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Delivered by Sam Gandy, MD, PhD Mount Sinai School of Medicine On behalf of Paul S. Aisen, MD

DIAGNOSING EARLY AD A US PERSPECTIVE ON PROPOSED CRITERIA: NEXT STEPS AND IMPACT ON RESEARCH TRIALS. Delivered by Sam Gandy, MD, PhD Mount Sinai School of Medicine On behalf of Paul S. Aisen, MD Department of Neurosciences University of California, San Diego.

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Delivered by Sam Gandy, MD, PhD Mount Sinai School of Medicine On behalf of Paul S. Aisen, MD

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  1. DIAGNOSING EARLY ADA US PERSPECTIVE ON PROPOSED CRITERIA: NEXT STEPS AND IMPACT ON RESEARCH TRIALS Delivered by Sam Gandy, MD, PhD Mount Sinai School of Medicine On behalf of Paul S. Aisen, MD Department of Neurosciences University of California, San Diego

  2. Brief History of AD Therapeutics • 1906: Dr. Alois Alzheimer describes AD • 1906-1970’s: General assumption that this is an unusual and untreatable degenerative disease of middle age • 1976: Dr. Robert Katzman editorial: The Prevalence and Malignancy of Alzheimer’s Disease • 1970’s: Cholinergic hypothesis suggests treatment strategy • 1986: First positive (?) treatment study (Dr. William Summers) • 1993: Tacrine is approved; 3 other similar drugs follow • 2003: Memantine is approved, representing a second therapeutic class for AD • NOTHING SINCE 2003

  3. Current Treatments Options for AD Are Suboptimal • Treatment effects are modest and short-lived with no effect on underlying disease progression • Cholinesterase inhibitors: • Donepezil, rivastigmine, and galantamine • Tolerability is limited by gastrointestinal side effects (nausea, vomiting, diarrhea, weight loss) • NMDA receptor antagonist: • Memantine • Improved tolerability profile but hallucinations, delusions, and agitation can occur • Indicated only for moderate-to-severe AD • There is an unmet need for well tolerated AD therapies that provide a broad and enduring clinical benefit across multiple domains • Cognition, overall function, behavior

  4. Effective preventive and/or disease-slowing therapy for AD may be our most urgent health care need

  5. 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

  6. Disease-Modifying Drug Development:Phase II/III problems • No short-term benefit expected, rather change in slope of decline • Placebo groups in mild AD studies don’t decline in 6 months; placebo decline minimal in 12 months • To see effect on slope, need hundreds or thousands of subjects followed for 18 months • Cannot see proof of efficacy in Phase II-type trial (in contrast to currently approved drugs)

  7. Recent AD Trials: promising targets, mostly negative trials • Negative Phase III: • Xaliproden (neuroprotection) • Tramiprosate (amyloid anti-aggregation) • Tarenflurbil (gamma secretase inhibitor) • Rosiglitazone (metabolic, anti-inflammatory) • Leuprolide (endocrine) • Dimebon (alone and add-on)) • Semagacestat (gamma secretase inhibitor) • Phase III in progress • Bapineuzumab, solanezumab (monoclonal anti-amyloid Abs) • IGIV

  8. So far, no successful disease-modifying trials in AD or prodromal AD • We need to: • Continue to search for better drugs • Continue to refine methods • Continue to explore earlier stages of disease

  9. AIBL: Amyloid deposition by PIB and by autopsy precedes AD dementia by 15 years CC Rowe et al, Neurobiol Aging, 2010

  10. Toward earlier disease-modification trials in AD • Move past the traditional definition: AD=AD dementia • Earlier AD: MCI v. “prodromal AD” • Much earlier: Preclinical AD and secondary prevention trials • Ultimate goal: Primary prevention of AD

  11. Primary prevention: • Inhibiting disease before it occurs • Secondary Prevention: • Detect and treat disease before symptoms occur Secondary prevention = very early treatment

  12. MCI criteria in ADNI • Age 55-90 • Memory complaints • Not demented • MMSE 24-30 • CDR=0.5; memory 0.5 or 1 • Logical Memory II 1.5 SD below age/education adjusted norms

  13. Prodromal AD • Symptomatic AD prior to the onset of the syndrome of dementia • Amnestic MCI anchored to AD using biomarkers (ie, using biomarkers to select individuals with MCI on the path to AD dementia)

  14. Value of CSF biomarkers in selecting MCI subjects who will progress to AD dementia ADNI MCI

  15. MCI Trials • FDA, EMA never accepted MCI as a treatable entity for drug development • Therefore, pre-dementia trials had to use time-to-dementia (a treatable entity) as outcome • But MCI trials have not been successful

  16. Issues with prior MCI trials • Subject selection • Variable conversion rate • Subjective endpoint • Artificiality of distinction between MCI and mild AD

  17. Better pre-dementia trial designs • Now that FDA and EMA seem amenable to the idea of pre-dementia AD (eg, by Dubois criteria) we can abandon time-to-dementia design • Operationalize Dubois criteria (eg MCI plus low CSF abeta42) • Primary outcome: continuous measure such as CDR-SB (to capture effect on primary manifestations of disease and establish clinical relevance) • Much more powerful than traditional MCI trial design

  18. MCI v. Prodromal AD • The concept of MCI remains highly useful to clinical practice • However, the concept of MCI is being abandoned in AD disease-modification trials, in favor of “Prodromal AD” (MCI plus biomarker evidence of AD)

  19. Moving earlier still • Before “prodromal AD” comes “preclinical AD”

  20. AD Diagnosis Marching Leftward No symptoms, biomarker evidence of amyloid dysregulation Very mild symptoms + amyloid biomarker Episodic memory impairment + any biomarker Dementia SECONDARY PREVENTION Modified Dubois criteria: “earlier AD” Dubois research criteria: “early AD” Standard diagnosis Presymptomatic= Preclinical AD Onset of AD path Aisen PS. Alzheimers Res Ther. 2009;1:2. doi:10.1186/alzrt2.

  21. Ventricular volume change in normals is linked to amyloid p<0.001 Amyloid positive Amyloid negative

  22. MMSE change in normals is linked to amyloid p=0.007 Amyloid negative Amyloid positive

  23. So ventricular volume and MMSE are candidate outcome measures for a secondary prevention trial in AD. • Data from AIBL confirms “amyloid-related” change in these measures.

  24. Secondary prevention (very early treatment of AD):target amyloid-related decline in cognitively normal older individuals

  25. Shifting regulatory views:secondary prevention of AD • Primary outcome: cognitive measure without requirement for clinical relevance • Biomarkers to demonstrate impact on disease mechanisms • Post-marketing follow-up

  26. ADCS A4 Trial Design (Sperling, Aisen)Anti-Amyloid treatment in Asymptomatic AD • Screen cognitively normal 70+ year-olds, perhaps enriched based on subjective memory concerns, family history or cognitive tests • Select those with amyloid in brain by PET (or LP) • Enroll in a 3 year RCT of an anti-amyloid rx • Primary outcome cognitive (FCSRT or other delayed recall, paragraph recall, orientation, exec fxn) • Amyloid PET to confirm target engagement • Biomarker profile to include CSF, structural MRI • Other outcomes: PRO, additional cognitive tests

  27. Is secondary prevention too late? • Think not, hope not • But …

  28. AD Progression: ADNI model Abnormal Primary Prevention Secondary Prevention Early Treatment FDG-PET MRI hippocampal volume ? CSF Aβ42 Amyloid imaging Cognitive performance CSF Tau Function (ADL) Time Normal Presymptomatic eMCI LMCI Dementia Aisen PS, Petersen RC, Donohue MC, et al. Alzheimers Dement. 2010;6:239-246.

  29. How will we get to primary prevention? • Clarify the transition from normal aging to AD • Identify those nearing that transition (epidemiology, genetics) • Demonstrate impact of therapeutics on the transition • Establish mid-life primary prevention

  30. Summary: Impact of new criteria on AD trial design • Mixing clinical and biomarker criteria: Utilizing biomarker data to move from MCI to Prodromal AD is advantageous to drug design • Relying on biomarker data: The optimal AD stage for disease-modification trials is before any clinical manifestations, ie, preclinical AD defined solely by biomarkers (Sperling et al, A&D, 2011)

  31. Conclusions: Lessons for design of disease-modification trials • AD is a gradually progressive disorder lasting many years; MCI and AD dementia are artificial, fuzzy constructs that may not be useful in trials • In pre-dementia AD, assessing treatment effects on continuous measures (eg CDR-SB) is much more powerful than time-to-dementia • Biomarkers are powerful but tricky • Probably wise to treat as early as possible • Very early treatment trials, ie, secondary prevention trials targeting amyloid-mediated decline, now feasible • Primary prevention is the ultimate goal

  32. Acknowledgments • NIA: ADCS, ADNI etc. • Alzheimer’s Association • From the ADCS/UCSD: Doug Galasko, David Salmon, Ron Thomas, Rema Raman, Anthony Gamst, Mike Donohue, Mike Rafii, Steve Edland, Jim Brewer, Adam Fleisher, many others • From ADNI: Mike Weiner, Ron Petersen, Laurel Beckett, many others • Many, many colleagues, individuals with (or at risk for) AD and their families

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