Originally published Jan. 10.
By Turna Ray
Takeda Pharmaceuticals is working with Zinfandel Pharmaceuticals to use a genetic test to determine which older people at high risk of getting Alzheimer's disease in the next five years should be enrolled in the development program for Actos as an Alzheimer's prevention drug.
This week, Takeda said it signed an exclusive, worldwide licensing agreement regarding Zinfandel's TOMM40 assay "as a biomarker for the risk of Alzheimer's disease in high-risk older adults with normal cognition." Under the terms of the deal, Zinfandel will receive an upfront payment of $9 million and could receive up to $78 million in milestone payments. Takeda maintains an exclusive license, as well rights to sublicense, develop, use, and commercialize the TOMM40 assay.
Actos (pioglitazone) is currently marketed by Takeda in the US as a type 2 diabetes drug. The payments made to Zinfandel by Takeda will fund a clinical trial to validate Zinfandel's TOMM40 test in conjunction with the efficacy of Takeda's Actos in delaying the onset of Alzheimer's.
The TOMM40 test being validated in the study is based on earlier research done by a team of investigators led by Allen Roses, director of Duke University's Dean Drug Discovery Institute and CEO at Zinfandel, which found that varying lengths of the TOMM40 rs10524523 poly-T polymorphism ─ located at intron 6 of the TOMM40 gene and linked to APOE3 and APOE4 polymorphisms ─ can be used to craft a three-allele risk prediction system for gauging those who are likely to see early onset or late onset of Alzheimer's disease.
The Alzheimer's prevention trial involving Actos will be prospectively designed to enroll around 1,600 people between the ages of 60 and 87. Study participants will be picked from the general population and given a neuropsychology test designed by a panel of experts involved with the design of the study. Only patients who pass the neuropsych test and are deemed to be "normal" will be enrolled in the trial.
Based on their age and TOMM40 status, patients who fall into the high-risk category for developing Alzheimer's in the next five years will be randomized to either the drug or placebo. Those who are deemed to be at low risk will be randomized to one of two placebo arms. Each arm will enroll approximately 384 patients, a number that investigators settled on after discussing the study design with the US Food and Drug Administration's Voluntary Exploratory Data Submissions program.
When the last recruited patient has been followed in the trial for three years, a safety monitoring group will assess whether the Alzheimer's prevention drug is safe and efficacious in the study population and, if deemed to be so, the trial could be terminated early. If the safety and efficacy of the drug cannot be gauged at the three-year point, then the study will continue for another two years.
Even if this trial doesn't prove that Actos can delay the onset of Alzheimer's disease, Zinfandel will still be able to validate the TOMM40 polymorphism as a risk predictor for the age of onset of Alzheimer's disease. "If the drug doesn't work, at the end of it, we don't have a drug for the prevention of Alzheimer's, but we do have the exquisitely accurate data for the relationship of age-of-onset curves to the length of the polyTs," Roses told PGx Reporter.
Roses estimated that the type of trial Zinfandel and Takeda are embarking on to validate the TOMM40 test would typically cost upwards of $25 million. "No one is going to do that for a diagnostic of any sort, and so the only way to do this would be to do it as part of a drug study," he noted.
When the study was being discussed with FDA's experts at the VXDS program ─ which works with sponsors to discuss preliminary genomics data without regulatory repercussions ─ the price tag for the trial was estimated to be between $50 million and $100 million, Roses said. He could not provide a firm estimate of how much the Alzheimer's prevention trial will end up costing, but said the price "really depends on whether we make an expensive priority of establishing prospective age curves for other imaging, biochemical, [and] immunological biomarkers [that are] currently only studied in retrospective studies, which are not adequate for individual predictions."
Furthermore, current allele frequencies are based on research done in the Caucasian population, and variability in other ethnic populations would need to be accounted for in later studies.
Previous studies conducted by Roses and colleagues and presented at international medical conferences suggest that the TOMM40 rs10524523 poly-T polymorphism, which is in linkage disequilibrium with APOE alleles, is associated with physical characteristics of Alzheimer's in pre-symptomatic subjects (PGx Reporter 07/14/10).
Roses' research shows that patients with APOE3 and a short version of TOMM40 will not get Alzheimer's until after age 80. However, the long version of TOMM40 occurring with either APOE3 or APOE4 means the person will likely get Alzheimer's before the age of 80. Further honing in on age of onset through TOMM40 genotyping, Roses and a team of researchers published a paper in The Pharmacogenomics Journal in 2009 reporting that among people harboring APOE ε3/4 polymorphisms who developed Alzheimer's after 60 years, those harboring long poly-T repeats linked to APOE ε3 developed late-onset Alzheimer's several years earlier than individuals with shorter poly-T repeats linked to APOE ε3 (see table below).
Roses and his research team investigated the linkage disequilibrium region containing APOE and TOMM40 via deep sequencing techniques to pick up all the polymorphisms, and then mapped the evolutionary relationship of the polymorphisms through phylogenetics. In the article published in TPJ, the authors explained that unlike genome-wide association studies, which focus on chunks of DNA associated with disease, the phylogenetic technique allowed them to spot groups of related haplotypes with a common ancestral history, or clades. These clades could then be enriched to look for variants linked to disease.
"Preliminary genome-wide screens are, therefore, valuable for flagging linkage regions of potential interest for a particular phenotype," the authors wrote in the paper. "Using a phylogenetic analysis of a previously flagged genomic region, we have discovered a polymorphic poly-T variant in TOMM40 that is linked to APOE."
Currently, there is no commercially available test that gauges TOMM40 polymorphisms to assess risk of developing Alzheimer's based on age. For the time being, Roses and his research team are allowing Alzheimer's researchers to use the TOMM40/APOE risk prediction model as part of their ongoing studies, at a low cost. An ethics panel involved with the conduct of the Alzheimer's prevention trial has mandated that the "test can only be used by people in validated research studies," Roses said.
For the commercially available test, "we are considering several different technologies, other than Sanger sequencing, and potential partners," Roses noted.
"A commercial test will need to be accurate and inexpensive, but [the trial] must also be viewed as a test validation [study,] which will establish accuracy of predictions." Roses noted that Zinfandel has filed patents for the test, which have not yet been issued, but have received a positive international review.
The fact that Takeda is studying a diabetes treatment for Alzheimer's is no surprise, since many researchers have characterized Alzheimer's as a form of diabetes of the brain.
Actos is an inhibitor of peroxisome proliferator-activated receptor gamma, or PPARg, a receptor that controls genes involved in the metabolism of glucose and lipid in the body, levels of which are abnormal in Alzheimer's patients. Studies have shown that stimulating this receptor in the brain can deter degradation of cognitive functions due to Alzheimer's.
Actos also falls in the category of thiazolidinedione drugs, which came under regulatory scrutiny in 2007 after a meta-analysis published in the New England Journal of Medicine by Cleveland Clinic cardiologist Steven Nissen associated Actos and GlaxoSmithKline's Avandia with a 43 percent increase in heart attacks and a 64 percent increase in cardiovascular deaths. More recent comparisons of the heart attack risks associated with the two drugs suggest that Avandia harbors higher risks than Actos.
Despite these findings, Avandia and Actos both remain on the market as type 2 diabetes treatments. However, the FDA last year limited Avandia's marketing to only those type 2 patients who have exhausted all other options.
Separately, however, Actos, which is Takeda's top-selling product with estimated annual sales of $4 billion, is not without its own regulatory problems. Last September, FDA said it is reviewing data suggesting that Actos may be linked to bladder cancer. Given that Actos is also slated to face generic competition starting 2012, an expansion of its indication to Alzheimer's disease would allow Takeda to continue to net significant revenues from the drug if it is launched for a different indication.
In a statement, Takeda estimated that 18 million people have Alzheimer’s disease around the world, and every five years the rate doubles for people between 65 and 85 years of age.
In the Sept. 13 issue of the Archives of Neurology, researchers led by David Geldmacher of the Department of Neurology in the University of Virginia published a pilot Alzheimer's study involving Actos. In that study, 29 patients who met the criteria for likely having Alzheimer's were randomized to receive Actos or placebo plus vitamin E daily for 18 months between 2001 and 2004.
"Pioglitazone was generally well tolerated in this pilot study," the authors concluded following the pilot investigation. "The tolerability of pioglitazone in this population and PPARg effects in laboratory models of Alzheimer's disease support further study of this drug class in earlier disease stages."
Even if initial studies conducted by Takeda and Zinfandel suggest that Actos can stave off the onset of Alzheimer's disease, there will still be many outstanding questions regarding dosing and at what age patients should start treatment if they are deemed to be at high risk for early-disease onset. "These questions will need to be figured out" in later studies, before the drug and test can be commercially sold together, Roses said.
Have topics you'd like to see covered in Pharmacogenomics Reporter? Contact the editor at tray [at] genomeweb [.] com.