British journal of clinical pharmacology · 2026
Model-informed drug development to support nemolizumab clinical development in adults and adolescents with moderate to severe atopic dermatitis.
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Fauchet Floris, Largajolli Anna, Jauslin Petra M, Schindler Emilie, Hamimed Mourad, Kantasiripitak Wannee, Gonçalves Antonio, Van Maanen Eline, Benkali Khaled, Saito Tomohisa, Silverberg Jonathan I, Wollenberg Andreas, Graeber Michael, Ulianov Liliana, Piketty Christophe, Loprete Luca, Duval Vincent, Wagner Nathalie
Аннотация
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.
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.