Model-informed drug development provide pivotal evidence for approval of semaglutide 1.7 mg in adolescents living with obesity
Anders Strathe1, Garrit Jentsch1, Jonas Kildegaard1, Nina Harder-Lauridsen1, Rune Viig Overgaard1
Novo Nordisk A/S
Introduction Once-weekly semaglutide subcutaneous 2.4 mg, a glucagon-like peptide-1 receptor agonist, was approved in 2021 to treat adults with an initial body mass index (BMI) of =30 kg/m² or =27 kg/m² in the presence of at least one obesity-related complication (tradename: WEGOVY®). Further, semaglutide 2.4 mg was approved in 2022 to treat adolescents ages 12 years and above with an initial BMI =95th percentile defined on sex- and age-specific BMI growth charts by FDA and EMA. Maintenance dose of 2.4 mg or maximum tolerated dose for adolescents was approved by EMA. An additional maintenance dose of 1.7 mg semaglutide was approved by FDA in 2023 for adults treated with Wegovy®. This triggered paediatric development for the additional maintenance dose to demonstrate that adolescents could benefit from the lower maintenance dose. A Model-Informed Drug Development (MIDD) strategy was proposed and agreed with the FDA in 2023 to establish pivotal evidence for efficacy and safety of a lower maintenance dose in adolescents. Objective To develop and execute a MIDD strategy for extrapolating pharmacokinetics, efficacy and safety from 2.4 mg to 1.7 mg semaglutide doses in adolescents with obesity and thereby waiving a paediatric clinical study. Methods The MIDD strategy was based on previously published population PK and PK/PD models that were developed on data from completed phase 2 and phase 3 weight management studies in adults [1], with an additional model evaluation for 1.7 mg dose in adults from East Asia [2]. The population PK and PK/PD models were adapted to data from a paediatric study investigating pharmacokinetics, safety and efficacy of 2.4 mg semaglutide in adolescents with obesity [3]. The joint adult-adolescent models were qualified using standard goodness of fit plots and visual predictive checks and parameter uncertainty was estimated using non-parametric bootstrap. The paediatric study was simulated 1000x using the observed demographic distribution in the paediatric study [3], where the structural parameters were drawn from the bootstrapped parameter distributions. Results Population PK analysis showed that body weight (BW) was the main covariate for PK in both adults and adolescents and that age caused no relevant change in the apparent clearance of semaglutide. The developed PK/PD model for semaglutide in weight management for adults was validated and found predictive of semaglutide 1.7 mg efficacy in adults from East-Asia. Based on this model, the efficacy of semaglutide 1.7 mg was established for adolescents aged 12 years and older, for relative change in BMI, and additional BMI related responder endpoints: Proportion of participants achieving 5%, 10%, and 15% reduction in BMI. Across these endpoints semaglutide 1.7 mg provided clear differentiation from placebo and incremental benefits were predicted with semaglutide 2.4 mg vs semaglutide 1.7 mg. Similar results were shown for percent change in BW. Model based simulations showed similar reporting of nausea and vomiting for semaglutide 1.7 mg and 2.4 mg doses, which was in line with the safety profile observed in adults [4]. Conclusion The MIDD strategy were considered adequate to demonstrate pharmacokinetics, efficacy and safety of semaglutide 1.7 mg as a maintenance dose in adolescents aged 12 years and older. The label text for Wegovy® in the United States Prescribing Information was successfully updated in 2024, solely based on modelling and simulation with a text that reflected the MIDD approach [5]: “Use of the 1.7 mg once weekly maintenance dosage of WEGOVY® in pediatric patients is also supported by additional exposure-efficacy and safety analyses in pooled adult and pediatric patients”.
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