The case for regulatory approval of amyloid-lowering immunotherapies in Alzheimer's disease based on clearcut biomarker evidence

Abstract

Decades of research have provided evidence that Alzheimer's disease (AD) is caused in part by cerebral accumulation of amyloid beta-protein (Aβ). In 2023, the US Food and Drug Administration gave full regulatory approval to a disease-modifying Aβ antibody for early AD. Secondary prevention trials with Aβ antibodies are underway. We summarize peer-reviewed evidence for targeting Aβ and argue that regulators should consider approving new agents working by similar mechanisms (Aβ antibodies and vaccines) based on robust amyloid lowering and reasonable safety. The urgent need to provide treatments to millions of mildly symptomatic patients suggests that AD should join other diseases for which standard approval is based on significant changes in mechanistically meaningful biomarkers coupled with safety. Robust amyloid lowering in secondary prevention trials of people who have amyloid plaques but are asymptomatic could also provide evidence of a change in the pathophysiological progression of AD as a basis for regulatory approval. HIGHLIGHTS: Thirteen key findings support amyloid beta as a cause of Alzheimer's disease (AD). Three immunotherapies lower amyloid and slow decline, allowing regulatory approval. New such agents could be considered for approval due to amyloid lowering and safety. Urgency suggests AD may join diseases with approval due to a key biomarker + safety.

Keywords: Alzheimer's disease; Alzheimer's disease prevention; active vaccines; amyloid beta protein; disease modification; immunotherapy; monoclonal antibodies; regulatory policy; surrogate markers; treatment.