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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


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.


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


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



Neuropathology of AD

● Neuritic plaques of aggregated beta-amyloid ● Neurofibrillary tangles of

hyperphosphorylated tau


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)


AD Biomarkers

● PET imaging of brain beta-amyloid protein in aggregated form ● Cerebrospinal fluid decreased beta-

amyloid and increased tau concentrations



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


● 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?


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/


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


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


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.


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


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)

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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.

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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?


Questions & Answers

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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


Role of Beta-Amyloid (cont’d)


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

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