PII-065

B. Wang,1 L. Yan,1 M. Hutmacher,2 L. Roskos3; 1MedImmune, Mountain View, CA, 2Ann Arbor Pharmacometrics Group, Ann Arbor, MI, 3MedImmune, Gaithersburg, MD

BACKGROUND: Benralizumab is a humanized afucosylated monoclonal antibody that specifically binds to interleukin-5 receptor α. Pharmacometrics assessments were performed on Phase IIb data to characterize the exposure-response relationship in adults with asthma. Stochastic simulations were conducted to determine whether adolescents can receive benralizumab adult dose in pivotal trials.
METHODS: In a 52-week Phase IIb study, adults with uncontrolled eosinophilic asthma received subcutaneous injections of placebo or benralizumab (2, 20, or 100 mg) on weeks 1, 4, 8, 16, 24, 32, and 40. Pharmacokinetic (PK) data, asthma exacerbation rate (AER), forced expiratory volume in 1 second (FEV1), and asthma control questionnaire (ACQ6) scores were modeled using a population approach.
RESULTS: The PK of benralizumab was dose-proportional. Majority of between-subject variability was not explained by weight. The estimated efficacy (Emax) for AER reduction was more pronounced in a subgroup with baseline eosinophil count ≥300 cells/µL. FEV1 also improved with increasing baseline blood eosinophil count. ACQ6 data were described by an indirect pharmacodynamic model. Clinical simulations suggest 30 mg every eight weeks can maintain the lower quartile of steady-state PK trough concentration above EC80 for all three efficacy endpoints. With a 40 kg lower body weight limit, the projected PK exposure in adolescents mostly overlaps with that in adults.
CONCLUSION: Exposure-response analyses and overall risk assessment identified 30 mg benralizumab as the optimal dose for adults with uncontrolled asthma. Stochastic simulations supported inclusion of adolescents (≥40 kg) in pivotal trials and for them to receive the adult dosage.