Experimental Therapies for Experimental Therapies for Alzheimer’s DiseaseAlzheimer’s DiseasePierre N. Tariot, MD

DirectorBanner Alzheimer's InstitutePhoenix, Arizona

Research Professor of PsychiatryUniversity of Arizona College of Medicine

Pierre N. Tariot, MD

DirectorBanner Alzheimer's InstitutePhoenix, Arizona

Research Professor of PsychiatryUniversity of Arizona College of Medicine

2

DisclosuresDisclosures

Consulting fees: Acadia, 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 Clinical Trials;

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: NIA, NIMH, Alzheimer’s Association,

Arizona Department of Health Services, and the Institute for Mental Health Research.

Investments: none to disclose. Patents: I am listed as a contributor to a patent, “Biomarkers of

Alzheimer’s Disease.” Speakers’ bureaus: NA.

Consulting fees: Acadia, 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 Clinical Trials;

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: NIA, NIMH, Alzheimer’s Association,

Arizona Department of Health Services, and the Institute for Mental Health Research.

Investments: none to disclose. Patents: I am listed as a contributor to a patent, “Biomarkers of

Alzheimer’s Disease.” Speakers’ bureaus: NA.

3

General Principles General Principles for Managing Illnessfor 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

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

44

Prevention, Risk Reduction, and/or Prevention, Risk Reduction, and/or Optimizing Brain Health?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. 2009;16:33-38.

Goals for the Treatment of Alzheimer’s

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

6

Pharmacologic Treatments for ADPharmacologic Treatments for ADMOA Cholinesterase Inhibitors

NMDA-Receptor Antagonist

Drug Donepezil Galantamine Rivastigmine Memantine

IndicationMild-moderate AD;

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

Initial dose

Tablet:5 mg qd

Tablet/oral solution:4 mg bid

ER capsule: 8 mg qd

Capsule/oral solution: 1.5 mg bidPatch: 4.6 mg qd

Tablet/oral solution: 5 mg qd

Maximal dose

Tablet:10 mg qd

Tablet/oral solution:12 mg bid

ER capsule: 24 mg qd

Capsule/oral solution: 6 mg bidPatch: 9.5 mg qd

Tablet/oral solution: 10 mg bid

National Institute on Aging. Alzheimer’s disease medications. November 2008. NIH PublicationNo. 08-3431. Available at: http://www.nia.nih.gov/Alzheimers/Publications/medicationsfs.htm. Accessed July 24, 2009.

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

7

Benefits cognition

Early-Stage DementiaEarly-Stage DementiaEarly-Stage DementiaEarly-Stage Dementia

Moderate DementiaModerate Dementia Moderate DementiaModerate Dementia

Benefits cognition Preserves global status Preserves ADLs Benefits behavior?

Disease SeverityDisease SeverityDisease SeverityDisease Severity

MCIMCIMCIMCI

Benefits cognition?

Benefits cognition Preserves global status Preserves ADLs Benefits behavior? Severe DementiaSevere Dementia Severe DementiaSevere Dementia

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

Cholinesterase Inhibitor Therapy Cholinesterase Inhibitor Therapy in ADin AD

8

Inconsistent effects

Mild-Moderate DementiaMild-Moderate DementiaMild-Moderate DementiaMild-Moderate Dementia

Moderate-Severe DementiaModerate-Severe Dementia Moderate-Severe DementiaModerate-Severe Dementia

Disease SeverityDisease SeverityDisease SeverityDisease Severity

MCIMCIMCIMCI

Role unknown

Memantine Therapy for AD* Memantine Therapy for AD*

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

9

Pharmacologic Treatments for AD: Pharmacologic Treatments for AD: Common Side EffectsCommon Side Effects

Cholinesterase InhibitorsNMDA-Receptor

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

• Dizziness• Headache• Constipation• Confusion

National Institute on Aging. Alzheimer’s disease medications. November 2008. NIH PublicationNo. 08-3431. Available at: http://www.nia.nih.gov/Alzheimers/Publications/medicationsfs.htm. Accessed July 24, 2009.

10Husain MM, et al. Neuropsychiatr Dis Treat. 2008;4(4):765–777.

How Might Promising Advances in AD How Might Promising Advances in AD Treatment Address Unmet Needs?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

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

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

Alzheimer’Alzheimer’ss

NormaNormall

TanglesTangles

PlaquesPlaques

Courtesy of Harry Vinters, MD.Courtesy of Harry Vinters, MD.

A Proposed Temporal Progression Of Alzheimer’s DiseaseGenetic Factors

APP mutationsPresenilin 1,2 mutations

APOE4 allelesAPOE2 allelesFamily history

Environmental factorsHead Injury

Toxins

Age Endogenous FactorsDiet

Cardiovascular risk factorsDiabetesSmoking

EducationMenopause

Physical ActivityIntellectual Activity

Protective FactorsEstrogen

Anti-inflammatory Drugs

Net effect = stress and vulnerability to stress

Molecular PhenotypeINITIAL STRESSORS

Proximal ApoptosisAPP dysregulation

Impaired neurotrophic functionOxidative stress

Excitotoxicity

FAILED STRESS RESPONSE

Cell cycle dysregulationKinase/phosphatase dysfunction

Protein misfoldingAltered DNA repair

Vascular/membrane dysfunction

CELL INJURY

InflammationCytoskeletal dysfunction

Synaptic dysfunctionMitochondrial damage

CELL DEATH

Distal apoptosisNeurotransmitter failure

The figure depicts apparently continuous processes, though they are likely to be asynchronous . Yaari and Tariot 2008

Neuropathology

Normal

Normal

Tangles, Plaques

Tangles, Plaques Neurodegeneration

Clinical Phenotype

Normal

Normal

Mild Cognitive Impairment

Dementia

1313

Interventions That Interventions That Might Might Prevent or Delay ADPrevent 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

14

The Search for New AD TherapiesThe 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

15

Overview of Supplements etc.Overview of Supplements etc.

Anti-oxidants: no pending treatment trials data; hope for prevention trial at some point, or via dietary study

Anti-inflammatory agents: all AD studies (-); MCI trial (-); ADAPT prevention trial results mixed: no cognitive benefit, possible risk reduction with naproxen only

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

Anti-oxidants: no pending treatment trials data; hope for prevention trial at some point, or via dietary study

Anti-inflammatory agents: all AD studies (-); MCI trial (-); ADAPT prevention trial results mixed: no cognitive benefit, possible risk reduction with naproxen only

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

16

Neurotransmitter TherapiesNeurotransmitter Therapies

Acetylcholine-releasing drugs

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

Serotonin: 5-HT4 partial agonists, 5-HT1A agonists/antagonists, 5-HT6 antagonists

Norepinephrine/dopamine: MAO-A and MAO-B inhibitors

GABA: GABA-B antagonists

Glutamate: AMPA potentiators

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

17

Glial Modulating DrugsGlial Modulating Drugs

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

RAGE receptor antagonists (TTP 488)

TNF alpha antagonists (etanercept)

18

Neuroprotective/Neurotrophic StrategiesNeuroprotective/Neurotrophic Strategies

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

Phosphodiesterase-4 (PDE4) inhibitors

Neurotrophic drugs

19

Dimebon/latreperdine clinical Dimebon/latreperdine clinical outcomesoutcomes 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

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. Lancet. 2008;372:207-215.

20

Dimebon Effects: ADAS-cogDimebon Effects: ADAS-cogP<0.0001 P<0.0001 P<0.0001

4.0 5.9 6.9

P=0.0077

2.0

–3.0

–2.0

–1.0

0.0

1.0

2.0

3.0

4.0

5.0

6.0

Mean

Ch

an

ge F

rom

Baselin

e S

core

Clinical Improveme

nt

Clinical Deterioratio

n

Baseline 12 26* 39 52

Dimebon-Placebo Difference

Week* Patients were moved to blinded extension.

Dimebon (n = 89)

Placebo (n = 94)

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

2121

Latrepirdine Study Results: Adverse EventsLatrepirdine Study Results: Adverse EventsAEs >3% in placebo group and at least twice the rate of latrepirdineAEs >3% in placebo group and at least twice the rate of latrepirdine

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

Adverse Event Latrepirdine (n=89) Placebo (n=94)

Delusion 2 (2.2%) 5 (5.3%)

Hallucination 0 (0.0%) 4 (4.3%)

Alanine aminotransferase 1 (1.1%) 3 (3.2%)

Aspartate aminotransferase 1 (1.1%) 3 (3.2%)

Constipation 0 (0.0%) 3 (3.2%)

22

Confirmatory Phase 3 dimebon Confirmatory Phase 3 dimebon Trial: NegativeTrial: 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

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

23

Other Phase 3 Dimebon studies: 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

24

Case Example: Why Amyloid Case Example: Why Amyloid MattersMatters

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?

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?

A Fibril

DiffusePlaque

A Monomer

APP

-Amyloid–related -Amyloid–related disease-modifying strategiesdisease-modifying strategies

Secretase modulators

A Oligomer

SenilePlaque

Deposition

Production

Aggregation

APPgene

?

Relkin, 2006.

Immunotherapy

Fibrillogenesis modulators

Cu++Chelator

Antisense

26

UnvaccinatedUnvaccinated VaccinatedVaccinated

Morgan et al. Morgan et al. Nature.Nature. 2000;408:982-985. 2000;408:982-985.

Amyloid Stain (Mouse Brain)Amyloid Stain (Mouse Brain)

Anti-amyloid Immunotherapy:Anti-amyloid Immunotherapy:Amyloid “Vaccine” Reduces Plaque Burden and Amyloid “Vaccine” Reduces Plaque Burden and Memory Loss in Transgenic Mouse Model of ADMemory Loss in Transgenic Mouse Model of AD

27

Active ImmunizationActive Immunization

Elan Phase II clinical trial of active immunization with an aggregated Aβ 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 Aβ response• This is seen with other active vaccines

– No clinical benefit seen in Aβ responders or non-responders on most clinical measures

Elan Phase II clinical trial of active immunization with an aggregated Aβ 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 Aβ response• This is seen with other active vaccines

– No clinical benefit seen in Aβ responders or non-responders on most clinical measures

—continued

Parietal neocortex, immunized ADParietal neocortex, immunized ADpatient in Elan AN-1792 Trialpatient in Elan AN-1792 Trial

Parietal neocortex, non-immunized Parietal neocortex, non-immunized patient at comparable stage of ADpatient at comparable stage of AD

Nicoll et al. Nicoll et al. Nat MedNat Med. 2003;9:448-452.. 2003;9:448-452.

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

29

Active Immunization: FollowupActive Immunization: Followup

Ongoing follow-up offered after active treatment stopped

288 had paired volumetric MRIs (Fox et al. 2005) Those with higher anti-AN1792 Aβs 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

Ongoing follow-up offered after active treatment stopped

288 had paired volumetric MRIs (Fox et al. 2005) Those with higher anti-AN1792 Aβs 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

30

Holmes et al followup (2008)Holmes et al followup (2008)

31

Holmes et al, cont’dHolmes et al, cont’d

32

Active Vaccination, cont’dActive 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.

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.

33

Active Vaccination, cont’dActive 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

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

34

Passive ImmunizationPassive 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 Aβ 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

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 Aβ 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

3535

Preclinical Data With AAB-001 Preclinical Data With AAB-001 (bapineuzumab)(bapineuzumab)

Reprinted with permission from Oddo S, et al. Neuron. 2004;43:321-322.

Early anti-Aβ administration clears also non-phosphorylated tau

200 µm

A

1mm

500 µm

1mm

Contralateral

Ipsilateral

B

D

F

C

E

G

250 µm

E F

G H

Contralateral Ipsilateral

Tau

sta

inin

g

Anti-Aβ injection

1mm

250 µm

Intra-hippocampal anti-Aβ clears extracellular and intracellular Aβ aggregates

3636

Phase 2 Trial of BapineuzumabPhase 2 Trial of BapineuzumabRandomized, multicenter, placebo-controlled, Randomized, multicenter, placebo-controlled, parallel-group, ascending-dose studyparallel-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.

37

Bapineuzumab Phase II ResultsBapineuzumab 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.

38

Bapi phase II (Salloway et al 2009)Bapi phase II (Salloway et al 2009)

39

Bapineuzumab Phase 2 Results: SafetyBapineuzumab 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

Salloway S, et al. Neurology. 2009.

AEs in ≥5% of pts and ≥2x more frequent with bapineuzumab vs placebo

%

Back pain 12.1 vs 5.5

Anxiety 11.3 vs 3.6

Vomiting 9.7 vs 3.6

V E 9.7 vs 0

Hypertension 8.1 vs 3.6

Weight loss 6.5 vs 1.8

Paranoia 6.5 vs 0.9

Skin laceration 5.6 vs 2.7

Gait disturbance 5.6 vs 1.8

Muscle spasm 5.6 vs 0.9

40

Bapineuzumab and Vasogenic Edema in Bapineuzumab and Vasogenic Edema in phase IIphase II

Salloway S, et al. Neurology. 2009.

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

41

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

42

Bapineuzumab: Phase III Summary 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

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

43

Passive Immunization, cont’d: IVIgPassive 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. 2005)

• Reported effects included increased plasma Aβ levels and decreased CSF Aβ consistent with expectations for increased clearance of Aβ from the brain.

• 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

44

33rdrd generation vaccines generation vaccines

2nd 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.

3rd generation vaccines use antibodies that target structures specific to amyloid aggregates and that do not react with normal human proteins.

2nd 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.

3rd generation vaccines use antibodies that target structures specific to amyloid aggregates and that do not react with normal human proteins.

45

Secretase PathwaySecretase 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

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

46

Anti-aggregant TherapiesAnti-aggregant Therapies

Tramiprosate (“Alzhemed”) failed in phase III trials

Elan has compound in phase II now

Tramiprosate (“Alzhemed”) failed in phase III trials

Elan has compound in phase II now

47

Anti Amyloid Therapy: Anti Amyloid Therapy: ConclusionsConclusions

• 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

48

Theories of How DamageTheories of How DamageOccurs in ADOccurs in AD

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

From Inside the Cell: Tangle FormationFrom Inside the Cell: Tangle Formation

TanglesTangles

thus creating tanglesthus creating tanglesthat disrupt cell functionsthat disrupt cell functionsand lead to cell death.and lead to cell death.

MicrotubulesMicrotubules

TauTauProteinsProteins

Tau proteins, whichTau proteins, whichnormally stabilizenormally stabilizemicrotubules in brain cells...microtubules in brain cells...

undergo abnormal chemicalundergo abnormal chemicalchanges and assemble into spiralschanges and assemble into spiralscalled paired helical filaments...called paired helical filaments...

AxonAxon

Paired HelicalPaired HelicalFilamentFilament

DendritesDendrites

NeuronNeuron

49

Antitangle Therapies for Alzheimer’s DiseaseAntitangle 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

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

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Methylthioninium Chloride Methylthioninium Chloride (rember™)(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

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.

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Where Do We Stand in Terms of Where Do We Stand in Terms of Pharmacotherapeutic Advances?Pharmacotherapeutic Advances?

DisappointmentsDisappointments– TarenflurbilTarenflurbil– TramiprosateTramiprosate– Vitamin EVitamin E– B6, B12, folate combinationB6, B12, folate combination– Omega 3 fatty acidOmega 3 fatty acid– StatinsStatins– GlitazonesGlitazones– ValproateValproate– LithiumLithium– Gingko biloba for preventionGingko biloba for prevention– NSAID’s for treatment, preventionNSAID’s for treatment, prevention– HRT for treatment, preventionHRT for treatment, prevention

• But important questions remainBut important questions remain

DisappointmentsDisappointments– TarenflurbilTarenflurbil– TramiprosateTramiprosate– Vitamin EVitamin E– B6, B12, folate combinationB6, B12, folate combination– Omega 3 fatty acidOmega 3 fatty acid– StatinsStatins– GlitazonesGlitazones– ValproateValproate– LithiumLithium– Gingko biloba for preventionGingko biloba for prevention– NSAID’s for treatment, preventionNSAID’s for treatment, prevention– HRT for treatment, preventionHRT for treatment, prevention

• But important questions remainBut important questions remain

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Where Do We Stand in Terms of Where Do We Stand in Terms of Pharmacotherapeutic Advances?Pharmacotherapeutic Advances?

Too soon to tellToo soon to tell– Methylthioninium Chloride (rember™)– Huperzine (ADCS trial showed +/- results)– Glitazones in MCI Phase IIIPhase III Latreperdine (dimebolin) Latreperdine (dimebolin)

Other potential antiamyloid therapiesOther potential antiamyloid therapies– BapineuzumabBapineuzumab– Other monoclonal Ab’sOther monoclonal Ab’s– IVIGIVIG– Secretase inhibitorsSecretase inhibitors– RAGE inhibitorRAGE inhibitor– Antiaggregant (scyloinositol derivative)Antiaggregant (scyloinositol derivative)– InsulinInsulin

Too soon to tellToo soon to tell– Methylthioninium Chloride (rember™)– Huperzine (ADCS trial showed +/- results)– Glitazones in MCI Phase IIIPhase III Latreperdine (dimebolin) Latreperdine (dimebolin)

Other potential antiamyloid therapiesOther potential antiamyloid therapies– BapineuzumabBapineuzumab– Other monoclonal Ab’sOther monoclonal Ab’s– IVIGIVIG– Secretase inhibitorsSecretase inhibitors– RAGE inhibitorRAGE inhibitor– Antiaggregant (scyloinositol derivative)Antiaggregant (scyloinositol derivative)– InsulinInsulin

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Rational PolypharmacyRational 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 following1:

– 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 anticipated1

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 following1:

– 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 anticipated1

1. Salloway S, et al. Alzheimers Dementia. 2008;4:65-79.

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Alzheimer’s Disease: The Alzheimer’s Disease: The Treatment HorizonTreatment 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

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

We Can Use Information From Multiple Sources We Can Use Information From Multiple Sources to Improve Diagnosis and Assess Treatmentto Improve Diagnosis and Assess Treatment

Cognitive ReserveCognitive ReservefMRIfMRI

Neuronal ActivityNeuronal ActivityFDG PETFDG PET

Plaque Load Plaque Load PIB-PETPIB-PET

Brain AtrophyBrain AtrophyStructural MRIStructural MRI

Genetic RiskGenetic RiskProfileProfile

Cognitive, Functional Cognitive, Functional ProfileProfile

DiagnosisDiagnosisTreatmentTreatment

BiomarkersBiomarkers

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 Aβ42, 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 Treatments1. 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 Opportunities1. 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