Background: Despite the available standard-of-care pharmacotherapies, heart failure (HF) is a growing pandemic with increasing burden. Treatments directly targeting the roots of the disease are scarce. MicroRNAs (miRNA) are transcriptional regulators and essential drivers of disease progression. We previously demonstrated that miR-132 is both necessary and sufficient to drive the pathological cardiomyocytes growth, a hallmark of adverse cardiac remodeling via strong effect on cardiomyocyte hypertrophy, calcium signaling and interstitial fibrosis. Thus, we proposed cardiac miR-132 as a target for HF therapy and developed CDR132L, a rationally designed synthetic oligonucleotide inhibitor with proven preclinical efficacy in heart failure early after myocardial infarction (MI). The safety and initial efficacy of CDR132L was recently tested in chronic HF patients in a Phase 1b study (NCT04045405).

Aim: The aim of the current study was to assess efficacy and provide additional insight of the mode of action of CDR132L in a clinically relevant large animal (pig) model of chronic heart failure following MI.

Method: In a chronic model of post-MI HF, slow-growing pigs (n=45) underwent 90 min left anterior descending artery occlusion followed by reperfusion. Animals were randomized 1-month post-MI and treated with CDR132L over 3 or 5 months (CDR132L 3x, 5x), or with placebo by monthly intravenous (IV) treatments in a blinded, randomized, placebo-controlled fashion. Efficacy was evaluated based on serial magnetic resonance imaging, hemodynamic, and biomarker analyses.

Results: The monthly treatment regime of CDR132L provided sufficient tissue exposure and sustained target inhibition. CDR132L was well tolerated in the treatment groups. CDR132L treatment regime reversed cardiac remodeling over the 6 months follow up period by significantly improving systolic (e.g. EF: 31.7% ± 3.7% vs 36.8% ± 6.7%* vs 38.1% ± 4.2%*, dP/dt_max: 1197.12 ± 291.14 vs 1611.17 ± 259.22 vs 1502.29 ± 213.96; placebo vs 3x vs 5x respectively; *p<.05) and diastolic function (e.g. dP/dt_min: -1807.36 ± 476.51 vs -2319.97 ± 508.18* vs -2176.63 ± 315.66, EDPVR: 0.09 ± 0.07 vs 0.04 ± 0.02* vs 0.03 ± 0.02*; placebo vs 3x vs 5x respectively; *p<.05). CDR132L’s beneficial effect on myocardial function could also be demonstrated by innovative strain analysis of cardiac MRI data. Both systolic and diastolic measures (LV longitudinal strain as well as the atrial peak longitudinal strain) were significantly improved in the treatment groups after 6 months post-MI.

Conclusion: Repeated dosing of CDR132L with monthly frequency provide safe and clinically relevant therapeutic efficacy in a model of chronic post-MI HF. CDR132L thus should be explored in Phase 2 efficacy studies for the treatment of heart failure.