Anti-Amyloid Therapies

1. Anti-Amyloid Therapies The Current State of Alzheimer’s Disease Treatment

2. Source • 2012: A Watershed Year for Alzheimer’s Disease Research • Journal of Nutrition, Health & Aging • Volume 17, Number 1, 2013 • M. Grundman, A. DiBernardo, N. Raghavan, M. Krams, E. Yuen • Received October 24, 2012 • Accepted for publication October 31, 2012

3. Two Anti-Amyloid Drugs • Bapineuzumab • Solanezumab • Mild to moderate AD • Target amyloid pathwayand downstream pathways

4. Bapineuzumab • In AD patients who were APOE4 carriers • “demonstrated a significant treatment difference in amyloid plaque accumulation” • “significant reduction in CSF p-tau” • In AD patients who were APOE4 non-carriers • “trend towards plaque reduction” • “significant reduction in CSF p-tau”

5. Bapineuzumab • Significant biomarker findings • reduction of plaques and tangles in all cases • However, “clinical efficacy was not demonstrated” • ADAS-COG • DAD

6. Solanezumab • Likewise “did not demonstrate significant clinical benefits” • ADAS-COG • ADCS-ADL

7. Why the Disconnect? • Possible explanations • Amyloid beta plaques and Tau tangles are merely markers for Alzheimer’s Disease and do not directly contribute to its symptoms • Certain “critical toxic Aβ species” were not sufficiently reduced • Aβ and Tau were not sufficiently reduced to be observed clinically • The disease had progressed too far to be affected by reductions of Aβ and Tau • The delay between biomarker and clinical effects was too long to be measured in the study

8. What’s Next? • Areas of Investigation • Initiate treatment prior to mild to moderate disease stage • Safely increase drug dose • Phase 3 testing actually used a reduced dose compared to Phase 2 • Other anti-amyloid approaches • Non-amyloid approaches • Such as targeting the Tau pathway