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Metis Cognition Ltd

Cognitive dysfunction in Parkinson’s and Alzheimer’s disease: Can we use the same tests for

exploratory and confirmatory trials?

John Harrison BSc (Hons), PhD, CSci, CPsychol

Honorary Senior Lecturer, Imperial College, London, UK.

Consultant Psychologist, Metis Cognition Ltd., Kilmington, UK.

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Financial disclosures

• In the past 12 months I have received consultancy payments and/or honoraria from the following organisations:

– Astra-Zeneca, Boehringer Ingelheim, Bracket (Clinical)

– CRF Health, EnVivo Pharma, ePharmaSolutions

– Eisai, Eli Lilly, Janssen AI, Lundbeck, MedAvante

– Merck, MyCog, Novartis, Nutricia, Orion Pharma

– Pharmanet/i3, Pfizer, Prana Biotech, Reviva

– Servier, Shire, TCG, TransTech Pharma and Velacor.

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Issues for consideration

• Issues relating to cognition test selection in early AD

• Issues relating to cognition test selection in early PD

• Options for test selection

– Traditional test selection

– Proposed test selection

• Conclusions and recommendations

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TRADITIONAL MEASURES AND PATTERNS OF COGNITIVE DECLINE IN ALZHEIMER’S DISEASE

Issues and examples

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Patterns of impairment in AD

Worst possible score = 12

Worst possible score = 10

• Most patients score at ceiling

• No difference between controls and MCI

Grundman MPH et al. (2004). Mild cognitive impairment can be distinguished from

Alzheimer’s disease and normal aging for clinical trials. Archives of Neurology;61: 59-66.

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New options in early AD

Cognition Composite Score:

ADAS-cog Word Recall, Word Recognition, and Orientation, and

COWAT and CFT

(Increase Indicates Improvement)

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-0.1

-0.05

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0 4 8 12 16 20 24

Study Visit (Week)

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EVP-6124 0.3 mg

EVP-6124 1 mg

EVP-6124 2 mg

Placebo

EVP-2 mg vs. Placebo

Week 23: P-value = 0.0037

Effect Size = 0.42

Presented at AAIC, July 2012. For a fuller account visit: http://www.alzforum.org/new/detail.asp?id=3214.

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PATTERNS OF COGNITIVE DECLINE IN PARKINSON’S DISEASE

Issues and examples

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Early PD - Patterns of Impairment

• Early PD – evidence of cognitive dysfunction in 33-50%1 of patients, largely in:

– Tests of executive function2

– Tests of attention3

– Timed motor tasks3

• Above tasks have been shown to be drug sensitive3,4

1) Emre M. (2003) Dementia associated with Parkinson’s disease. Lancet Neurology, 2:229-37; Robottom BJ & Weiner WJ (2009) Parkinson’s disease dementia. Current Psychiatry Reviews, 5: 218-225. 2) Henry J & Crawford J (2004) Verbal fluency deficits in Parkinson's disease: A meta-analysis, Journal of the International Neuropsychological Society, 10: 608-622. 3) Harrison J et al. (1995) Abnormal refractoriness in patients with Parkinson's disease after brief withdrawal of levodopa treatment. Journal of Neurology, Neurosurgery, and Psychiatry;59:499-506; Harrison J, Edgar, C, Wesnes, K. (2005) Reaction time tasks: Sensitive measures of drug efficacy in Parkinson’s disease clinical drug trials. 7th AD/PD meeting. Sorrento, Italy. 4) Emre M et al. (2004). Rivastigmine for the dementia associated with Parkinson’s disease. New England Jnl of Medicine 351:29-38.

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EMA Guidance Notes

• ‘PDD and Dementia with Lewy Bodies (DLB) are subsumed under the umbrella Lewy Body Dementia’ (p.8)

• ‘PDD cognitive deficits are characterised by impairment in executive function, attention and working memory’(p.8)

• ‘7.1 Pharmacodynamics: ‘As pharmacological effects on cognition and/or memory and/or psychological function and/or reaction time are expected, these should be studied.’ (p.11)

CHMP (2008) Guideline on clinical investigation of medicinal products in the treatment of Parkinson’s disease. Doc.Ref.CPMP/EWP/563/95 Rev. 1. London, EMEA. 9

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TRADITIONAL PARKINSON’S DISEASE TEST SELECTION

Traditional Approach

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AAV2-GAD gene therapy study

• Cognition tests selected to investigate safety

• Cognition assessment composed of: – Mattis dementia rating scale

– Symbol digit modality test

– Stroop color and word test

– Hopkins verbal learning test

– Controlled oral word association test

• Also employed: – Neuropsychiatric Inventory

– Beck Depression Inventory

LeWitt PA et al. (2011) AAV2-GAD gene therapy for advanced Parkinson’s disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurology:10:309-19. 11

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ONE SIZE FITS ALL? Suggested Approach

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Recommended Tests

• Psychomotor speed (Simple Reaction Time )

• Attention (Choice Reaction Time)

• Episodic visual memory (e.g. PAL tasks, One Card Learning)

• Working memory (e.g. N-back tasks, Digit Span)

• Episodic verbal memory task (e.g. ADAS-cog Word Recall, Hopkins Verbal Learning Test, Rey Auditory Verbal Learning Test)

• Planning and strategy (e.g. COWAT & CNT)

• Executive function (e.g. DSST, COWAT & CNT)

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Conclusions and recommendations

• Patterns of cognitive impairment in early PD & AD can be quite different

• However, our concerns in exploratory development extend to considerations of both safety and efficacy

• Consequently a broad assessment of cognition is recommended

• Employ brief, reliable and stable cognitive measures

• Maximise reliability through continuity

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Questions?

Email: john@metiscog.com Email: john.harrison@imperial.ac.uk

http://www.linkedin.com/in/drjohnharrison

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