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
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. - PowerPoint PPT Presentation
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DIAGNOSING EARLY ADA US PERSPECTIVE ON PROPOSED CRITERIA: NEXT STEPS AND IMPACT ON RESEARCH TRIALSDelivered by Sam Gandy, MD, PhDMount Sinai School of Medicine
On behalf of Paul S. Aisen, MDDepartment of NeurosciencesUniversity of California, San Diego
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
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
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Effective preventive and/or disease-slowing therapy for AD may be our most urgent health care need
Primary Prevention Secondary Prevention Early Treatment
?
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
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)
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
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