Experimental Therapies For Alzheimer's Disease
Transcript of Experimental Therapies For Alzheimer's Disease
![Page 1: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/1.jpg)
Experimental Therapies for Experimental Therapies for Alzheimer’s DiseaseAlzheimer’s DiseasePierre N. Tariot, MD
DirectorBanner Alzheimer's InstitutePhoenix, ArizonaResearch Professor of PsychiatryUniversity of Arizona College of Medicine
![Page 2: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/2.jpg)
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.
![Page 3: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/3.jpg)
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
![Page 4: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/4.jpg)
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 riskBassil N, Grossberg GT. Primary Psychiatry. 2009;16:33-38.
![Page 5: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/5.jpg)
Goals for the Treatment of Alzheimer’s
•Improve memory•Improve functional status•Improve behavioral symptoms•Slow progression•Delay or prevent onset
![Page 6: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/6.jpg)
6
Pharmacologic Treatments for ADPharmacologic Treatments for ADMOA 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
Tablet:5 mg qd
Tablet/oral solution:4 mg bid
ER capsule: 8 mg qd
Capsule/oral solution: 1.5 mg bid
Patch: 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.
![Page 7: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/7.jpg)
7
Benefits cognition
Early-Stage DementiaEarly-Stage Dementia
Moderate DementiaModerate Dementia
Benefits cognition Preserves global status Preserves ADLs Benefits behavior?
Disease SeverityDisease Severity
MCIMCI
Benefits cognition?
Benefits cognition Preserves global status Preserves ADLs Benefits behavior? Severe DementiaSevere Dementia
Class approved for mild-moderate AD Donepezil also approved for severe AD
Cholinesterase Inhibitor Therapy Cholinesterase Inhibitor Therapy in ADin AD
![Page 8: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/8.jpg)
8
Inconsistent effects
Mild-Moderate DementiaMild-Moderate Dementia
Moderate-Severe DementiaModerate-Severe Dementia
Disease SeverityDisease Severity
MCIMCI
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
![Page 9: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/9.jpg)
9
Pharmacologic Treatments for AD: Pharmacologic Treatments for AD: Common Side EffectsCommon Side Effects
Cholinesterase Inhibitors NMDA-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.
![Page 10: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/10.jpg)
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
![Page 11: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/11.jpg)
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.
![Page 12: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/12.jpg)
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 RESPONSECell cycle dysregulation
Kinase/phosphatase dysfunctionProtein misfoldingAltered DNA repair
Vascular/membrane dysfunction
CELL INJURYInflammation
Cytoskeletal dysfunctionSynaptic dysfunction
Mitochondrial damage
CELL DEATHDistal apoptosis
Neurotransmitter failureThe figure depicts apparently continuous processes, though they are likely to be asynchronous . Yaari and Tariot 2008
NeuropathologyNormal
Normal
Tangles, Plaques
Tangles, Plaques Neurodegeneration
Clinical PhenotypeNormal
Normal
Mild Cognitive Impairment
Dementia
![Page 13: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/13.jpg)
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
![Page 14: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/14.jpg)
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
![Page 15: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/15.jpg)
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
![Page 16: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/16.jpg)
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 agonists
MAO=monoamine oxidase; GABA=gamma-aminobutyric acid; AMPA=alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.
![Page 17: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/17.jpg)
17
Glial Modulating DrugsGlial Modulating Drugs
Affect glial cells directly (nitroflurbiprofen, ONO-2506, tacrolimus)
RAGE receptor antagonists (TTP 488)
TNF alpha antagonists (etanercept)
![Page 18: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/18.jpg)
18
Neuroprotective/Neurotrophic StrategiesNeuroprotective/Neurotrophic Strategies
Mitochondrial stabilizers (Dimebon/latrepirdine; also has multineurotransmitter effects)
Phosphodiesterase-4 (PDE4) inhibitors
Neurotrophic drugs
![Page 19: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/19.jpg)
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
Doody RS, et al. Lancet. 2008;372:207-215.
![Page 20: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/20.jpg)
20
Dimebon Effects: ADAS-cogDimebon Effects: ADAS-cogP<0.0001 P<0.0001 P<0.0001
4.0 5.9 6.9P=0.0077
2.0
–3.0–2.0–1.00.01.02.03.04.05.06.0
Mea
n Ch
ange
Fro
m B
asel
ine
Scor
e
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.
![Page 21: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/21.jpg)
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%)
![Page 22: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/22.jpg)
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
![Page 23: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/23.jpg)
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
![Page 24: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/24.jpg)
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?
![Page 25: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/25.jpg)
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
![Page 26: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/26.jpg)
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
![Page 27: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/27.jpg)
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
—continued
![Page 28: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/28.jpg)
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 ?
![Page 29: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/29.jpg)
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
![Page 30: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/30.jpg)
30
Holmes et al followup (2008)Holmes et al followup (2008)
![Page 31: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/31.jpg)
31
Holmes et al, cont’dHolmes et al, cont’d
![Page 32: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/32.jpg)
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.
![Page 33: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/33.jpg)
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
![Page 34: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/34.jpg)
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
![Page 35: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/35.jpg)
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
stai
ning
Anti-Aβ injection
1mm
250 µm
Intra-hippocampal anti-Aβ clears extracellular and intracellular Aβ aggregates
![Page 36: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/36.jpg)
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.
![Page 37: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/37.jpg)
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.
![Page 38: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/38.jpg)
38
Bapi phase II (Salloway et al 2009)Bapi phase II (Salloway et al 2009)
![Page 39: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/39.jpg)
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
![Page 40: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/40.jpg)
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
![Page 41: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/41.jpg)
41
PIB-PET data from phase II PIB-PET data from phase II (Rinne et al 2010)(Rinne et al 2010)
![Page 42: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/42.jpg)
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
![Page 43: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/43.jpg)
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
![Page 44: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/44.jpg)
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.
![Page 45: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/45.jpg)
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
![Page 46: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/46.jpg)
46
Anti-aggregant TherapiesAnti-aggregant Therapies
Tramiprosate (“Alzhemed”) failed in phase III trials
Elan has compound in phase II now
![Page 47: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/47.jpg)
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
![Page 48: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/48.jpg)
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
![Page 49: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/49.jpg)
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
![Page 50: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/50.jpg)
50
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
TauRx Therapeutics Ltd. Pipeline—Alzheimer’s disease. 2008. Available at: www.taurx.com/pipeline_first.aspx. Accessed June 8, 2009.
![Page 51: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/51.jpg)
51
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
![Page 52: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/52.jpg)
52
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
![Page 53: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/53.jpg)
53
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
1. Salloway S, et al. Alzheimers Dementia. 2008;4:65-79.
![Page 54: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/54.jpg)
54
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
![Page 55: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/55.jpg)
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
![Page 56: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/56.jpg)
![Page 57: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/57.jpg)
Why Now?
1. The urgent need2. Suggested but unproven “healthy lifestyle”
interventions3. Investigational AD-modifying treatments 4. The treatment of symptomatic patients may be
too little too late5. Biomarkers of AD progression & pathology
![Page 58: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/58.jpg)
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
![Page 59: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/59.jpg)
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
![Page 60: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/60.jpg)
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
![Page 61: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/61.jpg)
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
![Page 62: Experimental Therapies For Alzheimer's Disease](https://reader033.fdocuments.us/reader033/viewer/2022052419/58973c2c1a28ab8c138c69e6/html5/thumbnails/62.jpg)
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 possible2. 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 hypothesis4. To provide a foundation for other presymptomatic AD trials5. To complement, contribute to & benefit from other initiatives e.g., ADNI,
ADCS, DIAN , ADC program & public policy initiatives6. To give those at highest imminent risk for AD access to some of the
promising investigational treatments in RCTs