Relationship between beta‐amyloid (Ab) plaque reduction and clinical benefit: the rationale for aducanumab approval

Abstract

AbstractBackgroundAducanumab was approved in 2021 by the US FDA under the accelerated approval pathway. However, the Office of Clinical Pharmacology at FDA recommended the regular approval based on three key findings.MethodExposure‐response analyses were conducted to quantify the relationship between aducanumab longitudinal exposure and responses (standardized uptake values ratios for beta amyloid and various clinical endpoints) in all clinical trials. To explain the difference between aducanumab and other compounds with negative results in the past, publicly available data were combined with the aducanumab data to demonstrate the relationship between amyloid reduction and clinical endpoint improvement across multiple compounds with similar mechanism of action. The probability to observe the overall positive findings in the aducanumab program was quantified under the assumption that aducanumab is ineffective.ResultsPositive exposure‐response (disease progression) relationship for multiple clinical endpoints from all clinical trials was identified. Positive exposure‐amyloid reduction relationship was established. Consistent amyloid reduction‐clinical endpoint improvement relationship across multiple compounds was observed. If aducanumab is assumed to be ineffective, it is extremely impossible to observe the overall positive findings in the aducanumab program. These results provided convincing evidence to support aducanumab’s effectiveness.ConclusionFDA made the right decision for millions of Alzheimer patients. The observed clinical benefit from aducanumab treatment is clinically meaningful.