PI-068 - EXPOSURE-RESPONSE (E-R) OF DUPILUMAB IN PAEDIATRIC PATIENTS WITH MODERATE-TO-SEVERE ASTHMA.

C. Xu¹, T. Sheng¹, Y. Gao¹, M. Kamal², M. Hardin³, Z. Meng³; ¹Sanofi, Bridgewater, NJ, USA, ²Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA, ³Sanofi, Cambridge, MA, USA.

Background: Dupilumab is approved for treatment of patients aged 6 years and older with moderate-to-severe asthma. The pharmacokinetic-pharmacodynamic (PK-PD) analyses are aimed to develop empirical models which characterize the PK-PD relationship of key efficacy endpoints.

Methods: Efficacy endpoints including annualized rate of severe exacerbation events and change from baseline in pre bronchodilator % predicted forced expiratory volume in 1 second (FEV1pp) at Week 12 were collected from a phase 3 study (NCT02948959) in children 6 to < 12 years of age with asthma. Descriptive and model-based E-R analyses were conducted using the average concentration (Caverage) over the 52-week treatment period for analyses of severe exacerbation event and the trough concentration (Ctrough) for analyses of FEV1pp at Week 12.

Results: The E-R relationship between pre-bronchodilator FEV1pp and dupilumab Ctrough at Week 12 was best described by a log linear model. The most significant covariate for slope was baseline FEV1pp and age at onset of asthma. The E-R relationship between severe exacerbation rate and Caverage over the event observation period was best described by a log linear model. The only significant covariates for slope were baseline eosinophil and gender. PK-PD relationships of key efficacy endpoints in children were similar to those in adult and adolescent patients with asthma in the PK exposure range at therapeutic doses.

Conclusion: E-R relationships of severe exacerbation and FEV1pp are similar across age groups in adults, adolescents, and children. Results of the PK-PD analyses were consistent with the efficacy evaluations in the phase 3 study and supported the proposed posology in children 6 to < 12 years of age with asthma.