Experimental Therapies for Alzheimer’s Disease

Pierre N. Tariot, MD Director Banner Alzheimer's Institute Phoenix, Arizona Research Professor of Psychiatry University of Arizona College of Medicine

Disclosures

       

Consulting fees:

Clinical Trials;

Ac

adia, AC Immune, Avid, Baxter Healthcare Corp., Bristol Myers Squibb, Eisai, Inc., Epix Pharmaceuticals, Forest Laboratories, Memory Pharmaceuticals, Inc., Myriad Pharmaceuticals, Sanofi-Aventis, Schering-Plough, and Worldwide

Consulting fees and research support

from Abbott Laboratories, AstraZeneca, AVID, Elan, GlaxoSmithKline, Eli Lilly, Medivation, Merck and Company, Pfizer Inc., Toyama, and Wyeth Laboratories;

Educational fees

from Alzheimer’s Foundation of America;

Research support only:

NA.

Other research support

Health Research.

: NIA, NIMH, Alzheimer’s Association, Arizona Department of Health Services, and the Institute for Mental

Investments Patents

: : none to disclose.

I am listed as a contributor to a patent, “Biomarkers of Alzheimer’s Disease.”

Speakers’ bureaus:

NA.

2

General Principles for Managing Illness

           

Optimize physical, social, intellectual stimulation Importance of maintenance of medical and dental health Medication oversight Monitor for delirium Healthy diet Discuss possible changes in emotions and behavior that can occur, and how to mitigate them Review driving safety Discuss legal, financial issues Review relevant community resources Discuss coping strategies Discuss availability of clinical trials Establish ongoing monitoring plan

3

Prevention, Risk Reduction, and/or Optimizing Brain Health?



Social, mental, and physical activity shown to be inversely associated with risk for dementia and AD



Exercise speculated to enhance brain neurotrophic factors and modify apoptosis



Longitudinal cohort studies show risk of AD increased among people who have received shorter periods of education



Intellectually challenging activity has been associated with reduced risk of dementia in longitudinal studies



Reasonable to encourage patients to maintain or increase physical activity, exercise, cognitive and leisure activities, and social interaction, though it is not known whether these interventions reduce dementia risk Bassil N, Grossberg GT. Primary Psychiatry. 4

4

Goals for the Treatment of Alzheimer’s

•Improve memory •Improve functional status •Improve behavioral symptoms •Slow progression •Delay or prevent onset

Pharmacologic Treatments for AD

MOA Cholinesterase Inhibitors NMDA-Receptor Antagonist Drug Donepezil Galantamine Rivastigmine Memantine Indication

Mild-moderate AD; severe AD Mild-moderate AD Mild-moderate AD Moderate-severe AD

Initial dose Maximal dose

Tablet: 5 mg qd Tablet: 10 mg qd Tablet/oral solution: 4 mg bid ER capsule: 8 mg qd Tablet/oral solution: 12 mg bid ER capsule: 24 mg qd Capsule/oral solution: 1.5 mg bid Patch: 4.6 mg qd Capsule/oral solution: 6 mg bid Patch: 9.5 mg qd Tablet/oral solution: 5 mg qd Tablet/oral solution: 10 mg bid

ER = extended-release; MOA = mechanism of action; NMDA = N-methyl-D-aspartate.

National Institute on Aging. Alzheimer’s disease medications. November 2008. NIH Publication No. 08-3431. Available at: http://www.nia.nih.gov/Alzheimers/Publications/medicationsfs.htm. Accessed July 24, 2009.

6

Cholinesterase Inhibitor Therapy in AD

Disease Severity MCI Early-Stage Dementia



Benefits cognition?



Benefits cognition Moderate Dementia

   

Benefits cognition Preserves global status Preserves ADLs Benefits behavior?

Severe Dementia Class approved for mild-moderate AD Donepezil also approved for severe AD

   

Benefits cognition Preserves global status Preserves ADLs Benefits behavior?

7

Memantine Therapy for AD*

Disease Severity MCI



Role unknown Mild-Moderate Dementia



Inconsistent effects Moderate-Severe Dementia

   

Benefits cognition Preserves global function Preserves ADLs Benefits behavior *Approved for moderate-severe AD in the U.S., alone or in combination with cholinesterase inhibitors

8

Pharmacologic Treatments for AD: Common Side Effects

Cholinesterase Inhibitors

• Nausea • Vomiting • Diarrhea • Weight loss • Loss of appetite • Muscle weakness

NMDA-Receptor Antagonist

• Dizziness • Headache • Constipation • Confusion

National Institute on Aging. Alzheimer’s disease medications. November 2008. NIH Publication No. 08-3431. Available at: http://www.nia.nih.gov/Alzheimers/Publications/medicationsfs.htm. Accessed July 24, 2009.

9

How Might Promising Advances in AD Treatment Address Unmet Needs?

      

Disease modification

–

Increasing neuroprotection against existing Aβ plaques and neurofibrillary tangles

–

Reverse existing neuronal damage Improved efficacy

–

Not just cognition, but also ADLs and behavior Enduring response Delay in disability Fewer side effects Simple to administer Reduced number of treatment unresponsive patients Husain MM, et al. Neuropsychiatr Dis Treat. 2008;4(4):765–777.

10

Amyloid Plaques and Neurofibrillary Tangles in Alzheimer’s Disease and Normal Aging

Plaques Alzheimer’s Normal Tangles

Courtesy of Harry Vinters, MD.

A Proposed Temporal Progression Of Alzheimer’s Disease Genetic Factors APP mutations Presenilin 1,2 mutations APOE4 alleles APOE2 alleles Family history Environmental factors Head Injury Toxins Age Endogenous Factors Diet Cardiovascular risk factors Diabetes Smoking Education Menopause Physical Activity Intellectual Activity Protective Factors Estrogen Anti-inflammatory Drugs Net effect = stress and vulnerability to stress Molecular Phenotype INITIAL STRESSORS Proximal Apoptosis APP dysregulation Impaired neurotrophic function Oxidative stress Excitotoxicity FAILED STRESS RESPONSE Cell cycle dysregulation Kinase/phosphatase dysfunction Protein misfolding Altered DNA repair Vascular/membrane dysfunction Neuropathology Normal Normal Clinical Phenotype Normal Normal CELL INJURY Inflammation Cytoskeletal dysfunction Synaptic dysfunction Mitochondrial damage Tangles, Plaques Mild Cognitive Impairment CELL DEATH Distal apoptosis Neurotransmitter failure Tangles, Plaques Neurodegeneration Dementia The figure depicts apparently continuous processes, though they are likely to be asynchronous . Yaari and Tariot 2008

Interventions That Might Prevent or Delay AD

       

Antihypertensive therapy Hormonal agents (estrogen) NSAIDs (naproxen and celecoxib) High-dose vitamin B, folic acid supplementation Statins PPAR-gamma agonists Fish oil, omega 3 fatty acids Weight control, healthy diet 13

13

The Search for New AD Therapies

    

Drugs/nutraceuticals (based on epidemiologic observations)



Neurotransmitter-based therapies Glial modulating drugs Neuroprotective drugs Amyloid modulating drugs Tau modulating drugs

14

Overview of Supplements etc.

    

Anti-oxidants: for prevention trial at some point, or via dietary study no pending treatment trials data; hope Anti-inflammatory agents: naproxen only all AD studies (-); MCI trial (-); ADAPT prevention trial results mixed: no cognitive benefit, possible risk reduction with Hormonal therapies: largest AD treatment studies were (-); discouraging WHIMS results; but none started early enough, possibly wrong form used, so question may still be open.

Homocysteine-lowering: ADCS (B6+B12+folate) trial in AD completed, no benefit seen Omega-3-fatty acid: anti-amyloid/neuroprotective (ADCS), (-) results in AD; equivocal results in age associated memory impairment

15

Neurotransmitter Therapies



Acetylcholine-releasing drugs



Nicotinic agonists (alpha 7, alpha 4-beta 2)

 

Serotonin: 5-HT 4 partial agonists, 5-HT 1A agonists/antagonists, 5-HT 6 antagonists Norepinephrine/dopamine: MAO-A and MAO-B inhibitors



GABA: GABA-B antagonists



Glutamate: AMPA potentiators



Glycine: partial agonists MAO=monoamine oxidase; GABA=gamma-aminobutyric acid; AMPA=alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid.

16

Glial Modulating Drugs



Affect glial cells directly (nitroflurbiprofen, ONO-2506, tacrolimus)



RAGE receptor antagonists (TTP 488)



TNF alpha antagonists (etanercept)

17

Neuroprotective/Neurotrophic Strategies



Mitochondrial stabilizers (Dimebon/latrepirdine; also has multineurotransmitter effects)



Phosphodiesterase-4 (PDE4) inhibitors



Neurotrophic drugs

18

Dimebon/latreperdine clinical outcomes



Dimebon patients improved compared with placebo on 5 efficacy endpoints (n=183, MMSE 10-24; 6 mo followed by 6 mo blinded extension)

– – – –

Cognition: ADAS-cog, MMSE Overall global function: CIBIC Activities of daily living: ADCS-ADL Behavior: NPI



Results supported by HD study demonstrating effects on MMSE (P=0.03) in Dimebon-treated patients Doody RS, et al. 215.

Lancet . 2008;372:207-

19

Dimebon Effects: ADAS-cog

P =0.0077

Dimebon-Placebo Difference 2.0

–3.0

–2.0

–1.0

0.0

1.0

2.0

3.0

4.0

5.0

6.0

Dimebon (n = 89) Placebo (n = 94) P <0.0001

4.0

P <0.0001

5.9

P <0.0001

6.9

Clinical Improvemen t Clinical Deterioration Baseline 12 * Patients were moved to blinded extension.

Doody RS, et al. Lancet . 2008;372:207-215.

26* Week 39 52

20

Latrepirdine Study Results: Adverse Events

AEs >3% in placebo group and at least twice the rate of latrepirdine Adverse Event

Delusion Hallucination Alanine aminotransferase  Aspartate aminotransferase  Constipation

Latrepirdine (n=89)

2 (2.2%) 0 (0.0%) 1 (1.1%) 1 (1.1%) 0 (0.0%)

Placebo (n=94)

5 (5.3%) 4 (4.3%) 3 (3.2%) 3 (3.2%) 3 (3.2%)

Adapted with permission from Doody RS, et al. Lancet. 21 2008;372:207-215.

21

Confirmatory Phase 3 dimebon Trial: Negative



Enrollment in confirmatory trial of dimebon in mild-to moderate AD began Spring 2008

–

Pla, 5 TID, 20 TID

–

OLEX offered



Enrollment completed in June with 598 patients (initial goal was 525)



@ 70 sites in the US, Europe, and South America



Primary endpoints were ADAS-cog and CIBIC-plus

22

Other Phase 3 Dimebon studies:

•

12-month trial of Dimebon added to ongoing treatment with donepezil HCl tablets in mild-moderate AD

•

Pla, 5 TID, 20 TID

•

Enrollment began April 2009, with target enrollment of 1050 patients

•

6-month trial of dimebon added to ongoing treatment with donepezil in mod severe AD w behavioral symptoms

•

Pla vs 20 TID

•

6-month trial of dimebon added to ongoing treatment with memantine in mod severe AD

•

Pla vs 20 TID

23

Case Example: Why Amyloid Matters

   

Plaques are a hallmark of the illness The major (rare) causes of familial Alzheimer’s all involve abnormal processing of the amyloid protein Leads to highly toxic intermediates Can we block this cascade?

24

APP gene Antisense Production



-Amyloid–related disease-modifying strategies

APP A



Monomer Cu++ Chelator ?

Immunotherapy A



Oligomer Secretase modulators Aggregation A



Fibril Deposition Fibrillogenesis modulators Diffuse Plaque

Relkin, 2006.

Senile Plaque

Anti-amyloid Immunotherapy:

Amyloid “Vaccine” Reduces Plaque Burden and Memory Loss in Transgenic Mouse Model of AD Amyloid Stain (Mouse Brain)

Unvaccinated Vaccinated Morgan et al.

Nature.

2000;408:982-985.

26

Active Immunization



Elan Phase II clinical trial of active immunization with an aggregated A β in adjuvant (AN1792) (Gilman et al. Neurology. 2005)

– – – – –

n=372 terminated prematurely 18/300 receiving AN1792 developed a sterile meningoencephalitis related to cerebral T lymphocyte infiltration (0/72 on placebo) 59 (19.7%) developed adequate A β response

•

This is seen with other active vaccines No clinical benefit seen in A β responders or non responders on most clinical measures

—continued

27

Vaccination with AN-1792: First demonstration of reversal of AD neuropathology ?

Parietal neocortex, non-immunized patient at comparable stage of AD Parietal neocortex, immunized AD patient in Elan AN-1792 Trial

Nicoll et al.

Nat Med

. 2003;9:448-452.

Active Immunization: Followup

   

Ongoing follow-up offered after active treatment stopped 288 had paired volumetric MRIs (Fox et al. 2005) Those with higher anti-AN1792 A βs had greater:

–

decreases in WBV

–

ventricular enlargement Not correlated with impaired cognition



1-year follow-up of those who at least 1 dose of AN1792 showed that patients with an anti Aβ antibody response exhibited slower rates of cognitive and functional decline and reduced cerebral spinal fluid (CSF) concentrations of tau protein compared with nonresponders

29

Holmes et al followup (2008)

30

Holmes et al, cont’d

31

Active Vaccination, cont’d

  

2nd-generation vaccines use small pieces of Aß to avoid activating T-cells responsible for meningoencephalitis Since T cell epitopes exist mainly in the C-terminal portion of Aβ, vaccines using shorter N-terminal peptides are in development.

Since T helper 1 (Th1) immune responses activate encephalitogenic T cells and induce continuous inflammation in the CNS, vaccines inducing Th2 immune responses may hold promise.

–

N-terminal short Aβ peptides with Th2 adjuvant or Th2 stimulating molecules,

–

DNA vaccines,

– – –

recombinant viral vector vaccines, recombinant vegetables others.

32

Active Vaccination, cont’d

 

ACC-001 is in phase II testing in patients with mild-moderate AD. CAD106 consists of the first 6 N-terminal amino acids of Aβ attached to a virus-like particle, which is believed to stimulate B cells while preventing excessive T-cell activation thereby avoiding T-cell mediated adverse effects

33

Passive Immunization

 Monoclonal antibodies in development are designed to target 1 of 3 domains of the Aβ protein: the n-terminus, the middle portion, or the c-terminus. – It is possible that efficacy, safety, or both may be substantially different depending on the binding domain.

 Elan/Wyeth, bapineuzumab (AAB-001) is a humanized monoclonal antibody to N-terminus of A β in phase III development  Lilly, LY206430 (a humanized version of m266) targets A β and is in phase II (Bales et al.

Neurobiol Aging. 2004

)  Others are in development as well 34

Preclinical Data With AAB-001 (bapineuzumab)

A Contralater al Ipsilateral Intra-hippocampal anti-Aβ clears extracellular and intracellular Aβ aggregates Anti-Aβ injection Contralateral Ipsilateral E F 1mm B C 1mm 500 µm G H D E 1mm 250 µm F G Early anti-Aβ administration clears also non-phosphorylated tau Reprinted with permission from Oddo S, et al. Neuron.

2004;43:321-322.

35

35

Phase 2 Trial of Bapineuzumab Randomized, multicenter, placebo-controlled, parallel-group, ascending-dose study



234 patients enrolled



Randomization: Bapineuzumab or placebo (8:7)



Treatment: 6 infusions 13 weeks apart

–

4 dose cohorts: 0.15, 0.5, 1.0, and 2.0 mg/kg



Final Assessment: Week 78 Salloway S, et al. Neurology. 2009. In press. 36

36

Bapineuzumab Phase II Results



No drug-placebo differences on ADAS-cog, DAD, NTB, CDR-SB



Based on a post hoc analysis of E4 non-carriers, ADAS-cog, NTB, and CDR-SB significantly favored the drug Salloway S, et al. Neurology. 2009.

37

Bapi phase II (Salloway et al 2009)

38

Bapineuzumab Phase 2 Results: Safety

   

AEs generally mild-to-moderate, transient, not dose-related % of patients with SAEs similar between bapineuzumab and placebo except for vasogenic edema

–

In 0.5, 1.0, and 2.0 mg/kg cohorts 3 deaths in bapineuzumab treated patients, unrelated to treatment Selected AEs in <5% of bapineuzumab-treated patients: syncope, DVT, PE, and cataract AEs in ≥5% of pts and ≥2x more frequent with bapineuzumab vs placebo

Back pain Anxiety Vomiting V E Hypertension Weight loss Paranoia Skin laceration Gait disturbance Muscle spasm

Salloway S, et al. Neurology. 2009. %

12.1 vs 5.5

11.3 vs 3.6

9.7 vs 3.6

9.7 vs 0 8.1 vs 3.6

6.5 vs 1.8

6.5 vs 0.9

5.6 vs 2.7

5.6 vs 1.8

5.6 vs 0.9

39

Bapineuzumab and Vasogenic Edema in phase II

12/124 (9.7%) patients on bapi (0 on placebo) developed vasogenic edema (VE)

–

Most frequently detected by MRI, with few or no clinical symptoms, and resolved in weeks to months

–

10 ApoE4 carriers, 2 non-carriers



2 mg/kg (6 carriers, 2 non-carriers)

  

1 mg/kg (3 carriers) 0.5 mg/kg (0 carriers) 0.15 mg/kg (1 carrier)

–

6 of 12 patients resumed treatment with no VE recurrence Salloway S, et al. Neurology. 2009.

40

PIB-PET data from phase II (Rinne et al 2010)

41

Bapineuzumab: Phase III Summary

  

Mild-moderate (MMSE: 16-26) Infusion frequency: Q13 weeks; Infusion duration: 60 minutes Four trials ( Primary endpoints: ADAS-cog, DAD ; Secondary endpoints: NTB, CDR-SB; Other: MRI, LP)

–

301

•

E4- carriers: 0.5, 1.0 mg/kg (2.0 mg/kg discontinued 4/09)

–

302

•

E4+ carriers: 0.5 mg/kg

–

3000

•

E4- carriers: 0.5, 1.0 mg/kg (2.0 mg/kg discontinued 4/09)

–

3001

•

E4+ carriers: 0.5 mg/kg

42

Passive Immunization, cont’d: IVIg

• Beneficial results of monthly infusions of IVIg have reported in OL study by Dodel et al of 5 patients with mild-moderate AD ( J Neurol Neurosurg Psych • Reported effects included increased plasma Aβ levels and decreased CSF Aβ consistent with expectations for increased clearance of Aβ from the brain. . 2005) • Relkin et al report similar early experience with small OL study presented in abstract form (AAN. 2005) • Relkin et al have conducted a phase II trial showing encouraging effects • ADCS/Baxter have launched a phase III trial 43

3

rd

generation vaccines

   

2 nd generation vaccines and antibodies both target linear amino acid sequences found in APP and in amyloid deposits. Antibodies against normal human proteins can cause autoimmune side effects. It is difficult to make antibodies against self-proteins because of immune suppression of auto antibodies. 3 rd generation vaccines use antibodies that target structures specific to amyloid aggregates and that do not react with normal human proteins.

44

Secretase Pathway



Beta secretase

–

(“BACE”) inhibitor Most attractive theoretically?

– –

Prior agents have failed Several agents in/approaching



Gamma secretase inhibitor

–

Various agents have shown the desired biological effect

–

2 in phase II-III trials now (Lilly, BMS)

–

Others pending



Tarenflurbil (“Flurizan”), a putative gamma secretase modulator, failed to show benefit in phase III trial; concerns re lack of demonstration of target engagement

45

Anti-aggregant Therapies



Tramiprosate III trials (“Alzhemed”) failed in phase



Elan has compound in phase II now

46

Anti Amyloid Therapy: Conclusions

• • •

Many medications and immunotherapies exist that can alter the processing of amyloid in the lab and in animal models

•

They have shown at least some ability to alter blood, spinal fluid, PiB, and pathological measures of different types of amyloid in normals and/or people with AD

•

Effects on MRI, FDG PET, other biomarkers in humans unclear/unknown Dose ranges not established in all cases Clinical significance of encouraging proof of concept biomarkers remain unknown

47

Theories of How Damage Occurs in AD

From Inside the Cell: Tangle Formation

Axon Tangles Microtubules Tau Proteins Neuron Paired Helical Filament Tau proteins, which normally stabilize microtubules in brain cells...

Dendrites undergo abnormal chemical changes and assemble into spirals called paired helical filaments...

thus creating tangles that disrupt cell functions and lead to cell death.

Sources: Dr John Trojanowski and Dr Virginia M. Y. Lee. University of Pennsylvania Medical Center.

48

Antitangle Therapies for Alzheimer’s Disease

 

Minocyline Microtubule stabilizers

–

kinase inhibitors:

•

GSK 3: AstraZeneca compound in early development, large ADCS valproate trial was (-), ADCS lithium trial abandoned after (-) European Li trial completed

• •

vaccination approaches in early development CDK5

– – –

AZD-1080 AL-108 (NAP) PDE4 inhibitors

49

Methylthioninium Chloride (rember™)

 

Thought to inhibit tau aggregation by

–

Blocking the formation of Tau oligomers and their conversion to Paired helical filaments

–

Solvating / dissolving Tau oligomers and paired helical filaments into the short truncated monomers that comprise the proteolytically stable core of the Paired helical filaments

•

Once reduced to its constituent monomers, the truncated Tau monomers become susceptible to proteases and are of a size that can be cleared efficiently through the proteasomal clearance pathway Phase 3 trial underway TauRx Therapeutics Ltd. Pipeline—Alzheimer’s disease. 2008. Available at: www.taurx.com/pipeline_first.aspx.

Accessed June 8, 2009.

50

Where Do We Stand in Terms of Pharmacotherapeutic Advances?



Disappointments

–

Tarenflurbil

–

Tramiprosate

– – – –

Vitamin E B6, B12, folate combination Omega 3 fatty acid Statins

– – – – – –

Glitazones Valproate Lithium Gingko biloba for prevention NSAID’s for treatment, prevention HRT for treatment, prevention

•

But important questions remain

51

Where Do We Stand in Terms of Pharmacotherapeutic Advances?

  

Too soon to tell

–

Methylthioninium Chloride (rember ™)

–

Huperzine (ADCS trial showed +/- results)

–

Glitazones in MCI Phase III



Latreperdine (dimebolin) Other potential antiamyloid therapies

–

Bapineuzumab

–

Other monoclonal Ab’s

– –

IVIG Secretase inhibitors

– – –

RAGE inhibitor Antiaggregant (scyloinositol derivative) Insulin

52

Rational Polypharmacy



Because the number of possible combination therapies is too large to allow all combinations to be tested, combination and add-on therapies will be guided by rational polypharmacy on the basis of the following 1 :

– – – – – –

Complementary MOAs and relevant additive or synergistic effects Degree of disease progression Potential for drug-drug interactions Feasible administrative schedules Safety Tolerability



Disease modification may slow deterioration without improvement if existing symptoms, and concomitant therapy with symptomatic agents is anticipated 1 1. Salloway S, et al. Alzheimers Dementia . 2008;4:65-79.

53

Alzheimer’s Disease: The Treatment Horizon

    

Disease-modifying therapy Combination disease-modifying and symptomatic therapy Earlier recognition of Alzheimer’s disease Integration of biomarkers into clinical practice

–

Spinal fluid

–

Blood

– –

Imaging Genetics as well A host of unanswered questions

54

We Can Use Information From Multiple Sources to Improve Diagnosis and Assess Treatment Neuronal Activity FDG PET Biomarkers Cognitive Reserve fMRI Plaque Load PIB-PET Diagnosis Treatment Brain Atrophy Structural MRI Genetic Risk Profile Cognitive, Functional Profile

Why Now?

1. The urgent need 2. Suggested but unproven “healthy lifestyle” interventions 3. Investigational AD-modifying treatments 4. The treatment of symptomatic patients may be too little too late 5. Biomarkers of AD progression & pathology

What’s Holding Us Back?

1. Too many subjects, too much time & too much money using clinical endpoints 2. Insufficient evidence to support the “qualification for use” of AD biomarkers as surrogate endpoints 3. The safety & tolerability data needed to evaluate investigational AD-modifying treatments in presymptomatic AD trials

Biomarkers of AD Progression & Pathology*

• • • •

Structural MRI measurements FDG PET measurements Fibrillar Aβ PET measurements CSF Aβ 42 , alone or in combination with t-tau or p-tau levels *in both the symptomatic & presymptomatic stages of AD

But…

•

These biomarkers need to be further characterized & compared in RCTs

•

to determine the extent to which they can be budged by effective treatments

• •

to identify potentially confounding treatment effects unrelated to AD modification to determine the extent to which a treatment’s effects on biomarkers, alone or in combination, are “reasonably likely” to predict a clinical benefit

A Proposal to Accelerate the Evaluation of Presymptomatic AD Treatments

1. Presymptomatic AD treatment / surrogate marker development trials in people at the highest imminent risk of symptomatic AD

•

PSEN1 carriers close to their estimated median age at clinical onset

•

60-80 year-old APOE ε4 homozygotes 2. Infrastructure & national registry to support the conceptualization & implementation of other presymptomatic AD trials 3. Scientific & public policy recommendations for the accelerated evaluation of presymptomatic AD treatments

Presymptomatic Treatment / Surrogate Marker Development RCTs in People at the Highest Imminent Risk of Symptomatic AD: The Opportunities 1. To evaluate promising investigational treatments in presymptomatic RCTs sooner than otherwise possible 2. To generate data needed to support the use of biomarkers as reasonably likely surrogate endpoints in other presymptomatic AD RCTs

•

To help provide both the means & accelerated regulatory approval pathway needed to evaluate many different presymptomatic AD treatments at the same time 3. To provide the best test yet of the amyloid hypothesis 4. To provide a foundation for other presymptomatic AD trials 5. To complement, contribute to & benefit from other initiatives e.g., ADNI, ADCS, DIAN , ADC program & public policy initiatives 6. To give those at highest imminent risk for AD access to some of the promising investigational treatments in RCTs