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

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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