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Takeda, Zinfandel Launch TOMMORROW Trial to Evaluate Alzheimer's Onset Risk Algorithm, AD-4833

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This article has been updated from a previous version to correct the pioglitazone dose to be used in the TOMMORROW trial. It is 0.8 mg/day, not 0.6 mg/day. Originally published Sept. 3.

Takeda Pharmaceutical announced last week the launch of the Phase III TOMMORROW trial, through which the company is hoping to prove the efficacy and safety of low-dose pioglitazone, dubbed AD-4833, in delaying the onset of mild-cognitive decline due to Alzheimer's in individuals at high risk for the illness.

In the same trial, with the help of a genetics-based risk algorithm, researchers from Takeda and Zinfandel Pharmaceuticals, a company focused on using pharmacogenetics to improve Alzheimer's risk prediction and treatments, will determine whether normal study subjects are at high or low risk of Alzheimer's-related mild cognitive decline in the next five years. The partners are also hoping to validate and qualify this algorithm for assessing people's risk of Alzheimer's onset.

In TOMMORROW, approximately 5,800 normal subjects between ages 65 and 83 will enter a high-risk or a low-risk arm based on this genetics-based algorithm, which factors in people's age, and APOE and TOMM40 genotypes. In the high-risk arm, study participants will be randomized to receive either AD-4833 or placebo. In the low-risk arm, study subjects will only receive placebo.

The two placebo arms are intended to qualify the algorithm and validate a companion test that may be used to determine risk of Alzheimer's onset. The two high-risk cohorts, randomized to either AD-4833 or placebo, will evaluate the safety and efficacy of the drug. Takeda markets pioglitazone, under the brand name Actos, for type 2 diabetes.

According to Takeda, researchers are currently screening patients for enrollment in TOMMORROW, which will continue for five years, or until 410 people have developed mild cognitive decline due to Alzheimer's in the high-risk group. Approximately 50 sites worldwide, across North America, Europe, and Australia, are involved in the study.

In the part of the study investigating the biomarker risk algorithm, the primary endpoint is time to diagnosis of mild cognitive decline due to Alzheimer's for placebo-treated, high-risk subjects versus placebo-treated, low-risk subjects. In the part of the study assessing the efficacy of AD-4833, researchers will track in terms of time to diagnosis of mild cognitive decline how well low-dose pioglitazone delays Alzheimer's onset in high-risk patients compared to placebo. Researchers will also compare the effect of the drug and placebo on the progression of cognitive decline, functional decline, and other daily activities.

“Enrolling cognitively normal subjects … has its own challenges compared to enrolling subjects with early stage disease, such as mild cognitive impairment or mild Alzheimer's disease,” Stephen Brannan, head of Takeda's central nervous system development therapeutic area, told PGx Reporter in an email.

Takeda is building a registry of cognitively normal subjects who are interested in participating in a study like TOMMORROW. Some participating sites already have a large number of cognitively normal subjects in the registry and investigators are contacting them to see if they want to be screened for enrollment in the trial.

“The main challenge in enrolling “normal”/healthy individuals (prior to developing disease) is that it is impractical unless one has some way of identifying who is at high risk for developing the disease,” Brannan said. “This study is proceeding because we believe the biomarker algorithm that has been developed by Zinfandel can identify those at high risk of developing AD.”

The genomic risk algorithm to be used in the TOMMORROW study was developed by a research team led by Allen Roses, Jefferson-Pilot professor of neurobiology and neurology at Duke and CEO of Zinfandel. In 1992, Roses' lab at Duke identified the association between the APOE ε4 allele and heightened risk of late-onset Alzheimer's. More recently, Roses' team has published research showing that varying lengths of a TOMM40 poly-T polymorphism — located at intron 6 of the TOMM40 gene and linked to APOE ε3 and APOE ε4 polymorphisms — can be used to craft a three-allele risk prediction system for gauging the age of onset for Alzheimer's (PGx Reporter 1/12/2011).

Approximately 30 percent of Alzheimer's patients are APOE4 carriers, and according to past studies, depending on age, a person who carries two copies of the APOE4 allele has a higher risk of late-onset Alzheimer's than a non-carrier. With the addition of the TOMM40 genotype to APOE4 genotype and age, researchers at Takeda and Zinfandel are hoping to show that their biomarker risk algorithm will be applicable to 97 percent of the population compared to just 2 percent when just APOE4 homozygotes are considered.

At the Alzheimer's Association International Conference in Boston a few months ago, researchers from Takeda, Zinfandel, and Duke presented data establishing the analytical validity of this biomarker algorithm. Data from a simulation study showed the risk algorithm has a positive predictive value and a negative predictive value between 70 percent and 80 percent. Furthermore, the genomic risk algorithm "compares favorably" with imaging-based assays and cerebrospinal fluid biomarkers in determining whether individuals have cognitive decline due to Alzheimer's, researchers led by Michael Lutz of Duke University reported in a poster presented at AAIC (PGx Reporter 7/24/2013).

In the majority of studies evaluating Alzheimer's treatments, researchers are employing APOE4 genotypes, cerebrospinal fluid markers, such as amyloid-beta42 and total tau protein, or gauging amyloid markers via imaging-based assays to identify more accurately those with cognitive decline who are at risk for the disease.

However, the US Food and Drug Administration has been cautious in backing the use of biomarkers in Alzheimer's drug trials. In its draft guidance on developing drugs for early-stage Alzheimer's disease, the FDA said it supports the use of biomarkers to enrich trials with individuals most likely to progress to more "overt" dementia. However, the agency hasn't formally endorsed any specific diagnostic methods, noting the need to assess the sensitivity and specificity of markers in predicting those who actually have Alzheimer's.

If the genetics-based algorithm is qualified through the TOMMORROW trial, Takeda and Zinfandel will have developed a highly accurate biomarker test for identifying pre-symptomatic Alzheimer's patients. However, by employing a genomic algorithm factoring in age, and APOE/TOMM40 genotypes, the TOMMORROW study departs from the prevailing beta-amyloid-centered hypothesis dominating Alzheimer's research currently.

Roses has controversially argued that beta amyloid isn't the right drug target for Alzheimer's because although the buildup of amyloid plaque in the brain is part of the pathogenesis of the disease, it doesn’t cause it. Based on more than 20 years of research, he believes that certain APOE and TOMM40 genotypes have increased damaging effects on mitochondrial function within brain cells, which limits their ability to utilize oxygen and glucose. The failure of mitochondrial energy production results in the accumulation of amyloid and other aggregating proteins in the brain, and due to this, damaged mitochondria can't reach distant synapses of neurons and provide the energy needed to support new neurite formation. This, Roses hypothesizes, causes the kind of cognitive decline characteristic in Alzheimer's.

The decision to investigate a low-dose diabetes drug dovetails with this theory. Studies have shown that individuals with impaired ability to metabolize cerebral glucose exhibit cognitive impairment of the kind seen with Alzheimer's onset. In line with Roses' view that amyloid plaque seen in Alzheimer's patients forms in the brain due to diminished oxygen and glucose utilization in neurons, Takeda and Zinfadel are using a diabetes drug that has been shown to increase these key sources of energy in the brain in order to try to stave off cognitive decline due to Alzheimer's.

In recent years, Actos has made headlines for increasing risk of heart failure and bladder cancer. However, in the TOMMORROW study researchers will administer a 0.8 mg/day formulation of pioglitazone – significantly lower than the up to 45 mg/day Actos dose diabetes patients receive – which researchers believe will lower the risk of adverse events.

Takeda estimates that currently 36 million people globally are living with dementia. There is data suggesting that people with mild cognitive decline are at greater risk of developing Alzheimer's or another type of dementia. According to the Alzheimer's Association, a drug that could delay the onset of the disease would reduce the cost of patient care by $40 billion in 2020.

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