The API proposes to evaluate investigational amyloid-modifying treatments in healthy people who, based on their age and genetic background, are at the highest imminent risk of developing AD symptoms using brain imaging, cerebrospinal fluid (CSF), and cognitive endpoints
. This complements the newly established criteria for preclinical AD
, as well as other presymptomatic/preclinical AD treatment trials proposed by the Dominantly Inherited Alzheimer’s Network (DIAN)
, the AD Cooperative Study (ADCS), and others[66,67]
The API has several goals: 1) to evaluate investigational AD-modifying treatments sooner than otherwise possible; 2) to determine the extent to which the treatment’s effects on brain imaging and other biomarkers predicts a clinical benefit—information needed to help qualify biomarker endpoints for use in pivotal prevention trials; 3) to provide a better test of the amyloid hypothesis than clinical trials in symptomatic patients, when these treatments may be too little too late to exert their most profound effect; 4) to establish AD prevention registries needed to support these and other presymptomatic AD trials; and 5) to give those individuals at highest imminent risk of AD symptoms access to the most promising investigational treatments in clinical trials.
In one trial, we propose to study cognitively normal AD-causing presenilin 1
mutation carriers, at least 35 years of age (i.e., within 10 years of the carriers’ estimated median age at clinical onset), from the world’s largest early-onset AD kindred, located in Antioquia, Colombia
. This extraordinary kindred, which has been followed for more than 20 years by Dr. Francisco Lopera and his colleagues, and includes about 5,000 people[68,69,70,71,72,73,74,75,76,77,78,33,79,80,81,82,83]
, with a sufficient number of presymptomatic carriers in the targeted age group to make it possible to relate a treatment’s effects on both biomarker and clinical endpoints within 2–5 years. In the proposed trial, PS1
mutation carriers would be randomized to active treatment or placebo, non-carriers would be assigned to placebo, and genetic test findings would not be disclosed to the family members simply because they are participating in this trial
. In the other trial, we propose to study cognitively normal 60–80 year-old APOE ε4
homozygotes (and possibly heterozygotes), close to their estimated median age of clinical onset
. Including heterozygotes would depend on the safety and tolerability data for the chosen treatment, but would allow for both an increase in the available samples and an increase in the generalizablity of our findings[85,86]
For each subject group, we have proposed to conduct a 24 month double-blind, randomized, placebo-controlled trial using fibrillar amyloid PET, FDG PET, volumetric MRI, CSF, and cognitive endpoints
. Biological fluids and other MRI measurements would be used to permit exploratory studies. If after two years, the treatment is not associated with predicted effects on one or more of the biomarkers, the DSMB would declare futility, the trial would be discontinued, and the participants would be eligible to participate in a trial of the next most promising AD-modifying treatment. If, however, the treatment is associated with predicted biomarker effects, the trial would be continued to assess effects on our compound cognitive endpoint.
To support these and other presymptomatic AD trials, we plan to establish two AD prevention registries. We aim to enroll 2,000 members of the PS1 E280A kindred (along with DNA samples, PS1 E280A mutation testing and baseline cognitive assessments), about one-third of whom are projected to be mutation carriers, into the Colombian Registry by 2012. We aim to enroll several hundred thousand individuals in the US-based Alzheimer’s Prevention Registry, some of whom will be invited to provide saliva samples for DNA acquisition and APOE screening. In anticipation of the Colombian trial, we have begun to acquire and analyze brain imaging and CSF samples in the PS1 mutation carriers and non-carriers, a cyclotron/radiochemistry facility is being installed, and we have used data from the ongoing longitudinal study to estimate the sample sizes needed to detect a clinical effect using a composite cognitive endpoint.
While we believe that there is an opportunity to advance the evaluation of presymptomatic AD treatments, there is a responsibility to get it right. In October 2009, we hosted a meeting of 40 scientific advisors to get their input and help us to refine our proposal. In January 2010, we hosted a meeting with industry representatives to get their input and further refine our proposal
. In January 2011, we again met with industry representatives, academic advisors, and FDA and European Medicines Agency (EMA) officials, who provided thoughtful and encouraging feedback
. We have been communicating with pharmaceutical company leaders to explore their interest, the availability and timing of the most promising amyloid-modifying treatments, and to explore the scientific and logistical issues needed to prepare for our proposed trials. Selection of the drug will be made with the assistance of an independent academic advisory board, input from the affected kindred regarding potential benefits versus known adverse effects and previous use in human subjects, and will depend on factors such as target engagement, preclinical and clinical safety and tolerability data, dosing information, availability of the drug product, and in-kind industry support. We have proposed a mix of industry, philanthropic and federal funding, and we have indicated our intent to release the data to the public after the study is completed to help advance the use of biomarker and cognitive enrichment strategies and endpoints in future presymptomatic AD trials.
The proposed API treatment trials will help further develop the biomarker endpoints needed to evaluate a range of presymptomatic AD treatments, and will provide critically needed evidence to support the use of biomarker endpoints in the accelerated approval of presymptomatic AD treatments (i.e., to suggest that a treatment’s biomarker effects may be reasonably likely to predict a clinical benefit in these or other populations). We believe that by helping to determine the extent to which the best established brain imaging and CSF biomarkers of AD budge in response to treatment, the extent to which they move in the predicted direction, and the extent to which the treatment’s biomarker effects are associated with subsequent clinical benefit will help provide regulatory agencies the evidence they need to begin to consider approving presymptomatic treatments solely on biomarker endpoints in future trials. Moreover, these presymptomatic treatment trials will not only provide a better test of the amyloid hypothesis than clinical trials using the same treatment in symptomatic AD patient, but will also provide research participants at the highest imminent risk of symptomatic AD access to the most promising and suitable investigational treatments sooner than otherwise possible.