Findings from the first randomised trial assessing RNA therapy in heart failure
Results from the first randomised trial evaluating microRNA inhibition in heart failure were presented today at Heart Failure 2026, the annual congress of the Heart Failure Association of the European Society of Cardiology.
Globally, more than 55 million people live with heart failure, and the prevalence is rising, driven by the ageing population, improved survival after cardiovascular events and the increasing burden of comorbidities. Patients who have had a heart attack are at high risk of developing heart failure.
Explaining the rationale for the HF-REVERT trial, presenter Professor Johann Bauersachs from Hannover Medical School, Germany, said: “Despite progress made in the treatment of heart failure, a major unmet need exists for treatments that directly target pathophysiological processes. MicroRNA-132 is a regulatory (noncoding) RNA that is implicated in the progressive adverse cardiac remodelling observed in heart failure. Results from a phase Ib trial suggested that CDR132L, a novel antisense oligonucleotide that selectively blocks microRNA-132, was associated with cardiac functional improvements. We conducted the HF-REVERT phase II trial to investigate the efficacy and safety of CDR132L in patients with heart failure early after a myocardial infarction.”
HF-REVERT was a double-blind, placebo-controlled randomised phase II trial (NCT05350969).5 Key inclusion criteria were a diagnosis of acute myocardial infarction within 3–14 days, left ventricular ejection fraction (LVEF) ≤45% and elevated levels of the heart strain biomarker, N-terminal pro-B-type natriuretic peptide (NT-proBNP; ≥125 and <8000 pg/ml). Eligible participants were randomised to CDR132L 5 mg/kg, CDR132L 10 mg/kg or placebo, in addition to standard-of-care medical therapy. CDR132L was administered as three single intravenous doses 28 days apart. The primary endpoint was the percentage change in left ventricular end-systolic volume index (LVESVI) at 6 months from baseline.
A total of 280 patients were randomised. At baseline, the mean age was 61 years and 22% were female. The primary endpoint was improved across all groups but was not significantly different between CDR132L and placebo. The percentage change in LVESVI at 6 months from baseline 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).
Improvements in secondary endpoints, including LVEF, NT-proBNP and KCCQ overall summary score (a measure of well-being) were also not significantly different between CDR132L and placebo. Plasma levels of microRNA-132 decreased following CDR132L administration in a dose-dependent manner, indicating target engagement.
CDR132L was well tolerated with a similar proportion of patients experiencing adverse events with CDR132L 5 mg/kg (50%), CDR132L 10 mg/kg (54%) and placebo (44%). Five deaths occurred in the placebo group (all cardiovascular-related), with one death in the CDR132L 10 mg/kg group (lung cancer) and no deaths in the CDR132L 5 mg/kg group.
Two severity-defined and clinically important subgroups with higher anticipated mortality risk (patients with NT-proBNP above the median and patients with LVESVI above the median) demonstrated directionally consistent numerical trends favouring CDR132L treatment. Significant improvements for CDR132L versus placebo were also observed in some analyses using the per protocol population.
Professor Bauersachs concluded: “HF-REVERT represents the first randomised evaluation of microRNA inhibition to treat heart failure. There were no safety concerns, but also no significant difference in the primary endpoint between CDR132L and placebo. Investigations continue to assess whether certain patients with chronic heart failure, i.e., those with left ventricular hypertrophy, may benefit from treatment with CDR132L.”
