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Advisory Council February 2017 Meeting Presentation: Transforming Alzheimer's Disease Therapy Development

Friday, February 3, 2017

Printer Friendly Version in PDF Format (10 PDF pages)


Alzheimer's and Related Dementias Research: Transforming AD Therapy Development

Richard J. Hodes, M.D.
National Institute on Aging

Current AD Clinical Trials "Score Card"

Phase III Randomized, Double-blind, Placebo Controlled, Clinical Trials for AD - Failures due to lack of efficacy or unforeseen toxicity.

Agent Target/Mechanism Outcome
Atorvastatin HMG CoA reductase Negative
Dimebon Mitochondrial function Negative
Semagacestat Gamma secretase Negative
NSAIDs Inflammation Negative
Phenserine Cholinesterase/Amyloid Negative
Rosiglitazone PPAR gamma agonist Negative
Simvastatin HMG CoA reductase Negative
Tarenflurbil Gamma secretase Negative
Xaliproden Serotonin antagonist Negative
Bapineuzumab amyloid beta (passive immunization) Negative
Solanezumab amyloid beta (passive immunization) Negative*
IVIG amyloid beta (passive immunization) Negative

What may have gone wrong? An iceburg analogy

  • Above the surface
    • We are targeting the wrong pathophysiological mechanisms
    • Drugs do not engage with the intended target
    • Interventions are started at the wrong stage of the disease
    • Lack of translatable pharmacodynamic biomarkers
    • Poor predictive power of animal model preclinical efficacy testing
  • Below the surface
    • Insufficient understanding of disease complexity and the physiologic response to therapeutic intervention

Leveraging Trans-NIH Translational Programs

Program Journey charts.
*SBIR/STTR funding opportunities exist for the full spectrum of drug discovery/development

The Alzheimer's Pill

Magazine cover.
  • LM11A-31 - first in class, small molecule modulator of the P75 Neurotrophin Receptor
    • P1 -- Frank Longo MD and NeurotrophiX
  • The pre-clinical drug development and part of the IND-enablng studies for LM11A-31 were supported through NIA's
    • AD Translational Program
    • IND Toxicology Program
  • The Phase II trial is being supported through NIA's Pilot Clinical Trials Program

Accelerating Medicines Partnership

  • Managing Partner
    • Foundation for the National Institutes of Health
  • Alzheimer's Disease Program Partners
    • National Institute on Aging
    • National Institute of Neurological Disorders and Stroke
    • Food and Drug Administration
    • AbbVie Inc.
    • Biogen Inc.
    • GlaxoSmithKline
    • Eli Lilly and Company
    • Alzheimer's Association
    • Alzheimer's Drug Discovery Foundation
    • Geoffrey Beene
    • USAgainst Alzheimer's

Accelerating Medicines Partnership (AMP)

Alzheimer's Disease -- Two Projects

  • Target Discovery and Preclinical Validation to Find New Disease-Relevant Drug Targets
    • Generate "omic" data on ~2,500 brains
    • Integrate
      • Molecular profiling
      • Predictive Modeling
      • Experimental validation
    • Central Portal for Data Sharing
    • 6 Academic Teams -- NIA grants
  • Biomarkers to Characterize Existing and New Biomarkers
    • PET TAU and novel biomarkers
    • Added to three anti-amyloid prevention trials
      • A4
      • DIAN
      • API-ApoE4
    • GAAIN

Sage Bionetworks -- Synapse

Diagram showing the data flow of the AMP-AD Knowledge Portal.
* AMP-AD Knowledge Portal --
  • Data released as soon as QC is completed
  • Open and Controlled Access
  • No publication embargo imposed on the use of data after they have been made available through the public portal

Building on and expanding the AMP-AD Target Discovery Project

Molecular Mechanisms of the Vascular Etiology of Alzheimer's Disease

A collaboration between NIA and NINDS

  • ~$30 million over 5 years to support cross disciplinary research teams:
  • 5 research teams will generate various "omics" data from brain and peripheral fluids from individuals participating in several natural history and population studies and use network biology approaches to integrate these data with data on neuroimaging, vascular physiology and cognitive measures.
  • Predictions about molecular mechanisms will be explored in animal models (AD models and models of vascular/metabolic risk factors).
  • Goals and deliverables:
    • rapid and broad sharing of data
    • deeper understanding of the phenotypes of risk and the mechanisms linking vascular risk factors, cerebrovascular disease and AD
    • new disease-relevant therapeutic targets for prevention
    • molecular signatures that can be non-invasively measured and used for patient stratification

Alzheimer's Disease Preclinical Efficacy Database

AlzPED Home Page screen shot.

Alzheimer's Disease Translational Center for Animal Model Resources and Preclinical Efficacy Testing Multi Component Center

Program Scope and Goals:

  • Development and characterization of the new generation of AD Tg animal models, ensuring their maximal and rapid availability to researchers engaged in preclinical drug development
  • Extensive characterization and clinico-pathological staging of existing and new AD Tg mouse models with the corresponding stages of clinical disease
  • Development of translatable pharmacodynamic biomarkers for novel therapeutic targets
  • Establishment and implementation of guidelines for standardized best practices for the rigorous preclinical testing of AD candidate therapeutics in AD Tg models
  • Preclinical efficacy testing of selected candidate AD therapeutics (single or combinations of compounds) using standardized best practices
  • AD models distribution - rapid and free of legal barriers for use in therapy development.

RFA AG16-014 (U54): Indiana University/Jax Labs/Sage Bionetworks []


Diagram showing the years three programs span.
  • rich human and cell/animal models 'omics' data
  • network models of targets and disease pathways
  • "omics"- based biomarkers for target engagement and patient stratification biomarkes
  • cell and animal models characterized relative to human network


-new biomarker initiatives and clinical trials infrastructure-

Alzheimer's Biomarker Consortium -- Down Syndrome (ABC-DS)

  • Supported by NIA and NICHD
  • ~$37 million over 5 years, for two research teams
  • Biomarkers will be explored to track AD-related changes in the brain and cognition for ~500 adults with Down syndrome
  • Measures include PED, MRI, CSF and blood markers, DNA for GWAS, cognitive/memory tests
  • Research teams are collaborating and harmonizing measures and procedures
  • Data and samples will be made available

Alzheimer's Clinical Trials Consortium (ACTC)

Purpose: Establish a consortium to run trials focused on interventions that may prevent, delay, or treat the symptoms of AD and other age-related dementias.

  • Include multiple clinical trials sites and trial coordination and management infrastructure.
  • Conduct clinical trials (Phase I to III) of promising pharmacological and non-pharmacological interventions for cognitive and neuropsychiatric symptoms.
  • Provide a state-of-the-art clinical trial infrastructure to facilitate rapid development and implementation of protocols.

Related Recent Funding Initiatives

Newest Alzheimer's FOAs

  • Resource Leveraging
  • Caregiving
  • Clinical Care and Trials
  • Translational research
  • Basic research
  • Training

Alzheimer's Disease FOAs:

NINDS Funding Opportunity Announcements on Alzheimer's Disease-Related Dementias (ADRD) for FY 2017

Two new Funding Opportunity Announcements in partnership with NIA:

  • Leveraging Existing Resources for Research on Lewy Body Dementia (R03) RFA-NS-17-016 []
    • This FOA encourages researchers to take advantage of existing data and biospecimens housed in two large NIH-supported programs (i.e., ADNI/NACC and Parkinson's Disease Biomarkers Program databases) for the purpose of answering research questions about LBD and co-occurrence of dementia and parkinsonism.
  • Frontotemporal Degeneration (FTD) Sequencing Consortium: Discovery, Replication, and Validation (UG3/UH3) RFA-NS-17-017 []
    • This FOA supports the genetic discovery, replication and validation of disease-causing mutations, risk variants and genetic modifiers that contribute to FTD.
  • Applications are due Feb 10

Save the Dates!

AD Care and Services Research Summit
October 16-17, 2017
Bethesda, MD

Alzheimer's Disease Research Summit (III)
March 1-2, 2018
Bethesda, MD

February 3, 2017 -- Advisory Council Meeting #23

The meeting was held on Friday, February 3, 2017, in Washington, DC. The theme of this Advisory Council meeting was clinical trials for Alzheimer's disease and related dementias and recruitment challenges. Additional afternoon presentations included updates on progress towards a Care and Services Summit, federal workgroup updates, and preparation for the Advisory Council's 2017 Recommendations, due in April 2017. Material available from this meeting is listed below and is also available at

Comments and questions, or alerts to broken links, should be sent to


General Information




Presentation Slides



  • Welcome thru Perspectives -- [Video]

  • Rachel, Jessica, George Presentations -- [Video]

  • Keith Presentation and Panel Discussion -- [Video]

  • Public Comments -- [Video]

  • Care Summit and Milestones -- [Video]

  • Federal Workgroups and Adjourn -- [Video]