10/19/12 Psychopharmacology of AD/revised 11-07 1
Alzheimer’s Disease: Focus on Diagnosis and New Treatments
Murray A. Raskind, MD University of Washington VA Northwest Network Mental Illness Research, Education and Clinical Center (MIRECC) Seattle, WA
Murray A. Raskind, MD
● Consultant: Janssen Alzheimer Immunotherapy Research & Development, LLC
Disclosures
10/19/12 Psychopharmacology of AD/revised 11-07 2
Learning Objective
Evaluate the emerging treatments for Alzheimer’s disease and applicability to current practice
Keeping Expectations Modest
● If your primary goal is cure, switch to ophthalmology or orthopedics ● Maintaining quality of life and function and
relieving distress are important accomplishments ● Slowing disease progression is a primary
goal
Definitions of Cognitive Syndromes
● Dementia: Impairment of memory and other cognitive functions caused by damaged brain structure ● Delirium: Impairment of attention and
level of consciousness caused by disrupted brain physiology
Grossberg GT, Kamat SM. Alzheimer's: The Latest Assessment and Treatment Strategies. 2011.
10/19/12 Psychopharmacology of AD/revised 11-07 3
One in Eight Older Americans Has Alzheimer's Disease ● Alzheimer’s disease (AD) is the most
common cause of the dementia syndrome in later life ● 5.4 million cases in the United States
Alzheimer's Association. Alzheimer's Facts and Figures. 2012. http://www.alz.org/alzheimers_disease_facts_and_figures.asp.
Differential Diagnosis of Alzheimer’s Disease
● Dementia with Lewy bodies ● Vascular dementia ● Frontotemporal dementia ● Alcoholism-related dementia ● Severe depression
Grossberg GT, Kamat SM. Alzheimer's: The Latest Assessment and Treatment Strategies. 2011.
The Clinical Diagnosis of Typical AD
● First, insidious onset of gradually progressive memory and executive function impairment ● Then, worsening language function ● Then, episodic disruptive agitation and
other behavioral problems
Grossberg GT, Kamat SM. Alzheimer's: The Latest Assessment and Treatment Strategies. 2011.
10/19/12 Psychopharmacology of AD/revised 11-07 4
Neuropathology of AD
● Neuritic plaques of aggregated beta-amyloid ● Neurofibrillary tangles of
hyperphosphorylated tau
Grossberg GT, Kamat SM. Alzheimer's: The Latest Assessment and Treatment Strategies. 2011.
Genetics of AD
● The ε4 allele variant of apolipoprotein E is a major risk factor for AD ● Three rare, autosomal-dominant
mutations cause early-onset AD (mutations in presenilin 1, presenilin 2, and amyloid precursor protein genes)
Grossberg GT, Kamat SM. Alzheimer's: The Latest Assessment and Treatment Strategies. 2011.
AD Biomarkers
● PET imaging of brain beta-amyloid protein in aggregated form ● Cerebrospinal fluid decreased beta-
amyloid and increased tau concentrations
Grossberg GT, Kamat SM. Alzheimer's: The Latest Assessment and Treatment Strategies. 2011.
10/19/12 Psychopharmacology of AD/revised 11-07 5
Beta-Amyloid PET Imaging Ligands
● [11C] Pittsburgh Compound B (PIB) ● Currently available, but short half-life
(20 minutes), requires close proximity to cyclotron
● [18F]–AV-45 ● Recently approved by FDA ● Longer half-life (110 minutes), enhances
availability
Grossberg GT, Kamat SM. Alzheimer's: The Latest Assessment and Treatment Strategies. 2011.
● Genetic and preclinical data support pathogenic role of beta-amyloid in AD ● Question: If beta-amyloid is pathogenic in
AD, would drugs be effective “disease modifying” treatments if they either: ● Decrease beta-amyloid production? ● Increase beta-amyloid removal?
Grossberg GT, Kamat SM. Alzheimer's: The Latest Assessment and Treatment Strategies. 2011.
Role of Beta-Amyloid
Decreasing Beta-Amyloid Production Is Not Beneficial in AD
● Gamma secretase inhibitors not superior to placebo, and can potentially be harmful at high doses
Lowe D. […] gamma secretase inhibitor for Alzheimer's: worse than nothing. Corante: In the Pipeline [blog]. 2010. http://pipeline.corante.com/archives/2010/08/18/
10/19/12 Psychopharmacology of AD/revised 11-07 6
The Anti-Amyloid Antibodies Approach to Treating AD
● Transgenic AD mice show marked reduction in amyloid plaque deposition when actively immunized against beta-amyloid ● Active beta-amyloid immunization in
humans produced apparent reduction of amyloid plaque density, but no clear cognitive benefits ● 6% incidence of meningoencephalitis
Grossberg GT, Kamat SM. Alzheimer's: The Latest Assessment and Treatment Strategies. 2011.
Would Passive Monoclonal Anti-Amyloid Antibody Approaches Be More Effective and Less Toxic? ● Bapineuzumab*: N terminus-directed beta-
amyloid monoclonal antibody in clinical trials ● Primary efficacy outcomes in Phase 2 trial not
significant ● Signal for efficacy in ε4-negative subjects in
Phase 2 trial ● Solanezumab*: Mid-domain-directed beta-
amyloid monoclonal antibody in clinical trials ● Antibody design targets soluble beta-amyloid
* Investigational agents for use in AD; not FDA-approved for the prevention or treatment of AD
Grossberg GT, Kamat SM. Alzheimer's: The Latest Assessment and Treatment Strategies. 2011.
Recently Reported News
● Bapineuzumab was not superior to placebo in phase 3 trials in either ε4-positive or ε4-negative subjects1
● Solanezumab not superior to placebo in two large, phase 3 trials2
● But, analysis of the combined samples suggested small slowing effect on cognitive function at 18 months in the subjects with milder AD (this effect substantially smaller than seen with cholinesterase inhibitors)
● Would a higher dose of solanezumab produce a more clinically meaningful benefit?
1. Alzheimer's Association. Alzheimer’s Association Statement: Bapineuzumab Phase 3 Results. 2012. http://www.alz.org/documents_custom/bapineuzumabphase3results.pdf.
2. Alzheimer's Association. Alzheimer's Association News Website. 2012. http://www.alz.org/news_and_events_solanezumab_phase_3_results.asp.
10/19/12 Psychopharmacology of AD/revised 11-07 7
Cholinesterase Inhibitor Clinical Experience and Clinical Trials Support Its Reduction of AD Progression ● Persistent “symptomatic” treatment
appears to slow clinical progression ● Delayed-start design: persons first on
placebo and then switched to a cholinesterase inhibitor do not catch up ● Sounds like disease modification to me
Grossberg GT, Kamat SM. Alzheimer's: The Latest Assessment and Treatment Strategies. 2011.
Persistent Treatment With Cholinesterase Inhibitors and/or Memantine Slows Progression of AD ● 641 AD patients followed at Baylor
College of Medicine for over 20 years ● Persistent treatment with donepezil, other
cholinesterase inhibitors, and memantine slowed AD progression as assessed by multiple cognitive, functional, and global measures
Rountree SD, et al. Alzheimers Res Ther. 2009;1(2):7. PMID: 19845950.
Galantamine Shows Sustained Cognitive Benefits in AD Over 12 Months Including a Delayed Start Time
ADAS-Cog = Alzheimer's Disease Assessment Scale—Cognitive Raskind M, et al. Neurology. 2000;54(12):2261-2268. PMID: 10881250.
*
Data from historical placebo group (N = 122)
*p < .05 galantamine 24 mg/day, vs. placebo
# not significantly different from baseline
Galantamine, 24 mg/day (N = 172) Placebo/galantamine, 24 mg/day (N = 144)
Mea
n (±
SE
) cha
nge
in A
DA
S-C
og fr
om b
asel
ine
- 4 - 3 - 2 - 1
0 1 2 3 4 5 6 7
9 3Baseline 12 6
Double-blind Open-extension
Time (months)"
#
10/19/12 Psychopharmacology of AD/revised 11-07 8
Long-Term Data: Change From Baseline in ADAS-Cog/11 Scores
ADAS-Cog = Alzheimer's Disease Assessment Scale—Cognitive
Raskind MA, et al. Arch Neurol. 2004;61(2):252-246. PMID: 14967774.
Mea
n (±
SE
) cha
nge
from
ba
selin
e in
A
DA
S-C
og/1
1
-4
0
4
8
12
16
Baseline Months of Treatment
3 6 9 12 18 24 30 36
20
24
Placebo comparison (N - 186)
Galantamine 24mg–32mg/24mg (N = 194) Estimation of decline – Stern Equation
Clinical Improvement
Clinical Decline
Memantine in AD
● Memantine, a drug of unknown mechanism, has received FDA approval for moderate to severe AD1
● Some studies support adding memantine to a cholinesterase inhibitor* for long-term management of AD2
* Not an FDA-approved use of this agent
1. PI for memantine tablets. Drugs@FDA Website. 2006. http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/021487lbl.pdf.
2. Atri A, et al. Alzheimer Dis Assoc Disord. 2008;22(3):209-221. PMID: 18580597.
Clinical Connections
● There remain many unknowns in understanding Alzheimer’s disease ● New treatments offer hope but progress
is slow ● Is beta-amyloid the basic cause or a
“downstream” result? ● Will drugs targeting the hyperphosphorylated
tau of neurofibrillary tangles be effective?
10/19/12 Psychopharmacology of AD/revised 11-07 9
Questions & Answers
Co-sponsored by
Save the Date!
6th Annual Chair Summit September 26-28, 2013 Westin Tampa Harbour Island Tampa, Florida Check out www.cmeoutfitters.com for the most recent information on Chair Summit 2013. Registration will be open soon. See you in Tampa!
10/19/12 Psychopharmacology of AD/revised 11-07 10
Bapineuzumab Decreases 11C-PIB Aβ Load
• 28 AD patients assigned to bapineuzumab (n=20) or placebo (n=8).
• Treatment with bapineuzumab for 78 weeks reduced cortical 11C-PIB amyloid load compared to baseline and placebo.
• But, in this small subsample, effects on clinical endpoints were disappointing and did not appear related to effects on Aβ binding.
Rinne JO, et al. Lancet Neurol. 2010;9(4):363-372 "
Rinne JO, et al. Lancet Neurol. 2010;9(4):363-372 "
Bapineuzumab Decreases 11C-PIB Aβ Load
● If beta-amyloid is pathogenic in Alzheimer’s disease, would drugs be effective treatment if they either: 1. Decrease beta-amyloid production 2. Increase beta-amyloid removal
Grossberg GT, Kamat SM. Alzheimer's: The Latest Assessment and Treatment Strategies. 2011.
Role of Beta-Amyloid (cont’d)
10/19/12 Psychopharmacology of AD/revised 11-07 11
36-Month Galantamine Trial
● Does a greater rate of cognitive decline in dropouts than in 36-month completers explain results? ● No! Rate of decline prior to galantamine
discontinuation in dropouts was the same as in completers.
Raskind MA, et al. Arch Neurol. 2004;61(2):252-246. PMID: 14967774.
Comparison of Slopes of ADAS-Cog Decline Between Dropouts and Completers
ADAS-Cog = Alzheimer's Disease Assessment Scale—Cognitive Raskind MA, et al. Arch Neurol. 2004;61(2):252-246. PMID: 14967774.
Time (months)
-1 Patients taking galantamine who completed treatment Patients taking galantamine who discontinued treatment
Cha
nge
from
bas
elin
e in
A
DA
S-C
og/1
1
0 1 2 3 4 5 6 7 8 9
10 11
0 10 20 30 40