Abstract 15259: The Novel Antisense Oligonucleotide CDR132L Improves Cardiac Function in Heart Failure Across Different Species

Abstract

Introduction: The chronic progressive condition of heart failure (HF) is, to date, largely irreversible and continues to impose global morbidity. MicroRNAs exert substantial roles in HF progression by orchestrating pathological genes and pathways. Medications directly tackling the roots of the disease are rare, but inhibition of miR-132, a microRNA that was shown to be upregulated upon cardiac remodeling and HF, is a promising approach. Thus, CDR132L, a clinical-stage synthetic antisense oligonucleotide miR-132 inhibitor, can be an innovative therapy for patients with HF. Hypothesis: To examine the effect of CDR132L, different studies were conducted, including in mice and pigs and in a first-inhuman phase 1b safety and tolerability study that revealed preclinical and exploratory efficacy data. Results: MiR-132 transgenic mice developed reduced left-ventricular ejection fraction (LVEF) and cardiac dilatation. CDR132L treatment significantly improved LVEF and reversed cardiac dilatation. The results were confirmed in a porcine transverse aortic constriction model, where the LVEF was significantly improved in the CDR132L treatment group compared to control animals (48.9% vs. 36.1%). In post-MI HF pigs subjected to different treatment and dosing regimens, resulted in a significant and dose-dependent improvement of the cardiac function, illustrated by an up to 10.4% improvement in LVEF to the placebo group at day 56. During a monthly treatment, 87.5% of the animals treated 5x 5 mg/kg with CDR132L showed a ΔLVEF of >7% compared to the placebo group. Additionally, CDR132L improved contractility and the diastolic function by reducing cardiac stiffness. A successful translation of these preclinical results into humans was performed in a CDR132L safety and tolerability Phase 1b clinical trial in HF patients. In an exploratory analysis, the combined endpoint, consisting of patients with a decrease in NT-proBNP levels and/or an absolute increase in LVEF, was significantly met by 79% of the patients in the pharmacodynamically active CDR132L group. Conclusion: Pharmacological miR-132 inhibition by CDR132L improved cardiac function in multi-species models of HF, highlighting the therapeutic potential for clinical use in HF patients.