A $60 million, 6-year study is being launched to find and validate biologic and imaging markers that could be used as objective measures of therapeutic response in Alzheimer's disease.
The results of the Alzheimer's Disease Neuroimaging Initiative (ADNI) could dramatically shorten clinical trials of potential therapies by sidestepping the years of cognitive testing now necessary to determine a drug effects, according to experts interviewed for this article.
The time is ripe for an objective biologic marker of disease progression. Several potentially disease-modifying drugs are in phase II trials, with cognitive measures the only validated treatment outcomes. Relying solely on cognition to determine treatment effect is problematic in many ways, said Dr. Michael W. Weiner, ADNI's principal investigator and the director of the Veterans Administration's Center for Imaging of Neurodegenerative Disease, San Francisco.
Everyone with AD declines, but they don't do so in a linear fashion, Dr. Weiner said “There is a lot of variability in these kinds of measures. One day, a patient might do well, and the next, do poorly depending on his general health, emotional status, or a number of other factors. This variability really affects the ability to determine a true treatment effect.”
Nor, using cognitive outcomes alone, is it possible to distinguish between a drug's effects on disease progression and any memory-enhancing effects it also might exhibit, he said.
A validated biomarker, on the other hand, could show a drug's true effect, with profound influence on drug development, said Dr. John Q. Trojanowski, director of the Alzheimer's Disease Center at the University of Pennsylvania, Philadelphia, and leader of ADNI's biomarker core. “The pace of drug discovery would quicken incredibly, and the costs come down incredibly, if we had a chemical or imaging marker that reflected reversing or blocking disease progression.”
Funded by a mix of federal and private sources, ADNI will search for such markers in 800 patients aged 55–90 years: 200 with AD, 400 with mild cognitive impairment (MCI), and 200 healthy controls. Examining three imaging techniques and four biomarkers, the study aims to find predictors of progression in AD patients, and predictors of transformation from normal to MCI and from MCI to AD.
Since the study's main goal is to improve the climate for clinical trials, pharmaceutical companies have an enormous stake in its outcome. Faced with a cost of up to $1 billion to bring just one drug to market, it's not surprising that 13 of the world's largest drug makers have agreed to fund about a third of ADNI's cost. The National Institutes of Health is footing the rest of the bill.
“For an investment of a few million dollars, [pharmaceutical companies are] hoping for biomarkers that would enable them to bring the cost of their clinical trials down by millions of dollars,” said Dr. Trojanowski. “Chances are that this is a reasonable expectation.”
Patient enrollment wrapped up last year, and now the work is beginning at 57 centers across the United States and Canada. In addition to the baseline visit, AD patients will have three follow-ups (6, 12, and 24 months). Normal controls will have four follow-ups, including an additional visit at 36 months. MCI patients will be seen a total of six times: at baseline and at 6, 12, 18, 24, and 36 months.
Each cohort will have apolipoprotein E genotyping at baseline and undergo standard magnetic resonance imaging at all time points. Half also will receive fluorodeoxyglucose PET scanning at each time point, and another 25% will undergo the more sensitive 3-Tesla MRI, which allows metabolic and physiologic imaging.
A group of 120 patients also will be enrolled in a substudy of Pittsburgh compound B PET scanning. Because the compound binds to amyloid plaques in the brain, it offers a reliable way by which to trace disease progression and may be able to detect early pathologic changes before cognitive changes develop.
At all follow-up visits, patients will donate blood and urine for evaluation for these potential markers; 55% will undergo at least two lumbar punctures for the collection of cerebrospinal fluid. ADNI will focus on four of the most promising biomarkers:
▸ Homocysteine, while not diagnostically significant, may reflect disease progression.
▸ Isoprostanes, indicators of oxidative damage, have been shown to be increased in the hippocampi and CSF of AD patients.
▸ Phosphorylated tau and amyloid-β are the neuropathologic hallmarks of AD tangles and plaques, respectively.
Most research indicates that patients with low levels of amyloid-β and high levels of tau in CSF are more likely to have AD, although some recent studies have challenged this idea.