Search for Clinical Markers Could? Transform Alzheimer's Drug Research

Abstract

Michele G. Sullivan is with the Mid-Atlantic bureau of Elsevier Global Medical News.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 that are now necessary to determine a drug's effects, according to experts who were 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 a number of ways, said Dr. Michael Weiner, ADNI's principal investigator and the director of the Veterans Affairs Center for Imaging of Neurodegenerative Diseases, San Francisco.Although everyone with AD declines, he said, they don't do so in a linear fashion. “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 may also exhibit, he said.A validated biomarker, on the other hand, could show a drug's true effect —with profound effects on drug development, said Dr. John Q. Trojanowski, director of the Alzheimer's Disease Center at the University of Pennsylvania, Philadelphia, and leader of the initiative'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,” said Dr. Trojanowski.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.Improve the Climate for Clinical TrialsSince 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 as much as $1 billion to bring just one drug to market, it's not surprising that 13 of the world's largest drug manufacturers 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.”Work Begins at 57 CentersPatient enrollment wrapped up in August, 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 both 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.Focus on Four Promising BiomarkersAt 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.In fact, none of the biomarkers or imaging modalities included in the ADNI study has been validated in large numbers of patients. Without validation, none can be used as a primary outcome in drug trials, leaving researchers to fall back on imprecise cognitive measures for their main assessment of efficacy, Dr. Trojanowski explained.“If, instead, we could show that biomarkers were changing during a drug trial, in the same way that we can show changes in cholesterol or blood sugar in response to drugs, then we could have a very, very powerful new tool,” Dr. Trojanowski said.Worldwide EffortADNI is an important study in a worldwide effort to discover clinical markers of AD, the investigators agreed. Australia, Japan, and some European countries are undertaking similar projects. Termed “World Wide ADNI” this informal network will facilitate the performance of international treatment trials and, ultimately, the approval of disease-modifying treatments worldwide. Researchers from these studies are working to harmonize the methodologies, increasing the statistical power of their combined results, Dr. Trojanowski said.Dr. Weiner noted before ADNI has evaluated even a single patient, it has already changed the way scientists are attacking AD research. The bulk of AD biomarker and imaging research currently consists of small studies, each with a unique methodology. Understandably, researchers hold their information close to the vest until publication, with months and sometimes years elapsing between the study's conclusion and the sharing of its results.Researchers have “been studying their own patient groups with their own methods and that makes it very difficult to compare results and determine which measures are most effective and accurate,” Dr. Weiner said. “ADNI will change that practice.”Sharing of Methodology and ResultsNot only will all 57 ADNI study centers follow consistent protocols for all the imaging studies and biomarker collection, but also those protocols will be available to any researcher pursuing an independent study. The sharing of methodology and, eventually, of results, is another of ADNI's unique characteristics, Dr. Weiner explained.All data will be sent to centralized storage hubs, which will be freely available to anyone—researcher, physician, patient, or family member—who applies for access. The information won't be subject to embargo; scans and biomarker measurements will be available online as soon as they're processed.“We are going to share everything we get in an unprecedented way. Allowing other researchers to have immediate access to the data is going to maximize this study's effect.”This free exchange goes against the grain of traditional research, Dr. Weiner admitted. “It means that those of us doing the research might not be writing all the papers while it's going on—others will also have the opportunity to do this. But I believe that's a small price to pay for having thousands of scientists analyze these data in different ways. Out of our competing work, the truth will emerge.”For more information, including filing a request for access to eventual data, physicians should go to www.adni-info.org. Michele G. Sullivan is with the Mid-Atlantic bureau of Elsevier Global Medical News. 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 that are now necessary to determine a drug's effects, according to experts who were 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 a number of ways, said Dr. Michael Weiner, ADNI's principal investigator and the director of the Veterans Affairs Center for Imaging of Neurodegenerative Diseases, San Francisco. Although everyone with AD declines, he said, they don't do so in a linear fashion. “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 may also exhibit, he said. A validated biomarker, on the other hand, could show a drug's true effect —with profound effects on drug development, said Dr. John Q. Trojanowski, director of the Alzheimer's Disease Center at the University of Pennsylvania, Philadelphia, and leader of the initiative'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,” said Dr. Trojanowski. 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. Improve the Climate for Clinical TrialsSince 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 as much as $1 billion to bring just one drug to market, it's not surprising that 13 of the world's largest drug manufacturers 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.” 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 as much as $1 billion to bring just one drug to market, it's not surprising that 13 of the world's largest drug manufacturers 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.” Work Begins at 57 CentersPatient enrollment wrapped up in August, 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 both 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. Patient enrollment wrapped up in August, 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 both 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. Focus on Four Promising BiomarkersAt 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.In fact, none of the biomarkers or imaging modalities included in the ADNI study has been validated in large numbers of patients. Without validation, none can be used as a primary outcome in drug trials, leaving researchers to fall back on imprecise cognitive measures for their main assessment of efficacy, Dr. Trojanowski explained.“If, instead, we could show that biomarkers were changing during a drug trial, in the same way that we can show changes in cholesterol or blood sugar in response to drugs, then we could have a very, very powerful new tool,” Dr. Trojanowski said. 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. In fact, none of the biomarkers or imaging modalities included in the ADNI study has been validated in large numbers of patients. Without validation, none can be used as a primary outcome in drug trials, leaving researchers to fall back on imprecise cognitive measures for their main assessment of efficacy, Dr. Trojanowski explained. “If, instead, we could show that biomarkers were changing during a drug trial, in the same way that we can show changes in cholesterol or blood sugar in response to drugs, then we could have a very, very powerful new tool,” Dr. Trojanowski said. Worldwide EffortADNI is an important study in a worldwide effort to discover clinical markers of AD, the investigators agreed. Australia, Japan, and some European countries are undertaking similar projects. Termed “World Wide ADNI” this informal network will facilitate the performance of international treatment trials and, ultimately, the approval of disease-modifying treatments worldwide. Researchers from these studies are working to harmonize the methodologies, increasing the statistical power of their combined results, Dr. Trojanowski said.Dr. Weiner noted before ADNI has evaluated even a single patient, it has already changed the way scientists are attacking AD research. The bulk of AD biomarker and imaging research currently consists of small studies, each with a unique methodology. Understandably, researchers hold their information close to the vest until publication, with months and sometimes years elapsing between the study's conclusion and the sharing of its results.Researchers have “been studying their own patient groups with their own methods and that makes it very difficult to compare results and determine which measures are most effective and accurate,” Dr. Weiner said. “ADNI will change that practice.” ADNI is an important study in a worldwide effort to discover clinical markers of AD, the investigators agreed. Australia, Japan, and some European countries are undertaking similar projects. Termed “World Wide ADNI” this informal network will facilitate the performance of international treatment trials and, ultimately, the approval of disease-modifying treatments worldwide. Researchers from these studies are working to harmonize the methodologies, increasing the statistical power of their combined results, Dr. Trojanowski said. Dr. Weiner noted before ADNI has evaluated even a single patient, it has already changed the way scientists are attacking AD research. The bulk of AD biomarker and imaging research currently consists of small studies, each with a unique methodology. Understandably, researchers hold their information close to the vest until publication, with months and sometimes years elapsing between the study's conclusion and the sharing of its results. Researchers have “been studying their own patient groups with their own methods and that makes it very difficult to compare results and determine which measures are most effective and accurate,” Dr. Weiner said. “ADNI will change that practice.” Sharing of Methodology and ResultsNot only will all 57 ADNI study centers follow consistent protocols for all the imaging studies and biomarker collection, but also those protocols will be available to any researcher pursuing an independent study. The sharing of methodology and, eventually, of results, is another of ADNI's unique characteristics, Dr. Weiner explained.All data will be sent to centralized storage hubs, which will be freely available to anyone—researcher, physician, patient, or family member—who applies for access. The information won't be subject to embargo; scans and biomarker measurements will be available online as soon as they're processed.“We are going to share everything we get in an unprecedented way. Allowing other researchers to have immediate access to the data is going to maximize this study's effect.”This free exchange goes against the grain of traditional research, Dr. Weiner admitted. “It means that those of us doing the research might not be writing all the papers while it's going on—others will also have the opportunity to do this. But I believe that's a small price to pay for having thousands of scientists analyze these data in different ways. Out of our competing work, the truth will emerge.”For more information, including filing a request for access to eventual data, physicians should go to www.adni-info.org. Not only will all 57 ADNI study centers follow consistent protocols for all the imaging studies and biomarker collection, but also those protocols will be available to any researcher pursuing an independent study. The sharing of methodology and, eventually, of results, is another of ADNI's unique characteristics, Dr. Weiner explained. All data will be sent to centralized storage hubs, which will be freely available to anyone—researcher, physician, patient, or family member—who applies for access. The information won't be subject to embargo; scans and biomarker measurements will be available online as soon as they're processed. “We are going to share everything we get in an unprecedented way. Allowing other researchers to have immediate access to the data is going to maximize this study's effect.” This free exchange goes against the grain of traditional research, Dr. Weiner admitted. “It means that those of us doing the research might not be writing all the papers while it's going on—others will also have the opportunity to do this. But I believe that's a small price to pay for having thousands of scientists analyze these data in different ways. Out of our competing work, the truth will emerge.” For more information, including filing a request for access to eventual data, physicians should go to www.adni-info.org.