Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease, Schizophrenia, Bipolar Disorder
U.S. FDA Status: Alzheimer's Disease (Phase 3), Schizophrenia (Phase 3), Bipolar Disorder (Phase 3)
Company: Bristol-Myers Squibb, Intra-Cellular Therapies, Inc.
This serotonin 5-HT2A receptor antagonist was originally developed by Bristol Myers Squibb and licensed to Intra-cellular Therapies in 2005. This company is testing ITI-007 clinically for schizophrenia, bipolar depression, and insomnia, as well as for the treatment of agitation in dementia, including Alzheimer's disease.
This compound is being studied at different dose levels. At low doses, it reportedly engages primarily the 5-HT2A receptor, whereas at higher doses it also affects dopamine receptors, enhances glutamatergic transmission, and inhibits serotonin reuptake (see see Davis et al., 2015; Snyder et al., 2015; Davis et al., 2016).
In 2014, Intra-Cellular Therapies ran a Phase 1/2 dose-escalation study of up to 30 mg/d in 30 old healthy volunteers and people with a clinical diagnosis of dementia. This trial measured safety, exposure and, as exploratory outcomes, cognitive function and sleep. Agitation was to be measured but did not occur in this patient sample. Results were presented at the 2014 CTAD conference (see Dec 2014 conference news; Dec 2015 conference news).
In June 2016, a Phase 3 study began enrolling an anticipated 360 participants with a clinical diagnosis of Alzheimer's and agitation. The study will evaluate a one-month course of 9 mg/d of ITI-007 against placebo on the Cohen-Mansfield Agitation Inventory-Community version (CMAI-C) and the Clinical Global Impression for Severity of Illness (CGI-S). This trial will run through August 2018.
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- Davis RE, Vanover KE, Zhou Y, Brašić JR, Guevara M, Bisuna B, Ye W, Raymont V, Willis W, Kumar A, Gapasin L, Goldwater DR, Mates S, Wong DF. ITI-007 demonstrates brain occupancy at serotonin 5-HT₂A and dopamine D₂ receptors and serotonin transporters using positron emission tomography in healthy volunteers. Psychopharmacology (Berl). 2015 Aug;232(15):2863-72. Epub 2015 Apr 7 PubMed.
- Snyder GL, Vanover KE, Zhu H, Miller DB, O'Callaghan JP, Tomesch J, Li P, Zhang Q, Krishnan V, Hendrick JP, Nestler EJ, Davis RE, Wennogle LP, Mates S. Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission. Psychopharmacology (Berl). 2015 Feb;232(3):605-21. Epub 2014 Aug 15 PubMed.
- Davis RE, Correll CU. ITI-007 in the treatment of schizophrenia: from novel pharmacology to clinical outcomes. Expert Rev Neurother. 2016 Jun;16(6):601-14. Epub 2016 Apr 25 PubMed.
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