Efficacy and safety of CDR132L in patients with reduced left ventricular ejection fraction after myocardial infarction: Rationale and design of the HF‐REVERT trial

Author:

Bauersachs Johann1,Solomon Scott D.2,Anker Stefan D.3,Antorrena‐Miranda Isabel4,Batkai Sandor5,Viereck Janika5,Rump Steffen5,Filippatos Gerasimos6,Granzer Ulrich7,Ponikowski Piotr8,de Boer Rudolf A.9,Vardeny Orly10,Hauke Wilfried5,Thum Thomas511

Affiliation:

1. Department of Cardiology and Angiology Hannover Medical School Hannover Germany

2. Cardiovascular Division Brigham and Women's Hospital, Harvard Medical School Boston MA USA

3. Department of Cardiology (CVK) of German Heart Center Charité, BIH Center for Regenerative Therapies (BCRT) German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin Berlin Germany

4. Cardiology Department Hospital Universitario la Paz‐Idipaz Madrid Spain

5. Cardior Pharmaceuticals GmbH Hannover Germany

6. Department of Cardiology, School of Medicine Athens University Hospital Attikon, National and Kapodistrian University of Athens Athens Greece

7. Granzer Regulatory Consulting & Services GmbH Munich Germany

8. Institute of Heart Diseases University Hospital, Medical University Wroclaw Wroclaw Poland

9. Department of Cardiology Erasmus Medical Center Rotterdam The Netherlands

10. University of Minnesota Medical School Minneapolis MN USA

11. Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School Hannover Germany

Abstract

AimInhibition of microRNA (miR)‐132 effectively prevents and reverses adverse cardiac remodelling, making it an attractive heart failure (HF) target. CDR132L, a synthetic antisense oligonucleotide selectively blocking pathologically elevated miR‐132, demonstrated beneficial effects on left ventricular (LV) structure and function in relevant preclinical models, and was safe and well tolerated in a Phase 1b study in stable chronic HF patients. Patients with acute myocardial infarction (MI) and subsequent LV dysfunction and remodelling have limited therapeutic options, and may profit from early CDR132L treatment.MethodsThe HF‐REVERT (Phase 2, multicenter, randomized, parallel, 3‐arm, placebo‐controlled Study to Assess Efficacy and Safety of CDR132L in Patients with Reduced Left Ventricular Ejection Fraction after Myocardial Infarction) evaluates the efficacy and safety of CDR132L in HF patients post‐acute MI (n = 280), comparing the effect of 5 and 10 mg/kg CDR132L, administered as three single intravenous doses 28 days apart, in addition to standard of care. Key inclusion criteria are the diagnosis of acute MI, the development of systolic dysfunction (LV ejection fraction ≤45%) and elevated N‐terminal pro‐B‐type natriuretic peptide. The study consists of a 6‐month double‐blinded treatment period with the primary endpoint LV end‐systolic volume index and relevant secondary endpoints, followed by a 6‐month open‐label observation period.ConclusionThe HF‐REVERT trial may underpin the concept of miR‐132 inhibition to prevent or reverse cardiac remodelling in post‐MI HF. The results will inform the design of subsequent outcome trials to test CDR132L in HF.

Publisher

Wiley

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