Scenarios for the long‐term efficacy of amyloid‐targeting therapies in the context of the natural history of Alzheimer's disease

Abstract INTRODUCTION Recent clinical trials of amyloid beta (Aβ)‐targeting therapies in Alzheimer's disease (AD) have demonstrated a clinical benefit over 18 months, but their long‐term impact on disease trajectory is not yet understood. We propose a framework for evaluating realistic long‐term scenarios. METHODS Results from recent phase 3 trials of Aβ‐targeting antibodies were integrated with an estimate of the long‐term patient‐level natural history trajectory of the Clinical Dementia Rating‐Sum of Boxes (CDR‐SB) score to explore realistic long‐term efficacy scenarios. RESULTS Three distinct long‐term efficacy scenarios were examined, ranging from conservative to optimistic. These extrapolations of positive phase 3 trials suggested treatments delayed onset of severe dementia by 0.3 to 0.6 years (conservative), 1.1 to 1.9 years (intermediate), and 2.0 to 4.2 years (optimistic). DISCUSSION Our study provides a common language for long‐term impact of disease‐modifying treatments. Our work calls for studies with longer follow‐up and results from early intervention trials to provide a comprehensive assessment of these therapies' true long‐term impact. Highlights We present long‐term scenarios of the efficacy of AD therapies. In this framework, scenarios are defined relative to the natural history of AD. Long‐term projections with different levels of optimism can be compared. It provides a common language for expressing beliefs about long‐term efficacy.