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