The Potential for New Treatments for Alzheimers Disease: Where Are - - PowerPoint PPT Presentation

1

1

The Potential for New Treatments for Alzheimer’s Disease: ‘ Where Are We Headed ?’

• Dr. Howard Feldman

Professor of Neurology Executive Associate Dean, Research Faculty of Medicine University of British Columbia

2

2

Disclosure

 From 2009-2011, Dr. Feldman was on leave from

UBC and employed full-time at Bristol-Myers Squibb Company in Connecticut where he directed Global Clinical Research in Neuroscience

3

3

Objectives

 To understand the underlying basis of Alzheimer’s

disease and how the disease evolves

 To briefly review the current treatments of the disease  To anticipate new treatment approaches that are being

tested in research today

4

4

August D : The first clinical and pathological description of Alzheimer’s Disease (1906)



Memory:

 Rapidly worsening forgetfulness  Couldn’t negotiate around her

house



Language:

 Decreased comprehension  Errors in language 

Orientation

 Perplexed in the hospital  Entirely disoriented 

Behavior ■ Yelling loudly fearful



Other features

 Normal gait and extremities Alzheimer A Allgemeine Zeitschrift fur Psychiatrie 1907;64

5

5

Title “On the peculiar disease process of the cerebral cortex” Über eine eigenartige Erkrankung der Hirnrinde; Alzheimer 1906) Allgemeine Zeitschrift fur Psychiatrie 1907;64

Neuropathology of August D (1906)

• Dr. Alzheimer reported her case to a psychiatric

conference in Tübingen

3 Key Neuropathological Findings:



Damage to neurons and  numbers



Brain atrophy



Progressive accumulation of abnormal material in the brain and blood vessels – amyloid plaques (amyloid core) – neurofibrillary tangles (p-tau)

6

6

Amyloid Precursor Protein (APP)

NH2

γ - secretase β-secretase Protofibrils Oligomers

Amyloid β (Aβ) Species 1-40,1-42 Membrane

Brain Amyloid:

Processing to Neuritic Plaques and Blood Vessel Walls

Brain amyloid Blood vessel amyloid

7

7

Clark et al. JAMA. 2011;305:275-283.

7

PET Scanning to Image Brain Amyloid

β-Amyloid antibody 4G8 Immuno histochemistry

β-Amyloid burden = 7.92%

Mean cortical SUVR = 0.87, PET score = 0

SUVR

β-Amyloid burden = 0.15% Mean cortical SUVR = 1.17, PET score = 2 β-Amyloid burden = 1.63% Mean cortical SUVR = 1.68, PET score = 4

AV 45 Scans

8

8

Tau Processing to Tangles

Querfurth HW, LaFerla,FM N Engl J Med 2010:362:329-44

Tangles Tau Paired Helical Filaments Tau abnormalities can be measured in spinal fluid Tau protein

9

9

Serial MRI Scans Over 36 Months: Early AD

Courtesy of Dr. Nick Fox London UK

Medial Temporal Lobe Coronal MRI

10

10

Sperling R, et al. Alz and Dementia. 2011;7:280-292.

Clinical disease stage

Asymptomatic Mild Cognitive Impairment Dementia

Normal Biomarker magnitude Abnormal

Aβ accumulation (CSF/PET) tau-mediated neuronal injury (CSF) Brain structure (volumetric MRI) Cognition Clinical function Synaptic dysfunction (FDG-PET/fMRI)

Alzheimer’s Disease Pathogenesis: An Empiric Model

Aβ CSF PET FDG-PET fMRI Tau CSF vMRI Clinical function Cognition

11

11

The Pathogenic Cascade of AD

Synapse dysfunction Oxidative stress Inflammation Calcium dysregulation Impaired plasticity and neurogenesis Neuro- transmitter imbalances Antecedent events Genes/environment Aβ production, Aggregation, clearance Tangle formation

Modified from Mattson MP, et al. Nature 2004 Snowdon D et al JAMA 1996

Brain co-morbidities: infarcts, other protein aggregates, aging Evolution over Decades

12

12

Therapy for AD: The first hundred years and looking forward……….

The cholinergic hypothesis 1906 1910 2004 1982 1974 1997 Memantine NMDA Uncompetitive Receptor Antagonist 2010 2015 Acetylcholinesterase inhibitors (AchEI), ? First Disease Modifying Treatments Passive immunotherapy ■ IVIG ■ Bapineuzumab ■ Solaneuzumab

13

13

Rogers SL et al, Neurology 1998

Donepezil and Cognition Mild to Moderate AD (MMSE 12-24)

Decline

Placebo 5 mg/day 10 mg/day p < 0.0001

Total ADAS- Cog

(Mean±SE)

6 12 18 24 30

• 3
• 2
• 1

1 2 3 4

Memory Attention Language Praxis Orientation Reasoning

14

14

donepezil (endpoint) placebo (endpoint) 5 10 15 20 25 30 35 40 45 50

Moderately Improved Minimally Improved No Change Minimally Worse Moderately Worse Markedly Worse

Percentage of patients

• 1.9%

+17% +11 %

• 16.8%
• 8.2%

0%

Donepezil: Clinical Global Impression of Change Mild to Moderate AD

Rogers SL et al, Neurology 1998

15

15

Endpoint LOCF

/28 p<0.05 p<0.001

p<0.01

Worsening Improvement

Memantine and Neuropsychiatric Symptoms Moderate to Severe AD

p<0.001 p<0.05

• 2
• 1.5
• 1
• 0.5

0.5 1 1.5 2 2.5 3 4 8 12 16 20 24 28 Treatment week

LS mean change from baseline in NPI total score

Memantine Placebo

Pooled data, mod to severe AD (MMSE <20) NPI total score 6 RCTS

Gauthier S et al ICAD Poster Presentation 2006

16

16

Amyloid-Related Approach to Potential New Treatment

Courtesy of Dr. Norman Relkin, Weill Cornell Medical School, New York, NY.

Deposition Production Aggregation

Antisense

Si RNA

Senile Plaque APP APP gene Aβ Monomer Aβ Oligomer Aβ Fibril Diffuse Plaque

Secretase inhibitors & modulators Beta and Gamma Secretase inhibitors & modulators Fibrillogenesis modulators Scylloinositol Tramiprosate Immunotherapy Bapineuzumab Solaneuzumab IVIG Fe, Cu2+ Chelator PBT2

17

17

Amyloid and Tau Directed AD Clinical Trials

Phase III Results: Negative

 Xaliproden   Tramiprosate  Tarenflurbil   Semagacestat  Rage Inhibitor

Phase III Trials: in process

 Dimebon  Bapineuzumab  Solanezumab  Intravenous Gamma Globulin (IVIG)   TauRx

18

18

Bapineuzumab: Phase 2 Clinical Outcomes

Salloway S et al Neurology 2009

N= 234 5 arm trial

19

19

Summary

 There are no ‘new’ treatments today for AD

 Current standards include AchEIs and Memantine  Major unmet need for symptomatic and disease modifying

treatments

 Better understanding of the disease pathway and in-

vivo biomarkers

 Potential for earlier intervention; stage is set  Awaiting amyloid-lowering immunotherapy trials  Tau/microtubule targeted treatments starting in Clinic

 “Amyloid may be necessary but not sufficient to cause

• r treat the disease “

20

20

UBC CARD Research

Acknowledgments

Ian Mackenzie Claudia Jacova GY Robin Hsiung Blair Leavitt Pheth Sengdy Brad Hallam Dean Foti Lynn Beattie A Jon Stoessl Tom Ruth Dessa Sadovnick Sherri Hayden Emily Dwosh Rachel Butler Judy Illes Michele Assaly Benita Mudge Many others…….

Support from the Ralph Fisher & Alzheimer Society of BC Professorship in Alzheimer’s Research

Brain Research Center The ACCORD Study

Collaborations To our patients and families who trust and share in what we are trying to advance and participate in our studies…………..

21

21

The End…………………

22

22

Treatments Directed at Microtubules and Tau Pathology

Adapted from Brunden et al Nature Rev Drug Discovery 2009; Boutajangout et al J Neurosci 2010

Epothilone D Paclitaxol Davunetide HDAC Inhibitors Tideglusib GSK 3 Inhibitor Lithium, Valproate Davunetide NAP Immunotherapy directed at tau oligomers Methylene Blue

23

23

Tau Function & Potential Disease-Modifying Targets

 Tau protein binds & stabilizes microtubules  Phospho-Tau aggregates linked to neurodegeneration

by familial mutations & preclinical studies

 Complements Aβ approaches

2 3

Microtubule

Tau protein P Misfolded Hyperphosphorylated Tau Oligomers Tangles Microtubule Stabilizers (Epothilone) Kinase Inhibitors Gsk3b Refold/ Degrade

Neurodegeneration Cognitive deficits

24

24

Tau and MT Function: Tangle Formation

Brunden et al Nature Rev Drug Discovery 2009

25

25

MT Stabilization for Tauopathies

2 5

 Abnormal Tau disrupts microtubules in neurons from

mice, Drosophila, and Aplysia

 Microtubule abnormalities are prevented by low

concentrations of microtubule stabilizers, such as BMS-241027

 Studies at BMS and UPenn show that BMS-241027

prevents behavioral deficits and neurodegeneration in Tau transgenic mice

Shemesh and Spira (2010) Acta Neuropathol 120: 209

Control Neuron Neuron expressing mutant Tau

26

26

27

27

Paclitaxol and Mt human tau mRNA

Shemesh, O et al Neurobiol Dis (2011); Bruden KR et al J Neurosci 2010

28

28

Exploratory Discovery for Anti-Tau Therapies

2 8

 mEPSC Peak Amplitude and

Frequency are Reduced in TauP301L Neurons

 These deficits can be

rescued by compounds or shRNAs providing an assay to evaluate new targets

Tau-P301L Neurons Wild-type Neurons

20 pA 0.5 seconds

29

29

Normal and Hyperphosphorylation of Tau

30

30

Schematic Model of Fibrillar Tau and Neuropil Threads

Brunden et al Nature Rev Drug Discovery 2009

31

31

Current Research Approaches to Amyloid Immunotherapy: Enhancing Clearance

Therapy Bapineuzumab Solanezumab IVIg Other name(s) AAB-001 LY206430 IGIV 10% Corresponding mouse monoclonal 3D6 m266 N/A Aβ epitope N-terminus (1-5) Internal (16-23) Polyclonal Manufacturer Janssen AI Eli Lilly Baxter Clinical trial phase 3 3 3

Samadi and Sultzer. Exp Opin Biol Ther. 2011;1 Citron. Nat Rev Drug Discov. 2010;9:387-398.

Bapineuzumab Aβ 1-5 Solanezumab Aβ 16-23 Gantenerumab

Aβ

C-terminus N-terminus Ponezumab

32

32

Sites of Action for Anti-Aβ Therapies

Gandy et al. J Clin Invest. 2005;115:1121.

Bapineuzumab Gantenerumab Solanezumab Bapineuzumab Gammagard ??? BMS-708163 Bapineuzumab

33

33

Sites of Action for Anti-Aβ Therapies

Gandy et al. J Clin Invest. 2005;115:1121.

Bapineuzumab Gantenerumab Solanezumab Bapineuzumab Gammagard ??? BMS-708163 Bapineuzumab

34

34

DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA

Molecular Epitopes for Aβ Antibodies

Bapineuzumab Aβ 1-5 Solanezumab Aβ 16-23 Gantenerumab Amino terminal + central domain? Aβ epitope may play a role in mechanism Any predicted differences in efficacy or safety? Aβ

35

35

DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA

Molecular Epitopes for Aβ Antibodies

Bapineuzumab Aβ 1-5 Solanezumab Aβ 16-23 Gantenerumab Amino terminal + central domain? Aβ epitope may play a role in mechanism Any predicted differences in efficacy or safety? Aβ

36

36

Memantine and Cognition Moderate to Severe AD:

Mean Change From Baseline in SIB Score

• 12
• 10
• 8
• 6
• 4
• 2

2 4 12 28 Week

Memantine

Placebo End Point

*P=.002 P<.001 P=.068

Improvement Deterioration Memantine

Placebo

MMSE 3-14 Mean 7.9

Reisberg B, et al. N Engl J Med 2003;348:1333-1341

37

37

Donepezil and Neuropsychiatric Symptoms

Moderate -to-Severe AD

• 8
• 6
• 4
• 2

2 4

LS mean change from baseline ± SE

24 18 12 8 4 Better Worse Baseline ITT LOCF

Study week

Placebo

P = 0.0303 P = 0.0618 P=0.0083 P = 0.0005

Donepezil

Feldman H et al. Neurology 2001;57:613-620

38

38

Galantamine in Mild to Moderate AD

Individualized Assessment: Goal Attainment Scaling

ADAS Cog Goal Attainment Scaling

Dbl blind OL Dbl blind OL

Rockwood K et al Can Med Assoc J 2006; 174(8) 1099-105 Patients; caregivers; and clinicians:  set most goals in areas of cognition and function ((67% and 60%)  fewest in leisure and social activities (14% and 19%).

39

39

Patients with adverse events >3% and >2 fold rate vs other group

Doody RS et al. Lancet 2008; 372: 207–15; Data are number (%).

40

40

Adverse events and deaths

Doody RS et al. Lancet 2008; 372: 207–15; Data are number (%).

41

41

Scyllo-inositol in Mild to Moderate AD

 Phase 2 trial: ELND005 missed the primary endpoints of

improving ADCS ADL and NTB

 Design: 3 treatment arm dose finding trial (250, 1000 and

2000 mg doses)

 Treatment with 1,000 and 2,000 mg doses were d/ced

due to rates of infection and death .

 Biomarkers:  250 mg arm associated with significantly reduced CSF

beta amyloid 42 at 78 weeks compared with placebo. ─ But those patients also had significantly increased ventricular volume. ─ Ventricular dilation accompanies AD progression and can transiently reduce CSF beta amyloid concentration.

 Unclear if ELND005 ameliorates or accelerates disease

progression.

42

42

43

43

Current Therapies for AD

 Current therapies have short-term benefits  Effect sizes with AchEIs are small but reproducible

 Cognitive benefits translate into overall function  Descriptions of qualitative response around ‘intention’ and

‘engagement’

 Unmet needs

 Better options for neuropsychiatric symptoms  Treatment with larger effect sizes on cognition  Longer term effects and modification of underlying disease

─ Amyloid lowering and tau/microtubule approaches