Technology & Products
ITI-007

ITI-007 is the Company's novel clinical stage drug candidate designed to treat multiple symptoms associated with several neuropsychiatric and neurologic disorders. Owing to its unique mechanism of action, ITI-007 has been shown to improve sleep disturbances in patients with sleep maintenance insomnia at low doses, and at higher doses shows promise to treat symptoms that are commonly associated with schizophrenia, bipolar disorder, depression and other neuropsychiatric and neurologic disorders. In clinical trials conducted to date, the investigational new drug is safe and lacks adverse effects commonly accompanying antipsychotic, antidepressant, and sedative-hypnotic drugs. These encouraging initial results are being confirmed in further clinical investigations.

Clinical Development Plan for Schizophrenia

ITI-007 has been evaluated in several clinical trials demonstrating that it is safe and well- tolerated across a broad range of oral doses in healthy volunteers and patient populations. ITI-007 shows dose-dependent, linear pharmacokinetics after oral administration. Importantly, in a brain receptor occupancy study using positron emission tomography (PET), ITI-007 rapidly enters the brain and occupies target receptors in a dose-related manner. Moreover, PET data show that cortical serotonin 5-HT2A receptors are fully occupied at low doses of ITI-007, consistent with improved sleep maintenance in patients with insomnia at low doses. As the dose is increased, ITI-007 engages dopamine D2 receptors and serotonin transporters, key targets that mediate antipsychotic and antidepressant efficacy, respectively. In a Phase I/II study in patients with stabilized schizophrenia, we have safely administered a broad range of doses of ITI-007 that we believe to span a full range of target receptor occupancies. Our next step is to conduct a Phase II proof of efficacy trial in patients with acutely exacerbated schizophrenia. Other therapeutic indications to be explored include ITI-007 for treatment of bipolar disorder, treatment resistant depression, major depressive disorder (MDD), sleep disturbances in psychiatric and neurodegenerative diseases, posttraumatic stress disorder, behavioral disturbances in Alzheimer's disease and autism.

ITI-007's Unique Mechanism of Action

ITI-007 combines potent 5-HT2A receptor antagonism with dopamine receptor phosphoprotein modulation (DPPM) and serotonin reuptake inhibition for the treatment of schizophrenia. At dopamine D2 receptors, ITI-007 has dual properties acting as a post-synaptic antagonist and as a pre-synaptic partial agonist. ITI-007 also stimulates phosphorylation of glutamatergic NMDA NR2B receptors in a mesolimbic specific manner downstream of D1 receptor intracellular signaling. This mesolimbic selectivity, acting precisely in those brain areas thought to be important for antipsychotic efficacy, together with a broad serotonergic, glutamatergic, and dopaminergic receptor interaction profile, is expected to result in superior antipsychotic efficacy for positive, negative and cognitive symptoms associated with schizophrenia. The combination of ITI-007's high-potency blockade of 5-HT2A receptors and unique dopamine receptor activity should allow a personalized approach to patient treatment for schizophrenia by making it possible for the first time, to select a clinical dose capable of saturating 5-HT2A receptors while permitting the "dialing in" of an optimal amount of dopamine receptor modulation by simple dose adjustments using a single drug. The ability to optimize the level of dopamine receptor modulation holds promise for the reduction of psychotic symptoms without incurring high levels of dopamine antagonism that cause motor disturbances and other deleterious side effects. In addition, the wide separation of affinity at 5-HT2A and D2 receptors may allow for administration of the appropriate amount of dopamine modulation for antipsychotic maintenance therapy and the treatment of bipolar disorders. The serotonin reuptake inhibition allows for additional antidepressant efficacy for the treatment of schizoaffective disorder, co-morbid depression, and/or as a stand-alone treatment for major depressive disorder (MDD).