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
Disease-Modifying Strategies
APP Aβ Neuron death
β-secretaseγ-secretase
inflammationoxidative stressexcitotoxicitydirect toxicity
secretasemodulators
immunotherapyamyloid binders
anti-inflammatoriesantioxidantsneuroprotectants
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)
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
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
AIBL: Amyloid deposition by PIB and by autopsy precedes AD dementia by 15 years
CC Rowe et al, Neurobiol Aging, 2010
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
Primary prevention: Inhibiting disease before it occurs
Secondary Prevention: Detect and treat disease before symptoms
occur
Secondary prevention = very early treatment
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
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)
Value of CSF biomarkers in selecting MCI subjects who will progress to AD dementia
ADNI MCI
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
Issues with prior MCI trials Subject selection Variable conversion rate Subjective endpoint Artificiality of distinction between MCI
and mild AD
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
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)
Moving earlier still Before “prodromal AD” comes
“preclinical AD”
AD Diagnosis Marching Leftward
Standard diagnosis
Dubois research criteria:“early AD”
Modified Dubois criteria:“earlier AD”
Presymptomatic= Preclinical AD
No symptoms, biomarker evidence of amyloid dysregulation
Very mild symptoms + amyloid biomarker
Episodic memory impairment + any biomarker
Dementia
Onset of AD path
Aisen PS. Alzheimers Res Ther. 2009;1:2. doi:10.1186/alzrt2.
SECONDARY PREVENTION
Ventricular volume change in normals is linked to amyloid
p<0.001
Amyloid positive
Amyloid negative
MMSE change in normals is linked to amyloid
p=0.007
Amyloid positive
Amyloid negative
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.
Secondary prevention (very early treatment of AD):target amyloid-related decline in cognitively normal older individuals
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
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
Is secondary prevention too late? Think not, hope not But …
AD Progression: ADNI modelAbnormal
NormalTime
Presymptomatic eMCI LMCI Dementia
FDG-PETMRI hippocampal volumeCSF Aβ42
Amyloid imaging
Cognitive performance
Function (ADL)CSF Tau
Aisen PS, Petersen RC, Donohue MC, et al. Alzheimers Dement. 2010;6:239-246.
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