Summary: Type 2 inflammation represents a key pathogenic mechanism underlying multiple eosinophilic diseases, including severe eosinophilic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). Interleukin-5 (IL-5) plays a central role in eosinophil differentiation, activation, and survival, and its neutralization constitutes a well-established therapeutic strategy in disorders characterized by eosinophilia. Depemokimab (Exdensur®, GSK) is the first ultra–long-acting humanized IgG1 monoclonal antibody targeting IL-5, enabling administration once every 26 weeks (twice yearly). Its prolonged half-life (38–53 days) has been achieved through YTE modification in the Fc region, enhancing binding to the neonatal Fc receptor (FcRn), and through increased affinity for IL-5 via amino acid substitutions in the variable region of the heavy chain. In the replicated phase III SWIFT-1 and SWIFT-2 trials (n = 762), depemokimab 100 mg administered subcutaneously every 26 weeks reduced the annualized exacerbation rate in severe eosinophilic asthma by 54% compared with placebo (RR 0.46; 95% CI 0.36–0.59), with a 72% reduction in severe exacerbations requiring hospitalization or emergency department visits. In the phase III ANCHOR-1 and ANCHOR-2 trials (n = 528) involving patients with CRSwNP, depemokimab significantly reduced total endoscopic nasal polyp score (difference −0.7; p < 0.001) and nasal obstruction severity (difference −0.24; p = 0,003) compared with placebo. The safety profile was comparable to placebo across both indications. This review provides a comprehensive analysis of the preclinical, pharmacological, and clinical data on depemokimab, with particular emphasis on its mechanism of action, model- -informed clinical development strategy, pivotal trial outcomes, and positioning within the therapeutic landscape of eosinophilic diseases.