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
{"title":"A Characterization of the Nonclinical Pharmacology and Toxicology of Aficamten, a Reversible Allosteric Inhibitor of Cardiac Myosin.","authors":"Michael K Pugsley, Darren T Hwee, Brett R Winters, Jingying Wang, Eva R Chin, Bradley P Morgan, Fady I Malik","doi":"10.1177/10915818251326466","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818251326466"},"PeriodicalIF":1.2000,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Toxicology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1177/10915818251326466","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

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.

求助全文
约1分钟内获得全文 求助全文
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.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信