Abstract 15137: microRNA-132 Inhibition Improves Cardiac Function and Reduces Remodeling in Patients With Heart Failure With Reduced Ejection Fraction (HFrEF): An Exploratory Subgroup Analysis of the CDR132L First-in-Human Study

Abstract

Background: The CDR132L first-in-human (FiH) study examined safety, tolerability, pharmacokinetic, and exploratory pharmacodynamic effects of different ascending doses of the novel antisense oligonucleotide CDR132L targeting microRNA-132-3p (miR-132) in patients with stable heart failure (HF) of ischemic origin receiving standard-of-care (n=28). The study population was not stratified according to their left-ventricular ejection fraction (LVEF), and therefore heterogenous, but equally distributed among heart failure with reduced or preserved ejection fraction (HFrEF or HFpEF). Research question: In an exploratory post-hoc analysis of pharmacodynamic parameters we specifically focused on patients with HFrEF (with a LVEF<45% at baseline, n=14) and, based on our predictive PK/PD modeling, categorized patients into ‘non-pharmacodynamically active’ (non-PD active; placebo and 0.32 mg/kg CDR132L group) and 'pharmacodynamically active' (PD active; patients receiving 1, 3, or 10 mg/kg CDR132L). Results: The PD active group showed a significant median reduction in NT-proBNP by 37.1% between baseline and study endpoint (day 112) while this HF biomarker was increased by 17.7% in the non-PD active group (p=0.0152, Mann-Whitney U test). CDR132L treatment provoked a trend towards 6.1% improvement in LVEF. For the non-PD active group only +1.4% were noted. An additional biomarker related to HF and cardiac fibrosis, lipocalin-2 (NGAL), tended to decrease in the PD active, but not in the non-PD active group. Conclusion: Analysis of the HFrEF subgroup in this FiH trial, although limited by the small patient numbers, indicatively underlines the encouraging benefits of CDR132L, a novel antisense drug, on LV function and cardiac remodeling as established in previous large animal HF models.