MRI as a Potential Surrogate Marker in the ADCS MCI Trial

1. MRI as a Potential Surrogate Marker in the ADCS MCI Trial FDA PCNS Advisory Committee Meeting on Brain Imaging as an Outcome Measure in Phase III Trials for ADGaithersberg, MDNovember 18, 2002 Michael Grundman, M.D., M.P.H.

2. Decline in Mini-Mental State During Progression to AD Normal MCI AD

3. Mild Cognitive Impairment: Key Criteria • Memory Complaint Verified by Informant • Objective Memory Impairment • Generally Normal Cognition Other than Memory • Generally Normal Daily Function

4. Rate of Decline to AD among MCI Subjects and Normal Controls

5. MCI Trial with Vitamin E and Donepezil Vitamin E Memory Impairment Alzheimer’s Disease Donepezil Placebo 0 6 12 18 24 30 36 MONTHS

6. MCI Trial with Vitamin E and Donepezil • Recruit people with MCI • 3 Treatments • Vitamin E – 2000 IU/day • Donepezil – 10mg/day • Placebo • Study objectives • Prevent development of Alzheimer’s disease • Slow decline on cognition and function • Reduce rate of atrophy on MRI • 3 Year duration • 769 Participants • 69 Centers

7. Baseline Score on ADAS Cog Total in Normals, MCI and AD Normals MCI AD

8. MRI as Potential Surrogate Marker • Hippocampal atrophy on MRI has high face validity because it occurs early and appears to be substantially affected by the AD pathology and contribute to the memory impairment observed in AD.

9. Percent Annual Change in Hippocampal Volume by Clinical Group Clinical Group Percent Change Control -stable -1.7  0.9 MCI-stable -2.5  1.5 MCI-decliner -3.7  1.5 AD -3.5  1.8 Jack Jr. C.R., et al, Neurology 2000, Vol 55 p.484-489

10. Possible Stages of Decline in Hippocampal Volume Leading to AD Normal MCI AD

11. Mild Cognitive Impairment Trial: MRIs Performed to Date • Timing: MRIs Performed at Baseline, Time of Conversion or Study Completion • 193 Baseline Scans • 57 Second Scans

12. Neuroimaging Hypotheses • Hippocampal volume at baseline will correlate with cognitive and functional performance • MRI hippocampal volume at baseline will predict crossover to AD • Rate of volume loss will be greater in subjects who decline clinically • MRI volumetric analysis will be a useful surrogate for measuring therapeutic response

13. Hippocampal Volume is Correlated with Baseline Memory Function

14. NYU Delayed Paragraph Recall Scores (# Correct) were lower in Subjects with Smaller Hippocampal Volume

15. Baseline Hippocampal Volume Thus Far Appears to Predict Future Conversion to AD and Change on Clinical Measures

16. Conversion to AD by Hippocampal Volume at Baseline 1.0 0.9 0.8 Hippocampal Volume Probability of Not Converting to AD Top 50% Bottom 50% 0.7 0.6 0.5 0 200 400 600 800 1000 Time on MCI Study (days)

17. CDR Sum of Boxes Change Scores by Hippocampal Volume at Baseline 56 % 44 % Hippocampal Volume

18. Characteristics of an Optimal Surrogate Marker • Rapidly ascertainable • Correlated with the clinical outcome • Fully capture the treatment’s “net effect” • Able to be collected consistently • Precede clinical decline or failure

19. Observations that Would Support Brain Atrophy as a Surrogate Marker for Disease Modification Reduced rate of brain atrophy Slower rate of clinical decline Treatment

20. Determine Rate of Decline in Hippocampal Volume in Individual Subjects Hippocampal Volume Time in Study (Years)

21. Determine if the Mean Rate of Hippocampal Atrophy Accurately Predicts Clinical Outcome (AD) Non-Converters Percent Change in Normalized Hippocampal Volume Converters Time in Study (Years)

22. Determine if the Mean Rate of Hippocampal Atrophy is Slowed by Treatment Treatment Percent Change in Normalized Hippocampal Volume Placebo Time in Study (Years)

23. Possible Reasons Why Brain Atrophy May Not Always Be a Reliable Surrogate Marker • Brain atrophy may not always be in the direct causal pathway of the disease. Weight loss, diuretics or dehydration may also contribute to brain atrophy. • The intervention may reduce the rate of brain atrophy and not improve the clinical outcome. Agents that disrupt the BBB or induce an inflammatory response could lead to brain swelling but not improve clinical symptoms. • The intervention could interfere with causal pathways without slowing brain atrophy. Amyloid-lowering agents that are disease modifying might increase brain atrophy in the short run by ridding the brain of space occupying amyloid.

24. Body Mass Index and Mesial Temporal Cortex Volume in Alzheimer’s Disease Patients

25. Possible Reasons Why Brain Atrophy May Not Always Be a Reliable Surrogate Marker • The intervention could improve the clinical outcome without reducing the rate of brain atrophy. A clinical benefit might occur with agents that enhance synaptic transmission without altering the neurodegenerative process or resulting brain atrophy. • Unexpected adverse events could occur despite a beneficial effect on the surrogate. Clinical benefit and reduction in brain atrophy could occur with unacceptable side effects.

26. Conclusions • Erroneous decisions could be made based on rates of brain atrophy alone. It seems premature to accept differences in brain atrophy as a primary outcome measure in the absence of supportive clinical data. • In conjunction with slowing of decline on clinical measures and a good safety profile, slowing of brain atrophy could support a disease modification claim. • If brain imaging could be validated in AD or MCI trials for a particular agent it might be used to support an efficacy claim in subsequent trials while more clinical data was collected.