Intra-Cellular Therapies Announces Positive Top-line Results from Phase 1/2 Study

Intra-Cellular Therapies, Inc. recently announced topline results from Study ITI-214-104, a Phase 1/2 translational study of single ascending doses of ITI-214, a novel, selective phosphodiesterase-1 (PDE1) inhibitor, in patients with chronic systolic heart failure with reduced ejection fraction (HFrEF). ITI-214 is the first PDE1 inhibitor to be tested in patients with HFrEF.

In this study, ITI-214 improved cardiac output by increasing heart contractility and decreasing vascular resistance. Agents that both increase heart contractility (inotropism) and decrease vascular resistance (vasodilation) are called inodilators. Inodilators in current clinical use are associated with the development of arrhythmias, which are abnormal heart rhythms that when serious can impair heart function and lead to mortality.  ITI-214, which acts through a novel mechanism of action, was not associated with arrhythmias in this study and was generally well tolerated in all patients.

The results of Study ITI-214-104 are consistent with our prior findings in preclinical models of heart failure and indicate that single-dose administration of ITI-214 can improve heart function in patients with HFrEF. These findings warrant further investigation of acute and chronic PDE-1 inhibition with ITI-214 in this patient population.

“ITI-214 improved the strength of heart contraction on top of lowering blood pressure stress on the heart.  This occurred without impacting arrhythmia in patients with heart failure. These exciting results support a novel mechanism of action, and suggest that inhibition of the PDE-1 enzyme concurrent with standard-of-care may benefit heart failure patients without incurring the risks associated with inodilators in current clinical use,” said David Kass, MD, the Abraham and Virginia Weiss Professor of Cardiology at Johns Hopkins University School of Medicine, who was involved in the study.

“Based on these findings, ITI-214 has the potential to be a safe, once-a-day oral inodilator with a novel mechanism of action that could have utility in clinical situations where there is great unmet medical need, ranging from the treatment of acute heart failure to the maintenance of patients with stable chronic HFrEF,” said Sharon Mates, PhD, Chairman and CEO of Intra-Cellular Therapies, Inc.

The initiation of Study ITI-214-104 followed findings in preclinical models that ITI-214 had improved cardiac output through a mechanism of action different from those of available heart failure therapies. These findings in preclinical models of heart failure were published by researchers at Johns Hopkins University and Intra-Cellular Therapies scientists in the journal Circulation.  Currently available heart failure drugs that strengthen heart contractions, such as PDE3 inhibitors (amrinone and milrinone) and beta-adrenergic agonists (dobutamine), are associated with potentially dangerous complications, such as arrhythmias. ITI-214 does not interact with the beta-adrenergic signaling pathway and does not stimulate abnormal rhythms in an animal model of heart failure.  These experimental results demonstrated that ITI-214 may exert its effects via distinct pathways, one of which involves adenosine A_2B receptor signaling, and suggest that ITI-214 may represent a mechanistically novel and potentially safe approach for the treatment of human heart failure.

Study ITI-214-104 was a randomized, double-blind, placebo-controlled study of escalating single oral doses of ITI-214 (10, 30, and 90 mg) in patients with HFrEF NYHA class II-III.  The primary objective of the study was to determine the effects of ITI-214 on cardiac function, using echocardiography with Doppler imaging, in patients with reduced ejection fraction (≤35%) who were already maintained on standard-of-care treatment.  Safety was evaluated by monitoring for hemodynamic effects and changes in cardiac rhythm.

Thirty-five patients were enrolled in this study, 9 in each of three dose cohorts and 8 in the placebo arm. The mean age of the patients was 54; 57% were male, and 57% were black. The etiology of the heart failure was ischemic heart disease in 31% of the patients. The mean left ventricular ejection fraction at screening was 25%.

In this study, compared to placebo, single doses of ITI-214 increased mean left ventricular (LV) power index and cardiac output while systemic vascular resistance and mean arterial blood pressure decreased. Reported adverse events were all mild to moderate and consisted of three occurrences of orthostatic hypotension and three episodes of non-postural hypotension. Patients were monitored by continuous telemetry, and no changes in heart rhythms were noted. No serious adverse events were reported. Further details of these results will be presented at upcoming medical conferences.

According to the US Centers for Disease Control and Prevention, heart failure affects about 6.5 million adults in the US and contributes to an estimated one in eight deaths. Heart failure is a chronic condition marked by weakening of the heart muscle that leads to shortness of breath and general body weakness that worsens with physical exertion. There is no cure for heart failure, and there is significant unmet need, particularly for safe agents that can both increase the strength of the heart as well as reduce vascular afterload.

Currently available heart failure drugs that can improve the contractile strength of the heart muscle, such as the PDE3 inhibitors amrinone and milrinone, and the beta-adrenergic agonist dobutamine, increase cyclic AMP and thereby increase intracellular calcium in cardiac muscle cells. Both approaches are associated with safety risks, most notably arrhythmia.

PDE1 inhibition also modifies cyclic AMP, but it does so in a different manner linked with a novel intracellular pathway that involves adenosine A_2B receptor signaling but not beta-adrenergic signaling to stimulate heart contractility. ITI-214 did not cause calcium levels to rise in cardiomyocyte cells. In all of the studies to date, activation of the PDE1-regulated pathway has not triggered arrhythmia.

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 generally well tolerated with a favorable safety profile in six Phase 1 clinical trials. ITI-214 works by slowing the breakdown of cyclic nucleotides (cAMP, cGMP), thus 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.

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. ITI-214 is an inodilator that can improve cardiac function by both increasing the force of heart contractions and reducing the resistance to pushing blood through the vascular system. Preclinical research has shown that ITI-214 increases cardiac contractility and decreases vascular resistance without increasing abnormal heart rhythms, and the clinical results announced herein indicate that similar, potentially therapeutic physiologic effects can be attained in heart failure patients. ITI-214 is being developed for the potential treatment of heart failure with reduced ejection fraction (HFrEF).

Previous studies have described the mechanism of action of ITI-214 in the brain. The mechanism of action of ITI-214 and our other PDE1 inhibitors suggests therapeutic potential across a variety of diseases including neurological and cardiovascular diseases.

Intra-Cellular Therapies is a biopharmaceutical company founded on Nobel prize-winning research that allows us to understand how therapies affect the inner-workings of cells in the body. The company leverages this intracellular approach to develop innovative treatments for people living with complex psychiatric and neurologic diseases. For more information, visit www.intracellulartherapies.com.