ITI-007 (LUMATEPERONE) FOR THE TREATMENT OF AGITATION IN PATIENTS WITH DEMENTIA, INCLUDING ALZHEIMER'S DISEASE

Abstract

Lumateperone (ITI-007) is an investigational drug that provides selective and simultaneous modulation of serotonin, dopamine, and glutamate neurotransmission. Lumateperone has a dose-dependent pharmacological profile. At low doses, lumateperone acts primarily as a potent 5-HT2A receptor antagonist with low levels of striatal D2 receptor occupancy and modest interactions with serotonin transporters and dopamine D1 receptors with indirect enhancement of glutamate. There are no currently approved treatments for agitation and aggression associated with dementia. Various medications are prescribed off-label but are frequently ineffective and associated with deleterious side effects. Given its pharmacological and clinical profile, lumateperone is currently being studied in a Phase 3 clinical trial for the treatment of agitation associated with dementia. A Positron Emission Tomography (PET) study evaluated ITI-007(10–40 mg) in healthy volunteers. Low doses of lumateperone were evaluated in patients with primary insomnia. Multiple ascending doses of lumateperone were evaluated in healthy geriatric volunteers. Repeated daily doses of lumateperone were evaluated for safety in patients with dementia. In the PET study, ITI-007 (10 mg) demonstrated high occupancy (>80 %) of cortical 5-HT2A receptors and low occupancy of striatal D2 receptors (∼12 %). In a Phase 2 trial in patients with primary insomnia, ITI-007 (1 – 10 mg) was shown to restore natural sleep patterns with no next-day hang-over effects. A study in healthy elderly subjects showed that low doses of ITI-007 (7.5, 15.0 and 30 mg, QAM for 7 days) were safe and well-tolerated and showed no clinically significant impact on the extrapyramidal, endocrine, and cardiovascular systems. In elderly patients with dementia, ITI-007 was safe and well-tolerated and improved measures of cognition. Lumateperone represents a potential new approach for the treatment of a broad array of neuropsychiatric symptoms, including the treatment of agitation in patients with dementia. Not only is there evidence to suggest improvements in sleep, cognition, learning and behavioral disturbances, but ITI-007’s benign safety and tolerability profile would make it an important novel and safe treatment option for this patient population.