Delcasertib Fails to Prevent Reperfusion Injury Post MI



NEW ORLEANS – The investigational agent delcasertib failed to reduce myocardial infarct size or improve clinical outcomes when given during percutaneous coronary intervention for acute MI in the phase IIb PROTECTION AMI trial.

Delcasertib is a highly selective inhibitor of delta protein kinase C, which has been implicated in mitochondrial injury during ischemic reperfusion injury and apoptosis or necrosis. Based on a previous study showing delcasertib reduced biomarkers of infarct size, "we had expected a 20% reduction in infarct size, and we did not observe that across all dosages," lead author Dr. A. Michael Lincoff said in presenting the results of the phase IIb PROTECTION AMI trial at the annual meeting of the American College of Cardiology.

During a panel discussion of the findings, Dr. Sanjay Kaul of Cedars Sinai Medical Center, Los Angeles, said delcasertib joins a long list of treatments targeting reperfusion injury where the promise of cardioprotection seen in experimental models has not translated into clinical trial evidence.

"Congratulations, Dr. Lincoff, on a well-performed and well-presented study, but unfortunately, another one bites the dust," he said.

Dr. Kaul said there are critical differences between animal models and humans – most notably that the timing of ischemia in humans is uncertain – and he asked whether the treatment was given too late, the dose was incorrect, and the intravenous route of administration was appropriate.

Dr. Lincoff replied that the lack of virtually any side effects associated with delcasertib, previously known as KAI-9803, allowed them to use very high doses that were shown to provide blood and tissue levels similar to those observed with intracoronary administration. Animal studies were also performed comparing intravenous with intracoronary administration and the effect was the same, even when delcasertib was administered after the ischemia had started. Typically, the drug was on board 17 minutes before PCI began.

Based on the results, Bristol-Myers Squibb has decided not to continue development of delcasertib, although study cosponsor KAI Pharmaceuticals has continued interest in evaluating the drug for such indications as stroke, coronary bypass surgery and kidney damage, said Dr. Lincoff, director of the Cleveland Clinic Coordinating Center for Clinical Research.

The phase IIb PROTECTION AMI analysis included 1,176 patients with acute ST-segment elevation myocardial infarction (STEMI), cardiac ischemia for at least 30 minutes, arriving for PCI within 6 hours of symptom onset and randomly assigned them to placebo or delcasertib IV infusion at 50 mg per hour, 150 mg/hour or 450 mg/hour immediately before PCI.

Among 911 evaluable anterior STEMI patients, there was no significant difference in the primary end point of infarct size as assessed by creatine kinase-MB area under the curve (AUC) between the placebo arm (6,471 ng-hr/mL) and delcasertib at the 50-mg dose (5,917 ng-hr/mL), the 150-mg dose (5,650 ng-hr/mL) or 450-mg dose (6,204 ng-hr/mL), Dr. Lincoff said.

ST segment recovery AUC on 24-hour ECG monitoring was also similar at 8,377 microvolt per minute, 7,707 microV-min., 7,779 microV-min. and 8,188 microV-min., respectively.

At 3-month follow-up, 8.6% of placebo-treated patients had a left ventricular ejection fraction of 30% or more compared with 5.1% treated with 50 mg delcasertib, 7.3% with 150 mg and 9.0% with 450 mg. Outcomes were also similar among 156 patients with inferior STEMI.

Recognizing that some patients may have arrived at the PCI lab and received delcasertib after already experiencing reperfusion injury, the researchers evaluated a prospectively defined subgroup of anterior MI patients based on pre-PCI TIMI (Thrombolysis in Myocardial Infarction) scores. Among these patients, there was a soft trend toward improved CK-MB AUC with delcasertib in patients with occluded TIMI flow (score 0/1), suggesting there may be some biological activity with the agent, Dr. Lincoff said. CK-MB AUC was 8,013 ng-hr/mL with placebo, 7,232 ng-hr/mL with delcasertib 50 mg, 6,872 ng-hr/mL with 150 mg, and 6,879 ng-hr/mL with 450 mg.

PROTECTION AMI was supported by Bristol-Myers Squibb and KAI Pharmaceuticals. Dr. Lincoff reported research funding and travel reimbursement from KAI and Bristol-Myers Squibb and has been an advisor to Bristol-Myers Squibb.

Recommended Reading

Analyses Find Calcium Plus Vitamin D Increases MI Risk
MDedge Cardiology
Low Guideline Compliance for AAA May Increase Rupture Risk After EVAR
MDedge Cardiology
Benefits of Using Lipid-Lowering Agents Persist After Trials End
MDedge Cardiology
Tai Chi Shown to Improve Quality of Life in Heart Failure Patients
MDedge Cardiology
Maximizing Stroke Risk Reduction in Elderly Hypertensives
MDedge Cardiology