Researchers will test promising drugs aimed at preventing Alzheimer’s and identify and validate biological targets for novel therapies, with approximately $45 million in new funding from the National Institutes of Health (NIH).
The initiative will support innovative new studies as part of an intensified national effort to find effective interventions for this devastating degenerative brain disease.
The studies are among the first to be developed with direction from the government’s national Alzheimer’s plan. Of the funding, $40 million is from an allocation from the NIH, with additional funding from the National Institute on Aging (NIA), the lead Institute within NIH for Alzheimer’s research.
The clinical trials investigate possible ways to stop the progression of the disease. The translational research study awards are focused on identifying, characterizing and validating novel therapeutic targets.
“We know that Alzheimer’s-related brain changes take place years, even decades, before symptoms appear. That really may be the optimal window for drugs that delay progression or prevent the disease altogether,” said NIA Director Dr. Richard Hodes. “The clinical trials getting under way with these funds will test treatments in symptom-free volunteers at risk for the disease, or those in the very earliest stages — where we hope we can make the biggest difference.”
Basic and genetic studies of the disease — from the abnormal proteins involved, to genetic influences, to inflammation and other Alzheimer’s-related brain changes — have advanced knowledge. “This has given us new insights into the biological underpinnings of this extremely complex disorder,” Dr. Hodes said.
The awards support the following clinical trials:
•The Alzheimer’s Prevention Initiative APOE4 Trial — Drs. Eric Reiman and Pierre Tariot, Banner Alzheimer’s Institute, Phoenix, and co-investigators. Fully funded in fiscal 2013 at $33.2 million — This five-year prevention trial proposes to test an anti-amyloid drug in cognitively normal older volunteers who are at increased risk of developing late-onset Alzheimer’s because they inherited two copies of the APOE4 allele, the best known genetic risk for late-onset disease.
The treatment, which has not yet been selected, will be tested in this randomized, controlled clinical trial at multiple sites. Participants will be assessed through cognitive tests, brain imaging and cerebrospinal fluid measurements to evaluate whether the drug impacts amyloid, other biological measurements and the memory and thinking problems related to the disease.
The study will test the role of amyloid in the development of Alzheimer’s and will, through imaging and biomarker techniques, help identify faster ways to evaluate other promising prevention therapies in the future. It is anticipated that the study will also be supported with private funding.
•Allopregnanolone Regenerative Therapeutic for MCI/Alzheimer’s: Dose Finding Phase 1 — Drs. Roberta Brinton and Lon Schneider, University of Southern California, Los Angeles. Fully funded in fiscal 2013 at $2.4 million — This early-phase clinical trial will evaluate over 12 weeks the safety and tolerability of increasing doses of allopregnanolone, a natural brain steroid, in treating mild cognitive impairment and Alzheimer’s disease.
The drug has been shown to promote the generation of new brain cells, reduce amyloid levels, and restore cognitive function in pre-clinical animal testing. NIA has supported Dr. Brinton’s research over many years, including basic science grants to understand allopregnanolone’s mechanism of action in the brain, a drug development grant which included development of optimal dose and formulation, and support for pre-clinical toxicology studies.
This support helped bring Dr. Brinton and colleagues to the stage of being able to go into a human Phase I trial.
Studies focused on the identification and validation of novel therapeutic targets for Alzheimer’s disease include:
•Pathway Discovery, Validation and Compound Identification for Alzheimer’s Disease — Drs. Philip De Jager, of the Brigham and Women’s Hospital, Broad Institute, Harvard University, Boston, and David Bennett, of Rush University Medical Center, Chicago. $1.7 million in fiscal 2013, with the potential of $7.9 million over five years .
The study will discover, characterize and validate complex molecular networks and candidate genes that influence susceptibility to cognitive decline and Alzheimer’s disease. Using cutting-edge computational methods, this multi-disciplinary team will analyze rich clinical, pathological, genomic and other large-scale molecular data collected from over 1,000 volunteers from the Religious Order Study and the Rush Memory and Aging Project.
Through a systems biology approach looking at biological interactions involved in the disease, the project ultimately seeks to identify compounds that normalize the activity of dysfunctional nodes in molecular networks and to identify drugs for several novel therapeutic targets. To accelerate the testing of promising therapies for future clinical trials, the researchers will focus on drugs that have already undergone Phase I testing in humans.
•The Dominantly Inherited Alzheimer Network Trials Unit Trial — Dr. Randall Bateman, Washington University, St. Louis, and co-investigators. $1.5 million in fiscal 2013, with the potential for $6 million over four years — The trial is testing new anti-amyloid-beta drug treatments in volunteers who have an inherited form of Alzheimer’s disease. While early-onset Alzheimer’s is rare, the knowledge gained from this study will be highly relevant to both early- and late-onset forms of the disease. This rare form can occur in people as early as their 30s. Amyloid plaques in the brain are a hallmark of Alzheimer’s and are thought to interfere with communication among brain cells, and anti-amyloid-beta therapies attempt to treat that process. Dr. Bateman will lead a team recruiting volunteers free of symptoms or in the earliest stages of the disorder.
The four-year trial, a multi-site international effort, will test three anti-amyloid-beta interventions: gantenerumab, solanezumab and a third, as yet undetermined, drug. This trial is also supported by the Alzheimer’s Association and the following companies: Roche, Lilly, Avid Radiopharmaceuticals and CogState.
•Integrative Biology Approach to Complexity of Alzheimer’s Disease — Dr. Eric Schadt of Icahn School of Medicine at Mount Sinai, New York City, and a team of investigators. $1.6 million in fiscal 2013, with the potential of $8.2 million over five years — This study will apply innovative analytical methods to large-scale molecular, cellular and clinical data from Alzheimer’s patients to construct biological network models and gain new insights into the complex mechanisms of the disease. Several cellular and animal models will be used to validate the actions of individual genes, as well as entire molecular networks predicted to drive the disease. The team will also employ a computational approach to test whether any existing drugs currently used for other conditions are capable of modulating the Alzheimer’s networks and can, therefore, be repurposed for Alzheimer’s treatment or prevention.
•A Systems Approach to Targeting Innate Immunity in Alzheimer’s — Dr. Todd Golde, University of Florida, Gainesville, and colleagues. $1.6 million in fiscal 2013, with the potential of $7.7 million over five years — This study builds on the genetic and pathological evidence that the innate immune system, which provides immediate defense against infection, and brain inflammation have a significant role in Alzheimer’s disease.
To identify and characterize novel therapeutic targets within the innate immune system, this study will use a systems biology approach to integrate genomic, gene expression, and pathological data from Alzheimer’s patients and Alzheimer’s mouse models and analyze them in novel ways. The team will test in animal models of the disease the validity and therapeutic potential of the key factors predicted by the analysis. This has the potential to speed the discovery and testing of Alzheimer’s disease prevention and treatment therapies by targeting the immune system.