Safety of Biological Therapies for Severe Asthma: An Analysis of Suspected Adverse Reactions Reported in the WHO Pharmacovigilance Database

Abstract

Background: The management of uncontrolled severe asthma has greatly improved since the advent of novel biologic therapies. Up to August 2022, five biologics have been approved for the type 2 asthma phenotype: anti-IgE (omalizumab), anti-IL5 (mepolizumab, reslizumab, benralizumab), and anti-IL4 (dupilumab) monoclonal antibodies. These drugs are usually well tolerated, although long-term safety information is limited, and some adverse events have not yet been fully characterized. Spontaneous reporting systems represent the cornerstone for the detection of potential signals and evaluation of the real-world safety of all marketed drugs.

Objective: The aim of this study was to provide an overview of safety data of biologics for severe asthma using VigiBase, the World Health Organization global pharmacovigilance database.

Methods: We selected all de-duplicated individual case safety reports (ICSRs) attributed to five approved biologics for severe asthma in VigiBase, up to 31st August 2022 (omalizumab, mepolizumab, reslizumab, benralizumab and dupilumab). Descriptive frequency analyses of ICSRs were carried out both as a whole class and as individual products. Reporting odds ratios (ROR) with 95% confidence intervals (CIs) were used as the measure of disproportionality for suspected adverse drug reactions (ADRs) associated with the study drugs compared with either all other suspected drugs (Reference Group 1, RG1) or inhaled corticosteroids plus long-acting β-agonists (ICSs/LABAs) (Reference Group 2, RG2) or with oral corticosteroids (OCSs) (Reference Group 3, RG3).

Results: Overall, 31,724,381 ICSRs were identified in VigiBase and 167,282 (0.5%) were related to study drugs; the remaining reports were considered as RG1. Stratifying all biologic-related ICSRs by therapeutic indication, around 29.4% (n = 48,440) concerned asthma use; omalizumab was mainly indicated as the suspected drug (n = 20,501), followed by dupilumab, mepolizumab, benralizumab and reslizumab. Most asthma ICSRs concerned adults (57%) and women (64.1%). Asthma biologics showed a higher frequency of serious suspected ADR reporting than RG1 (41.3% vs 32.3%). The most reported suspected ADRs included asthma, dyspnea, product use issue, drug ineffective, cough, headache, fatigue and wheezing. Asthma biologics were disproportionally associated with several unknown or less documented adverse events, such as malignancies, pulmonary embolism and deep vein thrombosis with omalizumab; alopecia and lichen planus with dupilumab; alopecia and herpes infections with mepolizumab; alopecia, herpes zoster and eosinophilic granulomatosis with polyangiitis related to benralizumab; and alopecia with reslizumab.

Conclusions: The most frequently reported suspected ADRs of asthma biologics in VigiBase confirmed the presence of well-known adverse effects such as general disorders, injection-site reactions, nasopharyngitis, headache and hypersensitivity, while some others (e.g. asthma reactivation or therapeutic failure) could be ascribed to the indication of use. Moreover, the analysis of signals of disproportionate reporting suggests the presence of malignancies, effects on the cardiovascular system, alopecia and autoimmune conditions, requiring further assessment and investigation.

Fig. 1

Flow chart for individual case safety report selection process in VigiBase. The sum of the reports by single asthma drug is higher than the total number of reports, since a single report could contain two or more biologic drugs as suspected. ICSRs individual case safety reports, ICSs/LABAs inhaled corticosteroids plus long-acting β-agonists, OCSs oral corticosteroids

Fig. 2

RORs of System Organ Classes comparing biologics used in asthma with biologics in all other indications (Part A) and with all other drugs in VigiBase (Part B). Blood blood and lymphatic system disorders, Card cardiac disorders, Cong congenital, familial and genetic disorders, Ear ear and labyrinth disorders, Endo endocrine disorders, Eye eye disorders, Gastr gastrointestinal disorders, Genrl general disorders and administration-site conditions, Hepat hepatobiliary disorders, Immun immune system disorders, Infec infections and infestations, Inj&P injury, poisoning and procedural complications, Inv investigations, Metab metabolism and nutrition disorders, Musc musculoskeletal and connective tissue disorders, Neopl neoplasms benign, malignant and unspecified (incl cysts and polyps), Nerv nervous system disorders, Preg pregnancy, puerperium and perinatal conditions, Prod product issues, Psych psychiatric disorders, Renal renal and urinary disorders, RG1 Reference Group 1, Repro reproductive system and breast disorders, Resp respiratory, thoracic and mediastinal disorders, RORs reporting odds ratios, Skin skin and subcutaneous tissue disorders, SocCi social circumstances, Surg surgical and medical procedures, Vasc vascular disorders

Fig. 3

Reports related to each single biologic used in asthma stratified by System Organ Classes (%). Blood blood and lymphatic system disorders, Card cardiac disorders, Cong congenital, familial and genetic disorders, Ear ear and labyrinth disorders, Endo endocrine disorders, Eye eye disorders, Gastr gastrointestinal disorders, Genrl general disorders and administration-site conditions, Hepat hepatobiliary disorders, Immun immune system disorders, Infec infections and infestations, Inj&P injury, poisoning and procedural complications, Inv investigations, Metab metabolism and nutrition disorders, Musc musculoskeletal and connective tissue disorders, Neopl neoplasms benign, malignant and unspecified (incl cysts and polyps), Nerv nervous system disorders, Preg pregnancy, puerperium and perinatal conditions, Prod product issues, Psych psychiatric disorders, Renal renal and urinary disorders, Repro reproductive system and breast disorders, Resp respiratory, thoracic and mediastinal disorders, Skin skin and subcutaneous tissue disorders, SocCi social circumstances, Surg surgical and medical procedures, Vasc vascular disorders

Fig. 4

RORs of some selected suspected ADRs comparing biologics used for asthma versus all other indications. Each category of adverse events was evaluated aggregating different PT terms, as follows: ‘Anaphylactic reactions’: Anaphylactic reaction; Anaphylactic shock; Anaphylactoid reaction. ‘Arthritis’: Arthritis; Arthritis infective; Osteoarthritis; Periarthritis; Polyarthritis; Rheumatoid arthritis; Spinal osteoarthritis. ‘Cardiac arrhythmias’: Arrhythmia; Arrhythmia supraventricular; Atrial fibrillation; Atrial tachycardia; Sinus tachycardia; Supraventricular tachycardia; Ventricular tachycardia; Atrioventricular block; Atrioventricular block complete. ‘Cardio-cerebral ischemic diseases’: Acute myocardial infarction; Cerebral infarction; Cerebral ischemia; Cerebral thrombosis; Cerebrovascular accident; Cerebrovascular disorder; Infarction; Ischemic stroke; Myocardial infarction; Myocardial ischemia; Thrombotic stroke. ‘Eye disorders’: Conjunctivitis; Keratitis; Ulcerative keratitis; Blepharitis; Eye pruritus; Dry eye; Eye swelling; Eye pain; Eye irritation; Eye disorder. ‘Hematological malignancies’: B-cell lymphoma; Cutaneous T-cell lymphoma; Lymphoma; Non-Hodgkin's lymphoma. ‘Muscular disorders’: Myalgia; Myopathy; Rhabdomyolysis. ‘Solid neoplasms’: Bladder cancer; Bone cancer; Brain neoplasm; Breast cancer; Colon cancer; Gastric cancer; Hepatic cancer; Lung neoplasm malignant; Malignant melanoma; Ocular neoplasm; Pancreatic carcinoma; Prostate cancer; Renal cancer; Skin cancer; Thyroid cancer; Uterine cancer. ‘Skin disorders’: Eczema; Pain of skin; Skin disorder; Skin discoloration; Skin hemorrhage; Skin plaque. ADR adverse drug reaction, PT preferred term, ROR reporting odds ratio, S suspected