CDR132L improves systolic and diastolic function in a large animal model of chronic heart failure

Abstract

Aims Cardiac miR-132 activation leads to adverse remodelling and pathological hypertrophy. CDR132L is a synthetic lead-optimized oligonucleotide inhibitor with proven preclinical efficacy and safety in heart failure (HF) early after myocardial infarction (MI), and recently completed clinical evaluation in a Phase 1b study (NCT04045405). The aim of the current study was to assess safety and efficacy of CDR132L in a clinically relevant large animal (pig) model of chronic heart failure following MI. Methods and results In a chronic model of post-MI HF, slow-growing pigs underwent 90 min left anterior descending artery occlusion followed by reperfusion. Animals were randomized and treatment started 1-month post-MI. Monthly intravenous (IV) treatments of CDR132L over 3 or 5 months (3× or 5×) were applied in a blinded randomized placebo-controlled fashion. Efficacy was evaluated based on serial magnetic resonance imaging, haemodynamic, and biomarker analyses. The treatment regime provided sufficient tissue exposure and CDR132L was well tolerated. Overall, CDR132L treatment significantly improved cardiac function and reversed cardiac remodelling. In addition to the systolic recovery, diastolic function was also ameliorated in this chronic model of HF. Conclusion Monthly repeated dosing of CDR132L is safe and adequate to provide clinically relevant exposure and therapeutic efficacy in a model of chronic post-MI HF. CDR132L thus should be explored as treatment for the broad area of chronic heart failure.

Novel antisense therapy targeting microRNA-132 in patients with heart failure: results of a first-in-human Phase 1b randomized, double-blind, placebo-controlled study

“…As tissue sampling by invasive myocardial biopsy for pharmacokinetic or miR-132 quantification was not considered to be ethically justified or acceptable to the potential study participants, we developed a pharmacokinetic/pharmacodynamic (PK/PD) modelling approach to predict effective CDR132L dose levels. Therefore, PK/PD data from cardiac tissue and plasma measurements in CDR132L studies in large animal models of HF with relatively large sample sizes 5 , 6 were combined with plasma miR-132 measurements from the present study regarding CDR132L PK and target engagement ( Figures 4 and 5 and Supplementary material online, Tables S3 and S4 ) to estimate dose ranges likely to deliver sufficient drug to suppress excess target in cardiac tissue. Methodological details appear in the Supplementary material online .…”

“…The mechanism of action of CDR132L is to prevent and revert pathological cardiac remodelling as described earlier. 3 , 5 , 6 A summary of the mode of action is provided in the Take home figure . Since novel generation ASOs are widely considered as safe treatment due to the high target selectivity and a well-established PK, 23 we performed the FiH study already in the target indication HF as advised in meetings with regulators [Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), MHRA, FDA].…”

“…These ATD calculations for monthly or quarterly HF therapy were based on a novel pharmacokinetic/pharmacodynamic modelling scheme combining human data from this clinical trial with plasma and cardiac tissue measurement from preclinical large animal studies. 5 , 6 Details appear in the Supplementary material online .…”

“…CDR132L, a synthetic locked nucleic acid antisense oligonucleotide (ASO) inhibitor with a fully phosphorylated backbone, is a first-in-class miR-132 inhibitor. 7 Preclinical investigations, 5–7 including large randomized, placebo-controlled studies in validated porcine models of subacute 5 and chronic HF 6 after myocardial infarction, found a favourable safety profile, efficient drug delivery to cardiac tissue, and potent, dose-dependent target reduction in myocardium and plasma. The results suggested a strong effect of CDR132L against adverse cardiac remodelling, a dose-dependent improvement in left ventricular ejection fraction (LVEF), and a reduction in the amino terminal fragment of pro-brain natriuretic peptide (NT-proBNP) concentrations.…”

“…In addition, positive effects on relevant echocardiographic, electrophysiological, and biochemical parameters of disease severity showed improved cardiac systolic and diastolic function. 3 , 5 , 6 …”