BETHESDA, MD. – The first-ever primary prevention trial for Alzheimer’s disease will investigate whether immunotherapy can delay – or even stop – the disease in a group of subjects who are genetically destined to develop it.
The $100 million project is one of the first to receive a special federal allocation for Alzheimer’s research, as envisioned in President Obama’s 2011 National Alzheimer’s Project Act.
Federal dollars will also support a second major clinical trial – a placebo-controlled study designed to evaluate the effect of intranasal insulin on cognition, function, and biomarkers in individuals with mild cognitive impairment and early Alzheimer’s.
These two projects will consume about half of the additional $50 million in Alzheimer’s project funding allocated by Congress for this fiscal year. Next year’s additional federal boost of $80 million will support more new studies, according to Dr. Ronald Petersen, chairman of the National Alzheimer’s Project Act’s Advisory Council on Alzheimer’s Research, Care, and Services.
"More studies are coming," he said at a research summit sponsored by the National Institute on Aging. These will include experiments with pluripotent stem cells, which have recently been differentiated into functional human Alzheimer’s neurons, and a large longitudinal study of the link between Alzheimer’s and cardiovascular disease.
Dr. Eric Reiman is one of three primary investigators on the 5-year immunotherapy trial. The placebo-controlled trial will give the humanized monoclonal antibody crenezumab to a group of about 300 members of an extended family in Colombia before they show symptoms of the disease. Many in this family express a mutation in the presenilin-1 gene that causes very early onset Alzheimer’s, with symptoms beginning before the age of 45 years. The trial will also include a smaller number of family members in the United States.
Dr. Eric Reiman
Half of the individuals will receive infusions of the drug, and half will receive a placebo. An additional group of individuals without the mutation will also receive a placebo, he added.
The participants will be followed for up to 5 years, with periodic cognitive, biomarker, and imaging assessments, said Dr. Reiman, executive director of the Banner Alzheimer’s Institute, Phoenix. After 2 years, a data safety monitoring committee will evaluate any progress and determine whether the trial should proceed.
Immunotherapy has walked a rocky path in Alzheimer’s drug development. The first active immunization clinical trial, which tested AN1792* in AD patients, was halted when a subset of patients developed meningoencephalitis. The first passive immunotherapy trial with bapineuzumab, showed vasogenic edema and microhemorrhages in 12 patients, but this drug continues to be studied.
The crenezumab study is unique in one other way, Dr. Reiman said in an interview: All of the data generated will become publicly available as soon as the trial is complete.
"We’ll be sharing all the data and samples in the hope of faster development of preventive treatments. We’re all in this fight together and given the stakes, it’s time for a paradigm shift that can – hopefully – launch a new era in Alzheimer’s prevention research."
In addition to its $16 million federal grant, the study will draw on $15 million in philanthropic funds from the Banner Institute, Dr. Reiman added.
Suzanne Craft, Ph.D., is heading the insulin study. The 5-year study will randomize 240 subjects with mild cognitive impairment or early Alzheimer’s to intranasal insulin or placebo for 12 months. At the end of that time, placebo patients will receive insulin in a 12-month open-label study. Subjects will be assessed periodically for changes in cognition, function, and cerebrospinal biomarkers.
An $8 million federal grant makes the study possible, said Dr. Craft, professor of psychiatry and behavioral sciences at the University of Washington, Seattle, and director of the Memory Disorders Clinic at the American Lakes division of the VA Puget Sound Health Care System.
Her earlier work with insulin showed tantalizing promise. A 104-subject, placebo-controlled study found that doses of both 20 and 40 IU of intranasal insulin preserved cognition and function in patients with mild cognitive impairment and early Alzheimer’s (Arch. Neurol. 2012;69:29-38). There was also some hint that these changes were associated with improved beta-amyloid biomarkers in cerebrospinal fluid. Patients assigned to placebo also showed declines in neuronal metabolism compared with those taking insulin.
Data from the new insulin study will also go into the public domain, Dr. Craft said in an interview.
"I think that as we make these data available to people with good ideas, we’ll see a proliferation of results from them," she said. "It’s essential to bring together investigators from all different disciplines to look at the question from different angles. It’s a crucial part of advancing our knowledge about this terrible disease."