Lumateperone


Lumateperone is a butyrophenone atypical antipsychotic developed by Intra-Cellular Therapies, licensed from Bristol-Myers Squibb, for the treatment of schizophrenia, and currently in development for bipolar depression and other neurological indications.
The most common side effects include sleepiness and dry mouth.

Medical uses

Schizophrenia

On December 20, 2019, the United States Food and Drug Administration approved lumateperone for the treatment of schizophrenia in adults. Lumateperone is FDA approved for this indication only at the 42 mg dose, despite being studied at lower doses and a higher dose.

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. A third trial, Study 402, aims to test lumateperone in addition to lithium or valproate, the data pertaining this trial is due out in 2020.
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, 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. 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.

Pharmacology

Mechanism of action

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

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. Lumateperone is a substrate for numerous metabolic enzymes, including various glucuronosyltransferase isoforms, aldo-keto reductase isoforms, and cytochrome P450 enzymes.
Lumateperone does not cause appreciable inhibition of any common CYP450 enzymes. It is not a substrate for p-glycoprotein.

Society and culture

Economics

The failure of Study 401 caused Intra-Cellular's stock price to fall. Their stock fell again on July 23, when the US Food and Drug Administration canceled a Psychopharmacologic Drugs Advisory Committee meeting.

History

Lumateperone was approved for medical use in the United States in December 2019, and became available in February 2020.
The FDA approved lumateperone based on evidence from three clinical trials that enrolled 818 adult participants with schizophrenia. The trials were conducted at 33 sites in the United States. Trials 1 and 2 provided data on the benefits and side effects of lumateperone, and Trial 3 provided data on side effects only.
Three trials provided data for the approval of lumateperone. In each trial, hospitalized participants with schizophrenia were randomly assigned to receive either lumateperone or a comparison treatment once daily for four weeks or six weeks. Neither the participants nor the health care providers knew which treatment was being given until after the trials were completed.
Trials 1 and 2 provided data for the assessment of benefits and side effects through four weeks of therapy. Benefit was assessed by measuring the overall improvement in the symptoms of schizophrenia. Trial 3 provided data for the assessment of side effects only during six weeks of therapy.