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A pharmacometrics-informed trial simulation framework for optimizing study designs for disease-modifying treatments in rare neurological disorders

The development of new treatments for rare neurological diseases (RNDs) may be very challenging due to limited natural history data, lack of relevant biomarkers and clinical endpoints, small and heterogeneous patient populations, and other complexities. A systematic approach is needed for comparing...

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Main Authors: Ryeznik, Yevgen (Author) , Hilgers, Ralf-Dieter (Author) , Heussen, Nicole (Author) , Comets, Emmanuelle (Author) , Mentré, France (Author) , Hendrickx, Niels (Author) , Karlsson, Mats O. (Author) , Hooker, Andrew C. (Author) , Hamdan, Alzahra (Author) , Chen, Xiaomei (Author) , Schüle-Freyer, Rebecca (Author) , Synofzik, Matthis (Author) , Sverdlov, Oleksandr (Author)
Format: Article (Journal)
Language:English
Published: 05 August 2025
In: CPT: pharmacometrics & systems pharmacology
Year: 2025, Volume: 14, Issue: 10, Pages: 1705-1714
ISSN:2163-8306
DOI:10.1002/psp4.70082
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1002/psp4.70082
Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/psp4.70082
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Author Notes:Yevgen Ryeznik, Ralf-Dieter Hilgers, Nicole Heussen, Emmanuelle Comets, France Mentré, Niels Hendrickx, Mats O. Karlsson, Andrew C. Hooker, Alzahra Hamdan, Xiaomei Chen, Rebecca Schüle, Matthis Synofzik, Oleksandr Sverdlov
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Summary:The development of new treatments for rare neurological diseases (RNDs) may be very challenging due to limited natural history data, lack of relevant biomarkers and clinical endpoints, small and heterogeneous patient populations, and other complexities. A systematic approach is needed for comparing various design and analysis strategies to identify “optimal” approaches for a clinical trial in a chosen RND with the given resource constraints. For this purpose, we propose a pharmacometrics-informed clinical scenario evaluation framework (CSE-PMx), which includes some important research hallmarks relevant to RND clinical trials: a disease progression model for simulating individual longitudinal outcomes, the choice of a suitable randomization method for trial design, and an option to perform subsequent statistical analysis with randomization tests. We illustrate the utility of CSE-PMx for an exemplary randomized trial to compare the disease-modifying effect of an experimental treatment versus control in patients with Autosomal-Recessive Spastic Ataxia Charlevoix Saguenay (ARSACS). In the considered example, our simulation evidence suggests that a nonlinear mixed-effects model (NLMEM) with a population-based likelihood ratio test analysis is valid, robust, and more powerful than some conventional methods such as two-sample t-test, analysis of covariance (ANCOVA), or a mixed model with repeated measurements (MMRM). Our proposed framework is very flexible and generalizable to clinical research in other rare disease indications.
Item Description:Gesehen am 15.12.2025
Physical Description:Online Resource
ISSN:2163-8306
DOI:10.1002/psp4.70082

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