ALZHEIMER EUROPE 10th Anniversary Meeting

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ALZHEIMER EUROPE10th Anniversary Meeting

• München, Germany

NEW TREATMENTS FOR ALZHEIMERS DISEASE A
CLINICAL PERSPECTIVE Pr. Hervé ALLAIN University
of Rennes, France
www.med.univ-rennes1.fr/etud/pharmaco
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PREREQUISITES

• 1. PATHOPHYSIOLOGICAL THEORIES
• A lot of...
• 2. ASSESSMENT AND EVALUATION
• Gold standard
• 3. BENEFIT FOR
• THE PATIENTS
• THE FAMILIES
• Daily living, Quality of life
• 4. DRUGS PART OF A THERAPEUTIC STRATEGY

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CROSS-TALKING
NEUROSCIENCES
PRESCRIPTION NDA (i.e. anticholinesterasics)
the gap

• Antiapoptosis
• Vaccination
• Inhibition of secretases
• Prions (proteins)

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TODAYs SITUATION (I)

• On the marketAnticholinesterasics CognexTM,
  AriceptTM, ExelonTM
• Drugs approvedGalantamine anticholinesterasic
  NicotinicMemantine Glutamate - NMDA
• RCT 1 but no indicationAnti-oxidants
  selegiline, TocopherolNootropics
  PiracetamGinkgo-Biloba EgB 761Calcium
  blockers Nitrendipine
• Psychotropics
• 1 RCT randomized clinical trials

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TODAYs SITUATION (II)

• 1. Symptomatic treatmentsi.e. memory-enhancing
  drugs
• cerebrovascular compounds
• psychostimulants (caffeine)
• eumetabolizers
• neurotransmitters Ach, AMPA, Nicotine
  (ABT-418)
• 2. Neurocytoprotective agents
• oestrogens (?)
• Dihydropyridines (calcium)
• Glutamate riluzole, salbeluzole
• Neurotrophins

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Pharmacologic rationale for memantineMöbius HJ
Alzheimer Dis Assoc Disord 1999 13 suppl 3 s172
- s178
M
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THE THERAPEUTICS OF TODAY (II)
MMS Severity
?
Psychotropics Antidepressants (avoid tricyclics)
25-
Antioxidants
?
Anticholinesterasics
Antipsychotics Risperidone Tiapride
10-
Time
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THE APPROACH BY SYMPTOMS

• 1 - BPSD
• An example Tiapride in agressivity and agitation
  in dementia(Allain,psychopharmacol ogy
  2000148361-6)
• 2 - The pharmacology of cognition
• AD is the paradigm of a cognitive disorder

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INFORMATION PROCESSING MODEL OF COGNITION

• Environment Attention Cognition
  Emotion
• Reward
• Behaviour Responses
• All those steps are within the brain

Motivation
Memory
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CAVEATS IN DRUG DEVELOPMENT

• 1. Length of clinical trials
• Neuroimaging as a biomarker ?
• 2. Outcome issues
• Daily living, QOL, NHP
• Cognition
• 3. Early diagnosis
• Mild Cognitive Impairment
• Still under debate
• 4. Therapeutic combination
• 5. The organisation of clinical research

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DRUGS (AND THEORIES) DROP-OUT
2000
1990
Metrifonate propentofylline
Antibiotics (bacterias, virus)
Free radicals
SBXanomeline and muscarinic agonist (M1)
Celocoxib (inflammation)
Anti ? secretase Anti TAU
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OUR RESEARCH ORGANISATION IN RENNES

• Dept of PHARMACOLOGY
• in vitro
• animals (behavior)
• neurochemistry

• BIOTRIAL S.A.
• Phases I/II
• healthy volunteers
• AD
• Safety

Dept of NEUROLOGY Phase III Pharmacoepidemiology M
ulticenter trials
INFORMATICS cyber-research e-course
www.med.univ-rennes1.fr/etud/pharmaco www.biotrial
.com
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NICOTINIC TREATMENTS

• ? Nicotinic receptors in AD (cortex)
• Mecamylamine (NR antagonist)
• memories, attention, reaction times (RT)
• Nicotine iV
• ? verbal learning errors, ? attention, ? RT
• ABT - 418
• NR agonist
• ? cognition, attention,
• anxiolytic

Lloyd GK, Williams M. JPET. 2000 292
461-467 Paterson D, Norberg A. Prog Neurobiol.
2000 61 75-111
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TROPHIC FACTORS

• Endogenous factors or similar
• Synthetic compounds
• Anti-apoptose drugs
• Real pathophysiology drugs

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SECRETASES

• 1. b secretase (BACE 1)
• membrane - tethered aspartyl protease
• APP amino-terminus
• 2. ? secretase
• cleaves APP within its transmembrane
• segment
• 3. Presenilin
• PS1 PS2 nicastrin
• Affect APP processing (and NOTCH)
• if mutation ? Ab fragment (42)
• components of a multiprotein ? secretase complex

SISODIA Science 2000 289 2296-7
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SPONGIFORM ENCEPHALOPATHY

• Role of PrP . Stress oxydation .
  Synaptophysine . Intra-cell signalling
• PrP-knocked-out no behavioral signs
• PrP ? PrPsc abnormal configurationPHARMACOLOGY
  OF PROTEINS

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APOPTOSIS AND TRANSCRIPTION FACTORS
Bax
JNK/ SAPK
Caspase - 7
Bid
Bad
PKC?
p53
Bim
TR3
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TAKE-HOME MESSAGES

• 1. One drug - one target
• 2. AD and related disorders
• i.e. vascular dementia
• 3. Utilisation of clinical research data
• i.e. SystEur
• A calcium blocker prevents AD and dementia,
• And then ?
• 4. What is the biological target ?
• Amyloïd ? Tau protein ? Protein configuration ...

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AD and VASCULAR DEMENTIA

• 1. MIXED DEMENTIA
• 2. COMMON MECHANISMS
• 3. DISCOVERY OF NEUROGLOBIN (NGB)
• T. Burmester et al Nature 2000 , 407 520-522
• lower expression of NGB (? O2 availability)
• lower resistance to ischaemia
• (i.e. hippocampus)
• 4. COMMON PHARMACOLOGY ?

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CONCLUSION

• THE PHARMACOLOGY OF AD IS  IN MUTATION 
• THE BREAKTHROUGH ARE
• Secretases (APP processing)
• Protein configuration
• Transcription Factors (cell death)
• THE GAP BETWEEN THE LAB AND HUMANS IS NARROWING

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www.med.univ-rennes1.fr/etud/pharmaco
www.biotrial.com Herve.Allain_at_univ-rennes1.fr