Advisory Council July 2019 Meeting Presentation: ADRD Therapeutic Approaches

07/29/2019

ADVISORY COUNCIL ON ALZHEIMER'S RESEARCH, CARE, AND SERVICES

Monday, July 29, 2019

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Approaches to Alzheimer's and Related Dementias Therapeutics

Richard Hodes, Brad Hyman, and Allan Levey
presenting for the Research subcommittee

1906

Photo image of Alois Alzheimer. Illustration of Alzheimer's tangles. Illustration of Alzheimer's plaques.
Alois Alzheimer time.com Alzheimer's drawings of tangles in 1906 Alzheimer's drawings of plaques in 1906

Biochemistry

Tangles Plaques
  • Neurofibrillary tangles made primarily of tau protein
  • Gene that makes tau (MAPT)
  • Tau found in other neurodegenerative diseases like frontotemporal dementia and PSP
  • MAPT mutations can lead to autosomal dominant frontotemporal dementia and PSP
  • Senile plaques made of amyloid
  • Gene that makes amyloid precursor protein (APP) cloned
  • Mutations in APP found to cause early onset autosomal dominant AD
  • Down syndrome and other causes of genetic amplification of APP associated with early onset AD

Therapeutics follow biochemical and genetic observations

Tangles Plaques
  • Early in phase III trials to study tau
  • Multiple shots on goal for amyloid
  • Recent highlights: inhibit the enzymes that make amyloid (e.g., BACE inhibitors)
  • Clear the plaques away from the brain (e.g., immunotherapy)
  • So far, no success in preventing further decline

Alzheimer's Disease Immunotherapy Phase III Trials

Illustration of trials.
* NIA sponsored (public-private partnerships)

Immunotherapy Clinical Trial for Individuals with Down Syndrome

Active Immunotherapy for Cognitive Decline in Adults with Down Syndrome

  • Rationale: Trisomy 21 leads to increased levels of APP
  • Goal: This study will investigate the safety, tolerability, as well as immunogenicity of an anti-amyloid vaccine in a Phase I clinical trial -- in adults with DS aged 35-55.
  • Outcomes: Effects on cognitive function and AD biomarkers will be secondary endpoints (Completion: 2021)

The Progression of Alzheimer's Disease and Related Dementias

Illustration of Alzheimer's progression.

Closer to a Blood Test for Alzheimer's Disease Amyloid-beta biomarkers & NfL

  • Nakamura, Akinori, Naoki Kaneko, Victor L. Villemagne, Takashi Kato, James Doecke, Vincent Dore, Chris Fowler, Qiao-Xin Li, Ralph Martins, Christopher Rowe, Taisuke Tomita, Katsumi Matsuzaki, Kenji Ishii, Kazunari Ishii, Yutaka Arahata, Shinichi Iwamoto, Kengo Ito, Koichi Tanaka, Colin L. Masters, & Katsuhiko Yanagisawa. High performance plasma amyloid-β biomarkers for Alzheimer's disease. Nature, volume 554, pages 249-254 (08 February 2018). https://www.nature.com/articles/nature25456

  • Ovod, Vitaliy, Kara N. Ramsey, Kwasi G. Mawuenyega, Jim G. Bollinger, Terry Hicks, Theresa Schneider, Melissa Sullivan, Katrina Paumier, David M. Holtzman, John C. Morris, Tammie Benzinger, Anne M. Fagan, Bruce W. Patterson, & Randall J. Bateman. Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimer's & Dementia, Volume 13, Issue 8, August 2017, Pages 841-849. https://www.sciencedirect.com/science/article/pii/S1552526017325189

  • Preische, Oliver, Stephanie A. Schultz, Anja Apel, Jens Kuhle, Stephan A. Kaeser, Christian Barro, Susanne Graber, Elke Kuder-Buletta, Christian LaFougere, Christoph Laske, Jonathan Voglein, Johannes Levin, Colin L. Masters, Ralph Martins, Peter R. Schofield, Martin N. Rossor, Neill R. Graff-Radford, Stephen Salloway, Bernardino Ghetti, John M. Ringman, James M. Noble, Jasmeer Chhatwal, Alison M. Goate, Tammie L. S. Benzinger, John C. Morris, Randall J. Bateman, Guoqiao Wang, Anne M. Fagan, Eric M. McDade, Brian A. Gordon, Mathias Jucker, & Dominantly Inherited Alzheimer Network. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease. Nature Medicine, volume 25, pages 277-283 (2019). https://www.nature.com/articles/s41591-018-0304-3

  • Palmqvist, Sebastian, Shorena Janelidze, Erik Stomrud, Henrik Zetterberg, Johann Karl, Katharina Zink, Tobias Bittner, Niklas Mattsson, Udo Eichenlaub, Kaj Blennow, & Oskar Hansson. Performance of Fully Automated Plasma Assays as Screening Tests for Alzheimer Disease-Related β-Amyloid Status. JAMA Neurol. Published online June 24, 2019. doi:10.1001/jamaneurol.2019.1632. https://jamanetwork.com/journals/jamaneurology/fullarticle/2736342

NAPA playbook

  • Discover new genes that contribute to AD and dementia
  • Develop new information about the brain changes that occur before and during the disease process
  • Tackle the disease at early stages and late stages, perhaps using different strategies at different stages
  • Develop new targets and new approaches
  • Find better ways of understanding person to person differences

Genetic Regions of Interest in Alzheimer's Disease

By year of discovery
Genetic areas of Alzheimer's Disease studied by year.
NOTE: Color indicates mechanism of action in the body. See key.

Accelerating Medicines Partnership (AMP)

ALZHEIMER'S DISEASE -- Target Discovery and Preclinical Validation Project
Illustration of the Target Discovery and Preclinical Validation Project.
NIA Program Director: Suzana Petanceska
Academic Teams:
  • P. De Jager, D. Bennett
  • E. Schadt, B. Zhang, S. Gandy, J. Zhu, M. Ehrlich
  • T. Golde, N.Price, N. Ertekin-Taner, S. Younkin
  • A. Levey, T. Montine, J. Troncoso, D. Geschwind
  • R. Kaddurah-Daouk
  • B. Yakner, L. Huei Tsai

Progress over 4 years:

  • Centralized data resource established- AMP-AD portal
  • All data sharing deliverables met
  • A variety of experimental validation models developed
  • Novel biomarker discovery initiated
  • Over 100 candidate targets nominated; currently undergoing data-driven prioritization for further preclinical validation
Agora Candidate Targets.
https://agora.ampadportal.org/

Geroscience: Interventions and Approaches

Illustration of Interventions: Senolytics, Stem-cell Therapies, Parabiosis, Elimination of Damaged Cell, Telomerase Reactivation, Epigenetic Drugs, Regulation of Molecular				 Chaperones, Dietary Restriction, Antioxidants.
Adapted from: Lopez-Otin, C et al. (2013). Cell 153: 1194-1217.

What is cell senescence?

Illustration of cell senescence. Arrows pointing toward cell: Telomere erosion, DNA damage, Oxidative stress, Tumor suppressor loss. Arrows pointing away from cell: Anatomic lesions, 				 Disrupted tissue homeostasis, Loss of regeneration capacity, Altered secretome.
Senescent cells secrete a large number of biologically active factors which affect the function of neighboring, non-senescent cells
Ruan, L. et al. (2018). J Cell Sci 131.

Treatment with Senolytics Extends Lifespan in Older WT Mice

Illustration of Senolytics Lifespan Trial in Mice.
Xu, M. et al. (2018). Nature medicine, 24(8):1246-1256.

Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline

Illustration of glial cells, as well as trial data.
  • Senescent cells drive neurodegenerative disease
  • Clearance of senescent cells through genetic manipulation or drug treatment decreases tau pathology and cognitive decline
Bussian, T. et al. (2018). Nature, 562(7728): 578-582.

Traditional Clinical Paradigm

Graphic of the Phases over the years.
Novel target (12 month endpoint): 18++ years
Courtesy of C Grossbreutz

NIA Pipeline of Discovery

Graphic of what is in the pipeline for Drug Discovery, Drug Development, Phase I/II Trials, and Phase III Trials.

Alzheimer's Disease Drug Development Pipeline -- 2019

Graphic of the 2019 Alzheimer's Drug Development Pipeline for Disease-Modifying Biologic, Disease-Modifying Small Molecule, and System-Reducing Small Molecule.
Cummings J., et al. Alzheimer's & Dementia: Translational Research & Clinical Interventions, Volume 5, 2019:272-293

Alzheimer's Disease Drug Development Pipeline -- 2019

Pie chart: Neuropsychiatric Symptoms (28%), Disease-Modifying Therapies (61%), Anti-Tau (4%), Anti-Amyloid & Anti-Tau (4%), Other MOAs (21%), Symptomatic Cognitive Enhancers (11%).
Cummings J., et al. Alzheimer's & Dementia: Translational Research & Clinical Interventions, Volume 5, 2019:272-293

Ongoing NIA AD/ADRD and Related Intervention and Prevention Trials (~200)

35 Early-stage Clinical Drug Development
(Phase I and Phase II Clinical Trials)
8 Late-stage Clinical Drug Development
(Phase II/III and Phase III Clinical Trials)
86 Non-Pharmacological Interventions 8 Clinical Therapy Development for the Neuro-psychiatric Symptoms of AD/ADRD 61 Care and Caregiver Interventions 5 Delirium/Post-Operative Cognitive Decline Trials
  • Amyloid (10)
  • Receptors (4)
  • Neuroprotection (4)
  • Metabolism and Bioenergetics (2)
  • Vasculature (2)
  • Growth Factors and Hormones (2)
  • Multi-target (2)
  • Inflammation (2)
  • Oxidative Stress (2)
  • Other (5)
  • Amyloid (6)
  • Vasculature (2)
  • Exercise (19)
  • Diet (6)
  • Cognitive Training (21)
  • Assistive Tech. (8)
  • Sleep (5)
  • Combination Therapy (10)
  • Other (17)
  • Pharmacological (5)
  • Non-Pharmacological (3)
  • Improving Care for PWD (25)
  • Improving care provided by family or informal caregiver (36)
  • Anesthesia (1)
  • Sleep (1)
  • Device (1)
  • Combination (1)
  • Cognitive training (1)

Physical Activity Clinical Trial for AD

  • Exercise in Adults With Mild Memory Problems (EXERT)
    • Goal: Test effects of physical exercise on cognition, functional status, brain atrophy and blood flow, and cerebrospinal fluid biomarkers of Alzheimer's disease, in adults ages 65 to 89 year with MCI (Completion: 2022)

Diet-Based Clinical Trial for AD

  • MIND Diet Intervention to Prevent Alzheimer Disease
    • Goal: Test the effects of a 3-year intervention of the MIND diet (Mediterranean-DASH Intervention for Neurodegenerative Delay) on cognitive decline and brain neurodegeneration among individuals 65+ years without cognitive impairment, who are overweight and have suboptimal diets (Completion: 2022)

Cognitive Training Clinical Trial for AD

  • Processing Speed Training to Preserve Driving and Functional Competencies in MCI
    • Goal: Test the capacity of an enriched version of processing speed training (PST) to preserve functional abilities in a clinical MCI population with quantified genetic and neuroimaging AD and comorbid cardiovascular disease biomarkers (Completion: 2020)

World Wide FINGERS & POINTER

  • The FINGER trial is the first large, long-term RCT indicating that a multi-domain intervention with exercise, diet, cognitive and social stimulation and management of vascular/metabolic risk factors may benefit cognition in subjects at risk of dementia.
  • U.S. POINTER:
    • The Alzheimer's Association has initiated a study designed to replicate the results of the Finnish trial in the U.S. (to test the generalizability of the FINGER findings in American older adults).
    • U.S. POINTER is a two-year clinical trial to evaluate whether lifestyle interventions that simultaneously target many risk factors protect cognitive function in older adults who are at increased risk for cognitive decline.

SPRINT-MIND Research Question
SPRINT Memory and Cognition in Decreased Hypertension

Illustration breaking down the question: Does intensive blood pressure control compared with standard control reduce the occurrence of dementia?
The SPRINT MIND Investigators for the SPRINT Research Group (2019). JAMA, 321(6):553-561.

SPRINT-MIND: Secondary Cognitive Outcome

  • The Intensive Treatment Group experienced a statistically significant reduction in the rate of developing MCI (19% reduction) as compared to the Standard Treatment Group
  • The Intensive Treatment Group experienced a statistically significant reduction in the rate of composite MCI and probable dementia (15% reduction) as compared to the Standard Treatment Group
  • Participants assigned to the intensive treatment had a non-statistically significant reduction in all-cause probable dementia.

The SPRINT MIND Investigators for the SPRINT Research Group (2019). JAMA, 321(6):553–561.

Important considerations in the next years

  • Continued improvements in neuroimaging for AD related molecular changes
  • Further understanding from genetics and other -omics research
  • New drug trials and personalized medicine approaches; using our understanding of the heterogeneity of disease to enrich trials with more homogeneous groups of participants
    • Those with genetic risk factors, e.g., individuals with Down syndrome
    • Those with related dementias
    • Biomarker advances will inform these efforts
  • Exploring diversity across all facets of disease research -- including recruitment challenges, genetic variability, other factors influencing risk, differential treatment effects, and more

Gene Therapy: a reality in treating devastating human diseases

Maguire, Albert M. Maguire, Francesca Simonelli, Eric A. Pierce, Edward N. Pugh, Federico Mingozzi, Jeannette Bennicelli, Sandro Banfi, Kathleen A. Marshall, Francesco Testa, Enrico M. Surace, Settimio Rossi, Arkady Lyubarsky, Valder R. Arruda, Barbara Konkle, Edwin Stone, Junwei Sun, Jonathan Jacobs, Lou Dell'Osso, Richard Hertle, Jian-xing Ma, T. Michael Redmond, Xiaosong Zhu, Bernd Hauck, Olga Zelenaia, Kenneth S. Shindler, Maureen G. Maguire, J. Fraser Wright, Nicholas J. Volpe, Jennifer Wellman McDonnell, Alberto Auricchio, Katherine A. High, & Jean Bennett. Safety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis. N Engl J Med. 2008 May 22; 358(21): 2240-2248. doi: 10.1056/NEJMoa0802315 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2829748/
Illustrations of Pupillary light responses for a control and patient 1.

Gene therapy success in infantile spinal muscular atrophy

Screen shot of the article AveXis Receives FDA Approval of Zolgensma, a Gene Therapy, for Spinal Muscular Atrophy for Patients Under Two Years of Age.
http://www.curesma.org/news/zolgensma-approved.html

New therapeutic approaches already leading to a sense of optimism despite recent disappointments

  • Already here:
    • Earlier diagnosis and interventions
  • On the way:
    • Gene therapy
    • Brain neuromodulation
    • Nonpharmacological interventions
    • New targets from genetic studies
    • New targets from AMP AD
    • New approaches to improve clinical trial design and hasten results
    • Numerous shots on goal...

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