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. 2024 Oct 12;17(10):1365.
doi: 10.3390/ph17101365.

Safety of Inclisiran: A Disproportionality Analysis from the EudraVigilance Database

Giuseppe Cicala  1 , Michelangelo Rottura  1 , Viviana Maria Gianguzzo  2 , Federica Cristiano  1 , Selene Francesca Anna Drago  1 , Giovanni Pallio  3 , Natasha Irrera  1 , Egidio Imbalzano  1 , Edoardo Spina  1 , Vincenzo Arcoraci  1
Affiliations

Safety of Inclisiran: A Disproportionality Analysis from the EudraVigilance Database

Giuseppe Cicala et al. Pharmaceuticals (Basel). .

Abstract

Introduction: 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. Methods: 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. Results: 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). Conclusions: 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.

Keywords: PCSK9 antagonist; adverse drug reactions; alirocumab; evolocumab; inclisiran; pharmacovigilance.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Flowchart study design. (A) Non-normalized analysis; (B) normalized analysis.
Figure 2
Figure 2
Number of ICSRs of the drugs study in the first 5 semesters post-marketing. SEM, semester.
Figure 3
Figure 3
MedDRA® system organ class according to study group.
See this image and copyright information in PMC

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