Drugs for dementia
Where have we got to…and
where are we going?
Professor Tony Bayer
School of Medicine, Cardiff Universit...
Dementia is a syndrome with many possible causes
– so no ‘magic bullet’
Other dementias
Frontal lobe dementia
Creutzfeldt-...
Dementia is associated with many varied symptoms
– so no symptomatic drug likely to improve them all
Assessment of meaningful change is difficult
– so showing the benefit of drugs is challenging
What a Trial’s Summary Data ...
Dementia only develops after pathological changes
in the brain are extensive
– so disease modifying treatment must start e...
Factors implicated in development of
Alzheimer’s disease

ABNORMAL AMYLOID
PROCESSING

ABNORMAL TAU
PROCESSING

NERVE CELL...
Cholinesterase inhibitors and memantine for
treatment of Alzheimer’s disease

NICE guidance (Jan 2011)
• donepezil, rivast...
RCT of donepezil &/or memantine &/or
placebo in patients with moderately
severe/severe AD (MMSE 5-13) who have
been on don...
Factors implicated in development of
Alzheimer’s disease

ABNORMAL AMYLOID
PROCESSING

ABNORMAL TAU
PROCESSING

NERVE CELL...
The amyloid cascade hypothesis & drugs in clinical trials

Statins - promotes
alpha secretase

Flurizan - modulates
gamma ...
Active and passive beta amyloid immunisation
against AD

• Amyloid deposits in brain
prevented or cleared when
immunisatio...
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
flui...
Drug development in Alzheimer's disease
Dementia and clinical trials
Where next?
• Disease modifying drugs need to start early
– Much of the damage been done by t...
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? by Professor Tony Bayer
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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? by Professor Tony Bayer

  1. 1. Drugs for dementia Where have we got to…and where are we going? Professor Tony Bayer School of Medicine, Cardiff University
  2. 2. Dementia is a syndrome with many possible causes – so no ‘magic bullet’ Other dementias Frontal lobe dementia Creutzfeldt-Jakob disease Progressive supranuclear palsy Many others Vascular dementias Multi-infarct dementia Binswanger’s disease Dementia with Lewy bodies Parkinson’s disease dementia Vascular dementias and Alzheimer’s Alzheimer’s disease Alzheimer’s disease and disease dementia with Lewy bodies 10% 30% Vasculopathies 30% 10% 10% 10% Proteinopathies
  3. 3. Dementia is associated with many varied symptoms – so no symptomatic drug likely to improve them all
  4. 4. Assessment of meaningful change is difficult – so showing the benefit of drugs is challenging What a Trial’s Summary Data Represent Using biomarkers
  5. 5. Dementia only develops after pathological changes in the brain are extensive – so disease modifying treatment must start early Clinical diagnosis % of end-stage AD 100 CLINICAL PHASE PRECLINICAL/ PRODROMAL PHASE ASYMPTOMATIC PHASE First symptoms 0 40 50 Estimated start of pathological changes 60 Age (years) 70 80
  6. 6. Factors implicated in development of Alzheimer’s disease ABNORMAL AMYLOID PROCESSING ABNORMAL TAU PROCESSING NERVE CELL DYSFUNCTION (loss of neurotransmitters e.g. ACh) DEMENTIA
  7. 7. 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
  8. 8. 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 201
  9. 9. Factors implicated in development of Alzheimer’s disease ABNORMAL AMYLOID PROCESSING ABNORMAL TAU PROCESSING NERVE CELL DYSFUNCTION (loss of neurotransmitters e.g. ACh) DEMENTIA
  10. 10. The amyloid cascade hypothesis & drugs in clinical trials Statins - promotes alpha secretase Flurizan - modulates gamma secretase Lilly - inhibits gamma secretase Alzhemed - antifibrillar Active and passive immunisation Adapted from Biochem. Soc. Trans. (2005) 33, 553-558 ?
  11. 11. 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?
  12. 12. Beta amyloid immunisation (AN1792) in AD Bayer et al, Neurology 2005; Holmes et al, 2008
  13. 13. Bapineuzumab (anti-amyloid antibody)
  14. 14. 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
  15. 15. Drug development in Alzheimer's disease
  16. 16. Dementia and clinical trials Where 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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