Advancing Drug Development Strategies in Progressive Supranuclear Palsy: A Model-based Clinical Trial Simulation Tool Approach
Authors: Morales Juan , Betourne Alexandre , Romero Klaus , Ma Shu , Zhang Yi 
Published: February 2025

Objectives: Progressive supranuclear palsy (PSP) is a rare progressive neurodegenerative condition associated with abnormal 4-repeat (4R) tau protein folding and aggregation in the brain, with a reported prevalence of 3-6 / 100,0001. Clinically, it is characterized by axial rigidity, oculomotor abnormalities, cognitive impairment with prominent postural instability and early falls, and it is ultimately fatal2. Currently, treatment is symptomatic, and there are no approved disease-modulating therapies3. The challenges in PSP drug development are multifaceted, and there exists an urgent need for innovative approaches to inform and refine clinical trial designs in the pursuit of effective PSP therapies. For this reason, the aim of this project was to inform PSP trial designs by developing a disease progression model-based clinical trial simulation (CTS) tool.Methods: De-identified patient-level data from a PSP natural history study and the placebo arms of randomized clinical trials were utilized for the development of this tool. The database was accessed through the Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP) of the Critical Path Institute. An analysis subset of 1006 participants and 5252 observations was generated after integrating and curating the patient-level PSP database. To describe PSP disease progression quantitatively, the Progressive Supranuclear Palsy Rating Scale (PSPRS) total score, which is a combination of 28 items from 6 categories4, was used. A non-linear mixed effects modeling approach was used to describe the longitudinal measures of PSPRS, considering inter and intra individual variability. Different base structural models (e.g.: standard logistic, gamma-Emax, Gompertz, and generalized Gompertz) were evaluated by comparing objective function values and information criterion in Monolix software. Candidate baseline covariates were tested in a stepwise fashion in conjunction with iterative goodness-of-fit assessment with typical diagnostic plots. This PSP disease progression model provided the foundation for the development of the CTS tool. A dedicated R shiny application was created to make the CTS tool more accessible and user-friendly.Conclusions: The developed model explained the PSPRS longitudinal trajectories in a diverse cohort of individuals with PSP. The gamma-Emax model was able to describe the variability in baseline disease stage and progression rate in patients at various disease stages, with baseline PSPRS value as the only covariate included in the final model. The developed model-based CTS tool, where users can specify the trial design (i.e., number of participants, trial duration and dropout rate), the participants’ characteristics, and hypothetical drug effect, provides a framework to perform PSP clinical trial simulations and quantify the power of the potential scenario, with the intention to assist in future trial design decision-making processes.Citations: 1. Wen, Y. et al. Clinical features of progressive supranuclear palsy. Front Aging Neurosci 15, 1229491 (2023).2. Höglinger, G. U. et al. Safety and efficacy of tilavonemab in progressive supranuclear palsy: a phase 2, randomised, placebo-controlled trial. Lancet Neurol 20, 182–192 (2021).3. Coughlin, D. G. & Litvan, I. Investigational therapeutics for the treatment of progressive supranuclear palsy. Expert Opin Investig Drugs 31, 813–823 (2022).4. Golbe, L. I. & Ohman-Strickland, P. A. A clinical rating scale for progressive supranuclear palsy. Brain 130, 1552–1565 (2007).