Stratified Medicine and Targeted Clinical Trials for Alzheimer’s Disease Drug Development in Light of Recent Phase III Trial Results: Example ApoE Genotype

Co-Chairs: Lon S. Schneider, MD; Terry Goldberg, PhD; Larry Ereshefsky, PharmD, BCPP 

The purpose of this panel is to provide audience members with a strong scientific and economic rationale for considering stratified approaches to clinical trials and in particular using APOE as a stratification variable in Alzheimer’s disease related trials. In a presentation entitled, “Stratified medicine for AD drug development,” Dr. Mark R. Trusheim will provide an overview of and an argument for use of stratified medicine techniques in clinical trial design, He will discuss a broad array of trials, but will focus on bapineuzemab (a monoclonal antibody to beta amyloid plaques). Using models that in combination address power, biology, and economics and can be manipulated to test a variety of strategies, he will demonstrate why it is scientifically sound and economically imperative to consider this approach. 

In a presentation entitled, “The impact of ApoE4 carriage on clinical trials,” Dr. Terry E. Goldberg will review basic APOE neurobiology, including its roles in lipid transport and amyloid clearance. He will present current novel work on isoform specific effects at the message, protein and biomarker levels. He will also review treatment impact of APOE4 individuals (who carry the risk allele) carriers in the context of clinical trials. Perhaps most strikingly he will review new data on the large protective effects of APOE2 on biomarkers and cognition and the implicatins that these have for clinical trial design and drug development. 

Dr. Eric Reiman will present his experiences in “Using registries and genotyping for trials: What are the implications and pragmatics.” He will address the use of registries and genotyping the Alzheimers Prevention Initiative. He will review his own experiences in accessing such cohorts and will discuss the scientific motivations for stratification by APOE and early intervention in PS1 mutation carriers. More specifically he will discuss proposed or possible trials using APOE genotype as an inclusion requirement for a range of drugs/prevention approaches. This will largely involve the exploitation of a registry of APOE e4 carriers established around Phoenix, aspects of planning or undertaking such a trial, its theoretical reasons, and outcomes including imaging as a potential surrogate or co-primary. 

In a talk entitled, ‘Simulating stratified medicine trials in AD,” Dr. Lon S. Schneider will present results of subanalyses of AD trials based on a post hoc stratification such as APOE 4 carriage have provided interesting and sometimes contradictory results. Although some results might be due to play-of-chance in underpowered subanalyses or to the metrics of the outcomes scales, other results may be due to actual interaction of the drug with the subgroup.  As APOE 4 is the strongest risk factor for AD, and to a large degree is associated with age of onset of AD in late-life it has received particular attention for stratified medicine.  After reviewing the few trials that published outcomes based on APOE 4 carriage, Schneider and colleagues will present simulations derived from a large ADCS and ADNI data base that empirically test the efficiency of developing a drug based on several trials scenarios of APOE 4 carriage. Questions around differential drop outs, heterogeneity of outcomes, and disease severity will be examined.

Discussion:  Next steps what can be done now?