Exposure-response analysis of tezepelumab in patients with severe asthma to guide phase 3 dose selection

Abstract

Background: Tezepelumab, a human anti-thymic stromal lymphopoietin monoclonal antibody, has demonstrated efficacy and safety in a placebo-controlled phase 2b dose-ranging study (Corren J et al. NEJM 2017;377:936-46) in adults with severe uncontrolled asthma. Objective: To characterize the exposure-response (ER) relationship for tezepelumab to determine optimal dose for phase 3 studies. Methods: Population pharmacokinetics were characterized using pooled data from 7 clinical studies. ER models for asthma exacerbation rate (AER) and fractionated exhaled nitrous oxide (FeNO) were developed with data from phase 2b study to support phase 3 dosing regimens in severe asthmatics. The effect of covariates, including but not limited to oral corticosteroid use, baseline blood eosinophils (EOS), and serum biomarkers (periostin and dipeptidyl peptidase 4), was analyzed. All modeling used a nonlinear mixed-effects approach. Results: Predicted percent of the maximal effect was 84%, 94%, and 98% for AER reduction and 81%, 93%, and 97% for FeNO reduction for 70 mg Q4W, 210 mg Q4W, and 280 mg Q2W tezepelumab doses, respectively. The estimated concentration achieving 90% of maximal effect (EC90) was 17 mg/L for AER. The simulations predicted that the percent of subjects reaching EC90 of AER were 4.5%, 88%, and 100% for 70 mg Q4W, 210 mg Q4W, and 280 mg Q2W doses, respectively. No clinically significant covariates of AER or FeNO response to tezepelumab were identified. Conclusions: The ER analysis supports that 210 mg Q4W is the optimal dose for phase 3 trials in severe asthmatics and that the efficacy of tezepelumab on exacerbations and FeNO reduction is not influenced by blood EOS or other T2 biomarkers.