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Developing New Therapies for Alzheimer's Disease: Promises & Challenges

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Developing New Therapies for Alzheimer's Disease: Promises & Challenges Powered By Docstoc
					Jeffrey Cummings, MD Mary S. Easton Center for Alzheimer’s Disease Research Deane F. Johnson Center for Neurotherapeutics David Geffen School of Medicine at UCLA Los Angeles, California, USA

Dr. Cummings has provided consultation to Acadia,  ADAMAS, Astellas, Bristol Meyers Squibb, Eisai,  EnVivo, Forest, GlaxoSmithKline, Janssen, Lilly,  Lundbeck, Medivation, Merck, Merz, Myriad,  Novartis, Noven, Pfizer, Prana, reMYND, Schering‐ Plough, Signum, Sonexa, Suven, Takeda, Wyeth  pharmaceutical companies. Dr. Cummings owns stock in ADAMAS, Prana,  Sonexa Dr. Cummings owns the copyright of the  Neuropsychiatric Inventory

Targeting Aß Why Aß may not be the best target for  Alzheimer’s type dementia Targeting tau Targeting “downstream” events Some unresolved issues

Amyloid-ß protein

Amyloid protein is the central cause of AD
Autosomal dominant AD ‐ over production Sporadic AD – mostly excessive accumulation

All AD have amyloid plaques All AD mutations cause Aß overproduction AD tg mice over produce Aß Predisposing genotypes increase Aß
ApoE‐4 allele SORL1 polymorphism

The oligomer is the neurotoxic species of Aß Monomers are not neurotoxic Plaques are  composed of nontoxic fibrillar  amyloid Aß 42 is the neurotoxic form of Aß Aß42 oligomerizes more readily than Aß 40  0r Aß 38

BetaSecretase

GammaSecretase

Aß Degra dation

ß-amyloid

Amyloid peptide (monomer/soluble) Amyloid oligomer (soluble)

Aß Fibrillization

Plaque (insoluble)

©Jcummings, 2009

Decrease production
Beta‐secretase inhibitors Gamma‐secretase inhibitors

Increase degradation
Rosiglitazone

Decrease aggregation
PBT2, AZD 103

Increase removal
Immunotherapy (AAB‐001, IVIg)

BetaSecretase

GammaSecretase

ß-amyloid

ß or Gamma secretase inhibitors and modulators Increase degradation Aggregation inhibitors

Plaque removal; decreased deposition

©Jcummings, 2009

APP
BetaSecretase

BACE inhibitors Difficult target Few agents in trials Few anticipated off‐ target effects Example
Memapsin 2 inhibitors

Crystal structure of ß-secretase
©Jcummings, 2009

BetaSecretase

GammaSecretase

ß-amyloid

Protease inhibitors More tractable target Anticipated off‐target  effects Example
LY‐450139
Components of Gamma-secretase: PS1, nicastrin, APH-1, PEN-2
©Jcummings, 2009

BetaSecretase

GammaSecretase

ß-amyloid

Modulation of Gamma‐ Secretase Cleavage site change from  Aß 42 ‐> Aß 38 Less aggregation Less toxicity Fewer anticipated off‐ target effects Example Tarenflurbil Eisai compound
©Jcummings, 2009

BetaSecretase

GammaSecretase

ß-amyloid
• Insulin degrading enzyme (IDE) • Neprilysin • Inhibition of plasminogen inhibitor activator (inc plasmin) • Others - Rosiglitazone

Aß in IDE
©Jcummings, 2009

Aggregation
BetaSecretase GammaSecretase

LTP/memory effects Neurotoxicity

Inhibitors
Scyllo‐inositols
▪ AZD‐103

ß-amyloid

Metal‐protein  attenuating compounds
▪ PBT2

©Jcummings, 2009

ß-amyloid

Immunotherapies
Peripheral sink with  passive removal of Aß  from the brain Activated microglia with  active Aß removal

Vaccination Passive immunization
AAB‐001 (Bapaneuzumab) IVIg (Gammagard)

©Jcummings, 2009

Approaches to 
Decrease synthesis Increase degradation Decrease aggregation Decrease entry into the CNS Increase removal

None validated; one “win” will validate the Aß  hypothesis

Amyloid can exist in the brain with limited toxicity Cognitively normal aged persons may have  substantial Aß in the brain 20% of normal elderly have positive PIB scans  consistent with fibrillar Aß Focal Alzheimer clinical syndromes have extensive  Aß in the brain (e.g., logopenic form of AD) AD‐dementia and AD‐MCI patients have equivalent  PIB scans

PIB scans do not change with dementia severity  (suggesting stable Aß  levels) CSF Aß levels do not change after the onset of  dementia Removal of Aß plaques in vaccination trials has not  interrupted progressive dementia

If Aß can exist in the brain without toxicity, then Aß may not be the best anti‐AD therapy If Aß sets of a chain of events leading to dementia,  then Anti‐Aß therapy might prevent AD if given early

There is no evidence that ß‐ and gamma‐secretase  decrease in activity as AD advances BACE activity increases with oxidative stress Cognitive decline correlates with total Aß (soluble  and insoluble) Aß is toxic in some cell culture models in the  absence of tau

Tau protein

NFT correlate with dementia severity Tau aggregation can cause dementia in the absence  of Aß (frontotemporal dementia) APP tg mice lacking tau to not develop behavioral  deficits1 Temporal atrophy over one year correlated with CSF  p‐tau2 Tau hyperphosphorylation might be an  “implementation” pathway for Aß
(1Roberson ED et al, Science 2007; 316: 750-754; 2Leow AD et al, Neuroimage 2009; 45: 645-655)

Kinases phosphorylate tau GSK3‐ß inhibitors  (valproate, lithium) CDK5 inhibitors Phosphatases  dephosphorylate tau PP2A modulators  Other approaches Aggregation inhibitors

Aß peptide

Oligomer Plaque

Neurofibrillary Tangles

Oxidation

Ecitotoxicity

Inflammation

Mitochondrial Effects

Apoptosis

Synaptoxicity, Cell Dysfunction, and Cell Death
©Jcummings, 2009

Agent Dimebon AL 208 Methylene blue (Rember) Anavex 141 Bryostatin HDAC inhibitors Resveratrol

Process/Pathology Mitochondrial permeability transition pore inhibition Decrease tau hyperphosphorylation Dec tau aggregation Anti-apoptotic effects Increases synaptogenesis Restore transcriptional balance; neuroprotection Anti-oxidant; neuroprotection

Intracellular Aß

• Aß injury to mitochondria • Calcium enters cells (through mPTP) • Generation of reactive oxygen species • Caspase activation • Cell death • Therapeutic target - Dimebon

Cell Death
©Jcummings, 2009

Defining early AD Deciding when to go to Phase III Defining disease‐modification Determining a minimally clinically important  change Some unintended consequences of disease‐ modification

Current definitions define Alzheimer’s  dementia
DSM – dementia of the Alzheimer type NINCDS‐ADRDA – probable AD, requires the  presence of dementia

Disease‐modifying therapy should be  implemented early to minimize cognitive loss Definition of pre‐dementia AD is required

Episodic memory impairment Documented Progressive Isolated or part of a larger syndrome Biomarker evidence of AD Medial temporal atrophy on MRI Biparietal hypometabolism on FDG PET Amyloid signal on amyloid PET CSF:  decreased Aß, increased tau/p‐tau First degree relative with APP or PS mutation

(Dubois B, et al. Lancet Neurol 2007; 6: 734-746)

Includes both
MCI of the Alzheimer type Dementia of the Alzheimer type

MCI would no longer be a separate condition Assist in constructing trial populations and  drug development Facilitate regulatory discussions Likely to be highly specific with some  sacrifice of sensitivity; requires study Challenging to apply in clinical practice

Increasing Alzheimer’s Pathology Mild Cognitive Symptoms

No Symptoms
Time

Dementia

• Increasingly severe phenotype • Biomarkers assist in identifying the underlying pathology • Biomarker changes may precede clinically detectable changes
©Jcummings, 2009

Traditional Model
P1: Safety P2: Clinical  POC; Dose P3: Efficacy (Pivotal) FDA; Approval

Disease‐Modifying Drug Model
P1: Safety P2 P3: Efficacy (Pivotal) FDA; Approval

POC – proof of concept

Adequately powered,  18 mo P2 study IS P3

Proceed to P3 with  Pharmacologic, not Clinical POC
©Jcummings, 2009

Clinical evidence – requires larger sample (≈  400‐600 per arm) and long exposure (12‐18  months) Biomarkers
Limited experience in trials ADNI data are helpful  There is no established predictive relationship  between any treatment‐related biomarker change  and the clinical response to therapy

MRI – no precedent; standardization issues CSF Aß and tau – magnitude and time course  are uncertain PIB – plaques are themselves probably not  the main target; time course of reduction (if  any) is uncertain Aß production – promising; relationship to  clinical outcomes is uncertain

• •

No consensus definition of D‐M Two elements required
• Effect the underlying disease process leading to  cell death • Delay the progress of Alzheimer’s disease
Slowing of decline Delay of significant disease milestones Reduced slope of decline Increasing tx‐pbo difference over time
(Cummings JL. Alz Dem 2006; 2: 263-271)

D‐M:  Increasing Drug‐Placebo Different Over Time
20

10 1 2 3 Years
©Jcummings, 2009

MMSE

4

5

25% slowing is considered a reasonable therapeutic  target
Assuming 2 MMSE points loss per year 25% slowing ‐> 1 MMSE point difference at 2 years ‐> 2 MMSE points at 4 years

25% drug‐placebo difference would equate to 6  month delay after 2 years of treatment, 1 year delay  after 4 years of treatment

Would mean 25% longer in each stage of disease Long term persistence required for benefit Benefit limited Minimal acceptable difference
How much? Who defines? What is the role of FDA in this question? How will payers regard this?

The amyloid oligmer hypothesis informs  much of the current therapeutic quest in AD Aß therapeutics may involve production,  degradation, oligomerization, or removal of  Aß Aß therapies might be optimal for AD  prevention Tau abnormalities correlate with the  emergence of cognitive symptoms

Non‐Aß “Downstream” targets may offer  therapeutic opportunities There are many uncertainties in AD  therapeutics
When to treat How to know the target has been engaged Relationship of biomarkers to clinical outcomes Minimal acceptable clinical benefits


				
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Description: Multiple Therapeutic Approaches sought for A.D. as of November 2009