Novo Nordisk's RNA Therapy CDR132L Fails to Meet Primary Endpoint in Heart Failure Trial
核心洞察
CDR132L, a microRNA-132 (搜索) inhibitor developed by Novo Nordisk, failed to significantly improve heart remodeling compared to placebo in the HF-REVERT phase II trial involving 280 heart failure patients.
The study represents the first randomized trial evaluating microRNA inhibition for heart failure treatment, showing no safety concerns but also no statistically significant benefit on the primary endpoint.
Despite the setback, Novo Nordisk continues investigating CDR132L in other phase 2 trials for chronic heart failure patients with left ventricular hypertrophy, with results expected next year.
Novo Nordisk's experimental RNA therapy CDR132L has failed to demonstrate significant efficacy in treating heart failure patients following acute myocardial infarction, according to results from the first randomized trial evaluating microRNA inhibition in heart failure presented at Heart Failure 2026 in Barcelona, Spain.
The HF-REVERT phase II trial enrolled 280 patients who had experienced a heart attack within 3-14 days and developed heart failure, defined by a left ventricular ejection fraction of 45% or lower and elevated NT-proBNP biomarker levels. While CDR132L showed improvements in heart remodeling across all treatment groups, it failed to achieve statistical significance compared to placebo on the primary endpoint.
Trial Design and Patient Population
The double-blind, placebo-controlled study randomized patients to receive either CDR132L at 5 mg/kg, CDR132L at 10 mg/kg, or placebo, administered as three single intravenous doses 28 days apart alongside standard-of-care medical therapy. The study population had a mean age of 61 years, with 22% being female.
Key inclusion criteria included acute myocardial infarction diagnosis within 3-14 days, left ventricular ejection fraction ≤45%, and elevated NT-proBNP levels between 125 and 8000 pg/ml.
Primary Endpoint Results
The primary endpoint measured the percentage change in left ventricular end-systolic volume index (LVESVI) at 6 months from baseline, a key indicator of heart remodeling. Results showed improvements across all groups: -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 left ventricular ejection fraction, NT-proBNP levels, and KCCQ overall summary score also showed no significant differences between CDR132L and placebo groups.
Mechanism of Action and Target Engagement
CDR132L is an oligonucleotide-based inhibitor designed to selectively block microRNA-132 (搜索), a regulatory non-coding RNA implicated in progressive adverse cardiac remodeling observed in heart failure. The drug targets multiple disease pathways simultaneously, including diminished contractility, heart muscle overgrowth, fibrosis, and blood vessel formation in the heart.
Plasma levels of microRNA-132 (搜索) decreased following CDR132L administration in a dose-dependent manner, confirming target engagement despite the lack of clinical efficacy.
Safety Profile
The therapy demonstrated a favorable safety profile with no significant safety concerns identified. Adverse event rates were similar across groups: 50% with CDR132L 5 mg/kg, 54% with CDR132L 10 mg/kg, and 44% with placebo. Five deaths occurred in the placebo group (all cardiovascular-related), one death in the CDR132L 10 mg/kg group (lung cancer), and no deaths in the CDR132L 5 mg/kg group.
Subgroup Analysis and Future Directions
Two clinically important subgroups with higher anticipated mortality risk showed directionally consistent numerical trends favoring CDR132L treatment: patients with NT-proBNP above the median and patients with LVESVI above the median. Some analyses using the per protocol population also demonstrated significant improvements for CDR132L versus placebo.
Professor Johann Bauersachs from Hannover Medical School, the study's presenter, noted: "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."
Ongoing Clinical Development
Novo Nordisk, which acquired CDR132L through its $1 billion-plus acquisition of German company Cardior (搜索) in 2014, continues to evaluate the therapy in other phase 2 trials. The company is conducting the 8212-Preserved study in heart failure with preserved ejection fraction and left ventricular hypertrophy, and the 8282-Reduced study in heart failure with reduced ejection fraction and left ventricular hypertrophy, with results expected next year.
The investment in Cardior (搜索) was funded by cash generated from Novo Nordisk's successful GLP-1 agonist-based therapies for diabetes and obesity. Despite this setback, the company remains committed to exploring CDR132L's potential in specific heart failure patient populations where the therapy may demonstrate greater clinical benefit.