A Characterization of the Nonclinical Pharmacology and Toxicology of Aficamten, a Reversible Allosteric Inhibitor of Cardiac Myosin.

IF 1.2 4区 医学 Q4 PHARMACOLOGY & PHARMACY
Michael K Pugsley, Darren T Hwee, Brett R Winters, Jingying Wang, Eva R Chin, Bradley P Morgan, Fady I Malik
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Abstract

Aficamten (CK-3773274) is a cardiac myosin inhibitor in development for the treatment of hypertrophic cardiomyopathy (HCM), a commonly inherited heart condition often characterized as a disease of the sarcomere. Aficamten reduces pathologic cardiac hypercontractility by selectively binding to an allosteric site on cardiac myosin. To characterize the pharmacology and toxicology of aficamten, a series of nonclinical repeated dose studies were conducted. In a 10-day repeated dose pharmacology study in Sprague Dawley rats, aficamten produced dose-dependent reductions in left ventricular fractional shortening (FS) which were fully reversible within 24 h. Aficamten did not change the ratio of heart weight to tibia length (HW/TL) or left ventricular posterior wall (LVPW) thickness at any dose tested. At a supratherapeutic dose of 6 mg/kg/day, there was a significant increase in interventricular septum (IVS) thickness. Aficamten did not affect mRNA expression of the cardiac injury biomarkers BNP, β-MHC, or ANP. In repeated dose Good Laboratory Practice (GLP) regulatory toxicology studies in Sprague Dawley rats for up to 6 months and beagle dogs for up to 9 months, the primary adverse findings at supratherapeutic doses were consistent across all studies and observed in the heart consisting of atrial/ventricular dilatation that correlated with increased heart weights. These findings were largely reversible and consistent with excessive on-target pharmacology associated with cardiac myosin inhibition. The reversible nature of aficamten-associated adverse effects is supportive of its clinical safety as this property suggests that these findings, should they occur in humans, may also be reversible, limiting long-term human cardiac risk.

心脏肌球蛋白可逆变构抑制剂Aficamten的非临床药理学和毒理学研究。
Aficamten (CK-3773274)是一种正在开发的心脏肌球蛋白抑制剂,用于治疗肥厚性心肌病(HCM),这是一种常见的遗传性心脏病,通常以肌节疾病为特征。Aficamten通过选择性结合心肌蛋白上的变构位点来减少病理性心脏过度收缩。为了表征阿非卡坦的药理学和毒理学,进行了一系列的非临床重复剂量研究。在对Sprague Dawley大鼠进行的为期10天的重复给药药理学研究中,aficamten对左心室分数缩短(FS)产生剂量依赖性降低,且在24小时内完全可逆。在任何剂量下,aficamten均未改变心脏重量/胫长度(HW/TL)或左心室后壁(LVPW)厚度。超治疗剂量为6mg /kg/天时,室间隔(IVS)厚度显著增加。Aficamten不影响心脏损伤生物标志物BNP、β-MHC或ANP的mRNA表达。在长达6个月的Sprague Dawley大鼠和长达9个月的beagle狗的重复剂量良好实验室规范(GLP)调节毒理学研究中,所有研究中超治疗剂量的主要不良发现是一致的,并且在心脏中观察到心房/心室扩张与心脏重量增加相关。这些发现在很大程度上是可逆的,并且与心肌肌球蛋白抑制相关的过度靶向药理学一致。aficamten相关不良反应的可逆性支持其临床安全性,因为这一特性表明,如果这些发现发生在人类身上,也可能是可逆的,从而限制了人类心脏的长期风险。
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来源期刊
CiteScore
3.40
自引率
4.50%
发文量
53
审稿时长
4.5 months
期刊介绍: The International Journal of Toxicology publishes timely, peer-reviewed papers on current topics important to toxicologists. Six bi-monthly issues cover a wide range of topics, including contemporary issues in toxicology, safety assessments, novel approaches to toxicological testing, mechanisms of toxicity, biomarkers, and risk assessment. The Journal also publishes invited reviews on contemporary topics, and features articles based on symposia. In addition, supplemental issues are routinely published on various special topics, including three supplements devoted to contributions from the Cosmetic Review Expert Panel.
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