NAPA Research Milestones for Goal #1 -- To Treat or Prevent Alzheimer's Disease by 2025

07/16/2013

Table of Contents

PDF Versions

HTML Version

Comments and questions, or alerts to broken links, should be sent to napa@hhs.gov.


NAPA Research Milestone Chart

 

Drug Development: Repurposing and Combinations
Milestone Time to Complete 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027
Convene an advisory meeting of experts to advance rational drug repurposing/repositioning and combination therapy. 1 year                            
Initiate research programs for translational bioinformatics and network pharmacology to support rational drug repositioning and combination therapy. 3-5 years                    
Initiate early clinical development for at least 6 repurposed drugs or drug combinations. 2-4 years                      
Initiate at least 3 phase 3 trials with repurposed drugs or drug combinations. 3-5 years                    

 

Drug Development: Currently Known Targets
Milestone Time to Complete 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027
Initiate phase 2 (proof of concept) drug trials for agents against 3-6 currently known therapeutic targets. 2-4 years                      
Initiate phase 3 drug trials for agents against at least 3 currently known therapeutic targets. 3-5 years                    

 

Drug Development: Novel Targets
Milestone Time to Complete 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027
Establish a searchable, open access database for the purpose of identifying regions of the genome that contain novel targets. 4-5 years                    
Establish a consortium of genetics and genomics experts to execute a large scale sequencing project to identify AD risk and protective gene variants in subjects with late onset AD. 5-8 years              
Identify, characterize, and complete early validation for at least 6 novel therapeutic targets for AD. 5-7 years                
Initiate a drug discovery effort to develop novel therapeutic agents against at least 6 novel therapeutic targets. 5-7 years                
Initiate phase 2 (proof of concept) drug trials for agents against 3-6 novel therapeutic targets. 2-4 years                      
Initiate phase 3 drug trials for agents against at least 3 novel therapeutic targets. 3-5 years                    

 

Development of Non-Pharmacological Interventions
Milestone Time to Complete 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027
Convene an advisory meeting to delineate an interdisciplinary research agenda focused on advancing non-pharmacological interventions for the cognitive and behavioral symptoms of AD. 1 year                            
Convene an advisory meeting to inform the design of therapeutic approaches combining pharmacological and non-pharmacological treatments. 1 year                            
Initiate interdisciplinary research programs aimed at gaining an in depth mechanistic understanding of the impact of non-pharmacological interventions on AD. 5 years                    
Initiate Phase 2 and 3 clinical trials for at least 3 non-pharmacological interventions aimed at AD prevention. 4-5 years                    
Initiate Phase 2 and 3 clinical trials for at least 3 interventions combining pharmacological and non-pharmacological interventions for AD treatment or prevention. 4-5 years                    
Review results of past and existing grants for the purpose of developing new technologies that promote prevention and treatment trials. 1 year                            
Issue Funding Opportunity Announcements for research aimed at developing new technologies that improve clinical care, care giver support and in-home monitoring. 3-5 years                    

 

Biomarkers of Disease Progression
Milestone Time to Complete 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027
Initiate synthesis and testing of novel PET ligands and develop and test novel CSF/blood biomarkers for assessment of disease related pathological burdens. 5 years                    
Initiate development of imaging and/or fluid biomarkers to demonstrate target engagement for 5 novel therapeutic targets for AD. 5 years                    
Incorporate imaging and/or fluid biomarkers into Phase II (proof of concept) drug trials to provide proof of mechanism and/or evidence of target engagement for novel targets. 3-5 years                    
Incorporate imaging and/or fluid biomarkers into Phase III (pivotal) drug trials to select subjects and/or provide evidence of target engagement for novel targets. 3-5 years                    
Initiate studies to develop minimally invasive biomarkers for detection of cerebral amyloidosis and other AD pathophysiology. 5 years                    
Initiate studies to link peripheral blood-based biomarkers and central imaging and CSF biomarkers. 5 years                    
Launch research programs to develop and validate sensitive neuropsychological assessment measures to detect and track the earliest clinical changes of AD. 5 years                    
Develop and test methods for the standardization of immunoassays and mass-spectrometry and the collection and analysis of MRI and PET neuroimaging data. 5 years                    

 

Epidemiology
Milestone Time to Complete 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027
Establish an expert panel of epidemiologists and clinical scientists to make recommendations for best practices in the use of existing epidemiology of dementia databases. 1 year                            
Initiate expansion of epidemiology of dementia cohorts to include subjects in midlife and use data generated to inform clinical trial design. 5-7 years                

 

Research Resources
Milestone Time to Complete 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027
Develop a common Alzheimer's Disease research ontology for comparative analysis of US and international AD research portfolios and create a publicly available database (IADRP) that will house the AD portfolios. 2-3 years                        

 

Partnerships to Accelerate AD Drug Development
Milestone Time to Complete 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027
Convene an advisory meeting focused on facilitating public private partnerships (PPP) aimed at accelerating the development and testing of effective therapies for AD treatment and prevention. 1 year                            
Convene meetings of PPP working groups for the purpose of formulating concrete steps aimed at accelerating the timeframe of AD drug development. 1 year                            

 

Infrastructure
Milestone Time to Complete 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027
Create a network of Translational Centers aimed at preclinical development and testing of AD therapeutics. 3-5 years                    
Establish an NIH working group to develop an expedited review track for translational AD research applications. 1 year                            
Create a National IRB. 2 years                          
Establish a working group to identify standard outcome measures necessary for data comparisons across a variety of clinical studies. 1 year                            
Initiate 3-4 clinical research studies using common standard outcome measures. 3-5 years                    

 

Study Recruitment and Participation
Milestone Time to Complete 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027
Increase knowledge among research scientists of best practices for recruitment and retention of research participants. 2 years                          
Establish a working group including clinical trial recruitment experts to dynamically evaluate and update the materials and information provided in the central resource. 1 year                            
Increase awareness of large-scale registries that encompass the spectrum of the disease from healthy to at-risk asymptomatic to symptomatic individuals willing to participate in clinical research aimed at AD prevention and treatment. 2 years                          
Increase the rate of enrollment for AD clinical trials and increase the participation of underrepresented populations. 5 years                    

 


Full NAPA Research Milestone Statements and Success Criteria

 

Drug Development: Repurposing and Combinations
Milestone Success Criteria Time Required
Development of recommendations for rational repositioning and combination therapy development.

Development, negotiation, and implementation of appropriate agreements among the stakeholders involved in repositioning and combination therapy of drugs for AD. These agreements should address legal issues, intellectual property rights, and liability to expedite rigorous clinical testing of repurposed drugs.

1 year
2014

Identification of at least 6 existing drugs suitable for repurposing and/or combination therapy for AD prevention or treatment. The drugs selected for repurposing or combination therapy will be prioritized based on:

  • Evidence that they modulate disease relevant pathways/networks gained from computational and empirical approaches.
  • Preclinical proof-of-efficacy in a relevant model system.
  • Availability of biomarkers to monitor target engagement in humans.
  • Sufficient evidence of safety for the intended target population.
3-5 years
2015-2019
Completion of at least 4 phase II trials with repurposed drugs and/or drug combinations. Successful trials will provide conclusive evidence of therapeutic mechanism/target engagement. 2-4 years
2018-2021
Comprehensive success/failure analyses of data from at least 3 phase III trials. 3-5 years
2020-2024

 

Drug Development: Currently Known Targets
Milestone Milestone Time Required
Completion of 3-6 phase II drug trials for agents against currently known targets, providing conclusive evidence of therapeutic mechanism/target engagement. 2-4 years
2015-2018
Comprehensive success/failure analysis of data from at least 3 phase III trials. 3-5 years
2017-2021

 

Drug Development: Novel Targets
Milestone Milestone Time Required
At least one novel target, pathway or therapeutic approach identified through use of the database. 4-5 years
2013-2017
Identification of new risk and protective alleles for LOAD that lead to the identification of at least one novel therapeutic approach, drug target or pathway for prevention. 5-8 years
2013-2020
Validation based on availability of the following for each noveltarget: a systems-level understanding of the gene, protein and metabolic networks within which they operate, one or more cell based/animal models that are freely available to the research community, a quantitative assessment of the integrative response to the modulation of the target in one or more model organisms, and identification of pharmacodynamic biomarker(s) for target engagement. 5-7 years
2014-2020
Complete preclinical development, through IND filing, of therapeutics agents against at least 3 novel targets. 5-7 years
2017-2023
Completion of 3-6 phase II drug trials for agents against novel targets, providing conclusive evidence of therapeutic mechanism/target engagement. 2-4 years
2020-2023
Comprehensive success/failure analysis of data from at least 3 phase III trials. 3-5 years
2022-2026

 

Development of Non-Pharmacological Interventions
Milestone Milestone Time Required
Recommendations developed for advancing non-pharmacological interventions for AD treatment and prevention to enable successful implementation of effective non-pharmacological interventions. 1 year
2014
Recommendations developed for design of clinical trials combining pharmacological and non-pharmacological interventions. 1 year
2015
Identification of at least 3 new therapeutic targets for neuroprotection based on knowledge of mechanisms mediating the impact of non-pharmacological interventions of brain health in aging and AD.

Preclinical proof-of-concept for at least 3 types of non-pharmacological interventions that can inform clinical trial design.

5 years
2016-2020
Completion of at least 2 phase II trials for non-pharmacological interventions aimed at AD prevention. Successful trials will provide conclusive evidence of therapeutic mechanism.

Comprehensive success/failure analysis of data from at least one phase III trial.

4-5 years
2017-2021
At least 2 phase II trials completed for interventions combining pharmacological and non-pharmacological interventions for AD treatment or prevention with conclusive evidence of therapeutic mechanism.

Comprehensive success/failure analysis of data from at least one phase III trial.

4-5 years
2019-2023
At least two new technologies are developed, prove useful in formal or informal care, and are widely adopted. 1 year
2015

3-5 years
2016-2020

 

Biomarkers of Disease Progression
Milestone Milestone Time Required
Development and testing of 3-5 novel PET ligands and/or CSF/blood biomarkers for assessment of AD pathology. 5 years
2014-2018
Identification of 3 imaging and/or fluid biomarkers for which there is proof of engagement of novel therapeutic targets. 5 years
2014-2018
Initiation and completion of 5 Phase II (proof of concept) drug trials using imaging and/or fluid biomarkers for proof of target engagement. 3-5 years
2017-2021
Initiation of 3 Phase III (pivotal) drug trials using imaging and/or fluid biomarkers to select at risk subjects and/or for proof of target engagement. 3-5 years
2019-2023
Development and testing of 5 biomarkers that utilize biofluids or other minimally invasive imaging, electrophysiological recording, or other methodologies to assess the burden of AD pathophysiology that could be used in community based and epidemiological studies of AD. 5 years
2015-2019
Identification of 3 peripheral blood-based biomarkers that have a high correlation with central imaging and/or CSF biomarkers. 5 years
2016-2020
Development of at least one sensitive neuropsychological assessment measure that has been validated for the detection or tracking of the earliest clinical manifestations of AD. 5 years
2014-2018
CLIA laboratory qualification in US & the equivalent certification in the EU for at least one CSF biomarker of disease pathology. For neuroimaging data, qualification of at least one biomarker for use in clinical trials by the FDA and/or the EMA. 5 years
2014-2018

 

Epidemiology
Milestone Milestone Time Required
Clinical trialists and epidemiologists implement best practices and work together in the design of clinical trials for AD. 1 year
2014
Three or more active cohorts that cover age range from midlife to late-life as a study population for investigating and reporting findings on changing risk profiles from younger to older ages. 5-7 years
2014-2020

 

Research Resources
Milestone Milestone Time Required
Recruitment of all federal and non-federal funding agencies in the US as well as AD funding agencies from countries that have an AD National Plan to participate in this database. 2-3 years
2013-2015

 

Partnerships to Accelerate AD Drug Development
Milestone Milestone Time Required
Established working groups on: (i) Rapid Data Sharing and Analysis, (ii) Enabling Bidirectional Translation in AD drug development, (iii) Eliminating IP barriers for Target Validation through clinical proof of concept. 1 year
2013
Recommendations developed on (i) the creation of an open access, web based resource that integrates complete, diverse multidimensional biological and chemical data that will be useful in advancing information on drug targets, including mechanistic information that will aid in the development of measures of target engagement (PD readouts); (ii) creation of computational tools for development of biological network models of AD and normal aging; (iii) creation of tools that will foster development of bio network models that provide a predictive framework for using drugs in combination or singly (iv) removing legal and IP barriers surrounding data sharing.

One or more partnerships established to accelerate key steps in AD drug development.

1 year
2014

 

Infrastructure
Milestone Milestone Time Required
Creation of at least 3 Translational Centers that will apply the principles of quantitative and systems pharmacology to AD drug development. 3-5 years
2014-2018
New NIH policy in place for fast tracking of AD translational research application. 1 year
2015
Initiation of at least one multi-center clinical trial that utilizes a national IRB. 2 years
2014-2015
Identification of at least two standard outcome measures for data comparison in clinical research. 1 year
2014
Data comparisons conducted from clinical studies using common standard outcome measures. 3-5 years
2014-2018

 

Study Recruitment and Participation
Milestone Milestone Time Required
Central resources for both references and tools, including videos and presentation materials created and available. 2 years
2014-2015
Recommendations for successful recruitment methods. 1 year
2014
A central repository of AD related registries and cohorts created and publicized. 2 years
2014-2015
Increased rates of enrollment and inclusion of underrepresented populations for AD clinical trials as evaluated using the existing NIH system for NIH funded clinical research. 5 years
2014-2018

 


Alzheimer's Disease Research Summit Recommendations -- May 2012

Session 1: Interdisciplinary Approach to Discovering and Validating the Next Generation of Therapeutic Targets for Alzheimer's Disease

  1. Intensify scientific efforts to deepen the understanding of the complex pathobiology of Alzheimer's disease, and diversify target identification to better address the multifactorial nature of the disease. These efforts should include the use of systems biology approaches and tools, as well as cutting-edge stem cell technology.

  2. Develop a better systems-level understanding of how the many discoveries that have already been made (e.g., genetic, pathological, biochemical, radiological, neuropsychological) and the contributory factors that have already been identified (e.g., Aß, tau, apoE4, a-synuclein, TDP-43, aging, proteostasis failure, mediators of inflammation, comorbidities) are related mechanistically.

  3. Facilitate the conversion of existing genetic information into mechanistic insights and therapeutic advances and continue to generate new genetic data using exome and genomic sequencing approaches to identify rare genetic variants of large functional effect.

  4. Generate new experimental models (e.g., different animal species, human induced pluripotent stem [iPS] cells, in silico models) that better simulate the multifactorial etiology of Alzheimer's disease and use these models to identify modulators of disease pathways and to assess combination treatments which may be required to defeat this disease. Ensure that these new tools and models are freely shared.

  5. Develop in vivo imaging agents (tracers for PET scans) to assess target engagement and the burden of brain pathology to enable successful drug development for existing and new therapeutic targets.

  6. Develop robust biomarkers that can feasibly be obtained in large cohorts of volunteers, including metabolic signatures to develop and validate diagnostic, prognostic, and surrogate biomarkers for Alzheimer's disease and biomarkers for disease subtypes.

  7. Establish links among peripheral biochemical changes (e.g. blood-based markers) and imaging and cerebrospinal fluid changes to identify and validate peripheral biomarkers of disease.

  8. Enable rapid sharing of new data via web-based resources with the capacity to store large and diverse datasets (such as data about clinical phenotypes, genetics, epigenetics, proteomics, and metabolomics) that can be used for testing different models or hypotheses at the computational level.

  9. Enable analysis of new data before publication, using approaches such as collaborative challenges open to all citizens and scientists.

  10. Maximize the use of existing infrastructure and resources (e.g., research centers, biobanks, and repositories) by publicizing their availability to researchers.

  11. Facilitate the creation of new translational teams to expedite the discovery and validation of new therapeutic targets. These teams should include epidemiologists, basic research scientists, geneticists, computational biologists, medicinal chemists, pharmacologists, toxicologists, pharmacogenomics experts, clinicians, and project managers, collaborating within and across institutions.

Session 2: Challenges in Preclinical Therapy Development

  1. Develop infrastructure and resources to increase the likelihood that preclinical therapeutic development efforts for Alzheimer's disease will translate to success in the clinic by:

    • Creating expert advisory committees for all aspects of preclinical and early clinical drug development to assist academic drug discovery efforts
    • Establishing a network of Alzheimer's disease preclinical therapy centers integrated with existing and proposed translational infrastructure and resources (e.g., Alzheimer's Disease Neuroimaging Initiative, Alzheimer's Disease Centers)
    • Establishing an open-access resource for reviewing and publishing negative and discrepant data.

       

  2. Develop broad capabilities in quantitative and systems pharmacology to understand the impact of drugs on organisms, to predict dosing, to reduce toxicity, and to facilitate drug repurposing and the identification of combination therapies. This will require a wide collaboration among NIH Institutes, government, academia, industry, voluntary health organizations, and foundations including the establishment of new training programs.

  3. Increase the predictive power of preclinical testing in animal models by:

    • Establishing a standardized and rigorous process for the development and characterization of animal models, and ensuring their maximal and rapid availability to all researchers for preclinical drug development
    • Aligning the pathophysiological features of Alzheimer's disease animal models with the corresponding stages of clinical disease using translatable biomarkers
    • Establishing guidelines for rigorous preclinical testing in animal models and reporting of both positive and negative findings.

       

  4. Provide an expedited review track for applications focused on drug discovery, preclinical, and clinical drug development for Alzheimer's disease to mitigate difficulties with intellectual property and commercialization issues that are imposed by the current lengthy review/grant cycle at the NIH. Establish multi-disciplinary review panels with adequate expertise to evaluate all aspects of translational research.

Session 3: Whom to Treat, When to Treat, and What Outcomes to Measure

  1. Initiate treatment trials in asymptomatic, at-risk individuals (e.g., individuals at risk genetically, older adults positive for biomarkers for Alzheimer's disease) using uniform biomarkers and cognitive outcomes, informed by data from Alzheimer's disease trials using patients with more advanced disease.

  2. Collect DNA and other biosamples from these studies to enable subsequent interrogation based on treatment response and predictors of decline in the groups receiving placebo.

  3. Expand large-scale registries and natural history cohorts of healthy individuals from early midlife to late-life, as well as individuals with subjective and/or objective cognitive impairment and use the data generated to inform clinical trial design. These cohorts should be population-based and should oversample underrepresented ethnic minorities and groups with lower education.

  4. Develop, validate, and standardize sensitive neuropsychological and other clinical and behavioral measures to detect and track the earliest clinical manifestations of Alzheimer's disease and to predict long-term clinical and functional outcomes. These measures should be sensitive to change and capture the variability in cognitive function that may be an important predictor of treatment response.

  5. Optimize biomarkers for detecting and monitoring the progression of Alzheimer's disease, and focus particularly on standardization. These biomarkers will be used to elucidate the temporal trajectories over the course of preclinical and prodromal Alzheimer's disease, to assess the proximity to onset of clinical symptoms, and to predict long-term clinical response to treatment.

  6. Develop treatments for patients with symptomatic Alzheimer's disease and support proof of concept studies to validate novel targets for cognitive and neuropsychiatric symptoms across all disease stages.

  7. Develop approaches to stratify and individualize treatments based on the heterogeneity of symptomatic patient populations.

  8. Support broad infrastructure changes that will accelerate and improve the efficiency of prevention initiatives, including the formation of a national centralized Institutional Review Board for multi-center Alzheimer's disease trials and the development of agreements for data sharing of de-identified data from both placebo and treatment arms via public databases.

Session 4: Drug Repurposing and Combination Therapy

  1. Expand publicly available libraries of drugs, drug signatures, and Alzheimer's disease tissues and publicize their availability to the Alzheimer research community. Consider including cell-type and region-specific expression differences in the brain and periphery at varying stages of Alzheimer's disease, as different stages may require different drugs. Expression libraries from cognitively normal adults positive for amyloid imaging and CSF Alzheimer's biomarkers and from centenarians without dementia could be used to identify Alzheimer's disease-resistant expression signatures that correlate with specific drug signatures for prevention studies.

  2. Maintain rigor in the development of repurposed drugs with respect to scientific rationale, as well as design of clinical trials. Provide adequate prior clinical trial evidence for safety in populations with or at risk for Alzheimer's disease.

  3. The optimal therapy for Alzheimer's disease may involve the use of drug combination cocktails and require different composition of these cocktails at different stages of the illness. To facilitate the development of effective combination therapies, develop translational workgroups that include experts in network biology and network pharmacology.

  4. Encourage the evaluation of drugs that simultaneously target multiple disease pathways (e.g., insulin, selective estrogen receptor modulators).

  5. Develop translational groups across institutions that focus on specific therapy development efforts (e.g., apoE therapeutics, combinatorial therapeutic strategies, drug repurposing, neuropsychiatric symptoms).

Session 5: Nonpharmacological Interventions

  1. Integrate epidemiological studies with mechanistic research to explore underlying pathways by which risk and protective factors contribute to the disease process.

  2. Continue to identify the molecular mechanisms by which non-pharmacological interventions operate and employ systems biology approaches to examine brain health in relation to, and in concert with, other organ systems.

  3. Initiate rigorously designed clinical trials in asymptomatic and cognitively impaired older adults to establish the effectiveness of physical exercise, cognitive training, and the combination of these interventions for Alzheimer's disease treatment and prevention.

  4. Combine nonpharmacological (e.g., behavioral, lifestyle, environmental) interventions with pharmacological treatments to maximize possible therapeutic benefit. Use epidemiologic information, mechanistic research in animal models, and network analysis to inform trial design and drug selection.

  5. Develop standard outcome measures to enable data comparisons across studies. These include but are not limited to ecologically valid measures of real world function, quality of life, and physical and cognitive function.

  6. Pursue the science of behavioral change for successful implementation of effective nonpharmacological interventions.

  7. Invest in research to develop technologies that promote prevention and treatment trials, clinical care, caregiver support, and in-home monitoring.

Session 6: New Models of Public Private Partnerships

  1. Promote and enable partnerships across all sectors involved in basic, translational, and clinical research to successfully implement an integrated translational research agenda.

  2. Increase awareness of the importance and value of public private partnerships among federal agencies, other stakeholder organizations, and the public and engage the full spectrum of the Alzheimer's disease community in various partnership activities for the advancement of AD therapy development.

  3. Enable partnerships for:

    • Data sharing (with standardized ontologies and metadata)
    • Creating, validating and sharing tools for translational research (e.g., instruments and biomarkers, animal models, high-throughput screening assays, iPS cells).
    • Expanding the precompetitive space using new models of public private partnerships such as the Arch2POCM partnership for target validation and also for product development partnerships.

       

  4. Develop a National Institutional Review Board for Alzheimer's disease studies accessible to both public and private funding research organizations.


Return to

National Alzheimer's Project Act Home Page

National Plan to Address Alzheimer's Disease and Other NAPA Documents Page