drugs for dementia: where have we got to…and where are we going? by professor tony bayer
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Drugs for dementia Where have we got to…and
where are we going?
Professor Tony BayerSchool of Medicine, Cardiff University
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10% 30% 30% 10% 10% 10%
Dementia with Lewy bodies Parkinson’s disease dementia
Vascular dementias and Alzheimer’s
disease
Other dementias Frontal lobe dementia
Creutzfeldt-Jakob diseaseProgressive supranuclear palsy
Many others
Alzheimer’s disease and
dementia with Lewy bodies
Vascular dementiasMulti-infarct dementiaBinswanger’s disease
Alzheimer’s disease
Dementia is a syndrome with many possible causes – so no ‘magic bullet’
Vasculopathies Proteinopathies
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Dementia is associated with many varied symptoms– so no symptomatic drug likely to improve them all
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What a Trial’s Summary Data Represent
Assessment of meaningful change is difficult – so showing the benefit of drugs is challenging
Using biomarkers
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% o
f end-s
tag
e A
D
0
100
40 50 7060 80
Age (years)
ASYMPTOMATICPHASE
PRECLINICAL/PRODROMAL
PHASE
CLINICALPHASE
Estimated startof pathological changes
Clinical diagnosis
Dementia only develops after pathological changes in the brain are extensive
– so disease modifying treatment must start early
First symptoms
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Factors implicated in development of Factors implicated in development of Alzheimer’s diseaseAlzheimer’s disease
ABNORMAL AMYLOID ABNORMAL TAU PROCESSING PROCESSING
NERVE CELL DYSFUNCTION(loss of neurotransmitters e.g. ACh)
DEMENTIA
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Cholinesterase inhibitors and memantine for treatment of Alzheimer’s disease
NICE guidance (Jan 2011)
• donepezil, rivastigmine and galantamine should be considered for use in people with mild & moderate AD (guided by overall assessment rather than just MMSE)
or• memantine should be considered
for use in people with moderate & severe AD
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RCT of donepezil &/or memantine &/or placebo in patients with moderately severe/severe AD (MMSE 5-13) who have been on donepezil for at least 12 months
Howard et al 2012
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Factors implicated in development of Factors implicated in development of Alzheimer’s diseaseAlzheimer’s disease
ABNORMAL AMYLOID ABNORMAL TAU PROCESSING PROCESSING
NERVE CELL DYSFUNCTION(loss of neurotransmitters e.g. ACh)
DEMENTIA
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The amyloid cascade hypothesis & drugs in clinical trials
Adapted from Biochem. Soc. Trans. (2005) 33, 553-558
Statins - promotes alpha secretase
Flurizan - modulates gamma secretase
Lilly - inhibits gamma secretase
Alzhemed - anti-fibrillar
Active and passive immunisation ?
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Active and passive beta amyloid immunisation against AD
• Amyloid deposits in brain prevented or cleared when immunisation or antibody given to laboratory mice
• Would similar approach clear amyloid in patients?
• Would this help memory and thinking and slow progression?
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Beta amyloid immunisation (AN1792) in AD
Bayer et al, Neurology 2005; Holmes et al, 2008
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Bapineuzumab (anti-amyloid antibody)
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Bapineuzumab (anti-amyloid antibody)
• No further accumulation of amyloid on scanning
• Reduced phospho-tau in spinal fluid
• Functional benefit in mild AD
Another antibody (solanezumab) also showed cognitive & functional benefit in mild AD
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Drug development in Alzheimer's disease
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Dementia and clinical trialsWhere next?
• Disease modifying drugs need to start early– Much of the damage been done by the time the
patient presents with dementia• We need to consider new targets
– Is amyloid the cause, or just a byproduct? What about tau? What about inflammation?
• We need to have better outcome measures – Current assessments do not always reflect outcomes
that matter to patients and families. • We need more patients to enter clinical trials
– Recruitment into dementia clinical trials is a fraction of the number entering cancer trials
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