Benralizumab in Severe Eosinophilic Asthma: Toward Disease Control and Evolving Treatment Paradigms

Severe eosinophilic asthma (SEA) is a type-2 inflammatory phenotype driven by persistent eosinophilia, characterized by frequent exacerbations, progressive lung function decline, and substantial oral corticosteroid (OCS) dependence, for which conventional therapies remain insufficient in a significant minority of patients. Benralizumab-a humanized, afucosylated anti-interleukin-5 receptor alpha (IL-5Rα) monoclonal antibody-achieves near-complete depletion of eosinophils and basophils through dual receptor blockade and afucosylation-enhanced antibody-dependent cell-mediated cytotoxicity (ADCC), producing one of the most extensive anti-eosinophilic effects among currently approved biologics. Pivotal Phase 3 trials (SIROCCO, CALIMA, ZONDA) demonstrated annual exacerbation rate reductions of up to 51%, robust OCS-sparing with complete elimination in 52.7% of OCS-dependent patients, and significant improvements in forced expiratory volume in 1 second (FEV1). Long-term extension data over five years (MELTEMI) confirmed sustained efficacy and safety, without evidence of adverse consequences attributable to chronic eosinophil depletion. Landmark studies including PONENTE, SHAMAL, and ABRA have further extended benralizumab's clinical impact: enabling structured OCS elimination, demonstrating that well-controlled patients can reduce inhaled corticosteroids to as-needed therapy, and establishing biologic-based treatment of acute eosinophilic exacerbations as a viable new approach. Real-world evidence consistently corroborates trial findings, with clinical remission-defined as the composite achievement of exacerbation freedom, OCS independence, symptom control, and preserved lung function-reported in 17-44% of patients at 12 months and up to 91% in selected longer-term cohorts. Beyond asthma, benralizumab demonstrates meaningful activity in comorbid chronic rhinosinusitis with nasal polyps, eosinophilic granulomatosis with polyangiitis, and eosinophilic esophagitis. This review comprehensively examines benralizumab's molecular pharmacology, pivotal and real-world clinical evidence, comorbidity management, and its central role in driving the paradigm shift from symptom control toward clinical remission in severe eosinophilic airway disease.