HF-REVERT, the first randomized trial evaluating microRNA inhibition for heart failure, did not significantly improve cardiac remodeling outcomes compared with placebo, according to findings presented at Heart Failure 2026. However, the investigational RNA therapy CDR132L appeared safe and demonstrated biologic target engagement.
“Despite progress made in the treatment of, a major unmet need exists for treatments that directly target pathophysiological processes,” said presenter Johann Bauersachs of Hannover Medical School, Germany. He noted that microRNA-132 has been implicated in adverse cardiac remodeling and that earlier phase Ib findings suggested potential cardiac functional improvement with CDR132L.
HF-REVERT was a double-blind, placebo-controlled, randomized phase II trial that enrolled 280 patients with acute myocardial infarction within 3-14 days, left ventricular ejection fraction (LVEF) ≤45%, and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP). Patients were randomized to CDR132L 5 mg/kg, CDR132L 10 mg/kg, or placebo in addition to standard-of-care therapy. CDR132L was administered as three intravenous doses given 28 days apart.
The primary endpoint was the percentage change in left ventricular end-systolic volume index (LVESVI), a marker of adverse cardiac remodeling, at 6 months. Improvements in LVESVI occurred across all groups but did not differ significantly between CDR132L and placebo. Percentage change in LVESVI was −8.364% with CDR132L 5 mg/kg, −9.824% with CDR132L 10 mg/kg, and −7.611% with placebo (p=0.371 and p=0.257, respectively).
Secondary endpoints, including LVEF, NT-proBNP, and Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score, also did not significantly differ from placebo. However, plasma microRNA-132 levels declined in a dose-dependent manner following CDR132L administration, indicating biologic target engagement.
CDR132L was generally well tolerated. Adverse event rates were similar across groups. Five cardiovascular-related deaths occurred in the placebo arm, while one noncardiovascular death related to lung cancer occurred in the CDR132L 10 mg/kg group.
Patients with higher baseline NT-proBNP or LVESVI values showed directionally favorable numerical trends with CDR132L treatment. Some per-protocol analyses also demonstrated significant improvements versus placebo.
“HF-REVERT represents the first randomized evaluation of microRNA inhibition to treat heart failure,” Bauersachs said. “There were no safety concerns, but also no significant difference in the primary endpoint between CDR132L and placebo.”
Further studies are ongoing to assess whether patients with chronic heart failure and left ventricular hypertrophy may benefit from treatment with CDR132L.
