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Pushing back Alzheimer’s disease
OSAKA, Japan—Takeda Pharmaceutical Co. Ltd. and Durham, N.C.-based partner Zinfandel Pharmaceuticals brought in early summer with news of a biomarker-based algorithm to predict risk of developing Alzheimer's disease (AD), and now they are seeing late summer out with news of a Phase III trial of a low-dose pioglitazone to delay the onset of mild cognitive impairment (MCI) due to AD, as well as to further run the algorithm through its paces.
The early summer news was a July 17 announcement of data from a late-breaker poster presented at the Alzheimer's Association International Conference (AAIC) in Boston. That poster was presented on behalf of Zinfandel and Takeda, as well as wholly owned subsidiary Takeda Development Center Americas Inc.
In an AAIC session titled "Performance of a Genetics-Based Biomarker Risk Algorithm to Support a Clinical Trial to Delay Onset of Mild Cognitive Impairment (MCI) Due to Alzheimer's disease (AD)," principal investigator Dr. Michael W. Lutz, a senior research scientist in the Department of Neurology at Duke University School of Medicine, presented findings showing positive predictive and negative predictive values with addition of the TOMM40 gene in the range of 70 percent to 80 percent, comparing favorably with imaging and cerebrospinal fluid-based biomarkers.
"Compared to only using APOE status and age as factors, the addition of TOMM40 makes this a promising biomarker risk assignment algorithm," said Lutz at the time.
"With APOE and age, you could to some degree predict who was at high risk of Alzheimer's—with some 30 percent of the population, at least," Dr. Stephen Brannan, head of Takeda's CNS Development Therapeutic Area, tells DDNews. "That still left a lot of area uncovered, and TOMM40 fills in most of that gap. Working in the Alzheimer's field, you really need that predictive ability to determine who's at high risk to even begin doing a really effective development program for therapeutics and prevention efforts."
The late summer news was the Aug. 27 announcement that Takeda and Zinfandel were initiating a global Phase III clinical trial called TOMMORROW to further investigate the genetic-based biomarker risk- assignment algorithm's ability to predict risk of MCI due to AD within a five-year period, as well as to evaluate the efficacy of an investigational low-dose pioglitazone designated AD-4833 in delaying the onset of MCI due to AD in cognitively normal individuals who are at high risk as determined by the risk-assignment algorithm that combines the APOE and TOMM40 genotypes along with age factors.
TOMMORROW will enroll approximately 5,800 cognitively normal subjects aged 65 to 83, and will continue until at least 410 subjects in the high- risk group have been diagnosed as having MCI due to AD. Subjects in the high-risk group will receive either AD-4833 or a matching placebo.
"To date, there have been a number of avenues investigated with the goal of altering the course of Alzheimer's disease but results have been unsuccessful," said Dr. Allen Roses, CEO of Zinfandel, in the news release about the trial. "This is why the TOMMORROW trial is important. The potential to identify an individual's risk for developing MCI due to AD warrants further investigation."
"It's too impractical to run AD studies without a reliable predictive tool or set of predictive tools," Brannan says of the two-pronged purpose of the trial. "You'd need to have huge number of subjects in your clinical trial if you couldn't really identify in advance who is at high risk. The TOMMORROW trial is already quite large even using such predictive ability."
AD diagnoses are increasing as the world's population ages, and the rate of occurrence doubles every five years for those between 65 and 85 years of age, Takeda noted in its news releases about the predictive algorithm and TOMMORROW. Also, according to the Alzheimer's Association, a treatment breakthrough that at least slows the progression of AD could reduce the costs of AD care from $241 billion to $201 billion in 2020.
"The Boomer population, such as myself, is getting older," Brannan notes, "so there is an epidemiologic tidal wave coming in the next decade or so in terms of AD. The amount of time and effort and cost this is going to cost first- and second-world countries is very large, and if we can have some way to push out the impact even a little bit into the future, we could do great good for patients, caregivers and also public health."