Article elucidates ITI-214’s mechanism of action

Modulation of adenosine A2B receptor signaling pathway increases cardiac contractility without increasing intracellular calcium

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NEW YORK—Intra-Cellular Therapies Inc. (ITCI) has announced the online publication of an article in the journal Circulation describing the mechanism of action of its phosphodiesterase (PDE) type 1 inhibitor, ITI-214, and its potential use for the treatment of heart failure. In these preclinical studies, Johns Hopkins researchers in collaboration with ITCI scientists demonstrated that ITI-214 improved cardiac output through a different mechanism of action than available therapies for the treatment of heart failure. These studies suggest that ITI-214 may represent a novel approach for this indication.
ITI-214 is a potent and selective phosphodiesterase type 1 (PDE1) inhibitor. As the clinical lead compound in the company’s PDE1 portfolio, ITI-214 has been found to be generally well tolerated with a favorable safety profile in four Phase 1 clinical trials, in healthy volunteers as well as patients with schizophrenia. 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 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. ITI-214 is currently in development for the treatment of symptoms associated with Parkinson’s disease, and for the treatment of heart failure.
“Our results demonstrate that ITI-214, unlike other pharmacological approaches, increases heart contractility through a novel mechanism of action that may lead to efficacious and safer therapies for patients,” said Dr. David Kass, the Abraham and Virginia Weiss Professor of Cardiology at Johns Hopkins University School of Medicine and principal investigator of the study.
ITI-214 is currently in a Phase 1/2 clinical study for the treatment of Parkinson’s disease and a Phase 1/2 clinical study in heart failure. The heart failure study is assessing the impact of ITI-214 on cardiovascular function in humans and will help determine if the positive preclinical findings seen in animal models are translatable to humans.
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 existing heart failure drugs, ITI-214 did not cause calcium levels to rise in rabbit 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. Therefore, the pharmacological profile of ITI-214 introduces a new mechanism of action for the treatment of heart failure that is different from ß-adrenergic agonism and PDE3 inhibition.
Dr. Sharon Mates, chairman and CEO of Intra-Cellular Therapies, noted that, “ITI-214 offers a potential new treatment for heart failure with a novel mechanism of action that may provide an effective and safer alternative to existing therapies.”
In late August, the company also announced the expansion of its senior leadership team with the appointment of Dr. Suresh Durgam, senior vice president of Late-Stage Clinical Development and Medical Affairs. Durgam brings over 15 years of experience in neuropsychiatric drug development, including the development of antipsychotics and antidepressants.
“We are very pleased to welcome Dr. Durgam to Intra-Cellular, as he brings additional expertise to our clinical programs. We believe his contributions will be invaluable as we continue to advance lumateperone and our pipeline,” remarked Dr. Andrew Satlin, executive vice president and chief medical officer of Intra-Cellular Therapies.
Durgam most recently served in clinical development leadership roles at Allergan plc, where he was the clinical lead responsible for development of treatments for mood disorders, including rapid-acting antidepressant programs. Durgam was also the clinical development lead of the antipsychotic cariprazine, advancing the compound from Phase 1 to approval in schizophrenia and bipolar disorder. Durgam graduated with his medical degree from the Siddhartha Medical College in India, and received his residency training in psychiatry at Scott & White Clinic and Hospital – Texas A&M University System College of Medicine.
“I am excited to join Intra-Cellular Therapies. Lumateperone has a novel mechanism of action with the potential to address unmet medical needs in schizophrenia and other neuropsychiatric disorders including bipolar disorder, agitation associated with dementia and depression,” stated Durgam. “I look forward to contributing to the success of these programs and further broadening our scope into additional therapeutic areas.”

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