PS46: Progress on Finding Effective Treatments Using Disease Progression Modeling

Progressive diseases are characterized by a systematic pathological advance that can include abnormal biomarker activity, decreased function, and clinical symptoms. For example, in neurodegenerative diseases such as frontotemporal dementia (FTD), there is a cascade of pathological processes with early changes in neurofilament light chain (Nfl) and magnetic resonance imaging (MRI) measures and, later, progression to cognitive symptoms and clinical disease. Quantifying both the trajectory and heterogeneity of these changes, and their relationship to disease state, is key to addressing clinically relevant questions and designing well-powered clinical trials. In this session, we introduce and explore different aspects of disease progression modeling and discuss how to leverage disease progression models in innovative clinical trial design. In the first talk, we discuss the limitations of traditional statistical methods in clinical trials, such as the mixed model for repeated measures (MMRM), and explore disease progression models (DPMs) as an innovative alternative. DPMs leverage longitudinal information across the disease trajectory and have the potential to improve trial power and provide a more interpretable treatment effect. The second talk focuses on the inevitability of missing data due to progression. This talk will highlight concerns related to missing data and provide strategies for addressing mortality in progressive disease trials, describing their impact on the interpretation of results. Third, we provide a regulatory perspective on the use of disease modeling in clinical trials for neurodegenerative diseases, with illustrative examples in Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Talks will be followed by a roughly 15-minute Q&A period. Disease progression modeling provides a framework that enables researchers to ask the right questions about how progressive diseases advance and provides a flexible tool that will shape future clinical trial design as we search for treatments that can slow or halt disease progression.