Cicala Giuseppe, Rottura Michelangelo, Gianguzzo Viviana Maria, Cristiano Federica, Drago Selene Francesca Anna, Pallio Giovanni, Irrera Natasha, Imbalzano Egidio, Spina Edoardo, Arcoraci Vincenzo
Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy.
Pharmaceuticals (Basel). 2024 Oct 12;17(10):1365. doi: 10.3390/ph17101365.
The discovery of serine protease proprotein convertase subtilisin-kexin type 9 (PCSK9) has revolutionized pharmacological lipid-lowering treatments. The first PCSK9 antagonists (PCSK9-A), evolocumab and alirocumab, were approved in 2015. Targeting PCSK9 synthesis marked a major advancement in this field, leading to the development of inclisiran, a long-acting siRNA targeting PCSK9 mRNA. However, real-world safety data on this drug are still limited. Therefore, this study aims to provide a real-world safety evaluation of inclisiran, comparing its characteristics to those of PCSK9-As. A retrospective pharmacovigilance study was conducted using EudraVigilance (EV). Inclisiran-related individual case safety reports (I-ICSRs) from 01/01/2021 to 06/30/2023 were retrieved. ICSRs for evolocumab or alirocumab from 01/01/2015 to 06/30/2023 were collected as a reference group (RG). ADRs were classified using the MedDRA dictionary. Data were evaluated using descriptive and disproportionality analyses. Crude reporting odds ratio (ROR) with 95% confidence intervals (CI) were used as disproportionality measures. Of the 15,236 ICSRs, 3.7% (n = 563) involved inclisiran, with the rest in the RG. Most I-ICSRs involved female patients (51.7%) aged 18 to 64 (52.8%). The most-reported ADRs for inclisiran were "general disorders and administration site conditions" (n = 347) and "investigations" (n = 277). Significant disproportionality was found in I-ICSRs compared to the RG for "Myalgia" (ROR: 2.43; 95% CI: 1.94-3.04), "Low-density lipoprotein increased" (ROR: 11.95; 95% CI: 9.10-15.52), and "Drug ineffective" (ROR: 6.37; 95% CI: 4.64-8.74). The inclisiran safety profile aligns with the existing literature and pre-commercial data. However, further studies are needed to fully understand the observed differences with PCSK9-As.
丝氨酸蛋白酶枯草杆菌蛋白酶/kexin 9型（PCSK9）的发现彻底改变了药物降脂治疗。首个PCSK9拮抗剂（PCSK9-A）依洛尤单抗和阿利西尤单抗于2015年获批。靶向PCSK9合成标志着该领域的一项重大进展，促成了inclisiran的研发，这是一种靶向PCSK9 mRNA的长效小干扰RNA（siRNA）。然而，关于这种药物的真实世界安全性数据仍然有限。因此，本研究旨在对inclisiran进行真实世界安全性评估，并将其特征与PCSK9-A的特征进行比较。使用欧洲药品管理局药物警戒数据库（EudraVigilance，EV）进行了一项回顾性药物警戒研究。检索了2021年1月1日至2023年6月30日期间与inclisiran相关的个体病例安全性报告（I-ICSR）。收集了2015年1月1日至2023年6月30日期间依洛尤单抗或阿利西尤单抗的ICSR作为参考组（RG）。使用MedDRA词典对不良反应（ADR）进行分类。采用描述性分析和不成比例性分析对数据进行评估。使用95%置信区间（CI）的粗报告比值比（ROR）作为不成比例性衡量指标。在15236份ICSR中，3.7%（n = 563）涉及inclisiran，其余在参考组中。大多数I-ICSR涉及年龄在18至64岁之间的女性患者（51.7%）。inclisiran报告最多的ADR是“全身性疾病和给药部位状况”（n = 347）和“检查”（n = 277）。与参考组相比，在I-ICSR中发现“肌痛”（ROR：2.43；95%CI：1.94 - 3.04）、“低密度脂蛋白升高”（ROR：11.95；95%CI：9.10 - 15.52）和“药物无效”（ROR：6.37；95%CI：4.64 - 8.74）存在显著不成比例性。inclisiran安全性概况与现有文献和上市前数据一致。然而，需要进一步研究以充分了解观察到的与PCSK9-A的差异。
