Andrzej Bienczak (1), Marina Savelieva (1), Tian Liu (2), Eva Hua (2), Yan Ji (3), Miriam Porter (1), Thomas Severin (1), Manmath Patekar (1), Anton Drollmann (1)
(1) Novartis Pharma AG, Basel, Switzerland; (2) China Novartis Institutes for Biomedical Research Co. Ltd. Shanghai, China; (3) Novartis Pharmaceuticals, East Hanover, New Jersey, USA
Introduction:
The paediatric development program for ligelizumab in Chronic Spontaneous Urticaria (CSU) is an example of how modelling and simulation (M&S) can be utilized to inform design and dose selection at various stages of paediatric drug development. The program itself consists of three M&S simulation activities and two extrapolation analyses staggered around the availability of interim and final results from the Phase 2 and 3 studies in adults, adolescents and children. The first M&S activity in this program guided the design of adolescent dose finding study [1]. Here, we will discuss results of the recently completed second of the planned M&S activities.
Objectives:
- Describe the pharmacokinetics (PK) and exposure-response (E-R) relationship to ligelizumab in the adolescent CSU patients from Phase 2b study CQGE031C2202 (C2202) [2] and compare to adult CSU patients from Phase 2b study CQGE031C2201 [3]
- Provide assumptions for use of partial extrapolation in younger age groups
- Propose dosing algorithm to be tested in children
Methods:
Adult population PK (PopPK) and ER models were developed in Monolix 2019R2 using data from study CQGE031C2201 [3]. Ligelizumab PK in adults was described using a 2-compartmental PopPK model. Disease activity in CSU was assessed with weekly urticaria activity scores (UAS7) on scale 0 (no disease activity) to 42 (maximal disease activity). Longitudinal changes in UAS7 (modelled on transformed logit scale) in adults were described using an indirect response model for drug effect combined with an exponential decay model for placebo effect. The inhibitory effect of ligelizumab concentrations on the effect onset rate was expressed using a sigmoidal (hyperbolic) function with an EC50 and Hill coefficient. Step 1: adult PopPK and ER models were used to predict data collected in adolescent study CQGE031C2202 [2]. Trends in predicted and observed data were visually compared. Step 2: models were refitted on pooled adolescent and adult data. Step 3: simulations based on PK matching were conducted to propose doses to be tested in children.
Results:
Step 1: Adult models predicted ligelizumab concentrations and changes in UAS7 scores observed in adolescents indicating similarity between age groups. Step 2: Pooled adult/ adolescent analysis showed that ligelizumab PK was correlated with body weight (accounted for by allometric scaling on all volume and clearance parameters) but did not differ with age. Further, ligelizumab potency based on EC50 for UAS7 scores was comparable between adults and adolescents. Step 3: Following weight band-based dosing algorithm was proposed for children: dose equal to adult dose for above 40 kg, 50% of adult dose for 20 kg to 40 kg, 30% of adult dose for below 20 kg.
Conclusions:
In adolescent patients with CSU, ligelizumab exhibited PK and E-R consistent with those known in adults.
Similarity in ligelizumab PK and potency observed in adolescents and adults may permit the use of the same dose for treatment of CSU in both age groups, an approach that is currently being tested in the pivotal studies.
Confirmation of no significant age-related differences in ligelizumab PK and EC50 between adults and adolescents supported use of partial extrapolation for the paediatric development. Therefore, the dose selection for children was based on the assumption that similar PK exposures should provide similar response across all age groups.
References:
[1] Philip Lowe, Stephan Köhne-Voss, Richard Mills, Colm Farrell, “Ligelizumab Paediatric Investigation Plan: exposure-response analysis in adult chronic spontaneous urticaria with simulation-based design of adolescent dose-finding”, PAGE 2018
[2] Study to Investigate the Efficacy and Safety of QGE031 in Adolescent Patients with Chronic Spontaneous Urticaria (CSU). https://clinicaltrials.gov/ct2/show/NCT03437278?term=CQGE031C2202&draw=2&rank=2
[3] Maurer M, Giménez-Arnau AM, Sussman G, Metz M, Baker DR, Bauer A, et al., „Ligelizumab for Chronic Spontaneous Urticaria”, N Engl J Med 2019; 381:1321-32
Reference: PAGE 30 (2022) Abstr 10182 [www.page-meeting.org/?abstract=10182]
Poster: Drug/Disease Modelling - Paediatrics