The Microrna Inhibitor CDR132L in Patients with Reduced Left Ventricular Ejection Fraction after Myocardial Infarction: a Randomized Phase 2 Trial

MicroRNA-132 (miR-132) is a central regulator of adverse cardiac remodeling. Here we evaluated CDR132L, a synthetic antisense oligonucleotide miR-132 inhibitor, in a multinational, randomized, double-blind, placebo-controlled phase 2 trial (HF-REVERT) in patients with recent myocardial infarction (MI) and left ventricular (LV) systolic dysfunction. Within 3-14 days after MI, 294 patients were randomized to receive CDR132L 5 mg kg-1, CDR132L 10 mg kg-1 or placebo as three intravenous doses at 4-week intervals plus guideline-directed therapy. In total, 280 patients (245 men and 35 women) who received at least one dose of the study drug were included in the modified intention-to-treat population. CDR132L was well tolerated, with no hepatic, renal, hematologic or cardiac toxicity signals. The primary endpoint-the percentage change in LV end-systolic volume index at 6 months-improved in all groups but did not differ significantly between the CDR132L groups (5 mg kg-1 and 10 mg kg-1) and the placebo group. Secondary endpoints, including LV ejection fraction, global longitudinal strain and N-terminal pro B-type natriuretic peptide, were also not significantly different between the CDR132L and placebo groups. Prespecified exploratory analyses suggested potential benefits of CDR132L treatment in patients with advanced adverse remodeling at baseline, supporting further evaluation of CDR132L, including in chronic heart failure conditions. ClinicalTrials.gov: NCT05350969 .