Alzheimer’s Disease LandscapeAlzheimer’s Disease Landscape

James R. Burke, MD, PhDJames R. Burke, MD, PhDProfessor of Medicine (Neurology)Professor of Medicine (Neurology)Duke University Medical CenterDuke University Medical Center

9th June 20129th June 2012

Alzheimer’s DiseaseAlzheimer’s Disease

Most common cause of dementia Clinical

• Insidious onset of cognitive decline- prominent memory problems. Pathology Brain atrophy

• Amyloid plaques• Neurofibrillary tangles

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EtiologyEtiology

AgeAge GeneticsGenetics

• Autosomal Dominant - rare, Autosomal Dominant - rare, early-onset forms- All are early-onset forms- All are related to mutations in amyloid related to mutations in amyloid pathway.pathway.

• Late-onset AD- Apolipoprotein Late-onset AD- Apolipoprotein E- susceptibility gene. E- susceptibility gene. Individuals who inherit APOE 4 Individuals who inherit APOE 4 form are at increased risk of ADform are at increased risk of AD

AD Roses Sci Am Sci Med 1995, 2:16-25

Kawas C et al. Neurology 2000;54:2072-2077

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4EpidemiologyEpidemiology

Risk Factors for AD

• Age

• Genetics

• Education

• Head trauma

• Medical conditions:Hypertension, Diabetes mellitus, Hypercholesterolemia, Obesity, Smoking

1950 1980 2000 2020

>65 yrs <65 years

Source: U.S. Census Bureau

World-wide incidence of AD World-wide incidence of AD Ziegler Graham et al., 2008 Alz & Dementia 316-323Ziegler Graham et al., 2008 Alz & Dementia 316-323

AD incidence higher in US, Canada, and Europe

What accounts for differences in disease rates?

Obesity, diabetes, smoking,

hypertension?Lifestyle?Genetics?

Systematic review (1998-2005) AD incidence studies (n=27)

CCMS

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6Pathology/Pathophysiology:Pathology/Pathophysiology: Biomarkers and pathology precede symptomsBiomarkers and pathology precede symptoms

http://adni.loni.ucla.edu/about/biomarkers/

Braak and Braak

7DiagnosisDiagnosis

• History of insidious onset memory problems

• Impairments on cognitive testing- especially delayed memory

• No focal deficits on neurologic examination

• Neuroimaging- atrophy and absence of significant cerebrovascular disease

8Clinical features of ADClinical features of AD

•MCI due to AD- Forgetful, repetitive questions. No impairment in ADLs (2-5 years)

•Mild AD- Disoriented for date/time, word-finding difficulty, trouble organizing tasks at home and work. May be lost away from home. Depression common (2-4 years)

•Moderate AD- Decline in personal hygiene and dress, unable to perform routine tasks around the house. May wander from home. Agitation and sleep problems common. Cannot be left alone (2-10 years)

•Severe AD- Requires assistance in all ADL (bathing, dressing, feeding and toileting) Falls, infection, malnutrition common. Total care (1-3 years)

Biomarkers in ADBiomarkers in AD 9

Disease burdenDisease burden

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•AD is the 6th cause of death in the US.

•Average survival after diagnosis is 4 to 8 years

•Impact on family and caregivers World Alzheimer’s Report 2010

Cost Dementia vs National Economies

Alzheimer’s Association

$ Billions

11Treatment optionsTreatment options

• Cholinesterase inhibitors• Donepezil

• Galantamine

• Rivastigmine

• Tacrine

• NMDA receptor antagonist• Memantine

• Caprylidene

No Disease Modifying Therapies

Disease modificationDisease modification

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Figure quoted from: Hampel H et al. (2010)

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Perspectives: Drugs in Development

Roberson and Mucke Science 314: 781 (2006)

Amyloid

Neurofibrillary tangles (NFTs)

Inflammation

Energy

Folding and removal

Competitive landscape Competitive landscape

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Name Indication MoA Phase Estimated launch

Bapineuzumab* Mild to moderate ADHumanised monoclonal antibody to beta-amyloid

Phase III

Q3 2013 in US

Q2 2016 in Japan

Q2 2015 in 5EU

Gammagard* Mild to moderate ADPassive immunisation against beta-amyloid

Phase III 2015

LY2062430 (solanezumab)* Mild to moderate AD

Passive immunisation against soluble beta-amyloid

Phase IIIQ3 2013 in US and 5EU

ELND005 (scyllo-inositol) Mild to moderate AD

Beta-amyloid aggregation inhibitor

Phase II Q3 2014

MethylthioniniumChloride

Mild to moderate AD Tau aggregation inhibitor Phase IIQ1 2015 in US and Europe

Davunetide

AD, mild cognitive impairment, frontotemporal dementia and cognitive impairment in schizophrenia

Tau hyperphosphorylation

inhibitorPhase II Not known

Tideglusib ADAD GSK-3 beta inhibitorGSK-3 beta inhibitor Phase IIPhase II Not knownNot known

SB-742457 Mild to moderate ADMild to moderate AD 5-HT6 receptor antagonist5-HT6 receptor antagonist Phase IIPhase II Q1 2015 (US, 5EU)Q1 2015 (US, 5EU)

15Unmet medical needsUnmet medical needs

• Disease modifying therapies

• Prevention of symptom development

• Therapies for behavioral problems

• Effective management of sleep

Plassman et al. Ann Int Med, 2008 148:427-34

ConclusionsConclusions

Alzheimer’s disease is the most common cause of dementia with major costs for individuals, families and society.

No current therapies prevent development of symptoms or modify disease progression.

The aging of the population will lead to a dramatic increase in the number of individuals with Alzheimer’s disease.

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