Current Therapeutic Advances in Alzheimers Disease

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Current Therapeutic Advances in Alzheimers
Disease
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Optimal Treatment Approach to AD

• Prevention
• Early detection and intervention
• Prompt diagnosis and treatment
• Symptomatic therapy
• Therapy directed toward slowing the rate of
  decline

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AD as a Chronic Disease
Loses Independence
Mild Cognitive Impairment
Normal
Death
Dementia
Hippocampal Atrophy
Diffuse Cerebral Atrophy
Diffuse plaques
Neuritic plaques, tangles, neuron and synapse loss
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Possible Risk Factors for AD

• Age
• Family history
• Female gender
• Genes
• APP
• PS1
• PS2
• Apo E4

• Low education
• Head injury
• High fat diet
• Hypertension
• Fewer intellectual activities in midlife
• Sedentary lifestyle
• Low antioxidant intake
• Depression

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Antioxidants May Prevent AD

• Subjects with higher dietary intake of
  vegetables, vitamins E C had a lower risk of
  developing AD (Morris 2002)
• Vitamin E and C supplement users had less
  cognitive impairment and lower than expected
  incidence of AD
• (Masaki 2000 Morris 2002 Paleologos 1998)
• Subjects with higher plasma levels of vitamin C
  and beta carotene had better memory
  performance (Perrig 1997)

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High Fat Diet May Increase the Risk for
Alzheimers Disease

• For carriers of e4, risk for AD was over 7 times
  higher for those with a high fat diet compared to
  those with a low fat diet
• (Petot 2000)
• Previously high serum cholesterol level
  associated with increased likelihood of
  developing AD
• (Notkola 1998)
• Hypercholesterolemia accelerates the Alzheimers
  amyloid pathology in a transgenic mouse model
• (Refolo 2000)

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Docosahexaenoic Acid (DHA) Epidemiological Studies

• Autopsy study - PUFA content, including DHA, was
  decreased in the hippocampus and frontal gray
  matter of AD brains (Söderberg et al. 1991)
• Framingham cohort - low DHA was a predictor of AD
• (Kyle et al. 1999)
• Rotterdam study - fish consumption, a marker of
  n-3 PUFAs including DHA, was associated with a
  lower risk of developing AD
• (Kalmijn et al. 1997)

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Prevention Slow the Aging Process

• Eat a diet low in fat cholesterol ,
• Eat a diet rich in vegetables antioxidants
• Maintain a high level of intellectual activity
• Exercise
• Avoid head trauma

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Primary Prevention Studies in AD

• Estrogen
• Womens Health Initiative Memory Study
• AD Prevention Trial with Estrogens
• Ginkgo Biloba
• Cardiovascular Health Study, GuidAge
• Vitamins Multi-supplement (Vit E, homcysteine,
• B12, Folate)
• Omega - 3

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Cognitive Continuum
Mild Cognitive Impairment
Normal
Dementia
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MILD COGNITIVE IMPAIRMENTCRITERIA

• Memory complaint
• Normal general cognitive function
• Normal activities of daily living
• Memory impaired for age
• Not demented

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Individuals With MCI Develop Clinical AD At A
Much Higher Rate Than Normal Elderly
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Importance of MCI

• Fills a clinical niche between a diagnosis of
  normal and dementia (AD)
• Indicates an increased risk of DAT in future
  years
• May represent an opportunity to intervene before
  cognitive impairment becomes more severe
• Requires different trial designs than those for
  standard AD patients
• As an important risk factor for DAT, it may be a
  prevention target itself

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Memory Impairment Study
Evaluate Progression to Alzheimers Disease in
Memory Impaired People with Three Treatments
Vitamin E
Memory Impairment
Alzheimers Disease
Donepezil
Placebo
0
18
12
6
30
24
36
MONTHS
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Demographics
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Conversion to AD by visit and treatment
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Mean time to conversion
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Secondary cognitive outcomesANCOVA donepezil vs
placebo
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Vit E, MCI Study

• There was neither an overall effect of donepezil
  nor vitamin E (2000 IU) on progression to AD over
  36 months
• Donepezil appeared to reduce the risk of
  progressing from MCI to AD for up to 18 months
• Donepezil had an effect on overall function,
  memory and language for up to 18 months
• Vitamin E had no effect on progression to AD and
  had a minor effect on secondary outcomes

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Other MCI Trials

• Donepezil
• Rivastigmine
• Galantamine
• Rofecoxib
• Ginkgo
• Ampakine CX516

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Ginkgo biloba

• Le Bars et al (2000)
• Multicenter, randomized, double-blind, placebo
  controlled, 26-week (120mg/placebo) with 236 DAT
  patients
• Ginkgo was more effective than placebo, but
  effect size on ADAS-COG was small (1.7 points)
  no effect seen on CGIC
• A large 6 month trial of ginkgo in AD with 3
  treatment arms (120mg/240mg /placebo) has been
  completed and is undergoing analysis effects in
  BPSD

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Vitamin E

• In ADCS study of moderate AD patients vitamin E
  delayed time to important endpoints by about 6
  months
• delayed time to nursing home placement
• less worsening on CDR
• less decline in ADLs
• No significant toxicity
• Association Between Vit E and AchEI ?

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Anti-inflammatory drugs

• Epidemiologically, seems to protect against AD
• Inflammation is present in the AD brain
• Indomethacin clinical trial preliminary
• Prednisone treatment for one year failed to slow
  decline in AD
• Other trials are negative, including celecoxib
  and diclofenac
• Ongoing ADCS trial with rofecoxib and naproxen
  negative ?

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Statins

• In animals
• Increased dietary cholesterol increases amyloid
  deposition
• Cholesterol lowering agents are associated with
  reduced CNS amyloid deposition
• In humans
• Statins are effective lipid lowering agents,
  available with known safety
• Two manuscripts suggest statin use may be be
  associated with a reduced risk of dementia

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Ampakines (CX516 and others)

• Centrally active drugs that positively modulate
  AMPA receptors (enhance glutamate stimulated ion
  flux)
• Promote LTP and improve memory in animals
• Positive results reported in preliminary studies
  with young and elderly healthy volunteers
• Clinical trials underway in MCI

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Estrogen

• Epidemiologically, seem to protect against AD
• Biologically plausible
• ADCS trial showed no improvement or slowing of
  decline for women on estrogen therapy with
  well-established AD
• Three other trials are also negative for
  short-term improvement or slowing decline
• Increase risk of AD ? (2003)

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Nerve Growth Factor

• Potent neurotrophic factor for cholinergic
  neurons
• Improves function in animals with cholinergic
  lesions
• Intraventricular administration of NGF into the
  CSF results in Schwann cell hyperplasia
• May be possible to administer NGF directly into
  the brain parenchyma

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Metabolic processing of APP
a Secretory Pathway
b Secretory Pathway
g
a
b
APP
sAPP b
sAPP a
b-amyloid protein
Enhance glutamate transport functioning
Lack of synaptic and neuroprotective effects
?
Cell Adhesion
Block glutamate transport
Oxidative damage
Synaptotrophic
Neuroprotection
Neurotoxic
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Pathologic Changes in Alzheimers disease
phospho-tau
oxidation
A? 42
inflammation
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Secretase Inhibitor Therapy
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Vaccine Approach to Reduction of b-amyloid in
Brain

• RATIONALE
• Immunize transgenic mice that overproduce amyloid
  with b-amyloid
• Mice produce antibodies to b-amyloid
• Some antibodies cross the BBB
• Antibodies bind to amyloid and microglia remove
  the antibody/b-amyloid complex
• Brain levels of b-amyloid will fall
• RESULTS
• Young inoculated animals did not make amyloid
  plaques
• Older inoculated animals had fewer plaques than
  expected indicating plaque removal

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Immunization With Amyloid-b Attenuates Alzheimer
Disease-like Pathology in the PDAPP Mouse
Dale Schenk, Robin Barbour, Whitney Dunn, Grace
Gordon, Henry Grajeda, Teresa Guido, Kang Hu,
Jiping Huang, Kelly Johnson-Wood, Karen Khan,
Dora Kholendenko, Mike Lee, Zhenmei Liao, Ivan
Lieberburg, Ruth Motter, Linda Mutter, Ferdie
Sordiano, George Shopp, Nicki Vasquez, Christopher
Vandevert, Shannan Walker, Mark Wogulis, Ted
Yednock, Dora Games Peter Seubert
Nature 1999
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Vaccine Studies in Humans (AN1792, BetaBloc)

• Human Trials
• Initiated in 2000
• Phase 1a and 1b safety studies
• Questions Phase 2
• will humans make antibodies? yes
• will antibodies cross BBB? yes
• will kidney or other organ damage occur? No ?
• will amyloid levels? Yes autopsy
• SIDE EFFECTS leucoencephalitis
• NEW VACCINES studies being planned
• Antibody direct injection

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Potential Amyloid Treatment Strategies
? formation of b-amyloid b secretase
inhibitors g secretase inhibitors ? a
secretase activity ? b-amyloid fibril
formation enhance b-amyloid clearance
vaccination to remove b-amyloid
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Summary of Current Therapeutic Approaches for AD
Amyloid precursor protein (APP)
Dementia
donepezil rivastigmine galantamine huperzine ampa
kines
? secretase inhibitors ? secretase inhibitors
Ab formation/deposition/aggregation
Cholinergic / neurotransmitter defects
cholesterol lowering drugs (statins) Ab vaccine ?
sheet breaker peptides
NSAIDS
Oxidative stress/ tau phosphorylation/ NFTs
Inflammatory response /neuronal loss
vitamin E ginkgo biloba memantine tau kinase
inhibtors
NGF gene therapy AIT-082 estrogen
Neurodegeneration/synaptic loss
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DRUG DEVELOPMENT

• Phase I 30 of drugsfail, 1-2 years
• Phase II 50 of drugsfail, 2-3 years
• Phase III 10 of drugsfail, 2-4 years (Roses,
  2003)

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Regeneration and Aging Brain

• Removal of Growth Inhibition CSPG
• Manipulation of Intrinsic Regeneration
  Mechanisms Growth-associated proteins, GAP43,
  CAP-23
• Self-repair Activity and Rehabilitation

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Professor of MedicineDirector Alzheimer Clinical
and Research CenterToulouse University Hospital
Alzhemed A Potential Disease-Modifying
Treatment for Alzheimers Disease

• Dr. Bruno Vellas

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Alzhemed is being developed as a
disease-modifying treatment for AD

• Alzhemed is an oral investigational drug which
  acts early during amyloidogenesis without
  interfering with APP processing
• It binds to soluble Ab and maintains Ab soluble
  reduces number of plaques and their size
• Minimizes the interaction of Ab with
  extracellularmatrix
• Reduces Ab-induced neurotoxicity
• Reduces Ab-induced inflammatory response
• Favors clearance of Ab prior to fibril formation

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Alzhemed Animal Proof-of-Concept

• Alzhemed decreases the amyloid burden after an
  8-week treatment in TgCRND81

1. J of Biol Chem 276 21562-21570, 2001
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Pre-Clinical and Phase I Studies

• Pre-clinical studies
• Dogs and rats exposed for up to 39 weeks
• No significant effects on major organ systems
• Safe and well-tolerated upon chronic exposure
• AlzhemedTM is not metabolized
• Alzhemed crosses BBB (brain T1/2 20 h)
• Phase I
• 4 phase I studies in healthy subjects (n117)
• Safe and well-tolerated at the therapeutic doses
• Most frequent AEs nausea/vomiting (dose-related
  transient)

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AlzhemedTM Clinical Phase II Studyin
Mild-to-Moderate Alzheimers Disease (AD)
Patients
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Study Objectives

• Primary
• To evaluate safety, tolerability PK profile of
  AlzhemedTM in mild-to-moderate AD patients
• Secondary
• Effect on Aß42 levels in CSF
• Effect on MMSE, ADAS-cog, CDR-SB

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Study Design

• Multicenter (US), randomized, double-blind,
  placebo-controlled and parallel-designed study
• 58 mild-to-moderate AD patients (MMSE 13-25)

Placebo
Alz 50 mg BID, orally
/- AChEi
Alz 150 mg BID, orally
Alz 100 mg BID, orally
Alz 150 mg BID, orally
CSF Collection
CSF Collection
3 months
21 months
Open Label Extension
Double - Blind
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Patient Accountability
83 screened
3-month double-blind
58 enrolled
6 drop-outs
52 completed
42 enrolled
Open-Label
12 drop-outs
30 completed 12 months
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Baseline Characteristics
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GI Adverse Events All Causalities
Patient count ()
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CSF Alzheimed Study

• CSF samples were collected at baseline and after
  3 months of treatment to determine the
  concentrations of Alzhemed Ab42
• Alzhemed was detected in the CSF of the patients,
  suggesting that it crosses the BBB in AD patients
• Alzhemed was also found to reduce the CSF levels
  of Ab42 in a dose-dependent fashion. The
  decrease was as much as 70 in some patients.
• These results suggest that Alzhemed has a
  pharmacological effect on Ab42 in the brain of AD
  patients

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Dose Dependent decrease of Ab42 CSF Levels
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Psychometric Scores Over 3 Months
As expected, no change in psychometric scores
over 3 months
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AlzhemedTM Clinical Phase II Open-Label
Extension Study Preliminary Data
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GI Adverse Events in Open Label Extension Study
All Causalities Study
Patient count ()
Note GI adverse events are transient in most
cases
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CHANGE FROM BASELINE OF ADAS-COG AT 12 MONTHS
Am. J. Psych. 1513, 1994
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Change from baseline in ADAS-cog over 16 months
9/11 Mild AD improved or stable
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Change from Baseline in MMSE in Mild AD Patients
over 16 Months (n11)
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Change from Baseline in CDR-SB in Mild AD
Patients over 16 Months
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Alzhemed Summary

• AlzhemedTM is safe well-tolerated upon long
  term exposure
• Good PK profile ability to cross the BBB
• Pharmacological effect reduction of Aß42 CSF
  levels at 100 and 150 mg BID
• Results consistent with stabilisation of
  cognitive function in mild AD patients
• These promising results need to be confirmed in a
  large efficacy trial
• A Phase III study has recently been initiated in
  North America
• A second Phase III study is planned in Europe in
  Q1 2005

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European Alzheimers Disease Consortium

• The EADC is a European Union funded network of
  centres of excellence working in the field of
  Alzheimers Disease

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EADC Organisational Structure
EADC Steering committee
36 Centres
Data management
Alzheimer Europe
Special Interest Groups
Pharmaceutical industry
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EADC Co-ordinating Centres

• University of Toulouse, FranceProf. Bruno
  Vellas, Prinipal Investigator
• University of Stockholm, SwedenProf. Bengt
  Winblad, Co-investigator

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EADC Members
Dr. Frolich Lutz Pr. Kurz Alexander Dr. Werner
Hans Jorg Pr. Burns Alistair Pr. McKeith Ian Pr.
Sinclair Allan Pr. Whalley Lawrence Pr.
Scheltens Philip Pr. Olde Rikkert MGM Dr.
Bianchetti Angelo Dr. Frisonni Giovanni Dr. Hock
Christopher Pr. Michel Jean-Pierre Dr. Camus
vincent
Frankfurt-Germany Munchen-Germany Darmstadt-German
y Manchester-UK Newcastle-UK Birmingham-UK Aberde
en-UK Amsterdam-Holland Niimegen-Holland Cremona
-Italy Brescia-Italy Zurich-Switzeland Genève-Swi
tzerland Lausanne-Switzerland
Huddinge-Sweden Liège-Belgium Barcelona-Spain B
arcelona-Spain Barcelona-Spain Madrid-Spain Helsi
nki-Finland Bordeaux- France Lille-France Montpel
lier-France Nice-France Paris-France Paris-France
Toulouse-France
Pr. B Winblad Pr. Salmon Eric Dr. Blesa
Rafael Dr. Boada Marce Dr. Toni Salva Pr. Ribera
Casado Pr. Erkinjuntti Timo Pr. Orgogozzo
J-Marc Pr. Florence Pasquier Pr.Jacques
Touchon Pr. Phillipe Robert Pr. Françoise
Forette Pr. Bruno Dubois Pr. Bruno Vellas
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EADC Special Interest groups

• Cognitive Function
• E Salmon
• Behavioural Problems
• A Burns, P Robert
• Genetics
• A Kurz, R Blesa
• Neuro-imaging
• G Frisoni, P Scheltens
• Therapeutics
• L Froelich, B Dubois
• Basic research
• C Hock

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EADC Web Site

• Address Http//www.alzheimer-europe.org/eadc
• Contents
• description of EADC
• description of participating centres
• future research and recent publications
• special interest groups
• links EU, national networks, NIA, ADCS
• Contact
• Michèle Micas micas.m_at_chu-toulouse.fr
• Planned
• web access for data entry for EADC studies