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.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.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.
