Eosinophilic Depletion with Benralizumab, Mepolizumab, and Depemokimab: A Modeling Study.

Purpose: Anti-interleukin (IL)-5/IL-5 receptor therapies are an integral part of the management of patients with severe eosinophilic asthma. We modeled and compared the blood eosinophil (bEOS) depletion response following indicated dosing regimens with benralizumab, mepolizumab, and depemokimab. Methods: Pharmacokinetic (PK)/pharmacodynamic (PD) models were developed to describe antibody concentration and bEOS count in adults. Two PK/PD models were developed using digitized bEOS data reported for depemokimab and mepolizumab, respectively, and one PK/PD model was based on individual PK parameters and predicted bEOS data with benralizumab. Subjects were assumed to receive either benralizumab 30 mg every 4 weeks (Q4W) for the first three doses, then every 8 weeks, mepolizumab 100 mg Q4W, or depemokimab 100 mg every 6 months. Results: At 12 weeks, the predicted median bEOS depletion from baseline was 99.5% (90% prediction interval [PI]: 98.3-99.8) for benralizumab, 76.1% (90% PI: 47.6-89.0) for mepolizumab, and 82.0% (90% PI: 65.0-91.6) for depemokimab. Similar median bEOS depletion rates were predicted at 24 weeks: 99.3% (90% PI: 97.2-99.8) for benralizumab, 76.3% (90% PI: 48.3-89.3) for mepolizumab, and 80.7% (90% PI: 63.2-90.2) for depemokimab. The greater reduction in bEOS count achieved with benralizumab, compared with mepolizumab and depemokimab, was predicted to be sustained through 48 weeks of continued treatment. Conclusion: These PK/PD model simulations predict that benralizumab results in consistently higher bEOS depletion than mepolizumab or depemokimab at 12 and 24 weeks. These results are dependent on the quality of the models and digitized data utilized; other models and parameter estimates may produce different results.