Safety of Inclisiran: A Disproportionality Analysis from the EudraVigilance Database

• Published in: Pharmaceuticals (Basel, Switzerland) Vol. 17; no. 10; p. 1365
• Main Authors: Cicala, Giuseppe, Rottura, Michelangelo, Gianguzzo, Viviana Maria, Cristiano, Federica, Drago, Selene Francesca Anna, Pallio, Giovanni, Irrera, Natasha, Imbalzano, Egidio, Spina, Edoardo, Arcoraci, Vincenzo
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 12-10-2024; MDPI
• Subjects: adverse drug reactions; alirocumab; Analysis; Cholesterol; Clinical medicine; Connective tissue; Drugs; evolocumab; FDA approval; inclisiran; Low density lipoprotein receptors; Low density lipoproteins; Marketing; Metabolism; Patient compliance; PCSK9 antagonist; pharmacovigilance; Proteases; RNA; Statins; Stroke; Italy; inclisiran; alirocumab; adverse drug reactions; PCSK9 antagonist; pharmacovigilance; evolocumab
• ISSN: 1424-8247; 1424-8247
• 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.