Lumateperone

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.

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 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]

Lumateperone affects multiple systems (serotonergic, dopaminergic and glutamatergic) in the central nervous system. It acts as a antagonist of 5-HT_2A receptor and modulates D₁ and D₂ dopamine receptors where it is a partial agonist at presynaptic and partial antagonist at postsynaptic receptors. 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.[15]

After taking the medication by mouth, lumateperone reaches maximum plasma concentrations within 3-4 hours and has an elimination 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.[16]

The failure of Study 401 caused Intra-Cellular's stock price to fall.[17][18] Their stock fell again on July 23, when the FDA cancelled a Psychopharmacologic Drugs Advisory Committee meeting.[19][20]