Model-informed drug development to support nemolizumab clinical development in adults and adolescents with moderate to severe atopic dermatitis.

AIMS: Population pharmacokinetic (popPK) and pharmacokinetic-pharmacodynamic (PK/PD) models were developed to support clinical development of nemolizumab, a humanized monoclonal antibody targeting the IL-31 receptor α, in adolescents and adults with moderate-to-severe atopic dermatitis (AD).

METHODS

Starting from previous analyses, data from phase 2 to phase 3 studies in AD and prurigo nodularis were integrated into popPK model development. In initial PK/PD model development, a turnover model was used for Eczema Area and Severity Index (EASI) and Peak Pruritus Numerical Rating Scale (PP NRS) endpoints, while a continuous-time Markov model was used for Investigator's Global Assessment (IGA) scores. A model-informed drug development (MIDD) approach based on popPK and PK/PD modelling and simulations was applied to support dose selection in patients with AD.

RESULTS

Nemolizumab exposures decreased with increasing bodyweight. The popPK simulation predicted different median Ctroughs according to bodyweight <90 kg or ≥90 kg: 2.51 vs. 1.71 μg/mL, respectively. However, PK/PD simulations showed that the proportion of responders for EASI, PP NRS and IGA endpoints was similar in both groups: 37.5%, 55.6% and 31.6% vs. 35.1%, 53.4% and 26.3% for bodyweight <90 kg or ≥90 kg, respectively. Reduced response of IGA to nemolizumab treatment was identified for male subjects (23.4% vs. 34.0%) and severe baseline score (19.3% vs. 32.3%) with consistent trends between bodyweight group.

CONCLUSIONS

The overall MIDD approach supported the nemolizumab program by confirming the recommended dosing regimen of 30 mg every four weeks with a 60 mg loading dose in all patients with AD.