Transcript Presentation - American Society for Experimental NeuroTherapeutics

Of Mice and Men: How Temporal
and Other Biological Factors Affect
Interpretability of Animal Models
March 1, 2013
Gene G. Kinney, Ph.D.
Prothena Biosciences
American Society for Experimental NeuroTherapeutics | 15th Annual Meeting
Disclosure
Name of Commercial
Interest
•
•
Bristol-Myers Squibb;
Merck & Co.; Elan
Pharmaceuticals; Janssen
Alzheimer
Immunotherapy
Prothena Biosciences, Inc.
Type of Financial
Relationship
• Former employee and
current shareholder (Elan
and Bristol-Myers Squibb)
• Current employee and
shareholder
American Society for Experimental NeuroTherapeutics | 15th Annual Meeting
Learning Objectives
• Using animal models of Alzheimer’s disease and
anti-Aβ immunotherapy as a case study,
illustrate:
• The strengths and limitations of animal model results
for predicting clinical efficacy
• The importance of iterative translation during clinical
development
≠
http://3.bp.blogspot.com/8mjLTwgy_3w/UG2cW1Da9VI/AAAAAAAAEME/Mw3nTKKAWoA/s1600/dem
entia_83248459.jpg
American Society for Experimental NeuroTherapeutics | 15th Annual Meeting
Exemplifying the obvious
• Most cases of Alzheimer’s disease
are diagnosed§ at age ≥ 65 yrs
with a median survival of 4-8 years
post-diagnosis
• In a “modestly aggressive” mouse
model of AD (PDAPP) the average
age for onset of pathology is ~12
months of age*
• It is generally believed that
Alzheimer’s disease pathology can
begin ≥ 20 yrs prior to diagnosis
• The average lifespan of a PDAPP
mouse is ~18-32 mos
§Traditionally a
* some deficits generally attributable to soluble Aβ aggregates are
observed pre-pathology
differential diagnosis based on dementia. Recent
move to more biologically-based definitions.
http://ars.els-cdn.com/content/image/1-s2.0-S0924977X02001037-gr1.jpg
4
Alzheimer’s disease biology
• First identified in 1907 by Alois Alzheimer
based on post-mortem evaluation of
demented patients
– Extracellular plaques and intracellular tangles;
but cause or consequence?
Alois Alzheimer
Auguste D
Brunden et al., Nature Reviews Drug Discovery 8, 783-793
(October 2009)
5
plaques
Amyloid β
tangles
Tau
Production inhibitors
Immunotherapeutics
Clearance enhancers
Anti-aggregate and “plaque
buster”
Kinase inhibitors
(phosphorylation)
Microtubule stabilization
Development of the PDAPP mouse model
enabled initial immunotherapy studies
• Focus on pathological contributions to disease
• Development of the first plaque forming mouse model was
enabling for the testing of putative therapeutic approaches
designed to be “disease modifying”
Plaque formation
Non-Tg
PDAPP
Loss of synaptic
integrity
Loss of neuronal
integrity
Games et al., Nature, 373:523, 1995
6
Anti-Aβ immunotherapy: Background
• Anti-Aβ immunotherapy proposed as a therapeutic approach for the
removal of Aβ from the CNS (Schenk et al, Nature, 400:173, 1999)
Vehicle
Immunized
Reductions in dystrophic neurites and astrogliosis also
observed following immunization
UTC = untreated controls
SAP = immunization with serum amyloid P
PDAPP mice immunized between 6 wks and 13 mos
7
Translational aspects of anti-Aβ
immunotherapy
8
Anti-Aβ immunotherapy: Background
• Elan/Wyeth anti-Aβ vaccine (AN-1792) demonstrated activity
on some endpoints in clinical trials
– Reduction of senile plaque and cognitive benefit on NTB
9
Anti-Aβ immunotherapy: Background
• AN-1792 trials were discontinued following reports of
meningoencephalitis in ~6% of the active treatment group
– T-cell mediated response to the self-antigen is a likely cause
10
Translational aspects of anti-Aβ
immunotherapy
11
Next generation approaches include
passive and active immunization
Schenk, Nature Reviews Neuroscience 3, 824-828 (October 2002)
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Median Aβ burden values following
passive immunization: 6 mo treatment
TY11/15
10.23%
3D6
Treatment
% control
TY11/15
100
3D6
7
0.69%
PDAPP mice
(N>30/group)
treated with 3 or
10mg/kg/week at
12-18 months of age
Similar effects on:
• Neuritic dystrophy
• Brain Aβ levels (ELISA)
Seubert et al., Neurodegenerative Dis, 5:65, 2008
13
The discovery of the Pittsburgh Compound-B (PiB) tracer
allowed for PET imaging of amyloid deposition in AD
patients
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Bapineuzumab decreases amyloid burden in
human subjects using [11C] PiB PET imaging
• N=28 patients with mild to moderate
AD
• Randomized to intravenous
bapineuzumab (N=20) or placebo
(N=8) in three ascending dose cohorts
(0.5, 1.0, or 2.0 mg/kg)
Rinne JO et al., Lancet Neurol., 9:363, 2010
15
MRI observations consistent with transient edemic events were
observed following Bapineuzumab treatment
• 69-year-old APOE ε4 homozygote Female
• Treated with bapineuzumab 1.0 mg/kg IV. Remained asymptomatic despite the
appearance of multiple areas of ARIA evident on MRI. Patient was redosed at 0.5
mg/kg and followed for over 2 years without recurrence of ARIA
Salloway, S. et al. Neurology 2009;73:2061-2070
• Reported by Salloway et al., 2009 (Phase 2 data)
• Anti-Aβ edemic events appear sensitive to Bapineuzumab dose and APOE ε4
gene dose
• Events were transient in some cases and did not recur following redosing in a
limited data set
16
Clinical evidence suggests that ARIA may
be related to Aβ mobilization
17
Translational aspects of anti-Aβ
immunotherapy
18
Preclinical studies designed to further
understand the biology of ARIA
3
• The brain capillary network
appears to be involved in
antibody induced amyloid
removal
Normal
2
A. Wild Type
1.5
1
0.5
0
0
20
40
60
80
100
120
140
160
180
Region Label
3
3
Wild-type
Wild-type
2.5
• Aβ deposition on brain
vasculature may impair
vessel integrity, recovery
following removal of
vascular Aβ
Wild-type
B. PDAPP
Wild-type
Vascular
Aβ
2.5
PDAPP
2.5
2
2
1.5
1.5
1
1
0.5
0.5
0
0
0
20
40
60
80
100
120
140
160
180
Region Label
2.5
20
40
60
80
100
120
140
160
180
Vascular Wild
Perimeter
PDAPP – 3D6
Type
(9 months)
PDAPP – TY1115
PDAPP
(9 months)
C.
0
Region Label
3
2
1.5
1
• Key proteins involved in
resolution of edemic
events may be modulated
during the process of
immunotherapy induced
clearance of Aβ
0.5
0
0
20
40
60
80
100
120
140
160
180
Region Label
Vascular Perimeter
Zago et al., Alz. & Dement., In Press
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More work to do
How is the disease defined?
Alzheimer’s Pathology,
disease
– Dementia,
mix?
– MMSE;
ADAS-Cog;
etc. tools
Assessed
by broadCDR-SB
based cognitive
Dementia
Pathology
that may also incorporate function (e.g.,
MMSE, ADAS-Cog; CDR-SB); mixed
dementia also possible
Likely mixed (e.g., tau, α-synuclein, etc)
hAPP Tg mouse models
- Models
Spatial
learning
/ memory;
arereference
primarily driven
by pathology
Episodicassessment
memory of cognition tends to be
endpoints;
very precise (e.g., spatial reference
learning/memory; episodic memory, etc.)
Homogenous population, pathology driven in
specific tissues through use of promoters; often
involves point mutations for more aggressive
phenotype
Staging of disease
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Alzheimer’s disease
hAPP Tg mouse models
Stage at
Diagnosis
Generally believed to be advanced
pathology at point of diagnosis
Not applicable; diagnosis based on pathological
involvement
Optimal
point of
intervention
Extensive efforts to identify earlier
intervention times
• All currently completed disease
modification trials have studied
mild/moderate patients
Data suggests that earlier intervention is more
effective
• Late intervention may still be effective for
some experimental approaches
Even more work to do
How do key aspects of intervention therapy translate?
– Dementia,
Pathology, mix?
Alzheimer’s disease
– MMSE; ADAS-Cog; CDR-SB etc.
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Magnitude
of insol. Aβ
reduction
Modest reduction from baseline in treated
patients. Continued accumulation in
placebo patients.
Dose Level
Dose of bapineuzumab (and other
agents?) may be limited by ARIA
hAPP Tg mouse models
Spatial reference learning / memory;
~70 Episodic
to ≥90% reductions
memory depending on time of
-
intervention relative to pathology onset
Clear relationship between dose level, time of
intervention and duration of treatment
Contextual Fear Conditioning has been developed as a
sensitive functional cognitive measure
1mAmp
120s
Training (Day 1)
22
2s
1mAmp
120s
Context
Comery et al., J. Neurosci. 2005;25:8898-8902
2s
30s
Shock
Common Clinical Assessment Tools
http://www.mdanderson.org/publications/conquest/issues/2008-fall/old-drugs-new-possibilities-conquest-fall-2008-old-drugs-new-possibilities.html
http://ginny-livingwithlyme.blogspot.com/2012/10/spinal-tap-3.html
http://www.nimh.nih.gov/images/pubs/neuro-pet.jpg
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Summary
•
Although many (if not most) human diseases cannot be fully recapitulated by
animal models, key aspects of the disease process are reproduced
– Key breakthroughs in biological understanding of the disease processes
– Useful models for testing interventional therapy
•
Animal models are most effectively utilized when there is a full understanding
of the limitations around the translation of the models to human disease
– How is “efficacy” defined both pre-clinically and clinically
– Clinical trial design limitations must be considered
•
•
•
•
Heterogeneity of human subjects
Limitations around invasive endpoint assessment
Potential disconnect between “biological” and “pathological” disease definitions
Clinical development will often result in unpredicted findings necessitating
iterative translational approaches
– AN-1792 immunization in AD patients resulted in meningoencephalitis in ~6% of the active
treatment group
• New approaches to avoid Aβ directed T-cell responses are being tested clinically (passive and active
immunization)
– Reports of radiologically identified edemic events following passive immunization have led to
additional preclinical studies using the PDAPP mouse model
24
Acknowledgements
Elan Pharmaceuticals / Prothena
Biosciences / Janssen AI
Robin Barbour
Manuel Buttini
Dora Games
Michael Grundman
Stefan Heylen
Mike Lee
Ruth Motter
Sally Schroeter
Eric Yuen
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Bob Brashear
Ming Chen
Henry Grajeda
Terry Guido
Karen Khan
Enchi Liu
Dale Schenk
Peter Seubert
Wagner Zago
Wyeth / Pfizer
Davinder Gill
Steven Jacobsen
Tom Comery
Menelas Pangalos