Importantly, a critical component of the partnership is that industry partners will make the AMP data and analyses publicly accessible to the broad biomedical community.
In an interview with Neurology Today, Maria C. Carrillo, PhD, vice president for medical and scientific relations at the Alzheimer's Association, said AMP is consistent with — and will help to operationalize — the National Plan for Alzheimer's Disease. That plan, which grew out of the 2011 National Alzheimer's Project Act, calls for enhanced collaboration between industry, government, and academic research, and outlines a plan to prevent and effectively treat Alzheimer's disease by 2025. The Alzheimer's Association is a member of the steering committee for AMP for the Alzheimer's arm of the project.
“AMP will incorporate novel biological markers into ongoing Alzheimer's prevention trials, allowing a direct comparison of the ability of multiple markers to track the progression of very early stage Alzheimer's and potentially to predict clinical benefit of a therapy,” Dr. Carrillo told Neurology Today.
THE VISION FOR THE PARTNERSHIP
At the February press conference, NIH Director Francis Collins, MD, PhD, explained that the partnership grew out of a vision shared by the research community and industry that a new model for drug discovery was needed. While advances in genomics, proteomics, and imaging have vastly increased the number of potential targets for drug discovery, the current process for bringing a drug to the bedside is costly and fraught with error. “We want to increase the odds of picking the right targets and pick them at the very beginning of the development process, and so avoid wasting time and money chasing down duds,” he said.
“Researchers have increasingly been able to identify fundamental changes in genes, proteins, and molecules that predispose individuals to common disease,” Dr. Collins said. “In the last five years alone, genome-wide studies have identified more than a thousand risk factors....But the challenge is that only some of these biological clues will make good targets. And getting it wrong is costly.”
Dr. Collins noted that it requires an average of more than a billion dollars and 14 years to bring a discovery from the lab to the bedside. “The current failure rate is 99 percent and the most painful failures are in phase 3 trials when a drug is found not to be effective after years of research and millions of dollars....All who care about therapeutics agree we need new strategies to avoid those failures.”
Mikael Dolsten, MD, PhD, president of worldwide research and development at Pfizer Pharmaceuticals echoed Dr. Collins. “We are still navigating in a landscape where a lot of the richness of information is fragmented and not easily accessible to a fast moving drug development process. What we would like to have is a precise navigation system, a GPS for human disease.”
“In Alzheimer's, we would like to validate and expand a collection of biomarkers that will have prognostic value and which may show how patients improve or worsen, and which can be integrated into drug development,” Dr. Dolsten continued. “We also want to try to understand further the disease-causing pathway in the brain and collect from a number of studies some integrated networks for what is driving disease deterioration.”
The Alzheimer's arm of AMP includes $129.5 million in funding — roughly equally shared by government and industry — over five years. It will consist of two main components: incorporating selected biomarkers into ongoing NIH-funded clinical trials designed to delay or prevent disease onset; and conducting a large-scale analysis of human AD patient brain tissue samples to validate biological targets previously shown to play key roles in disease progression. “This proposal aims to establish an expanded set of biomarkers that can be embedded in therapeutic trials as well as identify new biological targets for drug development,” Dr. Carrillo told Neurology Today.
Dr. Carrillo emphasized the importance of shared information. “It is clear that if we discern new targets through our proteomics research, the best way to speed drug discovery will be to make this information available not just to the handful of researchers involved in that area but to everyone in the research community,” she told Neurology Today.
According to the NIH, tau imaging and EEG data for the project on biomarkers will be released in year two, as the data on changes from baseline measures from two years ago become available. Final data from randomized, blinded trials will be added after the end of the five-year studies, and will include both the imaging data and data from blood and spinal fluid biomarker studies. For the network analysis project, each individual project will generate several network models of late onset AD (LOAD) and will identify key drivers of disease pathogenesis by the end of year three. Years four and five will be largely dedicated to validating the novel targets and refining the network models of LOAD, including screening novel compounds or drugs already in use for other conditions that possess the ability to modulate the likely targets.
AD: PREVENTION AND THERAPY TARGETS
Dr. Carrillo highlighted three ongoing prevention studies, two of which are funded in part by the Alzheimer's Association, that will be augmented by AMP. These include the Dominantly Inherited Alzheimer's Network-Therapeutic Trials Unit (DIAN-TTU), the Alzheimer's Prevention Initiative APOE4 Trial, and the Anti-Amyloid Treatment in Asymptomatic AD (tA4-Trial).
DIAN is an international network of 11 leading research centers established in 2008 by funding from the National Institute on Aging to investigate Alzheimer's disease caused by rare, dominantly inherited genetic mutations. The APOE4 Trial, led by Eric Reiman, MD, and Pierre Tariot, MD, of the Banner Alzheimer's Institute in Phoenix, 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. A4, led by Reisa Sperling, MD, professor in neurology at Harvard Medical School and the director of the Center for Alzheimer Research and Treatment at Brigham and Women's Hospital, is a clinical study for individuals aged 65-85 who have normal thinking and memory function but who may be at risk for developing Alzheimer's because of evidence of the accumulation of amyloid.
In addition, AMP will help enable effective data integration across three new NIH-funded studies aimed at identifying and validating new therapeutic targets in human brain tissue.
“This part of the AMP project will conduct large-scale, systems biology analyses of human patient brain tissue samples with Alzheimer's disease to validate biological targets that play key roles in disease progression, and increase understanding of molecular networks involved in the disease, to identify new potential therapeutic targets,” Dr. Carrillo said. “This is an admirable marriage between the public and private research communities. We are hoping that after two or three years we will begin to see some movement with the opening of new therapeutic targets. And we hope this progress will help launch new clinical trials that clinicians can enroll their patients in.”
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