ntra-Cellular Therapies Announces Progression to Higher Dose Cohort in ITI-214 Study

Intra-Cellular Therapies announced the successful completion of the second dose cohort (single dose of 30 mg administered orally) in Study ITI-214-104 (Study ‘104), a proof-of-mechanism, translational medicine study of ITI-214, a novel phosphodiesterase-1 (PDE1) inhibitor, in patients with chronic heart failure. Clinical conduct of the third and last cohort, 90 mg, is now ongoing following review of safety and tolerability data from the 30 mg dose cohort, where no safety concerns were identified.

Study ‘104 is a randomized, double-blind, placebo-controlled study of escalating single doses of ITI-214 to evaluate hemodynamic effects and safety in patients with systolic heart failure. The primary objective of the study is to determine effects of ITI-214 on cardiac contractility and cardiac output in patients already maintained on standard-of-care treatment for chronic heart failure.

Initiation of Study 104 followed findings that ITI-214 improved cardiac output through a different mechanism of action than available heart failure therapies. These findings in a preclinical model of heart failure were published by researchers at Johns Hopkins University and ITCI scientists in the journal Circulation. Currently available heart failure drugs that strengthen heart contractions, such as the PDE3 inhibitors (amrinone and milrinone) and ß-adrenergic agonists (dobutamine), increase calcium entry into cardiac muscle cells and have potentially dangerous complications, such as irregular heartbeats. Unlike these drugs, ITI-214 did not cause calcium levels to rise in cardiomyocyte cells and did not interact with the ß-adrenergic signaling pathway. These experimental results demonstrate that ITI-214 exerts its effects via a separate pathway involving adenosine A2B receptor signaling, previously shown to be cardioprotective, and suggest that ITI-214 may represent a novel and potentially safer approach for the treatment of human heart failure.

"We are encouraged by the continuing safety of ITI-214 in patients with heart failure and our progress toward completion of this important mechanistic study," said Sharon Mates Ph.D., Chairman and CEO of Intra-Cellular Therapies "We believe ITI-214 offers a potential new treatment for heart failure with a novel mechanism."

Study ‘104 is a randomized, double-blind, placebo-controlled study of escalating single doses of oral ITI-214 to evaluate hemodynamic effects and safety in patients with systolic heart failure (NYHA class II-III heart failure). This single dose ascending Study evaluates three dose cohorts of ITI-214: 10 mg, 30 mg and 90 mg with 12 patients per cohort randomized to ITI-214 or placebo 9:3. The primary objective of the study is to determine effects of ITI-214 on cardiac contractility and cardiac output using echocardiogram with doppler imaging and hemodynamic monitoring in patients already maintained on standard-of-care treatment for chronic heart failure. Secondary objectives include safety and tolerability. This Study is being conducted at Johns Hopkins University and Duke Clinical Research Institute.

Heart failure affects about 5.7 million U.S. adults, according to the U.S. Centers for Disease Control and Prevention and contributes to an estimated one in nine deaths. Human heart failure is a chronic condition often marked by weakening of the heart muscle and its subsequent failure to pump enough blood. Currently, drugs are available to treat or manage heart failure symptoms, but drugs that improve the strength of the heart muscle’s contractions, carry the risk of dangerous complications such as developing irregular heartbeats. There is no cure. PDE1 inhibition may provide a new approach to treating heart failure that may not have the adverse events currently seen in available drugs.

ITI-214, is a potent and selective phosphodiesterase type 1 (PDE1) inhibitor. ITI-214 is the lead compound in the Company’s PDE1 portfolio and is in development for the treatment of symptoms associated with Parkinson's disease and for the treatment of heart failure. ITI-214 has been found to be generally well tolerated with a favorable safety profile in four Phase 1 clinical trials. ITI-214 works by slowing the breakdown of cyclic nucleotides (cAMP, cGMP), allowing these molecules to build up in the cells and to exert important functions. The PDE1 enzyme is highly active in pathological or disease states, and our PDE1 molecules are designed to reestablish normal function in these disease states through the inhibition of the PDE1 enzyme. ITI-214 may allow precise adjustment of cAMP and/or cGMP in cells in which it is present. In heart disease, excessive PDE1 activity may limit the beneficial effects of cAMP or cGMP, so inhibitors like ITI-214, have the potential to act as a therapy. Previous studies have described the mechanism of action of ITI-214 in the brain. The mechanism of action of ITI-214 suggests therapeutic potential across a variety of neurological and cardiovascular diseases.

Intra-Cellular Therapies is developing novel drugs for the treatment of neuropsychiatric and neurodegenerative diseases and diseases of the elderly, including Parkinson's and Alzheimer's disease. The Company is developing its lead drug candidate, lumateperone (also known as ITI-007), for the treatment of schizophrenia, bipolar disorder, behavioral disturbances in patients with dementia, including Alzheimer's disease, depression and other neuropsychiatric and neurological disorders. Lumateperone is under review by the FDA for the treatment of schizophrenia and is in Phase 3 clinical development for the treatment of bipolar depression. Intra-Cellular Therapies is also utilizing its phosphodiesterase (PDE) platform and other proprietary chemistry platforms to develop drugs for the treatment of CNS and other disorders. The lead molecule in the Company's PDE1 portfolio, ITI-214, is in development for the treatment of symptoms associated with Parkinson's disease and for the treatment of heart failure.

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