blue U.S. Food & Drug Administration (FDA)
green European Medicines Agency (EMA)
The hippocampus is a small brain structure key to storing and retrieving memories. Patients with Alzheimer’s Disease (AD) show early and progressive loss or atrophy of the hippocampus. Quantitative magnetic resonance imaging (MRI) is a noninvasive way to measure hippocampal atrophy and is used to assess disease progression in AD. Reductions in hippocampal volume represent the only correlate of cognitive impairment over time amongst all biomarkers studied to date. It is believed that effective disease modifying therapies will need to be administered to patients very early in the course of the illness.
To date, clinical trials in patients with Mild Cognitive Impairment have posed significant challenges since many patients that present with cognitive impairment do not have true Alzheimer’s disease. CAMD is advancing a qualification regulatory biomarker application that proposes that baseline measurement of low hippocampal volume by MRI in patients with episodic memory deficit is a useful means of predicting those patients more likely to evolve to AD dementia during the course of an AD clinical trial. This biomarker would aid in the selection of a cohort which will yield a relatively uniform clinical trial population more likely to progress to AD dementia.
Therapeutic intervention at an early, asymptomatic or mildly symptomatic stage of Alzheimer’s Disease (AD) is likely required to preserve cognitive function and delay disease progression. Attempts to identify patients at increased risk for progression to AD dementia based on clinical assessment have lacked desired diagnostic sensitivity and specificity. Accordingly, three National Institute on Aging and Alzheimer’s Association (NIA-AA)-sponsored workgroups recently recommended revised diagnostic guidelines for AD dementia, mild cognitive impairment (MCI) due to AD, and the definition of preclinical stages of AD. The proposed guidelines rely upon combined clinical and biomarker-based patient assessment and offer a framework for research on the relationship between the pathophysiology and the emergence of clinical symptoms.
In alignment with these guidelines, cerebrospinal Fluid (CSF), which may be acquired via lumbar puncture, is important as a biofluid signature of what is happening in the brain.
The CSF biomarkers being advanced for qualification by CAMD are as follows:
- Cerebrospinal Fluid (CSF) 42 amino acid-containing isoform of amyloid beta(Aβ42)
- Total tau (t-tau)
- Tau phosphorylated at threonine 181 (P-tau181)
CAMD’s qualification effort provides evidence to support the use of CSF Aβ42, t-tau and/or P-tau181 as biomarkers that can identify cognitively impaired subjects who are likely to progress to AD pathology for inclusion in research and drug registration clinical trials of candidate therapeutics for AD.
Disease Model of Mild & Moderate AD
blue U.S. Food & Drug Administration (FDA)
green European Medicines Agency (EMA)
A quantitative model that describes the natural history of cognitive change in Alzheimer’s Disease (AD) would be an enormously valuable tool in the development of novel therapies. Utilizing the extensive historical data available in the literature and from participating members, CAMD has developed such a model which can be used to simulate and test relevant characteristics of clinical trial designs for different hypothesized expected effects of a drug. The model is expected to yield useful information that can be incorporated into trial design such as dose selection, population inclusion, sample size estimates, and study duration.
Disease Model of MCI and Pre-symptomatic AD
In recent years, it has become clear that there is a very long prodromal period of Alzheimer’s Disease (AD) pathology that precedes onset of clinical symptoms by as much as 20 years. It is currently believed that novel disease modifying therapies will be efficacious only if one can initiate treatment early in the course of disease. To date, significant challenges have occurred in assessing effects of therapies in mild cognitive impairment (MCI) patients, largely due to the difficulty of identifying which patients will progress to true AD as opposed to other forms of dementia. Advances in pharmacometrics pose an exciting and promising avenue to address this issue. Following the successful development of its disease model of mild and moderate AD, CAMD is currently investigating the development of a modeling and simulation tool based on a quantitative model of early MCI subjects. Analysis of data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database to date suggests that patients at very early stages of dementia/MCI progress at a slower rate and show greater interindividual variability. As a result, the disease model would be essential in demonstrating the number of subjects and duration of treatment that is needed to test new therapies in newly diagnosed patients. This tool would be used to design and execute clinical trials in this area. Specifically, the tool would be used to inform clinical trial design in subjects with amnestic mild cognitive impairment likely to progress to AD dementia. The goal is for this work to serve as a resource for teams designing clinical trials across the industry. It is intended that teams will utilize this simulation tool to allow them to provide a quantitative rationale for selection of study design and inclusion criteria for specific compounds and for internal decision making during all clinical stages of development.
PD Imaging Biomarker
Approximately a million U.S. patients suffer from PD, a number that is expected to increase by 40% over the next 30 years. As the scientific community and pharmaceutical industry move to develop innovative disease modifying agents to augment the symptomatic treatment currently available, the need for accurate diagnosis of PD at a stage earlier than is currently feasible becomes a public health imperative. One of the main challenges for the disease modification approach is that by the time the disease is clinically apparent, the neurodegenerative process is far advanced. CAMD proposes to address this need through the qualification of a biomarker for PD, specifically, a reduction of dopamine transporter protein (DAT) activity. The SPECT (single photon emission computed tomography) ligand, N-xfluoropropyl-2b-carbomethoxy-3b-[4-iodophenyl] nortropane (FP-CIT) (DaTSCAN™ GE Healthcare) is currently approved for the diagnosis of PD to distinguish patients from those with essential tremor. The current proposed context of use is to expand the label to exclude all patients that have SWEDDS (scans without evidence of dopamine deficiency) from clinical trials of new candidate PD therapies. This imaging biomarker will be used to identify at the earliest stages of motor impairment patients with dopamine deficiency for the purposes of enrichment in clinical trials.
1Feasibility: During this phase, discussions are in progress to determine if the drug development tool has sufficient priority based on its potential impact on public health and value to both the industry and regulatory agencies to justify launching a project to proceed toward a regulatory qualification submission.
2Scoping: During this phase, the project’s goals, objectives, deliverables, timeline, and budget are being developed.
3Research: During this execution phase the project team is actively engaged in carrying out the research plan.
4Submission: During this phase, a qualification dossier that reports the results of the research project and supports the context of use of the novel drug development tool is being prepared and will be submitted to the agency as indicated by the color code.
5Qualification: During this phase, the regulatory agency is reviewing the submission and will issue an opinion regarding the proposed utility of the novel drug development tool. When qualification decisions are made, links to the regulatory decisions will be provided at this site.