Corrigendum: Adverse Drug Events (ADEs) Risk Signal Mining Related to Eculizumab Based on the FARES Database

Xi-Feng Wang ¹ Lu-Ri Bao ^2* Ta-La Hu ^1* Rui-Feng Xu ^1* Wu-Niri Gao ^1* Jing-Yuan Wang ² Jian-Rong Zhao ^1* Zhen-Li Fu ^3* Shu-Fang Wang ^4* Yan Meng ^1*

• ¹ The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
• ² Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
• ³ Second Hospital of Hohhot, Hohhot, Inner Mongolia Autonomous Region, China
• ⁴ Inner Mongolia Corps Hospital of the Chinese People’s Armed Police Force, Hohhot, China

1. IntroductionIn the complement pathway, activated C5 releases the allergenic toxins C5a and C5b, which interact with C6-C9 and membrane-inserted compartments to form membrane attack complexes (MACs) that lead to lysis, damage or activation of target cells[1]. Eculizumab（Soliris） is a recombinant humanized monoclonal antibody that specifically binds to the C5-terminal complement and inhibits the cleavage of C5 to C5a and C5b via complement activation[2]. It is currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis (gMG), and aquaporin-4 immunoglobulin G-positive optic neuromyelitis optica spectrum disorders (AQP4-IgG+NMOSD), which play important roles in the allopathic treatment of complement-associated immune disorders. Eculizumab was introduced introduced to China for treating PNH and aHUS in adults and children on September 5, 2018[3]. Relevant data suggest that eculizumab treatment leads to a decrease in transfusion dependency, a decrease in the incidence of hemolysis and thrombosis, and an improvement in quality of life[4]. Concerning eculizumab biosimilars, two variants are currently available: Bkemv (eculizumab-aeeb) and Epysqli (eculizumab-aagh). On May 29, 2024, the U.S. FDA granted approval to Amgen’s Bkemv as the first biosimilar interchangeable with AstraZeneca’s Soliris (eculizumab), for the reduction of hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH) and for the inhibition of complement-mediated thrombotic microangiopathy in patients with atypical hemolytic uremic syndrome (aHUS). Produced by Samsung Bioepis Co. Ltd., Epysqli was initially approved in the European Union, Iceland, Liechtenstein, and Norway on May 26, 2023, and received FDA approval on July 19, 2024. Given that biosimilars may have different therapeutic efficacy and safety profiles, it is important to investigate information about their availability and potential impact.Despite the promising therapeutic effects of eculizumab, its use since its introduction has been found to increase the risk of certain pathogenic infections, particularly meningococcal infections, for which the FDA black box warns[5]. Other common adverse reactions include headache, nasopharyngitis, nausea, vomiting, diarrhea, hypertension and upper respiratory tract infection[6]. It is therefore crucial to determine the real-world risk of ADE associated with eculizumab to ensure its safe and rational use.The Adverse Drug Event (ADE) Spontaneous Reporting System database is a major source for mining signals of adverse drug reactions[7]. The FAERS database, with data from national health workers or patients, reflects to some extent the occurrence of drug ADEs in the real world and can therefore help to uncover adverse reactions that are difficult to detect in premarket clinical studies of drugs[8]. Given that the adverse reactions in the eculizumab specification are primarily from clinical trials，we utilized the FAERS database for disproportionality analyses to monitor and evaluate the long-term safety of eculizumab, providing a comprehensive and valuable reference for its safety in the real world.2. Materials and methods2.1 Data sourcesWe implemented a retrospective pharmacovigilance study using data from the FAERS database from January 2007 to the third quarter of 2023. FAERS can be accessed at https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html. Documents in FAERS describe demographic and management information (DEMO), drug information (DRUG), reporting source (RPSR), preferred terms (PT) for adverse event coding (REAC), patient outcomes (OUTC), therapeutic period of the reported medication (THER), indications for use of medication (INDI), and deleted cases (DELE)[9]. In this study, all the ASCII packet data for 67 quarters from the first quarter of 2007 to the third quarter of 2023 were extracted and imported into SAS 9.4 software for data cleaning and analysis.2.2 Data processingWe screened 19,418,776 patients from the FAERS database. First, we removed duplicate records (3,124,816); selected the PRIMARYID, CASEID, and FDA_DT fields of the DEMO table according to the FDA-recommended method for removing duplicate reports; sorted them by CASEID, FDA_DT, and PRIMARYID; and retained the largest FDA_DT value for reports with the same CASEID, followed by retaining the largest PRIMARYID value for reports with both the same CASEID and FDA_DT. We ultimately included 46,316 reports with eculizumab as the primary treatment and 146,126 cases of adverse events for further analysis (Figure 1). The 3D structure of eculizumab was derived from PubChem (https://pubchem.ncbi.nlm.nih.gov)[10].2.3 Data mappingThe most current MedDRA dictionary (MedDRA 26.1) was applied to describe ADEs in the FAERS database in terms of system organ class (SOC) and preferred terms (PT).Table 1 shows the screening conditions for the target drug population. The field (DRUGNAME) in the FAERS database indicates the name of the drug, and the field (PROD_AI) indicates the product composition. At the same time, the degree of suspicion was limited to the report of the "Primary Suspect Drug (PS)".2.4 Data miningMany organizations have used disproportionality analyses to identify adverse drug reactions (ADEs) from spontaneous reporting data[11]. Disproportionality analysis mainly serves as a mechanism to formulate hypotheses regarding potential causal connections between pharmaceuticals and their adverse outcomes. This should precede a detailed clinical evaluation of the specific individual case reports involved. The method relies on comparing the observed to the expected frequencies of reports for each specific drug-adverse event pairing[12]. Therefore, this study used the reporting odds ratio (ROR), the proportional reporting ratio (PRR)[13], the Medicines and Health care Products Regulatory Agency (MHRA)[14], (which also belongs to the PRR, and the difference from the previous PRR is that the thresholds are set differently), the Bayesian confidence propagation neural network (BCPNN)[15] and the multi-item Gamma Poisson Shrinker (MGPS) to tap into the ADE risk signals associated with eculizumab, and the higher the values of the four parameters are, the stronger the signal value[16] (Tables 2 and 3). In this study signal strength was judged according to 0 < IC-2SD ≤ 1.5 weak signal (+); 1.5 < IC-2SD ≤ 3.0 medium intensity signal (++); 3.0 < IC-2SD high intensity signal (++++) in BCPNN[17]. The drug label for eculizumab was obtained from Daily Med (https://daily med.nl m.nih.gov/Daily Med/index.cfm)[16].3. Results3.1 Annual Distribution of Eculizumab-Related ADE ReportsAccording to the FAERS database, there were a total of 19,418,776 ADE reports from the first quarter of 2007 to the third quarter of 2023