Batkai Sandor, Genschel Celina, Viereck Janika, Rump Steffen, Bär Christian, Borchert Tobias, Traxler Denise, Riesenhuber Martin, Spannbauer Andreas, Lukovic Dominika, Zlabinger Katrin, Hašimbegović Ena, Winkler Johannes, Garamvölgyi Rita, Neitzel Sonja, Gyöngyösi Mariann, Thum Thomas
CARDIOR Pharmaceuticals GmbH, Feodor-Lynen-Str. 15, Hannover 30625, Germany.
Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany.
Eur Heart J. 2021 Jan 7;42(2):192-201. doi: 10.1093/eurheartj/ehaa791.
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.
心脏miR - 132激活会导致不良重塑和病理性肥大。CDR132L是一种经过合成优化的先导寡核苷酸抑制剂，在心肌梗死（MI）后早期心力衰竭（HF）中已证明具有临床前疗效和安全性，并且最近在一项1b期研究（NCT04045405）中完成了临床评估。本研究的目的是评估CDR132L在心肌梗死后慢性心力衰竭的临床相关大型动物（猪）模型中的安全性和疗效。
在心肌梗死后心力衰竭的慢性模型中，生长缓慢的猪接受90分钟的左前降支动脉闭塞，随后再灌注。动物被随机分组，并在心肌梗死后1个月开始治疗。以盲法随机安慰剂对照的方式，在3个月或5个月内每月静脉注射（IV）CDR132L（3次或5次）。基于系列磁共振成像、血流动力学和生物标志物分析评估疗效。治疗方案提供了足够的组织暴露，并且CDR132L耐受性良好。总体而言，CDR132L治疗显著改善了心脏功能并逆转了心脏重塑。除了收缩功能恢复外，在这个慢性心力衰竭模型中舒张功能也得到了改善。
每月重复给药CDR132L是安全的，并且足以在心肌梗死后慢性心力衰竭模型中提供临床相关的暴露和治疗效果。因此，CDR132L应作为慢性心力衰竭广泛领域的治疗方法进行探索。
