87
Company Confidential www.p1vital.com 1 ECNP Summer School – 28 June 2016 How pharmaceutical companies develop new drugs Gerry Dawson P1vital LTD.
Company Confidential www.p1vital.com 1
ECNP Summer School – 28 June 2016
How pharmaceutical companies develop
new drugs
Gerry Dawson
P1vital LTD.
www.p1vital.com
Overview
1
Introduction
Drug Targets
Developing a drug
New Approaches You Decide
www.p1vital.com
Discovery
Exploratory Development
Full Development Registration
Project Team
and Plans
Synthesis
of Compounds Screening
Studies in Healthy
Volunteers (Phase I)
Early Safety
Studies
Candidate Formulations
Developed
Extensive Safety Studies
NDA/MMA
Studies in 100-300
Patients (Phase II)
Clinical Data
Analysis
Candidate Medicine Tested in
3-10,000 Patients (Phase III) Large Amounts of
Candidate Medicine
Synthesized
The Long Road to a New Medicine
Drug
Slide 3
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Source: Pharmaceutical Research and Manufacturers of America, PhRMA Annual Membership Survey, 2008; CDER
R&D Output Across The Industry is Flat… P
hR
MA
R&
D S
pe
nd
(M
illi
on
s o
f D
oll
ars
)
Nu
mb
er
of
NM
E A
pp
rova
ls b
y F
DA
NMEs Approved
0
5,000
10,000
15,000
20,000
25,000
30,000
35,000
40,000
45,000
50,000 1
99
0
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
0
10
20
30
40
50
60
Slide 4
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Evolving nature of drug approvals
Efficacy
Safety
1970s
Efficacy
Safety
Differentiated
1990s
Efficacy
Safety
Differentiated
Reimbursable
2010s
Slide 5
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Consolidation Has Not Fixed The Problem
Source: Expert Opin Drug Discov 5:813-818 (2010)
Slide 6
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How Does Pharma Emerge From The Crisis?
“We should remember that genomics obeys the
First Law of Technology:
we invariably
overestimate the short-
term impacts of new
technologies and
underestimate their
longer-term effects.”
Francis Collins, NIH
Director
Feb, 2001 Feb, 2001 2011
• New technology should provide the answers
• Molecular biology
• Genomics
• Epigenetics
• Each advance produces more opportunities, and more challenges
Slide 8 Slide 8
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~100 Discovery Approaches
1 –2 Products
High Risk Process
12-15 years, €1.3B*
Attrition is High in the R&D Process
Discovery Exploratory Development
Idea Drug 11 - 15 Years
Full Development
Phase I Phase II Phase III
0 15 5 10
Preclinical Pharmacology
Preclinical Safety
Millions of
Compounds Screened
Clinical Pharmacology & Safety
*Source: DiMasi & Grabowski, Managerial Decision Econ, 2007;28:469-479
Slide 9
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Costs of Drug Development
Current cost of new drug
> £1billion
Success rate
1/10 per new compound
Development Compounds
1970 ~ 10
1995 ~ 12
2000 ~ 15
2004 ~ 40
Active Phase 1 R&D projects
1998=521, 2008=1,265.
Technology driven productivity
Slide 10
Slide 10
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Bottlenecks
Identifying new targets
Preclinical safety
Phase 1 clinical trials
Making Go No/Go decisions on adverse events and
pharmacokinetics
Phase 2 clinical trials
Making Go No/Go decisions based on efficacy
Slide 11 Slide 11
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Sales in CNS estimated to exceed £45,000
million in 2009
Source: (Lehmann Brothers Universe)
£0
£10,000
£20,000
£30,000
£40,000
£50,000
£60,000
Global sales 2009 Estimate £m
Slide 12 Slide 12
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R&D productivity decline
The gap between R&D spend and NMEs is growing
R&D spend was fuelled by sales of antidepressants and cardiovascular drugs
Expectation was that neuroscience would deliver new NMEs
Source: CMR 2008 Factbook and CDER
0
5
10
15
20
25
30
35
40
45
50
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
R&D expenditure UK£ billions No. of NME approvals
Slide 13
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Oncology and CNS top therapeutic
areas in R&D April 2009
0%
5%
10%
15%
20%
25%
30%
35%
% R&D projects
Source: EvaluatePharma April 2009
Slide 14 Slide 14
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CNS has one of the lowest
success rates
Low percentage of success in CNS drug development
second only to oncology and women’s health
Arthritis
+ pain
Cardio-
vascular
CNS Infectious
diseases
Oncology Optha-
mology
Metabolic
disease
Urology Women’s
health
All
11%
20
15
10
5
0
Per
cent
age
of s
ucce
ss
Slide 15
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Lack of efficacy is the main
reason for failure
In 1991 unpredictable PK was the main reason for failure
In 2000 lack of efficacy was the main reason for failure
In 2007 lack of efficacy remains the main reason for failure
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
1991 2000 2007
Kola and Landis 2004 Nature review Drug Discovery and CMR 2008 Factbook
Slide 16
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Phase 2 has the lowest success rate
0%
10%
20%
30%
40%
50%
60%
70%
80%
Phase1 Phase2 Phase3
Source: CMR 2008 Factbook
Slide 17 Slide 17
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Human Studies Phases I,II, III
Drug Candidate safety testing
Animal Studies - knockout mice
- antagonists
Studies of
Disease Mechanisms
Lead Search -robotic assay; -chemical diversity
Target -receptor; -ion channel; -transporter;
-enzyme; - signalling molecule
Drug Approval
and Registration Lead optimisation
-selectivity; -efficacy in animal models;
-pharmacokinetics
Molecular Studies
The Drug Discovery Process
Slide 18
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Research Project Selection
Is there a medical need?
Is there a rational scientific approach?
What is the long-term perspective?
What is the competitive environment?
Do we have in-house expertise and resources?
Slide 19 Slide 19
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Strategy for Drug Discovery
Understand the molecular basis of a disease
Select a therapeutic target (e.g. a ‘receptor’ in the brain)
Link the therapeutic target to a defined mechanism of
action
Discover a compound that is safe, effective and novel
Slide 20 Slide 20
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Drug Targets
Current Targets of drugs in psychiatry/neurology
15 Targets of currently used drugs
Potential Targets
>80 Neurotransmitter/neuropeptide receptors
>30 Ion channels expressed by nerve cells
>160 Orphan GPCRs
>20 CNS specific transporters and enzymes
Slide 21 Slide 21
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BZs are:
Anxiolytic
Muscle Relaxant
Anticonvulsant
Hypnotic
BZs also:
Daytime somnolence
Interact adversely with ethanol
Impair memory
Induce dependence
Cause tolerance
Have abuse potential
What are the in vivo properties
of BZs?
Slide 22
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BZs are:
Anxiolytic
Muscle Relaxant
Anticonvulsant
Hypnotic
BZs also:
Daytime somnolence
Interact adversely with ethanol
Impair memory
Induce dependence
Cause tolerance
Have abuse potential
What are the in vivo properties of BZs?
Do different GABA-A receptor subtypes mediate these various effects?
1. Using GABA-A subtype selective compounds
2. Generating transgenic mice insensitive to BZs at one or more subtype
Slide 24
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Develop compounds that are:
1. Agonists at a2/a3 subtypes
2. Have minimal effects at a1 or a5 subtypes
With the aim that:
1. Anxiolytic activity is retained, but
2. Daytime somnolence, amnesia, dependence and
withdrawal are reduced
Aims
Slide 25
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There are multiple GABA-A receptors
subtypes in the brain
a a a
a a
a
GABAA subunits
Some subtypes bind benzodiazepines
a12 a22 a32 a52
a
a
a
a
a
a
a
a a
a
Slide 26
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F r its c h y a n d M o h le r , 1 9 9 5
GABAA Receptors Containing α1, α2, α3 & α5 subunits have
distinct distributions consistent with different functions
Slide 27
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α1 His101Arg Knock-in Mice
S u b u n it S e q u e n c e D ia ze p a m b in d in g
a 1 8 6 N N L M A S K I W T P D T F F H N G K K S V A H N M T M P N K 1 1 6
a 2 8 6 N N L M A S K I W T P D T F F H N G K K S V A H N M T M P N K 1 1 6
a 3 1 1 1 N N L L A S K I W T P D T F F H N G K K S M A H N M T T P N K 1 4 1
a 4 8 4 N N M M V T K V W T P D T F F R N G K K S V S H N M T A P N K 1 1 4
a 5 9 0 N N L L A S K I W T P D T F F H N G K K S I A H N M T T P N K 1 2 0
a 6 8 5 N L M N V S K I W T P D T F F R N G K K S I A H N M T T P N K 1 1 5
a 1 H 1 0 1 R 8 6 N N L M A S K I W T P D T F F R N G K K S V A H N M T M P N K 1 1 6
M o d if ie d f r o m B e n s o n e t a l ., ( 1 9 9 8 ) F E B S L e t t, 4 3 1 :4 0 0 -4 0 4
Rationale
Normal behaviour of knock-in mice should be the same as Wild Type mice
When diazepam is administered, there is a loss of a1 subunit-mediated effects
see also Rudolph et al., 1999, Nature, 401:796-800
M o u s e D ia ze p a m - in d u c e d b e h a v io u rs C o n c lu s io n
W T A + B + C + D N o r m a l b e h a v io u r a l p r o fi le
a 1 H 1 0 1 R B + C + D a 1 c o n ta in in g G A B A A r e c e p to r s m e d ia te b e h a v io u r A
a 2 H 1 0 1 R A + C + D a 2 c o n ta in in g G A B A A r e c e p to r s m e d ia te b e h a v io u r B
a 3 H 1 2 6 R A + B + D a 3 c o n ta in in g G A B A A r e c e p to r s m e d ia te b e h a v io u r C
a 5 H 1 0 5 R A + B + C a 5 c o n ta in in g G A B A A r e c e p to r s m e d ia te b e h a v io u r D
Slide 28
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BZ Binding Sites Decrease in α1H101R
Knock-in Mice
Total number of GABAA receptors unaltered
α1H101R receptors have normal GABA response
W ild T y p e m ic e
C o m p o u n d a 1 a 2 a 3 a 4 a 5 a 6
D ia z e p a m (V a liu m ® )
[3 H ]R o 1 5 -1 7 8 8 (f lu m a z e n il)
[3 H ]R o 1 5 -4 5 1 3
[3 H ]R o 1 5 -4 5 1 3 + d ia z e p a m
a 1 H is1 0 1 A rg m ic e
C o m p o u n d H a 1 R a 2 a 3 a 4 a 5 a 6
D ia z e p a m (V a liu m ® )
[3 H ]R o 1 5 -1 7 8 8 (f lu m a z e n il)
[3 H ]R o 1 5 -4 5 1 3
[3 H ]R o 1 5 -4 5 1 3 + d ia z e p a m
W ild T y p e m ic e
C o m p o u n d a 1 a 2 a 3 a 4 a 5 a 6
D ia z e p a m (V a liu m ® )
[3 H ]R o 1 5 -1 7 8 8 (f lu m a z e n il)
[3 H ]R o 1 5 -4 5 1 3
[3 H ]R o 1 5 -4 5 1 3 + d ia z e p a m
a 1 H is1 0 1 A rg m ic e
C o m p o u n d H a 1 R a 2 a 3 a 4 a 5 a 6
D ia z e p a m (V a liu m ® )
[3 H ]R o 1 5 -1 7 8 8 (f lu m a z e n il)
[3 H ]R o 1 5 -4 5 1 3
[3 H ]R o 1 5 -4 5 1 3 + d ia z e p a m
Slide 29
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Diazepam is Less Sedating in α1H101R Mice
Mice trained to walk on rotarod for 2 min
Latency to fall off or complete trial (120
sec.) is recorded after dosing
0 10 20 30
0
20
40
60
80
100
120
Diazepam, mg per kg T
ime o
n r
ota
rod,
sec.
* = significantly different from WT
* *
*
WT
a 1H101R
α1-containing GABAA receptors play a role in sedation
Slide 30
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What happens when a GABA
molecule binds?
closed
open
closed
open
Slide 31 Slide 31
Cl-
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What happens when a BZ
molecule binds?
BZ agonist increases GABA binding
site affinity
BZ agonist increases probability of
channel opening while agonist is
bound
closed
open
Slide 32 Slide 32
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Make a compound that does not bind to α1
Place your bets – stake €10M
Slide 33
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Make a compound that does not bind to α1
Place your bets – stake €10M
Slide 34
You lose! – not possible to make an α1 selective compound
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1 0 0 0 0 1 0 0 0 1 0 0 1 0 1
1
0.8
0.6
0.4
0.2
0
Ki 250 nM
Ki 25 nM
[Benzodiazepine] (nM)
Selective affinity
1 0 0 0 1 0 0 1 0 1
1
0.8
0.6
0.4
0.2
0
Ki 25 nM
Ki 25 nM
[Benzodiazepine] (nM)
Selective efficacy
A compound can have selective
affinity or efficacy
Slide 35
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Make a compound that has selective efficacy
Place your bets – stake €30M
Slide 36
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Make a compound that has selective efficacy
Place your bets – stake €30M
Slide 37
You win! – It is technically possible but takes 3 years
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L-838,417 has high affinity for BZ-
sensitive GABAA receptors
N
N
NN
O
F
F
NN
N
L-838,417
Receptor combination
Binding Ki (nM)
a 0.8
a 0.7
a 0.7
a 267
a 2.2 a 2183
Mouse brain 1.2
Slide 38
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….but is an antagonist at the
a1-subtype
100nM L-838,417 100nM L-838417
0
2 0
4 0
6 0
8 0
1 0 0
a 3 3 2
a 1 3 2
a 2 3 2
a
-1 0 -9 -7-8
L o g [ L - 8 3 8 ,4 1 7 ]
% p
ote
nti
ati
on
of
GA
BA
EC
20
a a
Slide 39
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Sub nM affinity for BZ-sensitive GABAA
receptors
L-838417 Receptor
combination
Efficacy % relative to diazepam
a
a
0
a
40
a 40
40
TPA123 TPA023
20
40
40
40
0
30
15
<5
Slide 40
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Vehicle
Diazepam
(10 mg/kg)
Diazepam rate decreasing effects
in the rat chain-pulling test
10 20 30 40 50 60 0
20
40
60
80
100
Time (mins)
% B
asel
ine
chai
n p
ulls
/min
Slide 41
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Subtype selective compounds do not reduce
response rates in the rat chain-pulling test
Vehicle
3 mg/kg
10 mg/kg
30 mg/kg
Diazepam
10 mg/kg
0
20
40
60
80
100
* *
* *
*
0 10 20 30 40 50 60
Time (min)
Mea
n %
bas
elin
e ra
te
a1 is responsible for rate reducing effects
but are anxiolytic effects retained?
100
Vehicle
3 mg/kg
10 mg/kg
30 mg/kg
10 mg/kg Diazepam
0
20
40
60
80
0 10 20 30 40 50 60
Time (min)
L-838417 TPA 023
Slide 42
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Elevated plus maze - unconditioned
anxiety
5 minute trial
Rats spend typically spend <1 min exploring the open arms
Slide 43
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L-838417 TPA 023
Subtype selective compounds are
anxiolytic in the elevated plus maze
* * * *
Veh 10 3 1 CDP 0
10
20
30
40
0
25
50
75
0 Veh 0.3 1 3 CDP 0
10
20
30
40
Percent open arm time
0
20
40
60
80
Percent open arm entries
Perc
en
t o
pen
arm
tim
e
Pe
rce
nt o
pe
n a
rm e
ntrie
s
* * *
Pe
rce
nt
op
en
arm
tim
e P
erc
en
t op
en
arm
en
tries
Slide 44
www.p1vital.com
Route = PO squirrel monkey
Pre-treatment = 30 mins
* p< 0.05 compared to Vehicle
0
20
40
60
80
100
Veh 0.5 1.0 mg/kg
Per
cen
t o
f P
reC
S r
esp
on
din
g
2.0
*
Diazepam TPA023
TPA023 is anxiolytic in primate
0
20
40
60
80
100
mg/kg
Per
cen
t o
f P
reC
S R
esp
on
din
g
Veh 3.0 0.3
*
*
1.0
*
Slide 45
Great but what about side effects?
www.p1vital.com
100 80 60 40 20 0 0 0
20
40
60
80
100
120
L-830,982 Diazepam
Receptor occupancy, %
Tim
e o
n R
ota
rod
, (s
).
100 80 60 40 20 0 0
20
40
60
80
100
120
Receptor occupancy, %
Tim
e o
n R
ota
rod
, (s)
Rotarod + Ethanol
Diazepam
TPA023
TPA023 has a modest interaction
with ethanol
Slide 46
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Which subtypes mediate the effects of BZs?
BZ Property a1 a2/3/5
anxiolysis - exploration - +++
- plus maze - +++
- FPS - +++
Somnolence +++ (+)
Ethanol potentiation +++ +
Cognition + +
Dependence James Rowlett/Nancy Ator
Abuse potential
}
Slide 47
Summary of pre-clinical data
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Go to safety and toxicology – 1 year
Place your bets – stake €10M
Slide 48
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No Go – BZs have abuse potential
FDA say does you compound have abuse potential?
Do abuse potential study
Stake €2 M - 1 year development delay
Slide 49
Patent life (20-4) = 16yrs
Lost sales = €1 b.
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Abuse Potential - Baboon Self Administration
Food available 24 hr
food delivered after 30 lever presses
Cocaine (0.32 mg/kg i.v.) available every 3 hrs (max. 8 injections/day)
cocaine delivered after 160 level presses
Food
Hopper
Food Lever
FR 30 FR 160
Light on - Cocaine
available
Cocaine Lever
Slide 50
Evaluating abuse potential
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Baboon Self Administration
Experimental DesignDesign
Cocaine (IV)
0.32 mg/kg
> 6/day
Mean no.
inject./day
3 days 5 days 5 days 5 days
Cocaine
> 6/day
3 days
TPA 023 (IV)
Baboons cycle between cocaine and drug/vehicle
Results: mean number of injections per day during the final 5 days
Slide 51
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Self-administration of Lorazepam and TPA023 in Baboon
TPA 023 has no abuse potential in baboons
Lorazepam
TPA023
0
1
2
3
4
5
6
7
8
Me
an
In
jectio
ns D
ays 1
1-1
5 V .0032 0.01 0.032 0.1 0.32
Dose (mg/kg, i.v.)
Data from Nancy Ator, Johns Hopkins Univ., Baltimore
TPA023 - Lack of abuse potential
Slide 52
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No abuse potential in baboon!
Place your bets
Stake €10 M - 1 year safety study in you male adults
Slide 53
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No abuse potential
Place your bets
Stake €10 M - 1 safety study in you male adults
Slide 54
Hold on - Does compound actually get into baboon brain
and occupy receptors?
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No abuse potential
Place your bets
Stake €10 M - 1 safety study in you male adults
Slide 55
Does compound actually get into baboon brain and
occupy receptors?
Conduct baboon PET study – 1 year delay cost - €3M
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Baboon PET Scans Following TPA023 Treatment
at full receptor occupancy (0.32 mg/kg) TPA023 has no abuse potential
0
0.5
1
1.5
2
2.5
3
3.5
4
0 15 30 45 60 75 90
time (min)
SU
V
Occ. Cx.
Pons
0.32 mg/kg
Fr. Cx.
CB
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
0 15 30 45 60 75 90
time (min)
SU
V
Occ. Cx.
Pons
Veh.
B a s e lin e 0 .0 0 3 2 m g / k g 0 .0 3 2 m g / k g 0 .3 2 m g / k g
O c c u p a n c y : N / D (± 10 % ) 7 4 % 10 0 %
R. Hargreaves, MRL, West Point, PA
Slide 56
Baboon PET Studies – TPA023
www.p1vital.com
MRK-409 (MK-0343) Non-sedating anxiolytic
in preclinical species
N
N
NN
O
N
N
N
F
F
a a a a8
9
10
11
Ki =0.22 nM
0.40 nM0.21 nM 0.23 nM
pK
i
a a a a0.0
0.2
0.4
0.6
0.8
1.0
Rela
tive e
ffic
acy
0.23
0.45
Rel. eff.=0.18 0.18
Veh. 0.03 0.1 Veh. 0.3 1 30
20
40
60
80
100
*
* *
MRK-409,mg/kg p.o.
*
MRK-409,mg/kg p.o.
Expt. 1 Expt. 2
% b
ase
line
re
sp
on
din
g
Vehicle 1 3 100
20
40
60
80
100
MRK-409, mg/kg p.o.
% b
ase
line
re
sp
on
din
g
B. Sedation - Lever-pressingA. Anxiolysis - CER
Slide 57
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Conduct clinical study?
Place your bets
Stake €10 M - 1 year safety study in you male adults
Slide 58
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MRK-409 (MK-0343) induced sedation at
very low dose
Phase I maximum tolerated single dose = 1 mg
Dose-limiting adverse events (1.5 and 2 mg) = somnolence
0
20
40
60
80
100
1000303 10
Plasma MRK-409, ng/mL
300100 3000 10000
% O
ccupancy
Rat plasma EC50 = 115 ng/mL
0 4 8 120
5
10
15
20
25
30
0.5
1
1.5
0.05
0.1
0.25
2
Time, hr.
Pla
sm
a M
RK
-409,
ng/m
L
Total dose, mg
Plasma Cmax for sedation = 20-30 ng/mL mg
Based on rat plasma-occupancy relationship 20-30 ng/mL = low occupancy
What is the human plasma-occupancy relationship?
Slide 59
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No abuse potential
Place your bets (stake so far = €53 M)
Stake €5 M - 1 year PET study in you male adults
Slide 60
At what receptor occupancy does sedation occur?
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MRK-409 (MK-0343) induced sedation at
very low receptor occupancy
[11C]flumazenil PET studies showed occupancy at 1 mg <10%
Sedation/somnolence occurs at low levels of occupancy
No margin between sedation and potential anxiolysis
S c a n 1 S c a n 2 S c a n 3 S c a n 4
-1 h r 2 h r 6 h r 1 0 h r
S N 1 0 3
S N 1 0 5
S N 1 0 6
S N 1 1 1
S U VS U V
S c a n 1 S c a n 2 S c a n 3 S c a n 4
-1 h r 2 h r 6 h r 1 0 h r
S N 1 0 3
S N 1 0 5
S N 1 0 6
S N 1 1 1
S U VS U V
S c a n 1 S c a n 2 S c a n 3 S c a n 4
-1 h r 2 h r 6 h r 1 0 h r
S N 1 0 3
S N 1 0 5
S N 1 0 6
S N 1 1 1
S U VS U VP la c e b o
M R K -4 0 9
-1 h 2 h
M R K -4 0 9
S c a n t im e :
S c a n 1 S c a n 2 S c a n 3 S c a n 4
-1 h r 2 h r 6 h r 1 0 h r
S N 1 0 3
S N 1 0 5
S N 1 0 6
S N 1 1 1
S U VS U V
S c a n 1 S c a n 2 S c a n 3 S c a n 4
-1 h r 2 h r 6 h r 1 0 h r
S N 1 0 3
S N 1 0 5
S N 1 0 6
S N 1 1 1
S U VS U V
S c a n 1 S c a n 2 S c a n 3 S c a n 4
-1 h r 2 h r 6 h r 1 0 h r
S N 1 0 3
S N 1 0 5
S N 1 0 6
S N 1 1 1
S U VS U VP la c e b o
M R K -4 0 9
-1 h 2 h
M R K -4 0 9
S c a n t im e :
1 mg
1 mg
Development of MRK-409 halted – Start again?
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Conclusions
Even the best characterised animal models do
not predict effects in humans
Path forward is in the clinic from Bed to Bench
patient back to animal – probably
Mantra – ‘Fail early, fail cheap’
90% No/Go, early decisions are cost effective
We failed cheap despite €50M+ costs
Phase 3 failure costs €300M+ costs
• NK-1, bitopertin
Experimental Medicine solutions
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Alzheimer’s disease
Alzheimer’s disease the most common cause of dementia affects 4 million US citizens
As more and more Americans live longer, the number affected by Alzheimer's disease will continue to grow unless a cure or effective prevention is discovered.
Current therapies (cholinesterase inhibitors) have significant limitations Side-effects including nausea, diarrhoea, vomiting
Little or no effect on disease progression
Need for an well tolerated treatment that slows or halts disease progression
Registration trials require large numbers of patients
Potential for Experimental Medicine studies to select best compound(s) for late stage trials
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Human spatial memory & fMRI
Develop spatial learning and memory paradigms that
engage hippocampal processing
Image participants to ensure hippocampal activation during task
Test participants during encoding and recall to determine differential
activation
Determine effects of age on performance
Determine effects of drugs on performance
Optimise fMRI methods for clinical trials
Virtual reality task developed and validated
Arena maze (human analogue of Morris water maze)
• Easy to administer, flexible designs, validated with scopolamine and
healthy elderly participants
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Morris Water Maze
• Rats are placed in a 2m diameter pool containing a hidden platform
• Rat finds platform and notes position in relation to a number of visual cues
• Time taken to swim to platform is recorded over a series of trials (= learning)
• Platform removed and time spent in platform quadrant is recorded (probe trial =
memory)
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Arena pole paradigm: encoding
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Arena pole paradigm: retrieval
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Experimental setup
Play M`ovie
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Study 2: Aging effects
Procedures
Groups
Young healthy adults (Mean age = 24 years
age range = 20-26, n=11)
Elderly healthy adults (Mean age = 72 years
age range = 64-79, n =9)
Young participants trained on 18 trials to criterion
Older participants trained on 36 trials to criterion
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15 s
2.5 min
Rest
Encoding
Retention
Rest
Visual
Control
Rest
15 s
30 s
30 s
30 s
30 s
1 trial
fMRI Design
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Behavioural Results: Young vs Old
Young Old 0
5
10
15
20
25 M
ea
n D
isp
lace
me
nt E
rro
r
Older participants performed significantly worse across three
experimental blocks of trials (each block = 6 trials, t17 = -3.542, p = .003]
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Encoding Retrieval
Study 2 Young Male
(20-26 years old)
Study 2 Elderly Male
(65-79 years old)
Reduced Hippocampal Activation
in Elderly Subjects
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Encoding Retrieval
Study 2 Young Male
(20-26 years old)
Study 2 Elderly Male
(65-79 years old)
Reduced Hippocampal Activation
in Elderly Subjects
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Encoding Retrieval
Study 2 Young Male
(20-26 years old)
Study 2 Elderly Male
(65-79 years old)
Reduced Hippocampal Activation
in Elderly Subjects
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Effects of scopolamine on behavioural
performance and fMRI measures
20 young participants
Scopolamine 0.4 mg vs placebo
Cross-over study
fMRI measurement
3-Tesla MRI
Antonova E, at l. J Psychopharmacol. 2011, 25:1256-65.
.
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Behavioural results: scopolamine vs
placebo
Scopolamine significantly impaired performance
Placebo group: Mean displacement error = 10.67, SD = 4.22
Scopolamine group: Mean displacement error = 14.39, SD = 7.37
0
2
4
6
8
10
12
14
16
Displacement Error
Placebo
Scopolamine
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Hippocampal activation in placebo
condition
Placebo -Encoding Placebo - Retrieval Hippocampus
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Reduced hippocampal activation
induced by scopolamine
Placebo
>
Scopolamine
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Morris Water Maze Model of Cognition
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Morris Water Maze
Path-length at the beginning and at the end of the
training period
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Morris Water Maze: Scopolamine
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Spatial Memory Flat Mapping & fMRI
Develop spatial learning/memory paradigms that
engage hippocampal processing
Image subjects to ensure hippocampal activation
during task
Test subjects during encoding and recall to determine
differential activation
Determine effects of age on performance
Determine effects of drugs on performance
Optimise fMRI methods for clinical trials
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Arena Pole Paradigm: Encoding
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Arena Pole Paradigm: Retrieval
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Arena Pole Paradigm: Visual
Control Task
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Experimental Setup
Play Movie
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Future Developments
Software validated with young healthy volunteers given
placebo, scopolamine and butylscopolamine
Flat mapping development parallels testing Flat mapping.ppt
Spatial learning in a natural environment
(e.g. shopping trip)
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