EMBRACE-STEMI: Drug targeting mitochondria does not reduce infarct size
SAN DIEGO — The novel drug Bendavia did not meet any of its primary or secondary endpoints in a trial assessing its use prior to primary PCI in patients with STEMI, according to data presented at the American College of Cardiology Scientific Sessions.
Patients assigned Bendavia, a cell-permeable and mitochondrial inner membrane-targeting peptide, before undergoing angioplasty or receiving a stent to clear blocked arteries after MI showed no significant reduction in scarring compared with patients assigned placebo.
Among patients with a first anterior STEMI due to a proximal or mid left anterior descending artery (LAD) occlusion who undergo successful PCI, Bendavia was safe and well-tolerated but did not meet its primary endpoint, researchers found.
The phase 2a, prospective, multicenter, double blind EMBRACE-STEMI trial was the first randomized, controlled trial of Bendavia (Stealth BioTherapeutics).
C. Michael Gibson
“The mitochondria — the powerhouse of the cell — is one of the key players in reperfusion injury,” researcher C. Michael Gibson, MD, professor of medicine at Harvard Medical School, said in a press release. “The goal of Bendavia is to help the mitochondria stay functional, and therefore to reduce the amount of tissue damage and injury.”
Researchers randomly assigned 297 patients with first-time anterior STEMI across 24 hospitals in four countries to receive either IV Bendavia (Stealth Biotherapeutics) or placebo at a rate of 0.05 mg/kg for 1 hour. Treatment was administered at least 15 minutes prior to and 1 hour after primary PCI due to a proximal LAD occlusion.
The primary endpoint was the area under the curve (AUC) for leakage of the creatinine kinase-MB enzyme within 72 hours of successful PCI. The clinical endpoint was a composite of all-cause mortality, new onset congestive HF more than 24 hours after PCI during index hospitalization and rehospitalization for congestive HF. Infarct size as indicated by cardiac MRI was a secondary endpoint, along with infarct size as indicated by the AUC for troponin I, microvascular dysfunction on MRI, TIMI myocardial perfusion grade and the corrected TIMI frame count after PCI and ST segment resolution.
The primary analysis included 118 evaluable patients, with 60 receiving placebo and 58 treated with Bendavia. Hypertension was significantly more common among placebo recipients (60% vs. 37.9%; P = .02).
Researchers observed a 10% reduction in scarring within 6 hours of surgery as indicated by the AUC for creatinine kinase-MB enzyme. This observation was in keeping with results from animal studies of the drug, but was not statistically significant, Gibson said during a press conference. He added that the trial was “grossly underpowered” to detect a difference within this sample size, and that between 800 and 1,000 patients would be necessary for the difference to be statistically significant.
There was a trend toward improved heart pumping function within 8 hours of treatment, which was similar to results from studies of Bendavia in animal models. An exploratory prespecified analysis of congestive HF symptom onset indicated a trend toward reduction of symptomatic HF within the first 8 hours post-PCI (8.6% of Bendavia recipients vs. 18.3% of placebo recipients; P = .18).
No significant difference was observed between treated patients and placebo recipients for any of the evaluated secondary endpoints or incidence of adverse events. In a subgroup analysis of patients with hypertension, researchers observed a significant reduction in infarct size (P = .03) and a borderline-significant reduction in edema volume (P = .053) on MRI at 4 ± 1 days after PCI. Complete ST segment resolution was also more common among hypertensive Bendavia recipients compared with placebo recipients (66.7% vs. 44.1%; P = .05).
“The drug did not reduce the primary endpoint of the study except in those subgroups,” Gibson concluded. However, he added, the data from this trial supports two ongoing studies assessing Bendavia in patients with HF. An observed significant reduction in change to creatinine levels within 12 hours of PCI (P = .03) is also being prospectively evaluated, he said.
“This is what we do in phase 2 studies: We explore,” Gibson said. “Sometimes you don’t hit on the primary endpoint, but you create hypothesis-generating information that is tested in other studies, which is what has been done here.” – by Adam Taliercio
Gibson CM. Joint ACC/JAMA Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Sessions: March 14-16, 2015; San Diego.
Disclosure: Stealth BioTherapeutics funded the study. Gibson reports receiving consulting fees/honoraria from Bayer, BCRI, Cardiovascular Research Foundation, Janssen
Pharmaceuticals/Johnson & Johnson/Ortho McNeil, St. Jude Medical, The Medicines Company and WebMD; financial ties with UpToDate in Cardiovascular Medicine; and research grants from Angel Medical, Bayer, CSL Behring, Ikaria, Janssen Pharmaceuticals/Johnson & Johnson, Portola, St. Jude Medical and Stealth Peptides.