Dupilumab dose selection for a phase 3 study in asthma patients: pharmacokinetic/pharmacodynamic (PK/PD) modelling and clinical trial simulation
Zhaoling Meng (1), Lei Ma (1), Tao Sheng (1), Qiang Lu (1), Meng Li (1), Lin Wang (1), Pavel Kovalenko (2), A. Thomas DiCioccio (2), Hui Quan (1)
(1) Research and Development, Sanofi, Bridgewater, NJ, USA, (2) Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA
Objectives: Dupilumab, an anti-IL-4Rα monoclonal antibody, is under development for multiple indications, including asthma. To select phase 3 doses in asthma, a phase 2b dose-ranging study was completed in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting beta agonist, randomized to dupilumab 200/300 mg every 2/4 weeks (q2w/q4w), or placebo (PBO) (NCT01854047).1 Exposure-response (PK/PD) modelling and clinical trial simulation (CTS) were conducted to aid optimal dose selection in the intended patient population, understand PK/PD relationships, and identify influential baseline covariates.
Methods: Functional dupilumab was measured by serum immunoassay. PK/PD models of severe exacerbation events and forced expiratory volume in 1 second (FEV1) were established based on observed efficacy data and dupilumab exposure (model-predicted area under the curve) from the phase 2b study, then used to predict the efficacy of various dose regimens, including those not clinically evaluated (e.g.200 and 300 mg weekly). Various phase 3 design scenarios were compared and their probability of success (POS) evaluated by CTS.
Results: The PK/PD relationship for recurrent severe exacerbation events and FEV1 were best described by a negative binomial Emax regression model (offset by patient treatment duration and accounting for over-dispersed event rates across patients) and by a non-linear Emax regression model, respectively. The model-predicted annual exacerbation rate ratios (95% CI) vs PBO were 0.365 (0.229–0.583) for 200 mg q2w and 0.314 (0.186–0.530) for 300 mg q2w. At Week 12, FEV1 change from baseline predicted differences (95% CI) vs PBO were 0.146L (0.078–0.213) for 200 mg q2w and 0.159L (0.087–0.23) for 300 mg q2w. The empirical models indicated a near-plateau effect at the study's high dose (300 mg q2w) for both endpoints; and predicted very limited additional clinical benefit with doses [300 mg weekly with 0.270 exacerbation rate ratio and 0.170L for FEV1 change] greater than 300 mg q2w. Of the 4 studied doses, the q4w regimens were predicted to be less efficacious vs q2w regimens. The model predicted results were similar to those observed. CTS provided quantitative POS for efficacy assessments with various doses.
Conclusions: PK/PD and CTS predictions were consistent with observed efficacy results in the phase 2b study. Modelling and simulation indicated the 200 and 300 mg q2w doses with highest POS for efficacy, thus supporting selection of doses for phase 3 asthma trials.
References:
[1] Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, Pirozzi G, Sutherland ER, Evans RR, Joish VN, Eckert L, Graham NM, Stahl N, Yancopoulos GD, Louis-Tisserand M, Teper A. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016;388:31-44.