Inclisiran: the preclinical discovery and development of a novel therapy for the treatment of atherosclerosis.

IF 6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Expert Opinion on Drug Discovery Pub Date : 2024-07-01 Epub Date: 2024-05-28 DOI:10.1080/17460441.2024.2360415
Donatos Tsamoulis, Loukianos S Rallidis, Constantine E Kosmas
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引用次数: 0

Abstract

Introduction: Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of global morbidity and mortality. Lipid lowering therapy (LLT) constitutes the cornerstone of ASCVD prevention and treatment. However, several patients fail to achieve therapeutic goals due to low treatment adherence or limitations of standard-of-care (SoC) LLTs. Inclisiran represents a pivotal low-density lipoprotein cholesterol (LDL-C) lowering agent aiming to address current unmet needs in LLT. It is the first available small interfering RNA (siRNA) LLT, specifically targeting PCSK9 mRNA and leading to post-transcriptional gene silencing (PTGS) of the PCSK9 gene.

Areas covered: Promising phase III trials revealed an ~ 50% reduction in LDL-C levels with subcutaneous inclisiran administration on days 1 and 90, followed by semiannual booster shots. Coupled with inclisiran's favorable safety profile, these findings led to its approval by both the EMA and FDA. Herein, the authors highlight the preclinical discovery and development of this agent and provide the reader with their expert perspectives.

Expert opinion: The evolution of gene-silencing treatments offers new perspectives in therapeutics. Inclisiran appears to have the potential to revolutionize ASCVD prevention and treatment, benefiting millions of patients. Ensuring widespread availability of Inclisiran, as well as managing additional healthcare costs that may arise, should be of paramount importance.

Inclisiran:治疗动脉粥样硬化的新型疗法的临床前发现和开发。
导言:动脉粥样硬化性心血管疾病(ASCVD)仍然是全球发病率和死亡率的主要原因。降脂治疗(LLT)是预防和治疗 ASCVD 的基石。然而,由于治疗依从性低或标准治疗(SoC)LLTs 的局限性,一些患者未能达到治疗目标。Inclisiran 是一种关键性的低密度脂蛋白胆固醇(LDL-C)降低药物,旨在解决目前低密度脂蛋白胆固醇治疗中尚未满足的需求。它是首个可用的小干扰 RNA(siRNA)LLT,特异性靶向 PCSK9 mRNA,导致 PCSK9 基因转录后基因沉默(PTGS):前景广阔的 III 期试验显示,在第 1 天和第 90 天皮下注射 inclisiran 后,低密度脂蛋白胆固醇(LDL-C)水平可降低约 50%,之后每半年注射一次加强针。这些研究结果加上 inclisiran 良好的安全性,使其获得了欧洲药品管理局(EMA)和美国食品和药物管理局(FDA)的批准。在此,作者重点介绍了这种药物的临床前发现和开发过程,并为读者提供了他们的专家观点:基因沉默疗法的发展为治疗提供了新的视角。Inclisiran似乎有可能彻底改变ASCVD的预防和治疗,使数百万患者受益。确保Inclisiran的广泛使用以及管理可能产生的额外医疗成本至关重要。
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来源期刊
CiteScore
10.20
自引率
1.60%
发文量
78
审稿时长
6-12 weeks
期刊介绍: Expert Opinion on Drug Discovery (ISSN 1746-0441 [print], 1746-045X [electronic]) is a MEDLINE-indexed, peer-reviewed, international journal publishing review articles on novel technologies involved in the drug discovery process, leading to new leads and reduced attrition rates. Each article is structured to incorporate the author’s own expert opinion on the scope for future development. The Editors welcome: Reviews covering chemoinformatics; bioinformatics; assay development; novel screening technologies; in vitro/in vivo models; structure-based drug design; systems biology Drug Case Histories examining the steps involved in the preclinical and clinical development of a particular drug The audience consists of scientists and managers in the healthcare and pharmaceutical industry, academic pharmaceutical scientists and other closely related professionals looking to enhance the success of their drug candidates through optimisation at the preclinical level.
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