Streamlining Clinical Development of C.E.R.A. (Continuous Erythropoietin Receptor Activator) in Pediatric Chronic Kidney Disease Patients by Integration of Clinical Trial and Real-World Data
Samer Mouksassi(1), Bradley A Warady (2), Claus P. Schmitt (3), Meyer Reigner S (4), Studer M (4), Chanu P (5) and Frey N (6)
1) Certara, Cairo, Egypt. (2) Children's Mercy Kansas City, University of Missouri – Kansas USA; (3) University of Heidelberg, Heidelberg Germany; (4) Hoffmann‐La Roche Ltd, Basel Switzerland (5) Clinical Pharmacology, Genentech/Roche, Lyon France (6) Roche Pharma Research and Early Development, Roche Innovation Center, Basel Switzerland
Background: Methoxy polyethylene glycol‐epoetin beta or continuous erythropoietin receptor activator (C.E.R.A.) is used for the treatment of anemia in adults with chronic kidney disease (CKD) and can be administered intravenously (IV) or subcutaneously (SC). EMA has recently approved C.E.R.A. for the maintenance treatment of symptomatic anemia associated with CKD in pediatric patients from 3 months to less than 18 years of age who are converting from another erythropoiesis stimulating agent (ESA) (June 2023). The approval in pediatric patients was based on results from two open-labeled pediatric Phase II clinical trials (IV study NH19707 N =63 and SC study NH19708 N=40) and one pediatric observational Real-Word Data (RWD) study (MH40258 N=229) and supplemented with modeling and simulation analysis. A previously pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation framework developed by Chanu et al.1, based on hemoglobin (Hb) data from clinical trial data and RWD, has led to a significant revision of the Pediatric Investigation/Study Plans (PIP/PSP) by replacing the original NH19708 Phase III design (N = 150 and 5+ years recruitment) by a Phase II design (N =40 and less than 3 years recruitment). This led to providing the patients with faster access to the drug while avoiding unnecessary clinical trial exposure and related monitoring burden in children2.
Objectives: Use a modeling and simulation framework to integrate phase 2 clinical trial data together with RWD to support C.E.R.A. filing in pediatric patients with CKD.
Methods: A previously developed population PK/PD model on adults (IV and SC administrations in patients with various dialysis modalities) and pediatric patients (IV administration in hemodialysis patients) was used as a starting point to analyze the data from NH19708 (SC administration in peritoneal and pre-dialysis patients). Models were assessed using standard goodness of fit and pcVPC. The RWD data included patients on haemo- or peritoneal dialysis who were given C.E.R.A. SC or IV during routine medical care. The observed and predicted median C.E.R.A. doses and mean Hb data in the pediatric clinical trials were compared visually with the observed RWD by route of administration and by dialysis modality to assess if clinical trials data could be reproduced in clinical practice.
Results: The population PK model showed a 2.18-fold increase of SC bioavailability in pediatric patients as compared to adult patients (0.67 versus 0.31). The population PK/PD model was updated mainly by:
- Including dialysis type as a covariate on baseline Hb (Hb0): Hb0 was estimated to be 9.44 g/dL in pre-dialysis patients while being 7% and 14% lower in peritoneal dialysis and haemodialysis paediatric patients, respectively.
- Including dialysis type as a covariate on the life span (LS) of the red blood cells: LS 82.33 days in pre-dialysis patients while being 18% and 38% shorter in peritoneal dialysis and haemodialysis patients, respectively.
These findings about Hb0 and LS are consistent with the current understanding of the pathophysiology of anemia due to CKD, with lower Hb0 and shorter LS associated with more advanced disease and haemodialysis compared to peritoneal dialysis and even more to pre-dialysis. No effects of age and or weight on system‑related parameters (LS and Hb0) or on drug related parameters (SC50 and Smax). The good alignment between clinical trial data and RWD confirmed the clinical experience of C.E.R.A. in the Real-World setting and thus contributed to the clinical evidence of the proposed dosing regimen for C.E.R.A. IV and SC in pediatric patients.
Conclusions: The application of PK/PD modeling and simulation was key in synthesizing the totality of evidence from clinical trial data as well as RWD. The model‑based approach, integrating clinical trial data and the RWD, highly contributed to accelerating the EMA approval of C.E.R.A. SC in the pediatric population.
References:
[1] Chanu P, Schaefer F, Warady BA, et al. Model‐based approach for methoxy polyethylene glycol‐epoetin beta drug development in paediatric patients with anaemia of chronic kidney disease. Br J Clin Pharmacol. 2020;86:801–811.
[2] European public assessment report (EPAR) https://www.ema.europa.eu/en/medicines/human/EPAR/mircera#ema-inpage-item-assessment-history
