New Clinical Trials
Dr. Reiman and coworkers were introduced to Francisco Lopera, MD, and his colleagues in Medellin, Colombia, who have been studying a large kindred of local families—about 5,000 people—whose lineage can be traced to a common ancestor. The kindred share a rare genetic mutation, presenilin 1, that typically triggers Alzheimer’s disease symptoms around age 45. It is the world’s largest kindred with known autosomal dominant Alzheimer’s disease, Dr. Reiman said.
As a result of this connection, the API obtained the participation of the kindred for a research opportunity. In late 2013, the API, in partnership with Genentech, the University of Antioquia, and the NIH, began a 60-month randomized, double-blind, placebo-controlled, parallel-group study of the investigational amyloid immunotherapy drug crenezumab in cognitively unimpaired members of this kindred. Crenezumab binds to soluble and fibrillar forms of amyloid beta, the main constituent of amyloid plaques in the brains of patients with Alzheimer’s disease. The trial also provides an opportunity to relate the treatment’s different effects on 24-month brain imaging and fluid biomarkers to its clinical effects to determine which biomarker effects are associated with a clinical benefit and could be used to evaluate the range of promising prevention therapies in future 24-month prevention trials.
The study, scheduled to end in 2020, will involve cognitively unimpaired kindred members ages 30 and older, including approximately 100 mutation carriers who will receive treatment, 100 carriers who will receive placebo, and 100 noncarriers who also will receive placebo. Subjects will be followed for 60 months, and the primary end point is change in API composite cognitive test score. Change in various other neurocognitive tests and brain imaging measures are secondary end points.
In an upcoming trial, the API will partner with Novartis to study two investigational drugs. Approximately 1,300 cognitively healthy APOE4 allele homozygotes ages 60 to 75 will be randomized to CAD106 (an injectable anti-amyloid immunotherapy), oral beta-secretase 1 (BACE-1) inhibitor CNP520, or placebo. It is slated to begin as soon as a safety profile is established for the BACE-1 inhibitor.
“In this case, the study is intended to detect an effect on either time to the clinical onset of Alzheimer’s disease, MCI, or dementia, or the rate of decline in the API composite cognitive test score,” Dr. Reiman said. “In addition to the other brain imaging and fluid biomarkers, this study will also include tau PET using Avid and Eli Lilly’s ligand AV1451 with support through the Accelerated Medicines Partnership.” Another unique feature of this study is the need to inform prospective participants about their genetic risk for Alzheimer’s disease and evaluate the impact of risk disclosure in the era of prevention trials, he added.
Paving the Way for Future Research
To help identify individuals in the 60- to 75-year-old age group for future studies, as well as to support other efforts, the API developed the online Alzheimer’s Prevention Registry. Registrants can receive information on the latest developments in Alzheimer’s disease prevention research, opportunities to participate in new prevention trials, and additional resources to learn more about Alzheimer’s disease. The registry now includes more than 140,000 individuals and is expected to grow rapidly in the coming months.
Dr. Reiman concluded by proposing what it will take to find effective prevention therapies within the next 10 years. “It will take the study of cognitively unimpaired persons at increased risk for Alzheimer’s disease. It will take the development of biomarker end points that are reasonably likely to predict a clinical benefit and their qualification for use in potentially license-enabling trials under regulatory agencies’ accelerated approval mechanism. It will take the use of these biomarker end points in roughly 24-month trials to evaluate the range of promising prevention therapies in persons who, based on their genetic information or biomarker measurements, are at increased risk for Alzheimer’s disease. It will take large enrollment registries and trial innovations to further accelerate the evaluation of these treatments. It will take new ways for different stakeholders to work together, commitments to share data and biological samples with the field, financial commitments from our elected officials, and a sense of urgency among us all.”
—Adriene Marshall