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Clinical Trials in Alzheimer’s Disease

ASENT Symposium Neuroprotection and Disease Modification: Successes, Failures and Lessons Learned. Clinical Trials in Alzheimer’s Disease. Paul S. Aisen, MD Professor, Department of Neurosciences, UCSD Director, Alzheimer’s Disease Cooperative Study. AD Therapeutics.

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Clinical Trials in Alzheimer’s Disease

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  1. ASENT Symposium Neuroprotection and Disease Modification: Successes, Failures and Lessons Learned Clinical Trials in Alzheimer’s Disease Paul S. Aisen, MD Professor, Department of Neurosciences, UCSD Director, Alzheimer’s Disease Cooperative Study

  2. AD Therapeutics • 1906 Alzheimer’s description • 1970’s Cholinergic hypothesis • 1985 first THA trial • 1993 Tacrine approved • 1997 Vitamin E • 1997 Donepezil • 2000 Rivastigmine • 2001 Galantamine • 2003 Memantine • 2008-2015 Disease-modifying therapy

  3. FDA Guidelines for AD Trials • Co-Primary outcome measures • Memory/cognition test, plus global or functional measure

  4. Therapeutic Strategies for AD • Symptomatic treatment • Disease-modifying treatment

  5. Symptomatic treatment

  6. 1.0 0.5 0 –0.5 –1.0 –1.5 –2.0 –2.5 ChEI Monotherapy in Mild to Moderate AD: Cognition (N = 286) Donepezil: MMSE * Improvement † ‡ * LS Mean Change in Score From Baseline (±SE) Decline Donepezil Placebo 0 12 24 36 52 LOCF *P<.001.†P<.05. ‡P=.001. Intent-to-treat population. LS = least squares; SE = standard error; LOCF = last observation carried forward. Source: Winblad B, et al. Neurology. 2001;57:489-495. Week

  7. Memantine Monotherapy in Moderate to Severe AD: Cognition (N = 252) SIB P<.001 2 0 -2 -4 Difference in SIB Score -6 -8 Memantine -10 Placebo -12 0 4 12 28 End Point (LOCF) Week 126 119 n = 107 96 124 n = 126 117 106 83 123 SIB = Severe Impairment Battery. Source: Reisberg B, et al. N Engl J Med. 2003;348:1333-1341.

  8. Disease-modification • Most important need • AD treatment- beyond symptomatic • MCI, primary prevention • Clear, specific targets • Methodologic problems may be the limiting issue

  9. Disease-Modifying Strategies anti-inflammatories antioxidants neuroprotectants immunotherapy amyloid binders secretase modulators inflammation oxidative stress β-secretase Neuron death APP Aβ γ-secretase excitotoxicity direct toxicity

  10. Disease-Modifying Drug Development for AD • May be no symptomatic effect • Goal is usually slowing the rate of decline • Implications: • Long trial • Many subjects • Slope analysis? • Still need co-primary outcome measures • If “disease-modifying” is to be specified in label: • May need two randomization steps in pivotal trials • Alternatively, need convincing biomarker evidence of disease modification

  11. Disease-Modifying RX:Phase II problem • No short-term benefit expected, rather change in slope of decline • Placebo groups in mild AD studies don’t decline in 6 months; minimal in 12 months • To see effect on slope, need hundreds or thousands of subjects (1500?-Myriad; 4000?-Elan) followed for 18 months • CANNOT SEE PROOF OF EFFICACY IN PHASE II-TYPE TRIAL

  12. Phase II • Aim for hints of clinical efficacy (Myriad) • Focus on biomarkers (Alzhemed, IgIV) • Or both

  13. Comparison between Tramiprosate and Tarenflurbil Phase II trials

  14. Comparison between Tramiprosate and Tarenflurbil Phase II trials Tramiprosate: CSF-Aß Results Tarenflurbil: Psychometric Results Source:www.myriad.com

  15. Disease-Modification:Trial Design Issues • Regulatory issues • Randomized start/withdrawal • Slope change • Use of biomarkers

  16. Symptomatic+dis mod Symptomatic Disease-modifying Placebo Cog 0 3 6 9 12 15 18 Cognitive Decline in AD Treatment Trials Months

  17. Symptomatic Placebo Randomized Start Design:Symptomatic Cog 0 3 6 9 12 15 18 21 24 27 30 33 36 Months

  18. Disease-modifying Placebo Randomized Start Design: Disease Modifying Drug Cog 0 3 6 9 12 15 18 21 24 27 30 33 36 Months

  19. Difficulties with long trials • Cumulative informative drop-outs • Site variance (Alzhemed) • Changes to background therapy

  20. Biomarkers • Plasma amyloid • CSF amyloid, tau • Oxidative, inflammatory markers • Imaging: structural, functional, amyloid

  21. In absence of symptomatic (ie, short-term) efficacy (no efficacy at 3-6 months), long term efficacy suggests disease modification • statistical evidence: growing group difference v. slope change by regression • Supported by mechanism, animal model data • Supported by biomarkers related to proposed mechanism (eg, for anti-amyloid rx, CSF Abeta or PET PIB; for anti-tangle, CSF tau), esp. if biomarker validated in animal studies

  22. Tramiprosate (AlzhemedTM)Phase III Study Design Placebo (n=315) CL-758007 Study entry AlzhemedTM 150 mg BID AlzhemedTM 100 mg BID (n=315) + AChEI +/- NMDA antagonist AlzhemedTM 150 mg BID (n=315) Titration Period Maintenance Dose Period Titration Period Maintenance Dose Period 78 Week Double - Blind 78 Week Open – label Extension

  23. Efficacy Endpoints • Primary endpoint • Approval: Change from baseline to month 18 in both ADAS‑cog and CDR-SB scores • Disease Modification Claim: Rate of brain volume change as measured by MRI • Secondary endpoints • Changes from baseline in the MMSE, CIBIC-plus, NPI and DAD scores • Changes from baseline in plasma & CSF Aβ, CSF tau

  24. Tramiprosate Phase III Summary • Primary analysis of North American Phase III trial is inconclusive with respect to tramiprosate treatment effect • Some descriptive data show numerical differences on the primary clinical endpoints data in favor of tramiprosate. • Some descriptive data show numerical differences between groups on the primary disease modification endpoint (MRI).

  25. Prevention Trials • MCI (secondary prevention?) • Subject selection • Operationalizing AD end-point • Significance of other end-points (cognition, function, global) • Primary Prevention • Enriching population; numbers required; duration • Operationalizing MCI/AD end-point • Significance of other end-points (cognition, function, global) • Simplifying trial design to allow large N • Biomarker targets • Treat plasma/CSF abeta? PIB? CSF tau?

  26. AD Trials: current status • FDA guidelines have remained consistent • ADAScog, SIB, CIBIC+ have performed adequately • 5 symptomatic drugs approved • But: • No successful MCI trials • No completed prevention trials • Disease-modification??

  27. AD Disease-Modifying Trials in Progress • Results soon: • Myriad Flurizan Phase III • Elan AAB-001 Phase II • Later: • Phase III: AAB-001, IgIV, Dimebon, Lilly gamma secretase inhibitor • Phase II: ELND005, ACC-001, Pfizer RAGE inhibitor, DHA

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