Alzheimer’s Research Updates 2014 ACL/CDC/NIA Alzheimer’s Webinar Series September 25, 2014
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DISCLOSURE STATEMENTS In compliance with continuing education requirements, all presenters must disclose any financial or other associations with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters as well as any use of unlabeled product(s) or product(s) under investigational use. CDC, our planners, presenters,and their spouses/partnerswish to disclose they have no financial interests or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters. Planners have reviewed content to ensure there is no bias. Please note that presentations and contentwill not include any discussion of the unlabeled use of a product or a product under investigational use with the exception of Dr. Craft’s discussion on intranasal insulin. She will be discussing an ongoing clinical trial of intranasal insulin for the treatment of Alzheimer’s disease. Dr. Craft’s research study receives investigational devices and drugs at no cost and with no restrictions from Kurve Technology (device) and Eli Lilly (insulin and placebo).
DISCLOSURE STATEMENTS (Cont.) In addition, please note Dr. Brinton's relationship with Sage Therapeutics (biotech partnership) and her patents for PhytoSERMs and Allopregnanolone for Neurodegenerative Disease.
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Brinton Disclosure of Interest Statement • Sources of Research Support • National Institute on Aging • Paul Slavik Trust • Norris Foundation • Biotech Partnership • Sage Therapeutics • Patents • PhytoSERMs • Allopregnanolone for Neurodegenerative Disease
Alzheimer's Phenotypes of Risk: Therapeutic Opportunities for Prevention and Treatment Webinar on Alzheimer’s Research Updates 2014 Roberta Diaz Brinton, Ph.D. University of Southern California, Los Angeles, CA Schools of Pharmacy, Engineering and Medicine http://pharmweb.usc.edu/brinton-lab
From Discovery to Clinical Trial Discovery Science IND-Enabling Translational Research FDA Investigational New Drug (IND) Clinical Trial
Multiple LOAD Etiologies Multiple Prodromal Phenotypes Multiple Progression Trajectories Alzheimer’s Disease Alzheimer’s Multiple Phenotypes = Multiple Targets = Multiple Therapeutics Roberta Diaz Brinton, Ph.D. NIA AD Summit 2012 Pre-Cambrian AD Therapeutics n n
Lessons learned: Multiple LOAD Etiologies Multiple Prodromal Phenotypes Multiple Progression Trajectories Alzheimer’s Disease Alzheimer’s • Transitions of aging to AD pathology involve a set of sequential, system-level adaptions. • The aging brain is a dynamic adapting system with survival back-up mechanisms. • Female and male brains bioenergetically age differently • Perturbing one component of the system induces adaptations in other components- not a course correction – becomes a different functioning system. • Windows of opportunity. Therapeutics have a limited window of opportunity. One type therapeutic will not fit all for all time. Roberta Diaz Brinton, Ph.D., NIA AD Summit 2012 n n
Alzheimer’s Multiple LOAD Etiologies Multiple Prodromal Phenotypes Multiple Progression Trajectories Alzheimer’s Disease n Women are an at-risk phenotype for Alzheimer’s disease. WHY??? WHY? n 64% 36% Women Male Alzheimer’s Association Facts & Figures 2011
Phenotype of Endocrine Aging of Female Brain: Time line to Alzheimer’s Perimenopausal Transition Average Age of Menopause Average Age of AD Diagnosis Perimenopause Risk of Alzheimer’s Disease Prodromal AD Hot Flush Insomnia Cognitive Deficits Mood Disorder Depression Inflammation METABOLIC SHIFT Age 45 51 75
Estrogen: Bioenergetic System Regulator Estrogen Nilsen, Irwin et al.,, J Neuroscience 2007; Brinton TINS 2008; Brinton TIPS 2008; Yao et al., Molecular Aspects of Medicine, 2011
Fatty Acid Metabolism Reproductive Senescence is Associated with Shifts in Bioenergetic and β-Amyloid Processing Gene Expression Mitochondrial Function Glucose Metabolism Beta Amyloid Processing
11% of Persons are Over 65 are Projected to Develop Alzheimer’s Rettberg, Mack, Hodis, Brinton
ELITE “Healthy Women” At Risk Hodis, Mack NIA - AG0025, R01AG024154 • Cluster 1 (n = 209) • Healthy Metabolic Profile • Low HOMA score • Low glucose • High HDL, low LDL • Low triglycerides • Low blood pressure • Cluster 2 (n = 191) • High Blood Pressure • Low glucose and HOMA • Lower HDL, higher LDL • Higher triglycerides • Very high blood pressure • Cluster 3 (n = 102) • Poor Metabolic Profile • High HOMA score • High glucose • High triglycerides • High HbA1c Plot of Canonical Variables Identified by Cluster Canonical 1 Canonical 2 Rettberg, Mack, Hodis, Brinton,
BASELINE COGNITIVE PERFORMANCE ** * Adjusted for stage of menopause and randomization to treatment group *
Estrogen Receptor-β PhytoSERMs for Management of Menopause and Age-Associated Memory Decline NIA R01 AG 033288 Team: Schneider / Brinton Develop a standardized formulation of ER-β selective phytoSERMs for vasomotor symptoms and to prevent for age-related cognitive decline and dementia. http://clinicaltrials.gov/ct2/show/NCT01723917?term=phytoserms&rank=1 AIMS Develop the formulation of ERβ-selective PhytoSERMs. Perform first-to-human, dose-ranging, placebo-controlled, bridging studies (phase 1b) in postmenopausal women with vasomotor and memory complaints to assess tolerability, feasibility, PK, potential outcomes, and potential peripheral biomarkers (peripheral lipid peroxidation and mitochondrial function) to support a subsequent proof of concept trial. Conduct a proof of concept (Phase 2a), double-blind treatment with placebo or 1 of 2 doses of PhytoSERMs for 12 weeks. 72 participants. Dose-ranging trial using doses obtained to assess tolerability, safety, potential efficacy, and biomarkers.
Allopregnanolone as a Regenerative Therapeutic Decline in Regenerative Capacity Hypometabolism / Mitochondrial Dysfunction Inflammation Allo Therapeutic Intervention Beta Amyloid Plaque Stages of Pathology Development in Alzheimer’s Disease White Matter Degeneration Usual Therapeutic Intervention Neurofibrillary Tangles Severe Brain Atrophy Prodromal Diagnosis Death
Allopregnanolone as a Regenerative and Disease Modifying Therapeutic Brinton, Nature Reviews Endocrinology, 9:241-250, 2013 Wang, et al.,JNeurosci. 11; 25(19): 4706-18, 2005
Allopregnanolone Restores Learning and Memory in Transgenic Mouse Model of Alzheimer’s Brinton, Nature Reviews Endocrinology, 9:241-250, 2013
Allopregnanolone as a Regenerative TherapeuticStage of Development IND-Enabling / FDA Approved IND Achieved Discovery & Mechanism of Allo Action- Achieved Translational Feasibility / Formulation Development Achieved Phase 1 Multiple Ascending Dose / 3 month Allo treatment
Predicted Therapeutic Window forAllopregnanolone as Regenerative Therapeutic Brinton, Nature Reviews Endocrinology, 9:241-250, 2013
Allopregnanolone as a Regenerative TherapeuticPhase 1 Multiple Ascending Dose and Safety Trial Phase 1: Determine Maximally Tolerated (Sedative) Dose 4 Ascending Doses / Once week/ for 3 months USC ADRC Participants: 16 post-menopausal women 16 men MCI due to AD or early AD 55-80 yrs of age Primary Outcomes: Maximally Tolerated Dose MRI for ARIA Secondary Outcomes: Exploratory Chronic Safety and Feasibility at 4-Doses MRI Based Biomarkers Cognition NIA UF1-AG046148 http://clinicaltrials.gov/ct2/show/NCT02221622?term=Allopregnanolone&rank=2
Lessons learned (recap): Multiple LOAD Etiologies Multiple Prodromal Phenotypes Multiple Progression Trajectories Health Span Alzheimer’s Disease Alzheimer’s • Transitions of aging to AD bioenergetic phenotype involve a set of sequential, system-level adaptions. • The aging brain is a dynamic adapting system with survival back-up mechanisms. • Female and male brains bioenergetically age differently • Perturbing one component of the system induces adaptations in other components- not a course correction – becomes a different functioning system. Systems biology therapeutics. • Windows of opportunity. Therapeutics have a limited window of opportunity. One type therapeutic will not fit all for all time. Multiple Phenotypes = Multiple Targets = Multiple Therapeutics n n Roberta Diaz Brinton, Ph.D. NIA Webinar 2014
Discovery ,Translation and Clinical Trial Teams and Supporters Discovery to Clinical Trial Roberta Diaz Brinton, Ph.D. Junming Wang, Ph.D. Ronald Irwin, Ph.D. Shuhua Chen, Ph.D. Jia Yao, Ph.D. Christine Solinsky Karren Wong Claudia Lopez Regulatory Ronald Irwin, Ph.D. Frances Richmond, Ph.D. Benson Kuo, Ph.D. Toxicology Kathleen Rodgers, Ph.D. Ronald Irwin, Ph.D. Clinical Lon S. Schneider, M.D. Wendy Mack, Ph.D. Helena Chui, M.D. Karen Dagerman Steve Paul, M.D. William Potter, M.D. AllocGMP & PK UC Davis Michael Rogawski, M.D. Gerhard Bauer, Ph.D. Brain Imaging Meng Law, M.D. Michael Weiner, M.D. Synarc Arthur Toga, Ph.D. DSMB Claudia Kawas, M.D. David Elashoff, Ph.D. Charles DiCarli, M.D. iPS Cells Justin Ichida, Ph.D. Christine Solinsky CROs SRI WIL Research Supporters National Institute on Aging Norris Foundation Whittier Foundation ADDF
New Advances in Prevention and Treatment of Alzheimer’s Disease Suzanne Craft, PhD Professor of Internal Medicine Research Director, Sticht Center on Aging
Disclosures • Suzanne Craft’s research study receives investigational device and drug at no cost and with no restrictions from Kurve Technology (device) and Eli Lilly (insulin and placebo)
Overview • A new view of a major path to Alzheimer’s disease: The epidemic of insulin resistance • How does insulin resistance and related conditions such as diabetes and hypertension increase the risk of Alzheimer’s disease? • Can treating insulin resistance optimize healthy brain aging, prevent or treat Alzheimer’s disease and other types of dementia?
Role of insulin in a healthy brain: Increases energy and blood flow in specific brain regions Increases levels of chemicals and connections used by brain cells to communicate Increases brain activity Protects against toxic proteins (amyloid) Enhances memory at optimal levels Insulin Resistance:A Major Pathway in Alzheimer’s disease
Insulin resistance: Cells in body and brain no longer respond to normal amounts of insulin Common causes: Poor diet, physical inactivity, obesity, chronic stress or sleep disruption, genetic vulnerability Conditions associated with insulin resistance are increasing dramatically Type 2 diabetes, pre-diabetes, obesity 65% of adults in U.S. > 60 years have one or more of these conditions Alzheimer’s Disease Insulin resistance, diabetes, prediabetes and obesity increase risk of Alzheimer’s disease Insulin Resistance:What happens when insulin can not function?
Novel Approaches to Boost Brain Insulin Function: Intranasal Insulin • Insulin administered through the nose reaches the brain in 15 minutes without changing blood sugar or insulin • Insulin flows along channels following nerves adjacent to upper nasal cavity [Thorne et al. 01] • Can providing insulin directly to the brain via intranasaladministration “normalize” brain insulin and improve memory in adults with AD?
Promising Early Results: Study of Nasal Insulin to Fight Forgetfulness (SNIFF) Intranasal Insulin (20 or 40 IU) for 4 months Placebo 104 Adults With Early AD Baseline Month 4 Cognition (ADAS-Cog) Functional Status (ADCS-ADL) Brain Energy Metabolism (PET scan)
Results: Cognitive and Functional Change over 4 Months Decline in Function Decline in Cognition
Intranasal Insulin Prevents Decline in Brain Energy Metabolism Slowing Down Disease Progression? 20 IU 40 IU
Next Steps for Intranasal Insulin as a Therapy for AD • Large trial of intranasal insulin has begun at 30 sites across the country this fall led by Wake Forest School of Medicine and the AD Cooperative Study Group in San Diego • One of 3 projects funded by the new National Alzheimer Project • If successful, seek FDA approval for intranasal insulin as a treatment for AD • To find out more about the insulin trial call Erin Caulder at 336-713-8847
Next Step for Insulin Resistance and AD Prevention is to Address Most Common Causes of Insulin Resistance: Poor Diet and Inactivity • Prevalence of insulin resistance-related conditions dramatically increased, likely due to: • Reduced physical activity • Increased intake of saturated fat and sugar: “Western Diet” vs. “Mediterranean Diet” • Mid-life inactivity and poor diet increase risk of Alzheimer’s disease Wake Forest Baptist Medical Center
Evolution of the Western Diet Pounds of sugar consumed per person per year Average number of calories consumed per day
Diet and Risk of AD Bayer-Carter et al. JAMA Neurology, 2011 • Compared effects of one month of “bad” diet (high saturated fat and sugar) with same calorie “good” diet (low sat fat and sugar) on AD brain markers (amyloid and inflammation) in spinal fluid of healthy adults * Changes reversed after resuming normal diet Good Bad Good Bad Change in Amyloid Change in Inflammation Wake Forest Baptist Medical Center
Preventing Insulin Resistance: EXERCISE • Most potent insulin sensitizing intervention • Effects of exercise on the brain include: • Increased brain energy metabolism • Increased brain volume • Protection against memory impairment in older adults • 6-month trial of aerobic exercise improved brain volume in older adults [Colcombe et al 2006] and cognition in early AD [Baker et al 2010]