Advisory Council April 2019 Meeting Presentation: Research Update

Monday, April 29, 2019

Printer Friendly Version in PDF Format (9 PDF pages)

Alzheimer's Disease and Related Dementias Research Update

Richard J. Hodes, M.D.
Director, NIA

Alzheimer's Disease Immunotherapy Phase III Trials

* NIA sponsored (public-private partnerships

Ongoing NIA AD/ADRD and Related Intervention and Prevention Trials (~140)

29 Early-stage Clinical Drug Development (Phase I and Phase II Clinical Trials)	6 Late-stage Clinical Drug Development (Phase II/III and Phase III Clinical Trials)	53 Non-Pharmacological Interventions	7 Clinical Therapy Development for the Neuro-psychiatric Symptoms of AD/ADRD	39 Care and Caregiver Interventions	3 Delirium/ Post-Operative Cognitive Decline Trials
Amyloid (8) Receptors (4) Metabolism and Bioenergetics (4) Vasculature (3) Growth Factors and Hormones (1) Multi-target (6) Oxidative Stress (2) Other (1)	Amyloid (5) Vasculature (1)	Exercise (13) Diet (5) Cognitive Training (14) Combination Therapy (7) Other (14)	Pharmacological (5) Non-Pharmacological (2)

NIA-AD clinical trials pipeline toward 2025

Diagram showing the multitude of clinical trials in the pipeline

NIA Pipeline of Discovery

Diagram showing the NIA clinical trials, by type of trial, in the pipeline

Repeated Diagram from previous slide showing the NIA clinical trials, by type of trial, in the pipeline. This diagram differentiates between Amyloid targets versus non-amyloid targets.

Genetic Regions of Interest in Alzheimer's Disease

By Year of Discovery

NOTE: Color indicates mechanism of action in the body. See key.

Accelerating Medicines Partnership (AMP) -- Alzheimer's Disease

COMPLETED:

Centralized data resource established -- AMP-AD Knowledge Portal
Rich genomic, proteomic, metabolomic human data (raw and processed) made available and being widely used -- over 2000 users to date.
Network models of disease pathways/targets developed
Over 100 novel candidate targets identified and being prioritized in collaboration with industry partners; experimental validation ongoing on over 20 candidate targets/pathways.
Animal models phenotype/evaluated relative to human networks
Web-based interface for sharing target nominations and analytical outputs developed - AGORA platform; 100 annotated target predictions and additional 480 key driver genes made publicly available.

AD Centers for Discovery of New Medicines - RFA AG 19-010

https://grants.nih.gov/grants/guide/rfa-files/RFA-AG-19-010.html
-Applications submitted Feb 2, 2019-
-NIA plans to commit ~$75M over 5 years to support 2 Centers-
Accelerate robust preclinical validation of candidate targets delivered by AMP-AD and other target discovery programs, through the development of open source tools, reagents and methods and by integrating a series of novel targets into drug discovery campaigns.

Center Structure

AHRQ-National Academies Study

Assessment of interventions to prevent AD-type dementia, amnestic MCI, and age-related cognitive decline
Insufficient evidence to justify a public health campaign
Encouraging but inconclusive evidence:
- Cognitive training
- Blood pressure management in hypertensives
- Increased physical activity

Screen shot of report cover for Preventing Cognitive Decline and Dementia: A Way Forward.

http://www.nationalacademies.org/dementia

SPRINT Study

The SPRINT Research Group (2015) NEJM 373(22):2103-16.

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

Does intensive blood pressure control compared with standard control reduce the occurrence of dementia?
- Randomized Controlled Trial Target Systolic Blood Pressure
  - Intensive Treatment Goal SBP < 120 mmHg (n= 4,278)
  - Standard Treatment Goal SBP < 140 mmHg (n= 4,285)

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

SPRINT-MIND: Secondary Cognitive Outcomes

19% reduction in the rate of developing MCI
15% reduction in the rate of composite MCI and probable dementia