Drugs for dementia: Where have we got to…and where are we going? by Professor Tony Bayer
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Transcript of Drugs for dementia: Where have we got to…and where are we going? by Professor Tony Bayer
Drugs for dementia Where have we got to…and
where are we going?
Professor Tony BayerSchool of Medicine, Cardiff University
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
Dementia is associated with many varied symptoms– so no symptomatic drug likely to improve them all
What a Trial’s Summary Data Represent
Assessment of meaningful change is difficult – so showing the benefit of drugs is challenging
Using biomarkers
% 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
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
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
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
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
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 ?
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?
Beta amyloid immunisation (AN1792) in AD
Bayer et al, Neurology 2005; Holmes et al, 2008
Bapineuzumab (anti-amyloid antibody)
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
Drug development in Alzheimer's disease
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