PARIS – including Alzheimer’s disease, on the strength of strong performances in phase 2 studies, Cedric O’Gorman, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
The drug acts synergistically through the serotonergic, dopaminergic, and glutamatergic systems, providing a unique mechanism of action well-suited for treatment of a range of neuropsychiatric disorders, observed Dr. O’Gorman, who was vice president of medical affairs at the drug’s developer, Intra-Cellular Therapies during the ECNP congress and is now senior vice president for clinical development and medical affairs at Axsome Therapeutics in New York.
Bruce Jancin/Frontline Medical News
At lower doses, lumateperone is a potent serotonin 5-HT2A receptor antagonist that shows promise as a treatment for primary insomnia as well as agitation and aggression in elderly patients with dementia. As the dose increases, lumateperone also serves as a mesolimbic and mesocortical dopamine receptor phosphoprotein modulator with dual properties, acting at the level of the dopamine D2 receptor both as a presynaptic partial agonist and a postsynaptic antagonist.
The drug also enhances NMDA- and AMPA-induced currents in medial prefrontal cortex pyramidal neurons via activation of the D1 receptor. These attributes provide antipsychotic and antidepressant efficacy.
Positron emission tomography studies in patients with schizophrenia have shown that lumateperone at 60 mg once daily effectively reduced psychosis symptoms at roughly 40% striatal D2 receptor occupancy, which is much lower than the occupancy level required by approved antipsychotic drugs. This attribute, coupled with the drug’s potent effects on serotonin 5-HT2A receptors, serotonin transporters, and D1 receptors, probably accounts for lumateperone’s antipsychotic efficacy and accompanying improved psychosocial function and minimal motor disturbances as demonstrated in the clinical trials, according to Dr. O’Gorman.
The two randomized, double-blind, multicenter, placebo-controlled phase 3 trials in schizophrenia totaled 1,146 patients. The trials included an arm in which patients were randomized to risperidone (Risperdal) at 4 mg/day. The lumateperone and risperidone groups showed similar improvement as measured by the Positive and Negative Syndrome Scale score.
However, lumateperone had a better safety profile, with significantly less weight gain than in the risperidone group. Moreover, lumateperone-treated patients didn’t experience the adverse changes in blood glucose, triglycerides, total cholesterol, and prolactin observed in the risperidone group.
The safety profile of lumateperone as documented in the various clinical trials to date is similar to placebo, Dr. O’Gorman reported.