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Lumateperone

Lumateperone
ITI-007.svg
Clinical data
Pronunciation/lməˈtɛpərɑːn/
loo-mə-TE-pə-ron
Trade namesCaplyta
Other namesITI-007; ITI-722
Routes of
administration
By mouth
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
FormulaC24H28FN3O
Molar mass393.506 g·mol−1
3D model (JSmol)

Lumateperone (INN; brand name Caplyta kəp-LY-tə, developmental codes ITI-007 and ITI-722) is a butyrophenone atypical antipsychotic developed by Intra-Cellular Therapies, licensed from Bristol-Myers Squibb, for the treatment of schizophrenia,[1] and currently in development for bipolar depression and other neurological indications.[2]

Medical uses

Schizophrenia

On December 20, 2019, the United States Food and Drug Administration approved lumateperone for use in adult schizophrenic patients.[3] The drug is expected to be ready for use in Spring of 2020.

Clinical Studies

Bipolar depression

Two phase III lumateperone monotherapy studies were conducted and completed for the treatment of bipolar depression, those being trial Study 401 and Study 404.[4] A third trial, Study 402, aims to test lumateperone in addition to lithium or valproate,[5][6] the data pertaining this trial is due out in 2020.[7][8]

Study 401 was conducted solely in the United States while Study 404 was a global study and included patients from the US.[9][10] Of the entire Study 404 population (381 patients), two-thirds were from Russia and Colombia. At the completion of the two monotherpay 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]

Pharmacology

Mechanism of action

Lumateperone affects multiple systems (serotonergic, dopaminergic and glutamatergic) in the central nervous system. It acts as a antagonist of 5-HT2A 0.54nM receptor and modulates D1 4.1nM and D2 3.2nM dopamine receptors where it is a partial agonist at presynaptic and antagonist at postsynaptic receptors. Serotonin transporters at 3.3nM. Through the mTOR pathway, lumateperone augments both NMDA and AMPA activity. Because of its complex pharmacology, it is not clear which of these activities are primarily responsible for its antidepressive and antipsychotic activities.[14]

Pharmacokinetics

Lumateperone has a Tmax of 3–4 hours and a half-life of 13 hours. The main metabolite is the reduction of the carbonyl to hydroxyl group by a ketone reductase. The N-methyl group is also dealkylated by CYP3A4.[15]

Society and culture

Economics

The failure of Study 401 caused Intra-Cellular's stock price to fall.[16][17] Their stock fell again on July 23, when the FDA cancelled a Psychopharmacologic Drugs Advisory Committee meeting.[18][19]

References

  1. ^ Celanire S, Poli S, eds. (13 October 2014). Small Molecule Therapeutics for Schizophrenia. Springer. pp. 31–. ISBN 978-3-319-11502-3.
  2. ^ "Another blow for Intra-Cellular". Evaluate.com. 24 July 2019. Retrieved 6 November 2019.
  3. ^ "FDA Approves Caplyta (lumateperone) for the Treatment of Schizophrenia in Adults". drugs.com. 23 December 2019.
  4. ^ Intra-Cellular Therapies Inc. (8 July 2019). "Intra-Cellular Therapies Announces Positive Top-line Results from a Phase 3 Trial of Lumateperone in Patients with Bipolar Depression". GlobeNewswire News Room. Retrieved 6 November 2019.
  5. ^ Intra-Cellular Therapies Inc. (8 July 2019). "Intra-Cellular Therapies Announces Positive Top-line Results from a Phase 3 Trial of Lumateperone in Patients with Bipolar Depression". GlobeNewswire News Room. Retrieved 6 November 2019.
  6. ^ "Why Intra-Cellular Therapies Is Tanking Today". finance.yahoo.com. Retrieved 6 November 2019.
  7. ^ "One out of two is not enough for Intra-Cellular". Evaluate.com. 8 July 2019. Retrieved 6 November 2019.
  8. ^ "Why Intra-Cellular Therapies Is Tanking Today". finance.yahoo.com. Retrieved 6 November 2019.
  9. ^ "Intra-Cellular Therapies Announces Top Line Results for Two Bipolar Studies". Trial Site News. 13 July 2019. Retrieved 6 November 2019.
  10. ^ Intra-Cellular Therapies Inc. (8 July 2019). "Intra-Cellular Therapies Announces Positive Top-line Results from a Phase 3 Trial of Lumateperone in Patients with Bipolar Depression". GlobeNewswire News Room. Retrieved 6 November 2019.
  11. ^ "One out of two is not enough for Intra-Cellular". Evaluate.com. 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". www.healio.com. 8 July 2019. Retrieved 6 November 2019.
  14. ^ Kumar B, Kuhad A, Kuhad A (December 2018). "Lumateperone: a new treatment approach for neuropsychiatric disorders". Drugs of Today. 54 (12): 713–719. doi:10.1358/dot.2018.54.12.2899443. PMID 30596390.
  15. ^ Vyas P, Hwang BJ, Brašić JR (November 2019). "An evaluation of lumateperone tosylate for the treatment of schizophrenia". Expert Opinion on Pharmacotherapy: 1–7. doi:10.1080/14656566.2019.1695778. PMID 31790322.
  16. ^ House DW, ed. (8 July 2019). "Intra-Cellular down 9% premarket on uneven results from lumateperone studies". Seeking Alpha. Retrieved 6 November 2019.
  17. ^ "Why Intra-Cellular Therapies Is Tanking Today". finance.yahoo.com. Retrieved 6 November 2019.
  18. ^ "Lumateperone schizophrenia drug seems to hit snag". www.mdedge.com. Retrieved 6 November 2019.
  19. ^ "Lumateperone for schizophrenia shows safety, tolerability in long-term study". www.mdedge.com. Retrieved 6 November 2019.

External links