Abstract
The purpose of this study was to analyze the important medical events (IMEs) of anti-severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) monoclonal antibodies using the reports from the United States Food and Drug Administration (US FDA) adverse event reporting system (FAERS) and to detect safety signals. In this study, data from the FAERS from January 2020 to December 2022 were used to investigate signals associated with five monoclonal antibody products (bamlanivimab, bamlanivimab/etesevimab, bebtelovimab, casirivimab/imdevimab, sotrovimab) in coronavirus disease 2019 (COVID-19) patients and one monoclonal antibody product (tixagevimab/cilgavimab) in patients wherein COVID-19 vaccination was not recommended. Disproportionality analyses were conducted using the reporting odds ratio, and an information component to identify safety signals. There were 17,937,860 drug AE reports associated with all drugs in the FAERS documented during research period. Among them, 42,642 were AE reports associated with anti-SARS-CoV-2 monoclonal antibodies. The SOCs including respiratory, thoracic and mediastinal, and vascular disorders were frequently reported for all the six products. The three most commonly detected IMEs were hypoxia, COVID-19 pneumonia, and anaphylactic reaction due to SARS-CoV-2 neutralizing antibodies. Even though the purposes of use were different, the types of signals between drugs were similar. Careful monitoring of these AEs should be considered for certain COVID-19 patients, at risk, when they are treated with monoclonal antibody products.
Keywords: COVID-19, SARS-CoV-2 neutralizing monoclonal antibody drugs, Adverse events, FDA adverse event reporting system, Emergency use authorization
Introduction
Due to the Coronavirus Disease 2019 (COVID-19) pandemic that manifested in December 2019, several therapeutics [1] have been developed and administered to treat COVID-19 infection, and prevent it from progressing to severe symptoms. Monoclonal antibody medicinal products inhibiting binding to the receptor binding domain responsible for binding to the human receptor angiotensin-converting enzyme 2 among the spike proteins of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) have been developed by a diverse range of companies [2], and among them six products have received emergency use authorization (EUA) in the United States [1].
When the disease manifested at the end of 2019, studies to develop a treatment began, and a new drug was promptly developed and commercialized within a year. Patients receiving the medication are broadly classified into two categories, depending on the purpose, as follows: (i) to treat infected patients, it is administered only to patients with mild or moderate symptoms and who have risk factors that are at high risk of progressing to severe symptoms, (ii) for prevention, it is administered to severely immunocompromised subjects, where it is challenging to induce effective immunity with a vaccine or where the vaccine cannot be administered due to adverse reactions to the vaccine [3].
The United States Food and Drug Administration (US FDA) has developed the FDA Adverse Event Reporting System (FAERS), which is publicly available, as a post-marketing safety surveillance database in which pharmaceutical companies, healthcare professionals, consumers, and their representatives voluntarily report adverse events (AEs) after administering drugs in the United States [4]. This information detects signals regarding the association between a drug and a reported AE, which can be used to specifically identify rare AEs that may not be detected in pre-marketing studies or clinical trials. Signal refers to information presenting a new potential causal relationship or a new aspect of a known relationship between a drug and an AE, which is worth analyzing among information obtained from one or more reporting sources, and is not limited to harmful relationships [5, 6]. It is recommended that the risks and benefits of a drug be evaluated periodically at intervals of more than three years because different risk–benefit balances may occur in one drug as the latest information on safety becomes available through pharmacovigilance [7]. Hence, the FAERS data are aggregated quarterly. Accordingly, this study analyzed FAERS data reported over the three years, from 2020 to 2022, when emergency use of SARS-CoV-2 neutralizing antibody drugs was implemented.
This study aims to analyse and detect signals by comparing the AEs of six SARS-CoV-2 neutralizing monoclonal antibody drugs [8], with all kinds of other drugs based on the FAERS data.
Materials and methods
Data collection
The FAERS database contains information on AE and medication error reports submitted to the US FDA spontaneously. Reported AE cases related to SARS-CoV-2 neutralizing monoclonal antibody drugs (bamlanivimab, casirivimab/imdevimab, bamlanivimab/etesevimab, sotrovimab, bebtelovimab, tixagevimab/cilgavimab) (Table 1) were analyzed using the FAERS. The FAERS database was investigated for reports on all FDA-approved SARS-CoV-2 neutralizing monoclonal antibody drugs in 2020 ~ 2022. Records without notification or case number and the name of the suspected drug or the adverse reaction were excluded.
Table 1.
List of SARS-CoV-2 neutralizing monoclonal antibody drugs
| No | Product name (substance) | Company | FDA EUA date | Dosage and route of administration (12 years of age and older weighing at least 40 kg) | Purpose |
|---|---|---|---|---|---|
| 1 | N/A (bamlanivimab) | Eli Lilly and Company | 2020.11.9 | 700 mg, Intravenous [18] | Treatment |
| 2 | REGN-COV (casirivimab/imdevimab) | Regeneron | 2020.11.21 | 600 mg each, Intravenous or Subcutaneous [19] | Treatment |
| 3 | N/A (bamlanivimab/ etesevimab) | Eli Lilly and Company | 2021.2.9 | 700 mg (bamlanivimab)/ 1400 mg (etesevimab), Intravenous [20] | Treatment |
| 4 | Xebudy (sotrovimab) | GSK | 2021.5.26 | 500 mg, Intravenous [21] | Treatment |
| 5 | N/A (bebtelovimab) | Eli Lilly and Company | 2021.5.26 | 175 mg, Intravenous [22] | Treatment |
| 6 | Evusheld (tixagevimab/ cilgavimab) | Astrazeneca | 2021.12.9 | 300 mg each, Intramuscular [23] | Prevention |
AEs were recorded using the preferred terms (PTs) from the Medical Dictionary for Regulatory Activities (MedDRA), and these PTs were categorized into their primary system organ classes (SOCs) in the MedDRA [8]. Only initial reports, where the role code was set to the primary suspect drug, were selected. Two or more PTs reported in one report were counted as different AEs [9, 10]. The important medical events (IMEs) terms list was used to identify the potentially important medical AEs based on their seriousness and clinical importance [11]. Serious adverse events (SAEs) were classified as death, life-threatening, hospitalization, disability, congenital anomaly/birth defect and requiring intervention to prevent. The signals of IMEs of SARS-CoV-2 neutralizing monoclonal antibody drugs were confirmed as to whether they were listed on the FDA drug label. An AE which was not listed on the FDA website (https://www.fda.gov/emergency-preparedness-drugs/emergency-use-authorizations-drugs-and-non-vaccine-biological-products) was regarded as an ‘unexpected AE’ [12].
Statistical analysis
Disproportionality was analyzed using the reporting odds ratio (ROR), and the information component (IC) to detect potential AEs from the FAERS database [13]. A two-by-two contingency table was used to detect spontaneous signals for a potentially increased risk of drug-related AEs. The ROR is estimated as the ratio for the odds of an AE reported for a monoclonal antibody in COVID-19 patients versus the odds of an AE reported for all other drugs in COVID-19 patients; a safety signal is detected if there are more than three AEs of interest and the lower limit of the 95% confidence interval (CI) of the ROR is greater than two, with an associated chi-square value with Yates’s correction of four or more [14, 15].
The IC is a measurement for strength of association between drugs and AEs using the Bayesian neural network method; a safety signal is detected if the lower limit of the 95% CI of the IC is greater than zero[16, 17]. Categorical demographic variables (sex, age) and severe groups were compared using the chi-squared tests. The significance level was set to p < 0.05.
Results
Characteristics of the spontaneous reports for SARS-CoV-2 neutralizing monoclonal antibodies from the FAERS
Table 2 shows the characteristics of the reports submitted to FAERS for each monoclonal antibody drug from 2020 to 2022. Among the AEs reported within this period, 15,403 were reported for bamlanivimab and 15,252 for casirivimab/imdevimab. Approximately 71.9% of the AEs reported were related to bamlanivimab (36.1%) and casirivimab/imdevimab (35.8%), which were granted emergency use authorization (EUA) in November 2020. In terms of the age of the individuals affected, 33.3% (14,215) of the patients were aged 60 ~ 79 years. The number of AE reports has been increasing from 2020 until the emergence of the Omicron variant in 2022. There were statistically significant differences (p < 0.001) in the gender and age of the reporters of adverse effects for the six drugs. In terms of SAEs, 7605 cases were reported for bamlanivimab, 12,310 for casirivimab/imdevimab, 2023 for bamlanivimab/etesevimab, 130 for sotrovimab, 0 for bebtelovimab, and 2759 for tixagevimab/cilgavimab. The most common SAE was hospitalization (44.2%) (Table 3).
Table 2.
Characteristics of adverse event reports of SARS-CoV-2 neutralizing monoclonal antibodies from 2020 to 2022
| Characteristics | Total n (%) | Bamlanivimab n (%) | Casirivimab/Imdevimab n (%) | Bamlanivimab/Etesevimab n (%) | Sotrovimab n (%) | Bebtelovimab n (%) | Tixagevimab/Cilgavimab n (%) |
|---|---|---|---|---|---|---|---|
| Number of reports | 42,642 (100) | 15,403 (36.1) | 15,252 (35.8) | 2913 (6.8) | 4487 (10.5) | 1355 (3.2) | 3232 (7.6) |
| Age, years | |||||||
| Under 20 | 864 (2.0) | 173 (1.1) | 450 (3.0) | 122 (4.2) | 59 (1.3) | 27 (2.0) | 33 (1.0) |
| 20 ~ 39 | 5758 (13.5) | 1117 (7.3) | 2892 (19.0) | 786 (27.0) | 585 (13.0) | 222 (16.4) | 156 (4.8) |
| 40 ~ 59 | 9802 (23.0) | 3157 (20.5) | 4402 (28.9) | 1000 (34.3) | 320 (7.1) | 304 (22.4) | 619 (19.2) |
| 60 ~ 79 | 14,215 (33.3) | 6993 (45.4) | 4585 (30.1) | 833 (28.6) | 472 (10.5) | 398 (29.4) | 934 (28.9) |
| Over 80 | 4154 (9.7) | 2305 (15.0) | 1294 (8.5) | 123 (4.2) | 179 (4.0) | 121 (8.9) | 132 (4.1) |
| Unknown | 7849 (18.4) | 1658(10.8) | 1629 (10.7) | 49 (1.7) | 2872 (64.0) | 283 (20.9) | 1358 (42.0) |
| Gender | |||||||
| Male | 16,896 (39.6) | 7552 (49.0) | 5947 (39.0) | 1087 (37.3) | 549 (12.2) | 408 (30.1) | 1353 (41.9) |
| Female | 20,868 (48.9) | 7564 (49.1) | 7861 (51.5) | 1723 (59.1) | 1197 (26.7) | 858 (63.3) | 1665 (51.5) |
| Unknown | 4878 (11.4) | 287 (1.9) | 1444 (9.5) | 103 (3.5) | 2741 (61.1) | 89 (6.6) | 214 (6.6) |
Table 3.
Serious adverse event (SAE) reports of SARS-CoV-2 neutralizing monoclonal antibodies from 2020 to 2022
| Total n (%) | Bamlanivimab n (%) | Casirivimab/Imdevimab n (%) | Bamlanivimab/Etesevimab n (%) | Sotrovimab n (%) | Bebtelovimab n (%) | Tixagevimab/Cilgavimab n (%) | |
|---|---|---|---|---|---|---|---|
| Adverse event (AE) | |||||||
| Non-serious | 17,815 (41.8) | 7798 (50.6) | 2942 (19.3) | 890 (30.6) | 4357 (97.1) | 1355 (100) | 473 (14.6) |
| Serious | 24,827 (58.2) | 7605 (49.4) | 12,310 (80.7) | 2023 (69.4) | 130 (2.9) | 0 (0.0) | 2759 (85.4) |
| Type of SAE | |||||||
| Death | 1289 (5.2) | 503 (6.6) | 328 (2.7) | 50 (2.5) | 19 (14.6) | 0 (0.0) | 389 (14.1) |
| Life-threatening | 979 (3.9) | 259 (3.4) | 513 (4.2) | 95 (4.7) | 3 (2.3) | 0 (0.0) | 109 (4.0) |
| Hospitalization | 10,965 (44.2) | 4546 (59.8) | 4950 (40.2) | 600 (29.7) | 41 (31.5) | 0 (0.0) | 828 (30.0) |
| Disability | 220 (0.9) | 24 (0.3) | 105 (0.9) | 15 (0.7) | 1 (0.8) | 0 (0.0) | 75 (2.7) |
| Congenital anomaly/birth defect | 6 (0.02) | 2 (0.0) | 4 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Required intervention to prevent permanent impairment/damage | 2167 (8.7) | 222 (2.9) | 1301 (10.6) | 505 (25.0) | 7 (5.4) | 0 (0.0) | 132 (4.8) |
| Others | 9201 (37.1) | 2049 (26.9) | 5109 (41.5) | 758 (37.5) | 59 (45.4) | 0 (0.0) | 1226 (44.4) |
Major adverse events and signals for SARS-CoV-2 neutralizing monoclonal antibodies
Based on the AEs determined from signals for the top three SOCs, the three most frequently detected IMEs are presented for each drug granted emergency use authorization (Table 4, Fig. 1).
Table 4.
The important medical events (IMEs) of SARS-CoV-2 neutralizing monoclonal antibodies identified as signal in each system organ class (SOC) from the FAERS database
| SOC | IME | Primary suspected cases, n | ROR (95%, CI) | IC (95% lower limit) | Drug label (FDA) |
|---|---|---|---|---|---|
| Bamlanivimab | |||||
| Respiratory, thoracic and mediastinal disorders | Hypoxia | 309 | 39.06 (34.83 ~ 43.79) | 5.13 (4.58) | Y |
| COVID-19 pneumonia | 256 | 34.04 (30.04 ~ 38.59) | 4.94 (4.36) | N | |
| Pneumonia | 177 | 2.32 (2.00 ~ 2.69) | 1.20 (1.03) | Y | |
| Vascular disorders | Syncope | 53 | 2.65 (2.03 ~ 3.48) | 1.38 (1.05) | Y |
| Pulmonary embolism | 45 | 2.80 (2.09 ~ 3.75) | 1.45 (1.08) | Y | |
| Anaphylactic reaction | 40 | 3.53 (2.58 ~ 4.81) | 1.77 (1.30) | Y | |
| Cardiac disorders | Atrial fibrillation | 81 | 3.56 (2.86 ~ 4.43) | 1.80 (1.45) | Y |
| Bradycardia | 58 | 5.14 (3.97 ~ 6.66) | 2.30 (1.78) | Y | |
| Pulseless electrical activity | 5 | 4.95 (2.06 ~ 11.92) | 1.86 (0.77) | N | |
| Casirivimab/Imdevimab | |||||
| Respiratory, thoracic and mediastinal disorders | Hypoxia | 236 | 29.75 (26.12 ~ 33.89) | 4.76 (4.18) | Y |
| COVID-19 pneumonia | 142 | 18.69 (15.82 ~ 22.08) | 4.11 (3.48) | Y | |
| Acute respiratory failure | 87 | 19.68 (15.91 ~ 24.34) | 4.12 (3.34) | N | |
| Vascular disorders | Anaphylactic reaction | 95 | 8.52 (6.96 ~ 10.44) | 3.02 (2.47) | Y |
| Syncope | 88 | 4.47 (3.62 ~ 5.51) | 2.12 (1.72) | N | |
| Distributive shock | 6 | 12.46 (5.57 ~ 27.86) | 2.72 (1.22) | N | |
| Nervous system disorders | Loss of consciousness | 73 | 3.05 (2.43 ~ 3.85) | 1.58 (1.26) | N |
| Unresponsive to stimuli | 55 | 12.84 (9.84 ~ 16.75) | 3.51 (2.70) | N | |
| Encephalopathy | 14 | 2.94 (1.74 ~ 4.98) | 1.46 (0.86) | N | |
| Bamlanivimab/Etesevimab | |||||
| Respiratory, thoracic and mediastinal disorders | Hypoxia | 62 | 40.47 (31.44 ~ 52.09) | 4.91 (3.82) | Y |
| COVID-19 pneumonia | 39 | 26.71 (19.46 ~ 36.66) | 4.31 (3.14) | N | |
| Acute respiratory failure | 30 | 35.35 (24.64 ~ 50.70) | 4.48 (3.13) | N | |
| Vascular disorders | Anaphylactic reaction | 25 | 11.72 (7.90 ~ 17.38) | 3.26 (2.20) | Y |
| Syncope | 17 | 4.51 (2.80 ~ 7.27) | 2.03 (1.26) | Y | |
| Pulmonary embolism | 11 | 3.61 (2.00 ~ 6.53) | 1.69 (0.94) | N | |
| Metabolism and nutrition disorders | Diabetic ketoacidosis | 8 | 9.03 (4.51 ~ 18.09) | 2.61 (1.30) | Y |
| Hypokalemia | 6 | 3.16 (1.42 ~ 7.05) | 1.44 (0.65) | N | |
| Type 2 diabetes mellitus | 3 | 2.63 (0.85 ~ 8.16) | 1.09 (0.35) | N | |
| Sotrovimab | |||||
| Respiratory, thoracic and mediastinal disorders | COVID19-pneumonia | 50 | 22.20 (16.79 ~ 29.36) | 4.17 (3.16) | Y |
| Hypoxia | 46 | 19.23 (14.38 ~ 25.74) | 3.99 (2.98) | Y | |
| Respiratory failure | 22 | 5.43 (3.57 ~ 8.26)) | 2.29 (1.51) | Y | |
| Vascular disorders | Anaphylactic reaction | 42 | 12.81 (9.45 ~ 17.36) | 3.48 (2.56) | Y |
| Anaphylactoid reaction | 6 | 35.84 (16.03 ~ 80.10) | 3.28 (1.47) | N | |
| Acute myocardial infarction | 5 | 4.10 (1.71 ~ 9.87) | 1.67 (0.70) | N | |
| Cardiac disorders | Bradycardia | 25 | 7.61 (5.13 ~ 11.28) | 2.74 (1.85) | Y |
| Atrial fibrillation | 22 | 3.31 (2.18 ~ 5.04) | 1.65 (1.09) | Y | |
| Cardiac arrest | 14 | 3.63 (2.15 ~ 6.14) | 1.73 (1.02) | N | |
| Bebtelovimab | |||||
| Respiratory, thoracic and mediastinal disorders | Hypoxia | 13 | 17.93 (10.38 ~ 30.97) | 3.45 (2.00) | Y |
| Respiratory distress | 11 | 24.39 (13.47 ~ 44.17) | 3.45 (2.00) | N | |
| Respiratory arrest | 4 | 7.64 (5.10 ~ 36.35) | 2.50 (0.94) | N | |
| Vascular disorders | Anaphylactic reaction | 32 | 9.23 (6.52 ~ 13.07) | 3.02 (2.14) | Y |
| Syncope | 20 | 3.26 (2.10 ~ 5.06) | 1.62 (1.05) | Y | |
| Pulmonary embolism | 3 | 2.11 (0.68 ~ 6.56) | 0.87 (0.28) | N | |
| Nervous system disorders | Unresponsive to stimuli | 23 | 17.25 (11.44 ~ 26.00) | 3.67 (2.43) | N |
| Loss of consciousness | 18 | 2.42 (1.53 ~ 3.85) | 1.22 (0.77) | N | |
| Seizure | 14 | 4.97 (2.94 ~ 8.42) | 2.12 (1.25) | N | |
| Tixagevimab/Cilgavimab | |||||
| Respiratory, thoracic and mediastinal disorders | COVID19-pneumonia | 11 | 6.70 (3.70 ~ 12.11) | 2.42 (1.34) | N |
| Hypoxia | 9 | 5.16 (2.68 ~ 9.94) | 2.08 (1.08) | Y | |
| pulmonary edema | 6 | 3.08 (1.38 ~ 6.86) | 1.41 (0.63) | N | |
| Vascular disorders | Anaphylactic reaction | 19 | 8.00 (5.09 ~ 12.56) | 2.75 (1.75) | Y |
| Deep vein thrombosis | 14 | 7.29 (4.31 ~ 12.33) | 2.58 (1.52) | N | |
| Pulmonary embolism | 12 | 3.55 (2.01 ~ 6.26) | 1.68 (0.96) | N | |
| Cardiac disorders | Atrial fibrillation | 25 | 5.24 (3.54 ~ 7.77) | 2.27 (1.53) | Y |
| Cardiac arrest | 18 | 6.50 (4.09 ~ 10.33) | 2.49 (1.57) | Y | |
| Bradycardia | 8 | 3.36 (1.68 ~ 6.73) | 1.56 (0.78) | N | |
Fig. 1.
Detected signals of adverse events associated with six SARS-CoV-2 neutralizing monoclonal antibodies (A. Bamlanivimab; B. Casirivimab/Imdevimab; C. Bamlanivimab/Etesevimab; D. Sotrovimab; E. Bebtelovimab; F. Tixagevimab/Cilgavimab, ROR reporting odds ratio)
Commonly detected IMEs for bamlanivimab were hypoxia (309 cases), COVID-19 pneumonia (256 cases), pneumonia (177 cases), atrial fibrillation (81 cases), bradycardia (58 cases), syncope (53 cases), pulmonary embolism (45 cases), anaphylactic reaction (40 cases), and pulseless electrical activity (5 cases).
The commonly detected IMEs for casirivimab/imdevimab were hypoxia (236 cases), COVID-19 pneumonia (142 cases), anaphylactic reaction (95 cases), syncope (88 cases), acute respiratory failure (87 cases), loss of consciousness (73 cases), unresponsive to stimuli (55 cases), encephalopathy (14 cases), and distributive shock (6 cases).
The commonly detected IMEs for bamlanivimab/etesevimab were hypoxia (62 cases), COVID-19 pneumonia (39 cases), acute respiratory failure (30 cases), anaphylactic reaction (25 cases), syncope (17 cases), pulmonary embolism (11 cases), diabetic ketoacidosis (eight cases), hypokalemia (6 cases), and type 2 diabetes mellitus (3 cases).
The commonly detected IMEs for sotrovimab were COVID19-pneumonia (50 cases), hypoxia (46 cases), anaphylactic reaction (42 cases), bradycardia (25 cases), respiratory failure (22 cases), atrial fibrillation (22 cases), cardiac arrest (14 cases), anaphylactoid reaction (6 cases), and acute myocardial infarction (5 cases).
The commonly detected IMEs for bebtelovimab were anaphylactic reaction (32 cases), unresponsive to stimuli (23 cases), syncope (20 cases), loss of consciousness (18 cases), seizure (14 cases), hypoxia (13 cases), respiratory distress (11 cases), respiratory arrest (4 cases), and pulmonary embolism (3 cases).
The commonly detected IMEs for tixagevimab/cilgavimab were atrial fibrillation (25 cases), anaphylactic reaction (19 cases), cardiac arrest (18 cases), deep vein thrombosis (14 cases), pulmonary embolism (12 case), COVID-19 pneumonia (11 cases), hypoxia (nine cases), bradycardia (eight cases), and pulmonary edema (six cases).
Based on the signals that are considered IMEs in each of the top three SOCs, AEs not reported in the FDA-approved labelling for bamlanivimab were COVID-19 pneumonia and pulseless electrical activity. AEs not reported in the FDA-approved labelling for casirivimab/imdevimab were acute respiratory failure, syncope, distributive shock, loss of consciousness, unresponsive to stimuli, and encephalopathy. AEs not reported in the FDA-approved labelling for bamlanivimab/etesevimab were COVID-19 pneumonia, acute respiratory failure, pulmonary embolism, hypokalemia, and type 2 diabetes mellitus. AEs not reported in the FDA-approved labelling for sotrovimab were anaphylactoid reaction, acute myocardial infarction, and cardiac arrest. AEs not reported in the FDA-approved labelling for bebtelovimab were respiratory distress, respiratory arrest, pulmonary embolism, unresponsive to stimuli, loss of consciousness, and seizure. AEs not reported in the FDA-approved labelling for tixagevimab/cilgavimab were COVID-19 pneumonia, pulmonary edema, deep vein thrombosis, pulmonary embolism, and bradycardia.
Discussion
In this study, we examined the signals for adverse events (AEs) of SARS-CoV-2 neutralizing monoclonal antibodies using the data mining parameters reporting odds ratio (ROR) and information component (IC), in reports submitted to FAERS. According to the FAERS public dashboard, six products were granted emergency use authorization (EUA) or approval during the study period [18–23], and the numbers of AEs reported for these drugs are as follows: bamlanivimab (15,403 cases), casirivimab/imdevimab (15,202 cases), bamlanivimab/etesevimab (2913 cases), sotrovimab (4487 cases), bebtelovimab (1355 cases), and tixagevimab/cilgavimab (3232 cases). Regdanvimab (brand name: Regkirona) [24], developed by a Korean company Celltrion, Inc., was excluded from the analysis, as it was approved in Korea and Europe but was not granted EUA in the United States (US). Hence, no reports were submitted to the FAERS for this drug.
This study observed that the number of AEs reported for the six drugs tended to be proportional to the time of emergency use authorized by the US FDA. In patients to whom bamlanivimab or casirivimab/imdevimab were administered, more than 15,000 AEs were reported. These two drugs have been approved for use since November 2020. However, relatively few AEs have been reported for FDA-approved drugs after 2021.
Analyzing adverse events of COVID-19 neutralizing antibody drugs ensures their safe and effective use. It identifies potential risks, balances benefits and harms, and supports regulatory approval. For the oral COVID-19 treatments baricitinib, molnupiravir, and ritonavir-boosted nirmatrelvir, which received FDA EUA, commonly observed adverse events including nausea, dyspepsia, diarrhea, dysgeusia, rash, and headache [25–27]. In contrast, monoclonal antibodies targeting specific sites had much fewer adverse events [28], and in clinical trials, administration-related adverse events such as anaphylactic reaction and infusion-related reactions were frequently observed with the parenteral route. Continuous monitoring captures rare side effects, builds public trust, and informs clinical guidelines. This analysis aids in optimizing treatment protocols and developing safer next-generation therapies. Additionally, it provides evidence essential for cost–benefit analyses and public health strategies. Overall, this evaluation is crucial for managing COVID-19 with these antibody drugs safely and effectively.
Monoclonal antibodies are proteins constructed in a laboratory that mimic the human immune system in its response to viruses, such as SARS-CoV-2, which causes COVID-19 infection. SARS-CoV-2 can mutate over time, causing some antibody drugs not to bind [29, 30]. Monoclonal antibody drugs have been recognized for their neutralizing effect against the SARS-CoV-2 delta variant and used as treatments [31]. However, the situation changed when the World Health Organization (WHO) designated the new SARS-CoV-2 Omicron variant (B.1.1529), as a variant of concern (VOC), in November 2021 [32]. This variant, which contains many mutations in the spike protein, showed significantly lower sensitivity to existing drugs used in vitro tests. Bamlanivimab/etesevimab or carsirivimab/imdevimab treatment was ineffective against the Omicron variant [19, 20]. While the reactivity of sotrovimab and bebtelovimab to the Omicron variant continued, there was a difference in the response pattern of the two drugs [21, 22]. Sotrovimab was observed to be active against the Omicron BA.1 and BA.1.1 subvariants, but less active against the Omicron BA.2 subvariant. Accordingly, the FDA restricted the use of sotrovimab in February 2022 and withdrew the EUA in April 2022. Bebtelovimab was maintained for in vitro activity against the Omicron subvariants [33].
Additional analyses confirmed the results of a recent study of bebtelovimab, indicating its effectiveness as a COVID-19 treatment. In addition, the FDA announced that Evusheld (tixagevimab/cilgavimab) would be withdrawn from the EUA in the US on January 26, 2023, as an option for pre-exposure prophylaxis [23]. Therefore, bebtelovimab is the only COVID-19 treatment available as of December 2023.
With regard to an analysis of demographic information, old age is well known as a risk factor for worsening of a patient's condition during a coronavirus infection [33, 34]. As expected, AEs were reported at a higher rate in older people over 60. In additionally, female were associated with any increased reporting of AEs, contrary to the belief that the infection rate is higher in men. Unlike vaccines administered to healthy people, neutralizing antibody treatments for COVID-19 are administered to patients with mild to moderate symptoms who are at risk on account of underlying diseases or immunosuppression, and the rate of SAEs among all reported AEs is 1.4 times higher in this group. Factors that worsen the progression of the disease through hospitalization and death are age (65 years or older), a smoking habit, and specific underlying diseases, such as cancer, chronic kidney disease, chronic obstructive pulmonary disease (COPD), heart diseases, immunocompromised conditions, obesity, sickle cell disease, or type 2 diabetes [35–40].
Among the six antibody therapeutics analyzed, five intended for therapeutic purposes and one (Evusheld) for prophylactic purposes, the observed severity of AEs revealed an 14.1% fatality rate for the prophylactic therapeutic. These results were from patients receiving prophylactic agents, who are immunocompromised and unable to receive vaccination, such as those undergoing cancer treatment or long-term immunosuppressive therapy, being inherently in a more severe disease state than the high-risk cohort initially targeted for COVID-19 treatment, leading to such outcomes. It reflects a similarity in the severity of adverse events observed in the study population to those seen in clinical trials. For patients receiving Evusheld for preventive purposes, there is a higher likelihood of progression to severe conditions. Therefore, intensive monitoring is necessary even after medication administration, and prompt medical intervention should be provided. However, the classification and types of adverse events according to the System Organ Class (SOC) predominantly appeared as respiratory, thoracic, and mediastinal disorders, vascular disorders, and cardiac disorders, which closely resembled those observed in the other five therapeutic monoclonal antibody drugs intended for treatment purposes.
In the case of sotrovimab and bebtelovimab, the number of reported serious AEs was lower than that of the total AEs, which is consistent with Phase 3 clinical trials that evaluated the effectiveness and safety of other antibody drugs [32, 41]. However, the incidence of SAEs was artificially low because only results obtained from a small number of patients were analyzed during a short clinical trial period of six months to one year. Therefore, there was no evidence that the incidence rate increased compared to the placebo group. In the case of other drugs that were first approved and administered in 2020 to early 2021, the reporting period for the patients’ conditions through the spontaneous adverse drug reaction (ADR) reporting system was relatively longer than that of sotrovimab and bebtelovimab, resulting in a high incidence of severe ADRs. In the analysis of AEs corresponding to important medical events (IMEs), the most reported AEs were hypoxia [41–43], COVID-19 pneumonia, pneumonia associated with respiratory, thoracic, and mediastinal disorders. COVID-19 is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), and the viral genetic sequence is a beta coronavirus closely related to the SARS virus. Thus, respiratory adverse reactions were predictable symptoms. However, none of the antibody drugs have been approved for administration to patients hospitalized with COVID-19 or requiring oxygen treatment [44]. Therefore, the symptoms are believed to be caused by worsening of COVID-19. The patients administered sotrovimab and bebtelovimab had a mild or moderate COVID-19 infection with high-risk factors. By definition, mild cases are confirmed patients showing clinical symptoms of COVID-19 without viral pneumonia or hypoxia, and moderate cases are patients with symptoms of pneumonia (fever, cough, difficulty breathing, or rapid breathing) but no symptoms of severe pneumonia [45]. Therefore, pneumonia and COVID-19 pneumonia were already sufficiently predicted AEs based on the disease status of patients eligible for treatment.
Vascular disorders were one of the significant adverse drug reactions (ADRs) from COVID-19 neutralizing antibody drugs. Syncope and anaphylactic reactions are representative examples and they were observed as SAEs in this study. Injection-related reactions, including anaphylactic reactions [46, 47], are typical symptoms that may appear during or after the administration of antibody drugs. Symptoms and signs may include bronchospasm, laryngeal irritation, throat irritation, hypotonia, syncope, and incontinence. Therefore, the labels of certain antibody drugs are required to state that administration be immediately discontinued, and appropriate treatment be performed if such clinical signs appear. The exception is tixageviamb/cilgavimab [47], which is administered intramuscularly, the remaining five products are drugs administered by infusion and their labels state that they require monitoring at the administration site for one to two hours after administration [18–22].
The selection criteria for clinical trials of SARS-CoV-2-neutralizing monoclonal antibodies for COVID-19 included people with hypertension or cardiovascular disease [36, 40, 48], and the label states arrhythmia (atrial fibrillation, tachycardia, or bradycardia) as a serious and unexpected AEs under the section of Warnings. However, it was not clear whether these were due to drug administration or the progression of COVID-19. In another study on cardiovascular adverse reactions to monoclonal antibodies against COVID-19, it was reported that more than 10% of ADRs were cardiovascular system abnormalities and that various cardiovascular AEs occurred for each antibody drug [48]. However, unlike reports stating that cardiovascular-related safety signals were not known for sotrovimab and tixagevimab/cilgavimab, ADRs such as atrial fibrillation, bradycardia, and cardiac arrest due to cardiac abnormalities were commonly identified as signals for both drugs in this study. Additionally, pulseless electrical activity was confirmed as arrhythmia [49].
In addition, when administering casirivimab/imdevimab and bebtelovimab, nervous system disorders were reported, and loss of consciousness, unresponsiveness to stimuli, encephalopathy, and seizure were elicited as a frequent signal. According to previous studies, when infected with COVID-19, neurological symptoms may appear due to the body's extensive immune response to infection rather than direct infection of the brain or the nervous system by the virus [50, 51]. Various neurological symptoms were reported when neutralizing antibodies were administered to infected patients. Additional studies are required to determine whether damage to the nervous system or other body organs is reversible after administration of antibody drugs or whether they cause more persistent or chronic disorders.
IMEs corresponding to the most frequently detected signal for the top three system organ classes (SOCs) reported in the six drugs was compared with the contents described in the EUA to identify AEs not stated on the label. Since the label of EUA is written based on unique clinical trial results for each antibody drug, there were minor differences between antibody drugs with the same mechanism, and many new signals were detected for each drug. As coronavirus treatments or preventive drugs were developed as antibody drugs; they received EUAs based on an average of two to three clinical trials. Several AEs, not revealed by the clinical trials were additionally collected through spontaneous AEs reporting [52]. Therefore, additional studies are required to determine the causal relationship between the drug and the additionally identified AEs.
This study has some limitations. First, due to the nature of the spontaneous reporting database, it was not clear whether the reported cases were caused by the suspected drug, the patient's underlying disease and progression of COVID-19, or other concomitant drugs. Second, since the control group consisted of all drugs excluding SARS-CoV-2 neutralizing monoclonal antibody drugs, these could not be compared with other oral drugs that were approved or approved for emergency use as COVID-19 treatments. Third, the inability to determine the total number of patients administered the medication is a limitation, as it prevents the accurate calculation of the adverse event ratio. Finally, SARS-CoV-2 neutralizing monoclonal antibody drugs approved in Korea are not approved in the US, so an analysis of the Korean Adverse Event Reporting System (KAERS) targeting Koreans is necessary.
In conclusion, in this study, we derived IMEs including hypoxia, COVID-19 pneumonia, and anaphylactic reactions, signals of SARS-CoV-2 neutralizing monoclonal antibody drugs, and also identified unknown AEs. It is expected that post-marketing drug AEs, which are not published due to the short drug development period, may be derived based on new signals and reflected in precautions for use in future drug labels.
Acknowledgements
This study was supported by Chosun University (2022).
Funding
Chosun University, 2022, SUNG HWAN KI
Data availability
The data presented in this study are available on reasonable request.
Declarations
Conflict of interest
Sung Hwan Ki was the Associate Editor of Toxicological Research while the manuscript of this article was submitted and peer-reviewed. Editorial Board Member status has no bearing on editorial consideration.
Contributor Information
Yun-Kyoung Song, Email: yksong@catholic.ac.kr.
Sung Hwan Ki, Email: shki@chosun.ac.kr.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data presented in this study are available on reasonable request.