Inc".
  7. "Intra-Cellular Therapies Announces Positive Top-line Results from a Phase 3 Trial of Lumateperone in Patients with Bipolar Depression" (Press release). Intra-Cellular Therapies Inc. 8 July 2019. Retrieved 6 November 2019 – via GlobeNewswire.
  8. "Intra-Cellular Therapies Announces Positive Top-line Results from a Phase 3 Trial of Lumateperone in Patients with Bipolar Depression" (Press release). Intra-Cellular Therapies Inc. 8 July 2019. Retrieved 6 November 2019 – via GlobeNewswire.
  9. "Why Intra-Cellular Therapies Is Tanking Today". Yahoo! Finance. Retrieved 6 November 2019.
  10. "One out of two is not enough for Intra-Cellular". Evaluate. 8 July 2019. Retrieved 6 November 2019.
  11. "One out of two is not enough for Intra-Cellular". Evaluate. 8 July 2019. Retrieved 6 November 2019.
  12. DeArment A (8 July 2019). "Intra-Cellular Therapies hits one, misses another in Phase III bipolar disorder program". MedCity News. Retrieved 6 November 2019.
  13. "Phase 3 data supports lumateperone for bipolar depression". Healio. 8 July 2019. Retrieved 6 November 2019.
  • "Lumateperone". Drug Information Portal. U.S. National Library of Medicine.
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