NEW YORK—Intra-Cellular Therapies Inc., a biopharmaceutical company focused on the development of therapeutics for central nervous system disorders, has announced topline results from ITI-007-200, a Phase 1/2 clinical trial designed to evaluate the safety, tolerability and pharmacokinetics of low doses of its lead drug candidate, ITI-007, in healthy geriatric subjects (trial part one) and in patients with dementia, including Alzheimer’s disease (trial part two). The data presented at the 2014 annual meeting of the American Neurological Association relate to part one of the trial. Additional data, including part two of the trial, will be presented at a future scientific conference.
The initial results demonstrated that ITI-007 is safe and well tolerated in healthy geriatric subjects and met the primary objectives of the study. Further, the results indicate a dose-related pharmacokinetic profile in geriatric subjects consistent with previous studies in younger subjects. This study marks an important milestone in defining the low dose range of ITI-007 to be developed for the treatment of behavioral disturbances associated with dementia and related disorders.
In these healthy geriatric subjects, ITI-007 was safe and well tolerated at doses up to and including 30 mg. Subjects did not exhibit extrapyramidal adverse events or clinically relevant changes in cardiovascular parameters. The tolerability and pharmacokinetic profile of ITI-007 in geriatric subjects indicate a wide safety window for ITI-007 in the elderly.
Previous positron emission tomography studies demonstrated that a 10 mg dose of ITI-007 represented an approximate 10 percent occupancy of D2 receptors in the striatum. Doses of ITI-007 ranging from 1 to 10 mg resulted in improved sleep in patients with primary insomnia (clinical trial ITI-007-004). Taken together, these data indicate that low doses of ITI-007 demonstrate proof of mechanism by engaging key brain targets and pharmacodynamic effects consistent with the mechanisms of action, and are safe and well tolerated in relevant patient populations. Based on previously reported data and the data from the geriatric study announced today, the company plans to further evaluate low doses of ITI-007 for the treatment of behavioral disturbances associated with dementia, including Alzheimer’s disease.
There is a large unmet medical need for a safe and effective therapy to treat the behavioral symptoms in patients with dementia, including Alzheimer’s disease. To date, the FDA has not approved any drug to treat the behavioral symptoms of dementia, including Alzheimer’s disease. As symptoms progress and become more severe, physicians often resort to off-label use of antipsychotic medications in these patients. Current antipsychotic drugs are associated with a number of side effects, which can be problematic for elderly patients with dementia. In addition, antipsychotic drugs may exacerbate the cognitive disturbances associated with dementia.
“Dementia is associated with behavioral symptoms including agitation, aggression and irritability. These symptoms often gradually increase in frequency and severity during the course of the disease, becoming distressing to patients and caregivers and contributing to early institutionalization,” said Dr. Sharon Mates, CEO and chairman of Intra-Cellular Therapies. “We believe the ITI-007-200 results are consistent with the existing favorable safety and tolerability profile of the drug and its pharmacokinetic profile. The results allow the future testing of a range of low doses of ITI-007 that offer the potential clinical benefits of optimal 5-HT2A antagonism and additional potential benefits offered by the gradual engagement of other receptors as the dose is increased. The outcome of ITI-007-200 represents an important step forward in the clinical development of ITI-007 for the treatment of behavioral disturbances associated with dementia and related disorders, an indication with no FDA-approved drugs.”
ITI-007 is Intra-Cellular Therapies’ lead product candidate, whose mechanism of action is believed to have the potential to yield a first-in-class antipsychotic therapy and, at lower doses, a first-in-class therapy for the behavioral disturbances associated with dementia. In preclinical and clinical trials to date, ITI-007 combines potent serotonin 5-HT2A receptor antagonism, dopamine receptor phosphoprotein modulation, glutamatergic modulation and serotonin reuptake inhibition into a single drug candidate. At dopamine D2 receptors, ITI-007 has been demonstrated to have dual properties and to act as both a postsynaptic antagonist and a presynaptic partial agonist. ITI-007 has also been demonstrated to stimulate phosphorylation of glutamatergic NMDA NR2B, or GluN2B receptors in a mesolimbic specific manner.
At the lowest dose studied to date (1 mg), ITI-007 has been demonstrated to act primarily as a potent 5-HT2A serotonin receptor antagonist. As the dose is increased, additional benefits are derived from the engagement of additional drug targets, including modest dopamine receptor modulation and modest inhibition of serotonin transporters.
The company believes that combined interactions at these receptors may provide additional benefits above and beyond selective 5-HT2A antagonism for treating agitation, aggression and sleep disturbances in diseases that include dementia, Alzheimer’s disease and autism spectrum disorders, while avoiding many of the side effects associated with more robust dopamine receptor antagonism. As the dose of ITI-007 is further increased, leading to moderate dopamine receptor modulation, inhibition of serotonin transporters and indirect glutamate modulation, these actions complement the complete blockade of 5-HT2A serotonin receptors. In this dose range, ITI-007 may be useful in treating the symptoms associated with schizophrenia, bipolar disorder, major depressive disorder and other neuropsychiatric diseases.