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WASHINGTON, DC—What would it take to evaluate the range of suggested treatments to postpone, reduce, or completely prevent the clinical onset of Alzheimer’s disease as quickly as possible? How can neurologists find and support the approval of drugs that work within the next 10 years? To answer these questions, Eric Reiman, MD, Executive Director of the Banner Alzheimer’s Institute (BAI) in Phoenix, and his colleagues Pierre Tariot, MD, and Jessica Langbaum, PhD, developed the Alzheimer’s Prevention Initiative (API) with valuable input from numerous academic, industry, regulatory, and other stakeholders. Dr. Reiman described API’s efforts at the 2015 Alzheimer’s Association International Conference.
Genotyping Study Provides Blueprint for Research
There are many promising but unproven prevention therapies, Dr. Reiman noted. They include lifestyle and dietary changes; dietary supplements; and repurposeable medications, such as those currently used for cholesterol or hypertension, as well as a growing number of investigational disease-modifying agents. “A therapy that delays the clinical onset of Alzheimer’s disease by only five years without also increasing lifespan has the potential to reduce the number of afflicted individuals by half. The hope is that we can do even better than that.”
As these treatments may need to be started before the clinical onset of symptoms to be effective, the vast resources required to test them in clinical trials can be prohibitive. “It could take 50,000 healthy late middle-age volunteers and a 20-year trial to wait for enough individuals in the placebo group to develop dementia.”
For Dr. Reiman and his colleagues, a clue to solving this problem was suggested in 1993 by the results of a retrospective case–control study by Duke University researchers. In this study of families with a history of late-onset Alzheimer’s disease, subjects’ risk of the disease increased from 20% to as much as 90% with increasing number of apolipoprotein E type 4 (APOE4) alleles, and the age of onset decreased from 84 to 68. While prospective cohort studies continue to clarify the absolute risk with each genotype, studies have consistently confirmed the association between APOE4 gene dose and the risk of Alzheimer’s disease, Dr. Reiman pointed out.
The Birth of the API
Building on this research, Dr. Reiman and colleagues began a study to track the disease before symptom onset. “We wondered if we could use brain imaging and other biomarker methods in cognitively unimpaired individuals at different levels of genetic risk for Alzheimer’s disease,” he explained.
Dr. Reiman, Richard Caselli, MD, of Mayo Clinic Arizona, and their colleagues began a longitudinal study of cognitively unimpaired persons in late middle-age with two, one, or no copies of the APOE allele to detect and track the preclinical stages of Alzheimer’s disease. Over the years, they have detected and tracked the brain imaging changes associated with Alzheimer’s disease. Based on their findings, Dr. Reiman initially proposed the idea of using brain imaging end points in APOE4 carriers to evaluate repurposed medications and lifestyle interventions that might reduce the risk of Alzheimer’s disease in 24-month proof-of-concept prevention trials.
However, he and his BAI colleagues soon realized that brain imaging and other biomarker end points would be unlikely to support the regulatory approval of prevention therapies unless they could provide evidence to suggest that the biomarker end points had “theragnostic value,” meaning that a treatment’s effects on the relevant biomarker endpoints were a reasonable way to predict a clinical benefit. In other areas of medicine, there have been instances in which a treatment’s biomarker effects failed to predict a clinical benefit, causing regulatory agencies to have that additional evidence to support the approval of treatments based solely on “surrogate biomarker end points.”
From their research findings and this particular insight came the idea to start the API. “Our goal was to help accelerate the evaluation of prevention therapies,” Dr. Reiman said. “In 2009, we began to vet our ideas with numerous academic and industry researchers, NIH officials, and other stakeholder groups in public meetings. We proposed potentially license-enabling prevention trials of investigational anti-amyloid treatments in research participants, who, based on their genetic background and age, are at particularly high risk for the clinical onset of Alzheimer’s disease. We incorporated elements that could help establish the theragnostic value of biomarkers and help the entire field along the way, and we set out to develop public–private partnerships to help address our goals more effectively than we could on our own.”
API has relied on the complementary experience, expertise, and goals of its academic and industry partners, BAI’s overarching strategy for the rapid evaluation of prevention therapies, and promising anti-amyloid agents from its selected industry partners. It secured initial funding to support its first two prevention trials. It also secured commitments from its industry partners to share trial data and biological samples with the field after the trials are completed to help find faster ways to conduct prevention trials in the future. “To prevent Alzheimer’s disease, it will take a commitment from all of us,” Dr. Reiman emphasized.
New Clinical Trials
Dr. Reiman and coworkers were introduced to Francisco Lopera, MD, and his colleagues in Medellin, Colombia, who have been studying a large kindred of local families—about 5,000 people—whose lineage can be traced to a common ancestor. The kindred share a rare genetic mutation, presenilin 1, that typically triggers Alzheimer’s disease symptoms around age 45. It is the world’s largest kindred with known autosomal dominant Alzheimer’s disease, Dr. Reiman said.
As a result of this connection, the API obtained the participation of the kindred for a research opportunity. In late 2013, the API, in partnership with Genentech, the University of Antioquia, and the NIH, began a 60-month randomized, double-blind, placebo-controlled, parallel-group study of the investigational amyloid immunotherapy drug crenezumab in cognitively unimpaired members of this kindred. Crenezumab binds to soluble and fibrillar forms of amyloid beta, the main constituent of amyloid plaques in the brains of patients with Alzheimer’s disease. The trial also provides an opportunity to relate the treatment’s different effects on 24-month brain imaging and fluid biomarkers to its clinical effects to determine which biomarker effects are associated with a clinical benefit and could be used to evaluate the range of promising prevention therapies in future 24-month prevention trials.
The study, scheduled to end in 2020, will involve cognitively unimpaired kindred members ages 30 and older, including approximately 100 mutation carriers who will receive treatment, 100 carriers who will receive placebo, and 100 noncarriers who also will receive placebo. Subjects will be followed for 60 months, and the primary end point is change in API composite cognitive test score. Change in various other neurocognitive tests and brain imaging measures are secondary end points.
In an upcoming trial, the API will partner with Novartis to study two investigational drugs. Approximately 1,300 cognitively healthy APOE4 allele homozygotes ages 60 to 75 will be randomized to CAD106 (an injectable anti-amyloid immunotherapy), oral beta-secretase 1 (BACE-1) inhibitor CNP520, or placebo. It is slated to begin as soon as a safety profile is established for the BACE-1 inhibitor.
“In this case, the study is intended to detect an effect on either time to the clinical onset of Alzheimer’s disease, MCI, or dementia, or the rate of decline in the API composite cognitive test score,” Dr. Reiman said. “In addition to the other brain imaging and fluid biomarkers, this study will also include tau PET using Avid and Eli Lilly’s ligand AV1451 with support through the Accelerated Medicines Partnership.” Another unique feature of this study is the need to inform prospective participants about their genetic risk for Alzheimer’s disease and evaluate the impact of risk disclosure in the era of prevention trials, he added.
Paving the Way for Future Research
To help identify individuals in the 60- to 75-year-old age group for future studies, as well as to support other efforts, the API developed the online Alzheimer’s Prevention Registry. Registrants can receive information on the latest developments in Alzheimer’s disease prevention research, opportunities to participate in new prevention trials, and additional resources to learn more about Alzheimer’s disease. The registry now includes more than 140,000 individuals and is expected to grow rapidly in the coming months.
Dr. Reiman concluded by proposing what it will take to find effective prevention therapies within the next 10 years. “It will take the study of cognitively unimpaired persons at increased risk for Alzheimer’s disease. It will take the development of biomarker end points that are reasonably likely to predict a clinical benefit and their qualification for use in potentially license-enabling trials under regulatory agencies’ accelerated approval mechanism. It will take the use of these biomarker end points in roughly 24-month trials to evaluate the range of promising prevention therapies in persons who, based on their genetic information or biomarker measurements, are at increased risk for Alzheimer’s disease. It will take large enrollment registries and trial innovations to further accelerate the evaluation of these treatments. It will take new ways for different stakeholders to work together, commitments to share data and biological samples with the field, financial commitments from our elected officials, and a sense of urgency among us all.”
—Adriene Marshall
WASHINGTON, DC—What would it take to evaluate the range of suggested treatments to postpone, reduce, or completely prevent the clinical onset of Alzheimer’s disease as quickly as possible? How can neurologists find and support the approval of drugs that work within the next 10 years? To answer these questions, Eric Reiman, MD, Executive Director of the Banner Alzheimer’s Institute (BAI) in Phoenix, and his colleagues Pierre Tariot, MD, and Jessica Langbaum, PhD, developed the Alzheimer’s Prevention Initiative (API) with valuable input from numerous academic, industry, regulatory, and other stakeholders. Dr. Reiman described API’s efforts at the 2015 Alzheimer’s Association International Conference.
Genotyping Study Provides Blueprint for Research
There are many promising but unproven prevention therapies, Dr. Reiman noted. They include lifestyle and dietary changes; dietary supplements; and repurposeable medications, such as those currently used for cholesterol or hypertension, as well as a growing number of investigational disease-modifying agents. “A therapy that delays the clinical onset of Alzheimer’s disease by only five years without also increasing lifespan has the potential to reduce the number of afflicted individuals by half. The hope is that we can do even better than that.”
As these treatments may need to be started before the clinical onset of symptoms to be effective, the vast resources required to test them in clinical trials can be prohibitive. “It could take 50,000 healthy late middle-age volunteers and a 20-year trial to wait for enough individuals in the placebo group to develop dementia.”
For Dr. Reiman and his colleagues, a clue to solving this problem was suggested in 1993 by the results of a retrospective case–control study by Duke University researchers. In this study of families with a history of late-onset Alzheimer’s disease, subjects’ risk of the disease increased from 20% to as much as 90% with increasing number of apolipoprotein E type 4 (APOE4) alleles, and the age of onset decreased from 84 to 68. While prospective cohort studies continue to clarify the absolute risk with each genotype, studies have consistently confirmed the association between APOE4 gene dose and the risk of Alzheimer’s disease, Dr. Reiman pointed out.
The Birth of the API
Building on this research, Dr. Reiman and colleagues began a study to track the disease before symptom onset. “We wondered if we could use brain imaging and other biomarker methods in cognitively unimpaired individuals at different levels of genetic risk for Alzheimer’s disease,” he explained.
Dr. Reiman, Richard Caselli, MD, of Mayo Clinic Arizona, and their colleagues began a longitudinal study of cognitively unimpaired persons in late middle-age with two, one, or no copies of the APOE allele to detect and track the preclinical stages of Alzheimer’s disease. Over the years, they have detected and tracked the brain imaging changes associated with Alzheimer’s disease. Based on their findings, Dr. Reiman initially proposed the idea of using brain imaging end points in APOE4 carriers to evaluate repurposed medications and lifestyle interventions that might reduce the risk of Alzheimer’s disease in 24-month proof-of-concept prevention trials.
However, he and his BAI colleagues soon realized that brain imaging and other biomarker end points would be unlikely to support the regulatory approval of prevention therapies unless they could provide evidence to suggest that the biomarker end points had “theragnostic value,” meaning that a treatment’s effects on the relevant biomarker endpoints were a reasonable way to predict a clinical benefit. In other areas of medicine, there have been instances in which a treatment’s biomarker effects failed to predict a clinical benefit, causing regulatory agencies to have that additional evidence to support the approval of treatments based solely on “surrogate biomarker end points.”
From their research findings and this particular insight came the idea to start the API. “Our goal was to help accelerate the evaluation of prevention therapies,” Dr. Reiman said. “In 2009, we began to vet our ideas with numerous academic and industry researchers, NIH officials, and other stakeholder groups in public meetings. We proposed potentially license-enabling prevention trials of investigational anti-amyloid treatments in research participants, who, based on their genetic background and age, are at particularly high risk for the clinical onset of Alzheimer’s disease. We incorporated elements that could help establish the theragnostic value of biomarkers and help the entire field along the way, and we set out to develop public–private partnerships to help address our goals more effectively than we could on our own.”
API has relied on the complementary experience, expertise, and goals of its academic and industry partners, BAI’s overarching strategy for the rapid evaluation of prevention therapies, and promising anti-amyloid agents from its selected industry partners. It secured initial funding to support its first two prevention trials. It also secured commitments from its industry partners to share trial data and biological samples with the field after the trials are completed to help find faster ways to conduct prevention trials in the future. “To prevent Alzheimer’s disease, it will take a commitment from all of us,” Dr. Reiman emphasized.
New Clinical Trials
Dr. Reiman and coworkers were introduced to Francisco Lopera, MD, and his colleagues in Medellin, Colombia, who have been studying a large kindred of local families—about 5,000 people—whose lineage can be traced to a common ancestor. The kindred share a rare genetic mutation, presenilin 1, that typically triggers Alzheimer’s disease symptoms around age 45. It is the world’s largest kindred with known autosomal dominant Alzheimer’s disease, Dr. Reiman said.
As a result of this connection, the API obtained the participation of the kindred for a research opportunity. In late 2013, the API, in partnership with Genentech, the University of Antioquia, and the NIH, began a 60-month randomized, double-blind, placebo-controlled, parallel-group study of the investigational amyloid immunotherapy drug crenezumab in cognitively unimpaired members of this kindred. Crenezumab binds to soluble and fibrillar forms of amyloid beta, the main constituent of amyloid plaques in the brains of patients with Alzheimer’s disease. The trial also provides an opportunity to relate the treatment’s different effects on 24-month brain imaging and fluid biomarkers to its clinical effects to determine which biomarker effects are associated with a clinical benefit and could be used to evaluate the range of promising prevention therapies in future 24-month prevention trials.
The study, scheduled to end in 2020, will involve cognitively unimpaired kindred members ages 30 and older, including approximately 100 mutation carriers who will receive treatment, 100 carriers who will receive placebo, and 100 noncarriers who also will receive placebo. Subjects will be followed for 60 months, and the primary end point is change in API composite cognitive test score. Change in various other neurocognitive tests and brain imaging measures are secondary end points.
In an upcoming trial, the API will partner with Novartis to study two investigational drugs. Approximately 1,300 cognitively healthy APOE4 allele homozygotes ages 60 to 75 will be randomized to CAD106 (an injectable anti-amyloid immunotherapy), oral beta-secretase 1 (BACE-1) inhibitor CNP520, or placebo. It is slated to begin as soon as a safety profile is established for the BACE-1 inhibitor.
“In this case, the study is intended to detect an effect on either time to the clinical onset of Alzheimer’s disease, MCI, or dementia, or the rate of decline in the API composite cognitive test score,” Dr. Reiman said. “In addition to the other brain imaging and fluid biomarkers, this study will also include tau PET using Avid and Eli Lilly’s ligand AV1451 with support through the Accelerated Medicines Partnership.” Another unique feature of this study is the need to inform prospective participants about their genetic risk for Alzheimer’s disease and evaluate the impact of risk disclosure in the era of prevention trials, he added.
Paving the Way for Future Research
To help identify individuals in the 60- to 75-year-old age group for future studies, as well as to support other efforts, the API developed the online Alzheimer’s Prevention Registry. Registrants can receive information on the latest developments in Alzheimer’s disease prevention research, opportunities to participate in new prevention trials, and additional resources to learn more about Alzheimer’s disease. The registry now includes more than 140,000 individuals and is expected to grow rapidly in the coming months.
Dr. Reiman concluded by proposing what it will take to find effective prevention therapies within the next 10 years. “It will take the study of cognitively unimpaired persons at increased risk for Alzheimer’s disease. It will take the development of biomarker end points that are reasonably likely to predict a clinical benefit and their qualification for use in potentially license-enabling trials under regulatory agencies’ accelerated approval mechanism. It will take the use of these biomarker end points in roughly 24-month trials to evaluate the range of promising prevention therapies in persons who, based on their genetic information or biomarker measurements, are at increased risk for Alzheimer’s disease. It will take large enrollment registries and trial innovations to further accelerate the evaluation of these treatments. It will take new ways for different stakeholders to work together, commitments to share data and biological samples with the field, financial commitments from our elected officials, and a sense of urgency among us all.”
—Adriene Marshall
WASHINGTON, DC—What would it take to evaluate the range of suggested treatments to postpone, reduce, or completely prevent the clinical onset of Alzheimer’s disease as quickly as possible? How can neurologists find and support the approval of drugs that work within the next 10 years? To answer these questions, Eric Reiman, MD, Executive Director of the Banner Alzheimer’s Institute (BAI) in Phoenix, and his colleagues Pierre Tariot, MD, and Jessica Langbaum, PhD, developed the Alzheimer’s Prevention Initiative (API) with valuable input from numerous academic, industry, regulatory, and other stakeholders. Dr. Reiman described API’s efforts at the 2015 Alzheimer’s Association International Conference.
Genotyping Study Provides Blueprint for Research
There are many promising but unproven prevention therapies, Dr. Reiman noted. They include lifestyle and dietary changes; dietary supplements; and repurposeable medications, such as those currently used for cholesterol or hypertension, as well as a growing number of investigational disease-modifying agents. “A therapy that delays the clinical onset of Alzheimer’s disease by only five years without also increasing lifespan has the potential to reduce the number of afflicted individuals by half. The hope is that we can do even better than that.”
As these treatments may need to be started before the clinical onset of symptoms to be effective, the vast resources required to test them in clinical trials can be prohibitive. “It could take 50,000 healthy late middle-age volunteers and a 20-year trial to wait for enough individuals in the placebo group to develop dementia.”
For Dr. Reiman and his colleagues, a clue to solving this problem was suggested in 1993 by the results of a retrospective case–control study by Duke University researchers. In this study of families with a history of late-onset Alzheimer’s disease, subjects’ risk of the disease increased from 20% to as much as 90% with increasing number of apolipoprotein E type 4 (APOE4) alleles, and the age of onset decreased from 84 to 68. While prospective cohort studies continue to clarify the absolute risk with each genotype, studies have consistently confirmed the association between APOE4 gene dose and the risk of Alzheimer’s disease, Dr. Reiman pointed out.
The Birth of the API
Building on this research, Dr. Reiman and colleagues began a study to track the disease before symptom onset. “We wondered if we could use brain imaging and other biomarker methods in cognitively unimpaired individuals at different levels of genetic risk for Alzheimer’s disease,” he explained.
Dr. Reiman, Richard Caselli, MD, of Mayo Clinic Arizona, and their colleagues began a longitudinal study of cognitively unimpaired persons in late middle-age with two, one, or no copies of the APOE allele to detect and track the preclinical stages of Alzheimer’s disease. Over the years, they have detected and tracked the brain imaging changes associated with Alzheimer’s disease. Based on their findings, Dr. Reiman initially proposed the idea of using brain imaging end points in APOE4 carriers to evaluate repurposed medications and lifestyle interventions that might reduce the risk of Alzheimer’s disease in 24-month proof-of-concept prevention trials.
However, he and his BAI colleagues soon realized that brain imaging and other biomarker end points would be unlikely to support the regulatory approval of prevention therapies unless they could provide evidence to suggest that the biomarker end points had “theragnostic value,” meaning that a treatment’s effects on the relevant biomarker endpoints were a reasonable way to predict a clinical benefit. In other areas of medicine, there have been instances in which a treatment’s biomarker effects failed to predict a clinical benefit, causing regulatory agencies to have that additional evidence to support the approval of treatments based solely on “surrogate biomarker end points.”
From their research findings and this particular insight came the idea to start the API. “Our goal was to help accelerate the evaluation of prevention therapies,” Dr. Reiman said. “In 2009, we began to vet our ideas with numerous academic and industry researchers, NIH officials, and other stakeholder groups in public meetings. We proposed potentially license-enabling prevention trials of investigational anti-amyloid treatments in research participants, who, based on their genetic background and age, are at particularly high risk for the clinical onset of Alzheimer’s disease. We incorporated elements that could help establish the theragnostic value of biomarkers and help the entire field along the way, and we set out to develop public–private partnerships to help address our goals more effectively than we could on our own.”
API has relied on the complementary experience, expertise, and goals of its academic and industry partners, BAI’s overarching strategy for the rapid evaluation of prevention therapies, and promising anti-amyloid agents from its selected industry partners. It secured initial funding to support its first two prevention trials. It also secured commitments from its industry partners to share trial data and biological samples with the field after the trials are completed to help find faster ways to conduct prevention trials in the future. “To prevent Alzheimer’s disease, it will take a commitment from all of us,” Dr. Reiman emphasized.
New Clinical Trials
Dr. Reiman and coworkers were introduced to Francisco Lopera, MD, and his colleagues in Medellin, Colombia, who have been studying a large kindred of local families—about 5,000 people—whose lineage can be traced to a common ancestor. The kindred share a rare genetic mutation, presenilin 1, that typically triggers Alzheimer’s disease symptoms around age 45. It is the world’s largest kindred with known autosomal dominant Alzheimer’s disease, Dr. Reiman said.
As a result of this connection, the API obtained the participation of the kindred for a research opportunity. In late 2013, the API, in partnership with Genentech, the University of Antioquia, and the NIH, began a 60-month randomized, double-blind, placebo-controlled, parallel-group study of the investigational amyloid immunotherapy drug crenezumab in cognitively unimpaired members of this kindred. Crenezumab binds to soluble and fibrillar forms of amyloid beta, the main constituent of amyloid plaques in the brains of patients with Alzheimer’s disease. The trial also provides an opportunity to relate the treatment’s different effects on 24-month brain imaging and fluid biomarkers to its clinical effects to determine which biomarker effects are associated with a clinical benefit and could be used to evaluate the range of promising prevention therapies in future 24-month prevention trials.
The study, scheduled to end in 2020, will involve cognitively unimpaired kindred members ages 30 and older, including approximately 100 mutation carriers who will receive treatment, 100 carriers who will receive placebo, and 100 noncarriers who also will receive placebo. Subjects will be followed for 60 months, and the primary end point is change in API composite cognitive test score. Change in various other neurocognitive tests and brain imaging measures are secondary end points.
In an upcoming trial, the API will partner with Novartis to study two investigational drugs. Approximately 1,300 cognitively healthy APOE4 allele homozygotes ages 60 to 75 will be randomized to CAD106 (an injectable anti-amyloid immunotherapy), oral beta-secretase 1 (BACE-1) inhibitor CNP520, or placebo. It is slated to begin as soon as a safety profile is established for the BACE-1 inhibitor.
“In this case, the study is intended to detect an effect on either time to the clinical onset of Alzheimer’s disease, MCI, or dementia, or the rate of decline in the API composite cognitive test score,” Dr. Reiman said. “In addition to the other brain imaging and fluid biomarkers, this study will also include tau PET using Avid and Eli Lilly’s ligand AV1451 with support through the Accelerated Medicines Partnership.” Another unique feature of this study is the need to inform prospective participants about their genetic risk for Alzheimer’s disease and evaluate the impact of risk disclosure in the era of prevention trials, he added.
Paving the Way for Future Research
To help identify individuals in the 60- to 75-year-old age group for future studies, as well as to support other efforts, the API developed the online Alzheimer’s Prevention Registry. Registrants can receive information on the latest developments in Alzheimer’s disease prevention research, opportunities to participate in new prevention trials, and additional resources to learn more about Alzheimer’s disease. The registry now includes more than 140,000 individuals and is expected to grow rapidly in the coming months.
Dr. Reiman concluded by proposing what it will take to find effective prevention therapies within the next 10 years. “It will take the study of cognitively unimpaired persons at increased risk for Alzheimer’s disease. It will take the development of biomarker end points that are reasonably likely to predict a clinical benefit and their qualification for use in potentially license-enabling trials under regulatory agencies’ accelerated approval mechanism. It will take the use of these biomarker end points in roughly 24-month trials to evaluate the range of promising prevention therapies in persons who, based on their genetic information or biomarker measurements, are at increased risk for Alzheimer’s disease. It will take large enrollment registries and trial innovations to further accelerate the evaluation of these treatments. It will take new ways for different stakeholders to work together, commitments to share data and biological samples with the field, financial commitments from our elected officials, and a sense of urgency among us all.”
—Adriene Marshall
