Randomized, Placebo-Controlled Phase 2b Study to Evaluate the Safety and Efficacy of Recombinant Human Lecithin Cholesterol Acyltransferase in Acute ST-Segment-Elevation Myocardial Infarction: Results of REAL-TIMI 63B.

Jose Lopez-Sendon, Marc S Sabatine, Richard T George, Yi-Ting Chang, Andrea L Vavere, Sami A Omar, Boaz Hirshberg, Liron Abuhatzira, Remo H M Furtado, Jose Carlos Nicolau, Jacek Kubica, Stephen B Wheatcroft, Oleg Averkov, Marc P Bonaca, Róbert G Kiss, Ton Oude Ophuis, Jindrich Spinar, Sabina A Murphy, Julia Kuder, Michael T Lu, Yoko Kato, Udo Hoffmann, Joao A C Lima, David D Berg, Brian A Bergmark, David A Morrow

Journal: Circulation 2022;146(12):907-916

PMID: 36039762

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Abstract

BACKGROUND

High-density lipoprotein plays a key role in reverse cholesterol transport. In addition, high-density lipoprotein particles may be cardioprotective and reduce infarct size in the setting of myocardial injury. Lecithin-cholesterol acyltransferase is a rate-limiting enzyme in reverse cholesterol transport. MEDI6012 is a recombinant human lecithin-cholesterol acyltransferase that increases high-density lipoprotein cholesterol. Administration of lecithin-cholesterol acyltransferase has the potential to reduce infarct size and regress coronary plaque in acute ST-segment-elevation myocardial infarction.

METHODS

REAL-TIMI 63B (A Randomized, Placebo‑controlled Phase 2b Study to Evaluate the Safety and Efficacy of MEDI6012 in Acute ST Elevation Myocardial Infarction) was a phase 2B multinational, placebo-controlled, randomized trial. Patients with ST-segment-elevation myocardial infarction within 6 hours of symptom onset and planned for percutaneous intervention were randomly assigned 2:1 to MEDI6012 (2- or 6-dose regimen) or placebo and followed for 12 weeks. The primary outcome was infarct size as a percentage of left ventricular mass by cardiac MRI at 10 to 12 weeks, with the primary analysis in patients with TIMI Flow Grade 0 to 1 before percutaneous intervention who received at least 2 doses of MEDI6012. The secondary outcome was change in noncalcified plaque volume on coronary computed tomographic angiography from baseline to 10 to 12 weeks with the primary analysis in patients who received all 6 doses of MEDI6012.

RESULTS

A total of 593 patients were randomly assigned. Patients were a median of 62 years old, 77.9% male, and 95.8% statin naive. Median time from symptom onset to randomization was 146 (interquartile range [IQR], 103-221) minutes and from hospitalization to randomization was 12.7 (IQR, 6.6-24.0) minutes, and the first dose of drug was administered a median of 8 (IQR, 3-13) minutes before percutaneous intervention. The index myocardial infarction was anterior in 69.6% and TIMI Flow Grade 0 to 1 in 65.1% of patients. At 12 weeks, infarct size did not differ between treatment groups (MEDI6012: 9.71%, IQR 4.79-16.38; placebo: 10.48%, [IQR, 4.92-16.61], 1-sided =0.79. There was also no difference in noncalcified plaque volume (geometric mean ratio, 0.96 [95% CI, NA-1.10], 1-sided =0.30). There was no significant difference in treatment emergent serious adverse events.

CONCLUSIONS

Administration of MEDI6012 in patients with acute ST-segment-elevation myocardial infarction did not result in a significant reduction in infarct size or noncalcified plaque volume at 12 weeks. MEDI6012 was well tolerated with no excess in overall serious adverse events.

REGISTRATION

URL: https://www.

CLINICALTRIALS

gov; Unique identifier: NCT03578809.

Address: CPC Clinical Research, Department of Medicine, University of Colorado Anschutz School of Medicine, Aurora (M.P.B.).; TIMI Study Group, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (D.A.M., B.A.B., D.D.B., J. Kuder, S.A.M., M.S.S.).; Division of Cardiology, Johns Hopkins University, Baltimore, MD (J.A.C.L., Y.K.).; Internal Cardioangiology Department, St. Ann University Hospital and Masaryk University, Brno, Czechia (J.S.).; Cardiovascular Imaging Research Center, Massachusetts General Hospital and Harvard Medical School, Boston (U.H., M.T.L.).; Canisius Wilhelmina Ziekenhuis, Nijmegen, The Netherlands (T.O.O.).; Department of Cardiology, Military Hospital, Budapest, Hungary (R.G.K.).; IdiPaz Research Institute, Hospital Universitario La Paz, UAM, Madrid, Spain (J.L.-S.).; Pirogov Russian National Research Medical University, Moscow (O.A.).; Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, UK (S.B.W.).; Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland (J. Kubica).; Instituto do Coracao, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo, Brazil (J.C.N., R.H.M.F.).; Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo, Brazil (R.H.M.G.).; Horizon Therapeutics, Gaithersburg, MD (L.A.).; Regio Biosciences, Rockville, MD (B.H.).; Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD (S.A.O., A.L.V., Y.-T.C., R.T.G.).

DOI: 10.1161/CIRCULATIONAHA.122.059325

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MeSH Terms: Anterior Wall Myocardial Infarction, Cholesterol, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lecithins, Lipoproteins, HDL, Male, Middle Aged, Phosphatidylcholine-Sterol O-Acyltransferase, ST Elevation Myocardial Infarction, Sterol O-Acyltransferase, Treatment Outcome