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Objectives: Amyloid-lowering strategies in AD, especially passively administered monoclonal antibodies, have been intensely debated. There is a common but not universal view that up to mid-2022, none has produced clear-cut evidence of slowing of cognitive decline. However, recent months have seen the emergence of new data on this approach to disease-modification.

Methods: The key molecular and clinical underpinnings of such treatments will be reviewed here. Several concerns about this therapeutic approach will be considered, and the strengths and weaknesses of the preclinical and clinical evidence will be critically analyzed.

Results: The rationale for lowering brain levels of amyloid b-protein (Ab) is supported by specific genetic findings in both early-onset (familial) and late-onset AD. Laboratory-based research on cellular and animal models has produced evidence of a link between Ab and abnormal tau accumulation and hyperphosphorylation. Human neuropathological and brain imaging data suggest a pathogenic relationship between progressive Ab deposition and the spread of tau aggregates in the brain. PET imaging and fluid biomarkers in large cohorts also support a temporal role for early Abdeposition. Of greatest relevance to the approach are peer-reviewed data from Phase 2 clinical trials and new findings that are emerging from completed Phase 3 trials. These outcomes can be juxtaposed to trial data and post-marketing experience from analogous efforts in other amyloidoses, e.g., transthyretin.

Conclusions: Despite several scientifically reasonable concerns about the rationale and utility of amyloid-lowering using monoclonal antibodies, the collective available data suggest that this approach represents the closest the AD field has come to disease modification and can be administered with careful attention to patient safety in a manner that can produce clinical benefits in very mild and mild patients with typical AD.

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Background:

Aducanumab was approved in 2021 by the US FDA under the accelerated approval pathway. Since then, there have been many misconceptions about the approval decision. It is high time to clarify the facts.

Method:

Exposure-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.

Results:

Positive 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.

Conclusion:

FDA made the right decision for millions of Alzheimer patients. The observed clinical benefit from aducanumab treatment is clinically meaningful.