OSAKA, Japan—Takeda Pharmaceutical Co. Ltd. and Durham,N.C.-based partner Zinfandel Pharmaceuticals brought in early summer with newsof a biomarker-based algorithm to predict risk of developing Alzheimer'sdisease (AD), and now they are seeing late summer out with news of a Phase IIItrial of a low-dose pioglitazone to delay the onset of mild cognitiveimpairment (MCI) due to AD, as well as to further run the algorithm through itspaces.
The early summer news was a July 17 announcement of datafrom a late-breaker poster presented at the Alzheimer's AssociationInternational Conference (AAIC) in Boston. That poster was presented on behalfof Zinfandel and Takeda, as well as wholly owned subsidiary Takeda DevelopmentCenter Americas Inc.
In an AAIC session titled "Performance of a Genetics-BasedBiomarker Risk Algorithm to Support a Clinical Trial to Delay Onset of MildCognitive Impairment (MCI) Due to Alzheimer's disease (AD)," principalinvestigator Dr. Michael W. Lutz, a senior research scientist in the Departmentof Neurology at Duke University School of Medicine, presented findings showingpositive predictive and negative predictive values with addition of the TOMM40gene in the range of 70 percent to 80 percent, comparing favorably with imagingand cerebrospinal fluid-based biomarkers.
"Compared to only using APOE status and age as factors, theaddition 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 wasat 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, andTOMM40 fills in most of that gap. Working in the Alzheimer's field, you reallyneed that predictive ability to determine who's at high risk to even begindoing a really effective development program for therapeutics and prevention efforts."
The late summer news was the Aug. 27 announcement thatTakeda and Zinfandel were initiating a global Phase III clinical trial calledTOMMORROW to further investigate the genetic-based biomarker risk-assignmentalgorithm'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 pioglitazonedesignated AD-4833 in delaying the onset of MCI due to AD in cognitively normalindividuals who are at high risk as determined by the risk-assignment algorithmthat combines the APOE and TOMM40 genotypes along with age factors.
TOMMORROW will enroll approximately 5,800 cognitively normalsubjects aged 65 to 83, and will continue until at least 410 subjects in thehigh-risk group have been diagnosed as having MCI due to AD. Subjects in thehigh-risk group will receive either AD-4833 or a matching placebo.
"To date, there have been a number of avenues investigatedwith the goal of altering the course of Alzheimer's disease but results havebeen unsuccessful," said Dr. Allen Roses, CEO of Zinfandel, in the news releaseabout the trial. "This is why the TOMMORROW trial is important. The potentialto identify an individual's risk for developing MCI due to AD warrants furtherinvestigation."
"It's too impractical to run AD studies without a reliablepredictive tool or set of predictive tools," Brannan says of the two-prongedpurpose of the trial. "You'd need to have huge number of subjects in yourclinical 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 85years of age, Takeda noted in its news releases about the predictive algorithmand TOMMORROW. Also, according to the Alzheimer's Association, a treatmentbreakthrough that at least slows the progression of AD could reduce the costsof 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 nextdecade or so in terms of AD. The amount of time and effort and cost this isgoing to cost first- and second-world countries is very large, and if we canhave some way to push out the impact even a little bit into the future, wecould do great good for patients, caregivers and also public health."