Teprasiran, A Small Interfering RNA, for the Prevention of Acute Kidney Injury in High-Risk Patients Undergoing Cardiac Surgery: A Randomized Clinical Study

Matthias Thielmann, Department of Thoracic and Cardiovascular Surgery, West-German Heart and Vascular Center Essen, University Duisburg-Essen, Essen, Germany.
David Corteville, Rochester Regional HealthFollow
Gabor Szabo, Central German Heart Center University Hospital Halle (Saale), University Clinic and Polyclinic for Cardiac Surgery, Halle, Germany.
Madhav Swaminathan, Division of Cardiothoracic Anesthesiology and Critical Care Medicine, Duke University Medical Center, Durham, NC.
Andre Lamy, David Braley Cardiac, Vascular and Stroke Research Institute, McMaster University, Hamilton, ON, Canada.
Lukas J. Lehner, Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin, Berlin, Germany.
Craig D. Brown, New Brunswick Heart Centre, The Saint John Regional Hospital, Saint John, NB, Canada.
Nicolas Noiseux, Division of Cardiac Surgery, University of Montreal Hospital Center, CHUM Research Center, Montreal, QC, Canada.
Mohamed G. Atta, Division of Nephrology, Johns Hopkins School of Medicine, Baltimore, MD.
Elizabeth C. Squiers, Coastal Vista Consulting L.L.C, Half Moon Bay, CA.
Shai Erlich, Quark Pharmaceuticals, Inc., Newark, CA.
Daniel Rothenstein, Quark Pharmaceuticals, Inc., Newark, CA.
Bruce Molitoris, Nephrology Division, Department of Medicine, Indiana University School of Medicine; Indiana Center for Biological Microscopy, Indianapolis, IN.
C David Mazer, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Institute of Medical Sciences and Departments of Anesthesia and Physiology, University of Toronto, Toronto, ON, Canada.

Department

Cardiology

Document Type

Article

Publication Title

Circulation

Abstract

Acute kidney injury (AKI) affects up to 30% of cardiac surgery patients, leading to increased in-hospital and long-term morbidity and mortality. Teprasiran is a novel small interfering RNA (siRNA) that temporarily inhibits p53-mediated cell death, which underlies AKI. This prospective, multicenter, double-blind, randomized, controlled Phase 2 trial evaluated the efficacy and safety of a single 10 mg/kg dose of teprasiran vs. placebo (1:1), in reducing the incidence, severity, and duration of AKI following cardiac surgery in high-risk patients. The primary endpoint was proportion of patients who developed AKI determined by serum creatinine (sCr) by post-operative day 5. Other endpoints included AKI severity and duration using various prespecified criteria. To inform future clinical development, a composite endpoint of major adverse kidney events at day 90 (MAKE90), including death, renal replacement therapy (RRT) and ≥25% reduction of estimated glomerular filtration rate (eGFR) was assessed. Both sCr and serum cystatin-C (sCys) were used for eGFR assessments. A total of 360 patients were randomized in 41 centers. 341 dosed patients were 73±7.5 years old (mean±SD), 72% were male, and median Euroscore-II (European System for Cardiac Operative Risk Evaluation) was 2.6%. Demographics and surgical parameters were similar between groups. AKI incidence was 37% for teprasiran vs. 50% for placebo-treated patients, a 12.8% absolute risk reduction (ARR), p=0.02; OR=0.58 (95% CI 0.37 to 0.92). AKI severity and duration were also improved with teprasiran: 2.5% of teprasiran vs. 6.7% of placebo-treated patients had Grade 3 AKI; 7% teprasiran vs. 13% placebo-treated patients had AKI lasting for 5 days. No significant difference was observed for the MAKE90 composite in the overall population. No safety issues were identified with teprasiran treatment. The incidence, severity, and duration of early AKI in high-risk patients undergoing cardiac surgery were significantly reduced following teprasiran administration. A Phase 3 study with a MAKE90 primary outcome which has recently completed enrollment was designed based on these findings (NCT03510897). URL: https://clinicaltrials.gov/ Unique Identifier: NCT02610283.

DOI

10.1161/CIRCULATIONAHA.120.053029

Publication Date

9-4-2021

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