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Fluid Biomarkers in Clinical Trials of Alzheimer's Disease Therapeutics.

Ritter A, Cummings J - Front Neurol (2015)

Bottom Line: Current treatments provide symptomatic relief but do not affect the underlying pathology of the disease.Insights gained from decades of research have begun to unlock the pathophysiology of this complex disease and have provided targets for disease-modifying therapies.Fluid biomarkers are important because they can provide information regarding the underlying biochemical processes that are occurring in the brain.

View Article: PubMed Central - PubMed

Affiliation: Cleveland Clinic Lou Ruvo Center for Brain Health , Las Vegas, NV , USA.

ABSTRACT
With the demographic shift of the global population toward longer life expectancy, the number of people living with Alzheimer's disease (AD) has rapidly expanded and is projected to triple by the year 2050. Current treatments provide symptomatic relief but do not affect the underlying pathology of the disease. Therapies that prevent or slow the progression of the disease are urgently needed to avoid this growing public health emergency. Insights gained from decades of research have begun to unlock the pathophysiology of this complex disease and have provided targets for disease-modifying therapies. In the last decade, few therapeutic agents designed to modify the underlying disease process have progressed to clinical trials and none have been brought to market. With the focus on disease modification, biomarkers promise to play an increasingly important role in clinical trials. Six biomarkers have now been included in diagnostic criteria for AD and are regularly incorporated into clinical trials. Three biomarkers are neuroimaging measures - hippocampal atrophy measured by magnetic resonance imaging (MRI), amyloid uptake as measured by Pittsburg compound B positron emission tomography (PiB-PET), and decreased fluorodeoxyglucose (18F) uptake as measured by PET (FDG-PET) - and three are sampled from fluid sources - cerebrospinal fluid levels of amyloid β42 (Aβ42), total tau, and phosphorylated tau. Fluid biomarkers are important because they can provide information regarding the underlying biochemical processes that are occurring in the brain. The purpose of this paper is to review the literature regarding the existing and emerging fluid biomarkers and to examine how fluid biomarkers have been incorporated into clinical trials.

No MeSH data available.


Related in: MedlinePlus

Standard parallel group design to demonstrate disease modification groups receiving active treatment and placebo would be compared on clinical measures while an effect on disease pathology would be demonstrated by showing differences on a biomarker measure of disease progression. A correlation between drug–placebo difference and a biomarker outcome could potentially support a claim of disease modification.
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Figure 2: Standard parallel group design to demonstrate disease modification groups receiving active treatment and placebo would be compared on clinical measures while an effect on disease pathology would be demonstrated by showing differences on a biomarker measure of disease progression. A correlation between drug–placebo difference and a biomarker outcome could potentially support a claim of disease modification.

Mentions: Several candidate agents with potential disease-modifying properties have advanced to Phase III testing, each has failed to meet clinical endpoints. A few trials have included biomarker data as secondary outcomes. Owing to the heterogeneity of the findings and lack of correlation with clinical metrics, these results are difficult to interpret. The slow progression of the disease, complicated pathophysiology, and difficulty in accurately modeling the pathology of sporadic AD in animal models present formidable challenges to clinical trial design and implementation. Biomarkers, however, have the ability to answer questions more quickly and effectively about target engagement, patient selection, and disease monitoring. In preclinical studies, biomarkers can be used to verify that a candidate agent is having its proposed effect on the biological systems it is designed to target. Because animal models are limited in their ability to replicate all of the behavioral and pathological features of AD (206), testing in multiple animals may improve the predictive value of clinical testing. Preclinical testing should also include biomarker data that are translatable to humans (including both CSF and serum). CSF testing in larger animals like guinea pigs and canines can provide valuable information about a candidate drug’s effects in the CSF and may improve upon information derived from mouse models (207). As a candidate compound advances to early clinical testing in humans, an early priority should be to confirm that biomarker changes demonstrated in preclinical testing are seen in humans (8). This can be tested with smaller, proof of concept trials that are powered to pre-specified endpoints. It is at this stage that go, no-go decisions can be made about advancing to longer, more expensive trials. If an agent is to be labeled with a claim of disease modification, support may come from biomarker data in Phase III trials. Figure 2 illustrates a potential model for a standard parallel group design. Groups receiving active treatment and placebo would be compared based on clinical measures and a biomarker known to exert an effect on the underlying pathophysiology. A drug–placebo difference would be supported by differences on clinical measures (cognition, function, or global outcomes); while an effect on disease pathology would be demonstrated by showing a significant difference on biomarker measures of disease progression (for example, CSF t-tau). A statistically significant correlation between these two measures could potentially be used to support a claim for disease modification (208).


Fluid Biomarkers in Clinical Trials of Alzheimer's Disease Therapeutics.

Ritter A, Cummings J - Front Neurol (2015)

Standard parallel group design to demonstrate disease modification groups receiving active treatment and placebo would be compared on clinical measures while an effect on disease pathology would be demonstrated by showing differences on a biomarker measure of disease progression. A correlation between drug–placebo difference and a biomarker outcome could potentially support a claim of disease modification.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4553391&req=5

Figure 2: Standard parallel group design to demonstrate disease modification groups receiving active treatment and placebo would be compared on clinical measures while an effect on disease pathology would be demonstrated by showing differences on a biomarker measure of disease progression. A correlation between drug–placebo difference and a biomarker outcome could potentially support a claim of disease modification.
Mentions: Several candidate agents with potential disease-modifying properties have advanced to Phase III testing, each has failed to meet clinical endpoints. A few trials have included biomarker data as secondary outcomes. Owing to the heterogeneity of the findings and lack of correlation with clinical metrics, these results are difficult to interpret. The slow progression of the disease, complicated pathophysiology, and difficulty in accurately modeling the pathology of sporadic AD in animal models present formidable challenges to clinical trial design and implementation. Biomarkers, however, have the ability to answer questions more quickly and effectively about target engagement, patient selection, and disease monitoring. In preclinical studies, biomarkers can be used to verify that a candidate agent is having its proposed effect on the biological systems it is designed to target. Because animal models are limited in their ability to replicate all of the behavioral and pathological features of AD (206), testing in multiple animals may improve the predictive value of clinical testing. Preclinical testing should also include biomarker data that are translatable to humans (including both CSF and serum). CSF testing in larger animals like guinea pigs and canines can provide valuable information about a candidate drug’s effects in the CSF and may improve upon information derived from mouse models (207). As a candidate compound advances to early clinical testing in humans, an early priority should be to confirm that biomarker changes demonstrated in preclinical testing are seen in humans (8). This can be tested with smaller, proof of concept trials that are powered to pre-specified endpoints. It is at this stage that go, no-go decisions can be made about advancing to longer, more expensive trials. If an agent is to be labeled with a claim of disease modification, support may come from biomarker data in Phase III trials. Figure 2 illustrates a potential model for a standard parallel group design. Groups receiving active treatment and placebo would be compared based on clinical measures and a biomarker known to exert an effect on the underlying pathophysiology. A drug–placebo difference would be supported by differences on clinical measures (cognition, function, or global outcomes); while an effect on disease pathology would be demonstrated by showing a significant difference on biomarker measures of disease progression (for example, CSF t-tau). A statistically significant correlation between these two measures could potentially be used to support a claim for disease modification (208).

Bottom Line: Current treatments provide symptomatic relief but do not affect the underlying pathology of the disease.Insights gained from decades of research have begun to unlock the pathophysiology of this complex disease and have provided targets for disease-modifying therapies.Fluid biomarkers are important because they can provide information regarding the underlying biochemical processes that are occurring in the brain.

View Article: PubMed Central - PubMed

Affiliation: Cleveland Clinic Lou Ruvo Center for Brain Health , Las Vegas, NV , USA.

ABSTRACT
With the demographic shift of the global population toward longer life expectancy, the number of people living with Alzheimer's disease (AD) has rapidly expanded and is projected to triple by the year 2050. Current treatments provide symptomatic relief but do not affect the underlying pathology of the disease. Therapies that prevent or slow the progression of the disease are urgently needed to avoid this growing public health emergency. Insights gained from decades of research have begun to unlock the pathophysiology of this complex disease and have provided targets for disease-modifying therapies. In the last decade, few therapeutic agents designed to modify the underlying disease process have progressed to clinical trials and none have been brought to market. With the focus on disease modification, biomarkers promise to play an increasingly important role in clinical trials. Six biomarkers have now been included in diagnostic criteria for AD and are regularly incorporated into clinical trials. Three biomarkers are neuroimaging measures - hippocampal atrophy measured by magnetic resonance imaging (MRI), amyloid uptake as measured by Pittsburg compound B positron emission tomography (PiB-PET), and decreased fluorodeoxyglucose (18F) uptake as measured by PET (FDG-PET) - and three are sampled from fluid sources - cerebrospinal fluid levels of amyloid β42 (Aβ42), total tau, and phosphorylated tau. Fluid biomarkers are important because they can provide information regarding the underlying biochemical processes that are occurring in the brain. The purpose of this paper is to review the literature regarding the existing and emerging fluid biomarkers and to examine how fluid biomarkers have been incorporated into clinical trials.

No MeSH data available.


Related in: MedlinePlus