Contact: Amanda Jekowsky, ajekowsk@acc.org, 202-731-3069

NOVEL DRUG PRODUCES NEGATIVE RESULTS IN REDUCING HEART INJURY AFTER BLOCKED ARTERIES ARE OPENED
Phase IIb Trial Fails to Find Level of Benefit Seen in Phase I/II after Heart Attack

New Orleans, LA – Delcasertib (previously known as KAI-9803), a novel drug that hinders an enzyme linked to reperfusion, did not significantly decrease heart tissue damage from artery-opening surgery, according to research from a Phase IIb study presented today at the American College of Cardiology’s 60th Annual Scientific Session. ACC.11 is the premier cardiovascular medical meeting, bringing together cardiologists and cardiovascular specialists to further advances in cardiovascular medicine.

Reperfusion is a flood of blood and oxygen due to opening clogged arteries. Reperfusion injury has been proven in animal models but is unconfirmed in humans. Delcasertib is a first-in-class non-toxic drug that inhibits PKC, an enzyme that has been implicated in reperfusion injury. It decreased reperfusion injury by up to 70 percent in animal models and appeared to reduce damage to heart muscle in a small Phase I/II clinical trial.

“We’ve made progress in reducing death rates. In many contemporary studies, 95 percent of patients hospitalized for a heart attack now survive, but we’re treating populations of patients who have chronic heart failure from the damage they experienced earlier,” said A. Michael Lincoff, M.D., director of the Cleveland Clinic Coordinating Center for Clinical Research, in Cleveland, Ohio, and the study’s principal investigator. “If we want to limit the size and impact of heart attacks, we have to look for ways to prevent heart attack damage in the first place.”

The Phase IIb trial is the final dose-finding study of delcasertib in a larger population. A total of 1,176 patients were randomly assigned to study arms at 114 sites in 18 countries. Of these, the 911 patients with anterior ST-elevation MI (STEMI), generally a more dangerous type of heart attack than inferior STEMI, were the primary cohort. They were randomly assigned to a control placebo group (683 patients) or to one of three delcasertib groups (228 patients) with doses of 50 mg/hr, 150 mg/hr or 450 mg/hr. The drug was administered intravenously immediately after randomization and before the artery was opened, and was continued for up to 2.5 hours after angioplasty – the most common procedure to open blocked arteries after a heart attack. There were no other changes in practice. Patients had angioplasty if suitable, with all other care administered according to the practice of each institution.

The main endpoints were enzyme measurements of infarct size (area of heart muscle death caused by a heart attack), electrocardiograph measurements, and left ventricle ejection fraction at three months, a measure of the pumping efficiency of the heart’s main chamber. By all three of these endpoints, there was no appreciable difference between the treatment and placebo groups. A smaller cohort (156 patients) with inferior STEMI was randomly assigned to placebo or the highest delcasertib dose. Results were also negative for this group.

About one-third of patients had a spontaneously opened artery before they came to the lab, the usual percentage for this natural occurrence. The two-thirds whose blocked arteries did not open naturally are at higher risk for injury. Among that group, there was a trend toward a dose-related reduction in heart damage, but the benefit did not reach statistical significance (p = 0.186).

“This field is one of the few in heart attack treatment that is littered with a number of promising but failed large clinical trials,” Lincoff said. “The non-significant benefit we saw in one subset of patients suggests some biological activity with PKC inhibition, which may be a promising platform to pursue for other indications with agents that use the same mechanism.”

The study was conducted by Cleveland Clinic and supported by KAI Pharmaceuticals in collaboration with Bristol-Myers Squibb. Lincoff receives research funding and travel reimbursement from KAI and Bristol-Myers Squibb and has been an advisor/consultant to Bristol-Myers Squibb.

Dr. Lincoff will be available to the media on Tuesday, April 5, at 9:45 a.m. CDT, in Room 338/339.
Dr. Lincoff will present the study, “Selective Inhibition of Delta Protein Kinase C to Reduce Infarct Size After Primary Percutaneous Intervention for Acute Myocardial Infarction – the PROTECTION-AMI Phase IIb Clinical Trial,” on Tuesday, April 5, at 8:00 a.m. CDT, in the Joint Main Tent: La Nouvelle.

The American College of Cardiology (www.cardiosource.org) represents the majority of board certified cardiovascular care professionals through education, research, promotion, development and application of standards and guidelines – and to influence health care policy. ACC.11 is the largest cardiovascular meeting, bringing together cardiologists and cardiovascular specialists to share the newest discoveries in treatment and prevention, while helping the ACC achieve its mission to address and improve issues in cardiovascular medicine.
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