Characterizing Adverse Events of Biologic Treatment of T2 Disease: A Disproportionality Analysis of the FDA Adverse Event Reporting System Free

Biologics are an emerging treatment for chronic rhinosinusitis with nasal polyps (CRSwNP). Dupilumab (anti-IL-4Rα) became the first biologic to receive FDA approval for CRSwNP [1], followed by omalizumab (anti-IgE) and mepolizumab (anti-IL-5). Our understanding of biologic-associated adverse events (AEs) is limited, as phase IV trials have not been conducted. Real-world AE studies are lacking, and, as such, current data derive from clinical trials [2, 3, 4].

Clinical trials for biologic CRSwNP treatment were promising, demonstrating improved symptomatology with mild AEs (online suppl. Table 1; for all online suppl. material, see https://doi.org/10.1159/000534545). The SINUS-24 and -52 trials cite injection-site reactions, conjunctivitis, and arthralgia as the most common dupilumab-associated AEs [2]. Omalizumab was associated with headache, injection-site reactions, and abdominal pain in POLYP 1 and 2 trials [3]. Oropharyngeal pain, arthralgia, and abdominal pain were the most common mepolizumab-associated AEs (SYNAPSE) [4].

Phase III trials implied favorable biologic safety profiles, yet real-world data show high discontinuation rates of 24.1% (dupilumab) [5] and 37.7% (omalizumab and mepolizumab) due to AEs [6]. Thus far, observational dupilumab studies have detected dermatologic [7‒10], injection-site [7], ophthalmologic, and musculoskeletal AEs [8]. Mepolizumab has been linked with musculoskeletal AEs (1.6%) [11], diarrhea (12%), pruritus (7%), and headache (6%) [12]. Lastly, omalizumab has been associated with anaphylaxis [13, 14]. These data suggest specific safety profiles among dupilumab, omalizumab, and mepolizumab, yet comparative studies are lacking. Meta-analyses insinuate the superiority of dupilumab over omalizumab and mepolizumab in terms of efficacy and safety, but head-to-head examinations are needed to solidify potential safety differences [15, 16, 17].

Identifying safety differences among the CRSwNP treatment biologics will be important in patient-centered decision-making, treatment algorithm development, and counseling. Thus far, CRSwNP management algorithms do not specify a first-line biologic, nor guidelines on which biologic is best for those with co-morbid conditions.

This analysis utilizes real-world data to characterize AEs associated with dupilumab, omalizumab, and mepolizumab. With the primary aim of identifying differences in outcomes and AE categories, we utilized the FDA Adverse Event Reporting System (FAERS) to conduct a disproportionality analysis. This analysis includes AEs associated with all biologic indications (asthma, atopic dermatitis, CRSwNP, etc.). Previous FAERS studies [7, 13] have described biologic-associated AEs, but this will be the first AE analysis to compare all three biologics.

FAERS is a publicly available, spontaneous reporting system containing de-identified cases [18]. Reports include drug name, outcome, patient demographics, and AE “preferred term” (PT) as defined by the standardized Medical Dictionary for Regulatory Activities (MedDRA) [19]. This retrospective analysis utilized quarterly files from Q1/2019–Q3/2022. Data were cleaned by removing incomplete and duplicate reports. FAERS reports include all potential offending drugs; therefore, only “primary suspect drug” (coded “PS”) cases were included. As shown in Figure 1, there is a discrepancy between number of patients and total AEs, as one report may contain multiple AEs (i.e., 1 patient with 2 AEs: fever and rash). Two datasets were constructed, one containing all AE information and another containing patient information (age, sex, and outcomes). The dataset containing all AE information has more AEs than patients because many patients report multiple AEs.

Dupilumab, omalizumab, and mepolizumab were the target drugs chosen because they are all FDA approved for treatment of CRSwNP. Of note, this analysis includes all prescription indications (asthma, atopic dermatitis, CRSwNP, etc.). Although FAERS allows for reporting of indication, this data point is often incomplete, or in some cases, multiple indications are listed. We found that after eliminating reports with missing indication data, selecting for only CRSwNP treatment, and removing reports with multiple indications (i.e., asthma and CRSwNP), the total number of reports was too small to complete a comparative disproportionality analysis. For this reason, all indications were included.

Demographic and outcome data were presented as means and standard deviations (continuous) and absolute (n) and relative (%) frequencies (categorical). AE data were presented as absolute (n) and relative (%) frequencies. Fisher’s exact tests were used to analyze each AE. Relative AE rates were determined using a biologic total AEs as the denominator (dupilumab denominator = 112,560, omalizumab denominator = 24,428, and mepolizumab denominator = 18,741). Fisher’s exact test compared a biologic AE to all other drugs in the database.

To determine the association between an AE and a specific biologic, the reporting odds ratio (ROR) is calculated. The ROR compares the proportion of AE reports for one drug to all other drugs using a 2 × 2 contingency table (Table 1) [20]. For example, if drug A has a total of 100 AEs, 10 of which are for “asthma,” and there are a total of 1,000 AEs related to all other drugs in the database, 100 of which are “asthma,” the “asthma” ROR for drug A is equal to (10/90)/(100/900) [21]. It is important to keep in mind that the category of “other drugs” encompasses all drugs that have been reported in the FDA Adverse Event Reporting System, such as opioids, antiepileptics, antidepressants, anxiolytics, and so on.

RORs and 95% confidence interval [CIs] were computed for each AE. A disproportionality signal was considered a positive association when the lower limit of 95% CI was greater than 1, with at least three reports [22]. Likewise, a lower limit 95% CI of less than 1 indicates a negative association as long as there are at least 3 AE reports. For this reason, we excluded AEs with less than 3 reports from the overall analysis.

Individual AEs were categorized based on classifications used by Swisher et al. [7] Specific AEs within each category can be found in online suppl. Tables 1–3. RORs were calculated for both AE categories and individual AEs. Categories with the strongest signals (i.e., pulmonary) were compared at the individual AE level (i.e., asthma). Heat maps were used to visualize differences in ROR. Scatter plots using the common logarithm of RORs (log [ROR]) and the common logarithm of inverse p values (−log[p]) visualized statistical significance and disproportionality signals. Data mining manipulation and statistical analyses were performed using R (v4.2.1) in RStudio Version 1.3.1093. Figures were illustrated using GraphPad Prism (v9.5.).

From Q1/2019–Q3/2022, there were 112,560, 24,428, and 18,741 unique AE reports associated with dupilumab, omalizumab, and mepolizumab, respectively. There were considerable proportions of dupilumab-associated dermatologic (21.75%), injection-site (7.98%), and ophthalmologic (7.76%) AEs. Omalizumab had many pulmonary (13.47%) and dermatologic (8.68%) AEs. Pulmonary-related events constituted the largest proportion of Mepolizumab AEs (24.48%). Categorized AEs are summarized in Table 2.

Categories with strong signals, which included pulmonary, dermatologic, and sinonasal/oropharyngeal/otologic, were compared among the three drugs (Fig. 2b–d). The strongest dupilumab-associated disproportionality signals were injection-site (ROR = 8.17, 95% CI: 7.98–8.37), dermatologic (ROR = 6.74, 95% CI: 6.64–6.84), and ophthalmologic (ROR = 6.20, 95% CI: 6.06–6.35). Omalizumab’s strongest signals were pulmonary (ROR = 3.26, 95% CI: 3.14–3.38), sinonasal/oropharyngeal/otologic (ROR = 2.70, 95% CI: 2.56–2.84), and dermatologic (ROR = 1.94, 95% CI: 1.86–2.03). The top signals for mepolizumab were pulmonary (ROR = 6.83, 95% CI: 6.61–7.07) and sinonasal/oropharyngeal/otologic (ROR = 1.59, 95% CI: 1.48–1.72). RORs and p values were visualized for pulmonary, dermatologic, sinonasal/oropharyngeal/otologic, and ophthalmologic categories in Figure 3. In these figures, dupilumab has many positive signals and statistical significance (based on Fisher’s exact test) in the dermatologic and ophthalmologic categories (Fig. 3a, c). There are also positive signals and statistical significance for various mepolizumab-associated AEs in the pulmonary category (Fig. 3d).

Omalizumab and mepolizumab had stronger signals in all pulmonary categories compared to dupilumab. Additional positive signals, such as asthmatic crisis, (omalizumab ROR = 19.50, 95% CI: 14.85, 25.60; mepolizumab ROR = 235.13, 95% CI: 198.67, 278.29) can be found in online supplementary Tables 1–3. Of the biologics, omalizumab had the strongest signal in the sinonasal/oropharyngeal/otologic category, with top signals for ear pain, nasal congestion, nasopharyngitis, and oropharyngeal pain.

Dupilumab and omalizumab had dermatologic signals. The strongest dupilumab-associated AEs were eczema (ROR = 34.12, 95% CI: 31.74, 36.68), dermatitis (ROR = 13.76, 95% CI: 11.96, 15.82), and skin exfoliation (ROR = 13.3, 95% CI: 12.38, 14.28). The strongest omalizumab signals were urticaria (ROR = 12.52, 95% CI: 11.54, 13.59), pruritus (ROR = 2.58, 95% CI: 2.32, 2.87), and angioedema (ROR = 8.82, 95% CI: 7.28, 10.68).

Top dupilumab-associated injection-site AEs are represented in Figure 4b. The strongest signals were injection-site irritation (ROR = 19.77, 95% CI: 16.03, 24.39), injection-site rash (ROR = 17.93, 95% CI: 16.05, 20.02), and injection-site swelling (ROR = 15.15, 95% CI: 14.09, 16.28). There were not sufficient injection-site-related AEs associated with omalizumab and mepolizumab for comparisons.

Dupilumab-associated ophthalmologic AEs are represented in Figure 4a. The strongest signals included eye pruritus (ROR = 30.74, 95% CI: 28.30, 33.39), conjunctivitis (ROR = 29.78, 95% CI: 26.75, 33.16), and dry eye (ROR = 19.38, 95% CI: 18.10, 20.76). Blurry vision (ROR = 3.80, CI: 3.52, 4.12) and visual impairment (ROR = 1.98, CI: 1.80, 2.19) were also associated with dupilumab. Due to the small number of ophthalmologic reports for omalizumab (1.52%) and mepolizumab (1.31%), comparisons could not be made.

Mepolizumab had greater proportions of hospitalizations and deaths (40.01%, 7.01%) than dupilumab (35.85%, p = < 0.001, 2.69%, p = < 0.001) and omalizumab (27.99, p = < 0.001, 5.76%, p = 0.006) (Table 3). All pairwise comparisons of hospitalization and death proportions were statistically significant (Fig. 5). Anaphylaxis signals also differed among the three drugs. Omalizumab had a strong anaphylaxis association (ROR = 20.80, 95% CI: 18.58, 23.29). Dupilumab and mepolizumab had negative anaphylaxis signals (ROR = 0.78, 95% CI: 0.62, 1.00) (ROR = 0.62, 95% CI: 0.33, 1.21) (Fig. 6).

Management of CRSwNP is transforming as we enter the era of biologics. Commenced by dupilumab, subsequent omalizumab and mepolizumab FDA approvals probe the question of biologic superiority. This FAERS analysis offers insight into the safety profiles of each CRSwNP biologic, which remain understudied outside phase III trials.

Meta-analyses and network analyses [15, 17] suggest that dupilumab has better safety and efficacy compared to omalizumab and mepolizumab for nasal polyp treatment. Death proportions were the smallest for dupilumab (2.69%). Mepolizumab had the greatest proportion of both hospitalizations and deaths, which were found to be associated with asthma-related events. Anaphylactic reactions were negatively associated with dupilumab and mepolizumab, while omalizumab had a strong anaphylaxis association (ROR = 20.80, 95% CI: 18.58, 23.29), which is consistent with prior studies [13, 14].

AE categorization revealed unique safety profiles among the biologics, with a large proportion of dupilumab-associated AEs being ophthalmologic (7.76%), dermatologic (21.75%), and injection-site-related (7.98%). Mepolizumab was associated with pulmonary-related AEs (24.48%), while omalizumab was associated with sinonasal/oropharyngeal/otologic (6.34%), pulmonary (13.47%), and dermatologic reactions (8.68%). Further analyses revealed similar differences in RORs, with dupilumab having unique positive signals for injection-site and ophthalmologic reactions.

Top dupilumab ophthalmologic reactions based on proportion and ROR included conjunctivitis (ROR = 29.78, 95% CI: 26.75, 33.16), eye pruritus (ROR = 30.74, 95% CI: 28.30, 33.39), and dry eye (ROR = 19.38, 95% CI: 18.10, 20.76), all of which were also prevalent in clinical trials [2]. In addition to these, dupilumab was associated with eye discharge (ROR = 11.95, 95% CI: 10.09, 14.15), ocular hyperemia (ROR = 15.15, 95% CI: 13.97, 16.42), visual impairment (ROR = 1.98, CI: 1.80, 2.19), and blurred vision (ROR = 3.80, 95% CI: 3.52, 4.12). Contrarily, omalizumab and mepolizumab had small proportions of ophthalmologic events and no positive disproportionality signals. Dupilumab was the only biologic with injection-site AE associations, a finding that also aligns with clinical trial data [2‒4]. Dupilumab and omalizumab had many positive dermatologic ROR signals, while mepolizumab did not.

It is important to note that some of the signals we report are very large. While this may indicate a strong association, this finding may also be due to low reporting of that particular AE among other drugs. If an AE is very rare, even a small number of reports can lead to a large ROR. To mitigate this, we have limited this study to AEs with a large number of cases; however, rare AEs may still skew the ROR calculation.

Mepolizumab and omalizumab were most strongly associated with pulmonary AEs; however, these data should be interpreted carefully, as these analyses are likely impacted by indication bias. Mepolizumab is not FDA approved to treat dermatologic conditions, which may account for the lack of dermatologic signals. Likewise, dupilumab is indicated for atopic dermatitis, and omalizumab treats urticaria, both of which were highly reported AEs with strong disproportionality signals. All three biologics treat asthma, a common AE with strong signals among all the biologics. Dermatologic and pulmonary AE data are likely influenced and limited by indication bias.

This study does not account for drug indication due to the reduction in cases after removing incomplete reports, reports with non-CRSwNP indications, and reports with multiple indications. Other reporting errors, such as omitted or incomplete data, limit complementary analyses. Our data had a significant amount of missing supplemental information; therefore, this analysis did not account for drug dosage, indication, or patient demographics. These covariates should be recognized as potential confounders.

This study is also limited by FAERS reporting methods, as data are reported by patients, providers, and pharmaceutical companies and are not verified. Additionally, it should be noted that a report alone cannot determine causation, and it is unclear if a particular drug is truly responsible for an AE. Underreporting may limit the sensitivity of signal detection in disproportionality models. The timeframe of this study (2019–2022) likely impacted reporting rates due to the COVID-19 pandemic [23]. This study was also susceptible to severity bias, as many reports resulted in hospitalization or death. Lastly, AE prevalence, incidence, or risk can be determined by this analysis [24]. Disproportionality analyses serve as a tool for hypothesis generation; therefore, our findings should be succeeded by clinical studies.

Algorithm development for CRSwNP treatment is ongoing, and a first-line biologic agent has yet to be established [25, 26]. As their use becomes increasingly prevalent in CRSwNP treatment, further studies are needed to determine superiority in safety and efficacy among dupilumab, omalizumab, and mepolizumab. This is the first pharmacovigilance study to compare dupilumab, omalizumab, and mepolizumab safety profiles; however, further studies are necessary to substantiate these findings.

The disproportionality analysis revealed unique AE profiles among these biologics. Ophthalmologic and injection-site AEs were associated with dupilumab. Dupilumab had associations with blurry vision and visual impairment. Omalizumab was the only biologic associated with anaphylaxis. As FAERS data collection continues, future investigations may provide more robust AE data by limiting the analysis to the CRSwNP population.

This study protocol was reviewed and considered exempt by the University of North Carolina at Chapel Hill Office of Human Research Ethics, approval number IRB 22-2233. Informed consent was not required, and this study was granted a waiver of informed consent by the Institution Review Board (IRB# 22-2233).

The authors have no conflicts of interest to declare.

The project described was supported by NIH grants KL2TR002490 to AJK. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. No authors have any financial conflicts of interest.

Taylor J. Stack (corresponding author): data acquisition, data interpretation, and wrote the manuscript; Sulgi Kim (co-author), Meredith M. Lamb (co-author), Meredith M. Lamb (co-author), Ibtisam Mohammad (co-author), Abdullah Zeatoun (co-author), and Erin Lopez (co-author): revision of the manuscript; Cristine Klatt-Cromwell (co-author), Brian D. Thorp (corresponding author), Charles S. Ebert Jr. (co-author), Brent A. Senior (co-author), and Daniel Alicea (senior author): final approval and revision of the manuscript; and Adam J. Kimple (co-author): study design and final approval and revision of the manuscript

Presented as an oral presentation at the ARS at COSM in Boston, MA on May 5–7, 2023.

All data generated or analyzed during this study are included in this article and supplemental files. Further inquiries can be directed to the corresponding author. The FAERS database is publicly available, and raw data can be acquired on the FAERS website.