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Biomarker: Clinical Validation for Intended Use
Joop van Gervenprofessor of clinical neuropsychopharmacologyCentre for Human Drug ResearchLeiden The Netherlands
to the memory of Hermann Fuder
Lecture Contents
What are biomarkers?question-based drug development
What can you do with them?examples from GABA-ergic research
Biomarker
Definitions
A characteristic that is objectively measured and evaluated as an indicator of normal biologicalprocesses, pathogenic processes, or pharmacologicresponses to a therapeutic intervention.(NIH Biomarkers Definitions Working Group, 2001)A quantitative measure that is on the causal pathbetween drug administration and effect. (EU COST-B Biomarker Working Party, Danhof, 2005)
type 0
phenotype
genotype
type 1
drug concentration
type 2
target occupancy
type 3
target activation
type 4
physiological
response
type 5
patho-
physiological
response
type 6
clinical
response
…the causal
path…
A Practical Biomarker
Definition: Tools to Answer
Questions
in Drug Development
populationaction site
pharmacology
clinical
window
drug development is case building
Question-Based Drug Development: main issues for early development
1. Does the drug reach its target?2. Does the drug have pharmacological activity/-ies?3. Does the drug affect intended (patho)physiological
processes?4. What is the window between desired and
undesirable effects?
Example 1
First-in-human studyFast- and short-acting benzodiazepinesNew sedative in anesthesiaTwo new compounds vs midazolam
Question-Based Development: Action Site 1: does the drug reach its target?
Membrane Receptors/Ion ChannelsGABA-A-receptorsglutamate NMDA channelL-type Ca2+ channel
Membrane Transporters5HT-transporterdopamine-transporterp-Glycoprotein
Vesicular Transportersvesicular Monoamine Transporter-2vesicular Acetylcholine Transporter
Neurotransmitter PrecursorsF-DOPA
EnzymesMAO-A, MAO-Bacetylcholinesterase
*
*18F-flumazenil
Question-Based Development: Action Site 1: does the drug reach its target?
•0 •50 •100 •150
•effect compartment concentration (µg/L)
•250
•300
•350
•400
•450
•500
•SPV
(de
g/se
c)
•1 mg •2 mg •3 mg •midazolam
single rising dose study of two novel benzodiazepines vs positive control
Ro 8684: shorter duration of action than
midazolamRo 6791: more potent than
midazolam,
equipotent at 3 mg (+20
µg/L)
•0 •60 •120 •180 •240 •300
•Time (min)
•200
•300
•400
•500
•SPV
(de
g/se
c)
Dingemanse J, Van Gerven JMA, Schoemaker HC et al. Integrated pharmacokinetics and pharmacodynamics of Ro 48-6791, a new benzo¬diazepine, in comparison to mida¬zolam during first administration to healthy male subjects. Br J Clin Pharmacol 1997;44:477-486
Van Gerven JMA, Roncari G, Schoemaker HC et al. Integrated pharmacokinetics and pharmacodynamics of Ro 48-8684, a new benzo¬diazepine, in comparison to midazolam during first administration to healthy male subjects. Br J Clin Pharmacol 1997;44:487-493
Question-Based Development: Action Site 1: does the drug reach its action site?
[C]
E
PK/PD
Question-Based Development: Pharmacology 2: does the drug have a pharmacological effect?
R
GABAA
Question-Based Development: Pharmacology 2: does the drug have a pharmacological effect?
concentration-related effects are pharmacological biomarkers!
A. Can biomarkers show competitive (dis)advantage?B. Can biomarkers predict adverse effects?C. Can biomarkers predict therapeutic doses?
Question-Based Development: Pharmacology 2: how relevant are the pharmacological effects?
effect profiling positive controls
NeuroCart: multimodal CNS-profiling in early drug development
• Saccadic and smooth pursuit eye movement
• Memory testing• Adaptive tracking • Finger tapping• Body sway• Visual analogue scales• Psychometric questionnaires• Electroencephalography• Polysomnography• Other CNS function tests
• Symbol Digit Substitution Test• Critical Flicker Fusion• Stroop Conflict Task
• Neuroendocrine
measures• Autonomic function tests
NeuroCart
Data-Intensive Phase 1N
euro
Car
tCNSpractice
Informed Consent XDemography XIncl./Exclusion XMedical history X Physical examination X Body Weight XVirology XThyroid function test XRoutine Lab +Urinalysis X X X
Urine drug screen X XConcomitant Medications X X X
Breath alcohol test XMeals/snack X X X X XDrug administration XVerbal learning XDelayed recall XCognitive testing X 2X X X X X X XAdaptive tracking X X X X X X X X X X X X X XSaccadic eye movements X X X X X X X X X X X X X XSmooth pursuit X X X X X X X X X X X X X XBody sway X X X X X X X X X X X X X XVAS (Bond & Lader) X X X X X X X X X X X X X XVAS (Bowdle) X X X X X X X X X X X X X XEEG X X X X X X X X X X X X X
PK blood sampling X X X X X X X X X X X X X XAuricular temperature X X X X X X X X XRespiratory rate X X XOrthostatic BP/Pulse X X
Supine BP /Pulse X X X X X X X X XResting 12-Lead ECG X X XAE follow up X X X X X X X X X XDischarge from unit X
Assessment
Screen -180 -120 -75 -60 -45 0h 30 60 75 90 105 120 135 150 180 195 210 240 12h 21h FU 255 270 6h 8h
PK/PD
Multimodal Pharmacological Effect Profiling: PK/PD-analyses show drug-specific pharmacological effect profiles
Trac
king
ave
rage
per
form
ance
(%)(c
hang
e)
-4
-3
-2
-1
0
1
2
3
4
Time (min)0 120 240 360 480 600
Sacc
adic
Peak
Velo
city (
deg/
sec)
350
400
450
500
550
600
Time (min)-60 0 60 120 180 240 300 360 420 480 540 600
LOG
Bod
y Sw
ay (m
m)
2.0
2.2
2.4
2.6
2.8
3.0
3.2
Time (min)-60 0 60 120 180 240 300 360 420 480 540 600
VAS
Aler
tnes
s (m
m)
30
40
50
60
70
Time (min)-60 0 60 120 180 240 300 360 420 480 540 600
Log
Body
Swa
y (m
m)
2.2
2.4
2.6
2.8
3.0
3.2
Time (min)-120 0 120 240 360 480 600 720 840
Del
ta V
AS A
lertn
ess
(mm
)
-60
-40
-20
0
20
40
Time (min)-120 0 120 240 360 480 600 720 840
Sacc
adic
Peak
Velo
city (
deg/
sec)
360
420
480
540
600
660
Time (min)-120 0 120 240 360 480 600 720 840
0 2 4 6 8 10
Time (h)
20
40
60
80
VA
S A
lertn
ess
(mm
)
Sacc
adic
peak
vel
ocity
(deg
/sec
)
410420430440450460470480490500510520530540550560570580590
Time (min)-120 0 120 240 360 480 600
Del
ta T
rack
ing
Perfo
rman
ce (%
)
-20
-15
-10
-5
0
5
Time (min)-120 0 120 240 360 480 600 720 840
Trac
king
Per
form
ance
(%)
-24
-18
-12
-6
0
6
Time (min)-120 0 120 240 360 480 600 720 840
LOG
Bod
y Sw
ay (m
m)
2.0
2.2
2.4
2.6
2.8
3.0
3.2
Time (min)-60 0 60 120 180 240 300 360 420 480 540 600
VAS alertness SPV adaptive tracking body sway
GABA-agonists
M-antagonists
CB1-agonists
…
Multimodal Pharmacological Effect Profiling: effect profiles are drug-class-specific
VAS EXTERNAL
-0.4
-0.2 0.0 0.2 0.4 0.6 0.8
EOD (5-95% CI)
VAS INTERNAL
-0.4
-0.2 0.0 0.2 0.4 0.6
EOD (5-95% CI)
SACCADIC PEAK VELOCITY
-150
-100 -50 0 50
EOD (5-95% CI)
SMOOTH PURSUIT
-30 -20 -10 0 10
EOD (5-95% CI)
ADAPTIVE TRACKING
-30 -20 -10 0 10
EOD (5-95% CI)
BODY SWAY
-0.5 0.0 0.5 1.0 1.5 2.0 2.5
EOD (5-95% CI)
SPO2 90%SPO2 80%
ACT-078573 400mg POACT-078573 1000mg PO
R213129 30mgOrg25935 0.5mg POTalnetant 200mg PO
MK0869 160mg PO+Amitriptyline MK0869 160mg PO
Scopolamine 0.5mg IVScopolamine 0.5mg IV
GPI1 750 mg POGPI1 300 mg POGPI1 100 mg PO
Lisuride 0.2 mg POHaloperidol 3mg POSulpiride 400 mg PORisperidone 2mg PO
SB742457 50mg PO + Risper 2mg SB742457 50mg POmCPP 0.5mg/kg POmCPP 0.1mg/kg IV
Sumatriptan 50mg PORizatriptan 10mg PO
Amitriptyline 50mg PODexfenfluramine 0.5mg/kg PO5HTP 300 mg PO + Carbidopa
5HTP 200mg PO+Carbidopa5HTP 200mg PO+Carb+Gran 2mg
5HTP 200mg PO+Carb+Dom 10 mg5HTP 200mg PO
5HTP 200 mg PO + Carbidopa5HTP 100mg PO + Carbidopa5HTP 100mg PO + Carbidopa
5HTP 100mg POORG26828 #5 ug/kg IV
ORG 28611#6 IVTHC 2+4+6+8mg IHTHC 2+4+6+6mg IHEthanol 0.6g/L TCIEthanol 0.6g/L TCIEthanol 0.6g/L TCI
Diaz 10mg PO+Ethanol 0.6g/L TCBreta 0.5mg SL+Ethanol 5.0% IV
Zolpidem 10mg POTemazepam IV Fast
Temazepam 20mg POTemazepam IV
SL651498 25mg POSL651498 2.5mg PORO488684 10mg IVRO486791 10mg IV
Nitrazepam 5mg PO (Jap)Nitrazepam 5mg PO
Midazolam 0.1mg/kg IVMidazolam 0.1mg/kg IVMidazolam 0.1mg/kg IV
Lorazepam 2mg POLorazepam 2 mg POLorazepam 2 mg PODiazepam 10mg POBretazenil 0.5mg SL
L-83982 2mg POL-830982 1.5mg POL-830982 0.5mg PO
L-830409 0.75 mg POL-830409 0.25 mg PO
Sleep deprivation 1 nightDuring nightSLEEP
PARTIALGABAA
GABAA
5HTP5HT5HT ANT
DOPAMINE ANTDOPAMINE
ETHANOL
OTHER
THC
O2
VAS ALERTNESS
-60 -40 -20 0 20 40
EOD (5-95% CI)
AVE1625 120 mg
Example 2
First-in-human studyNew hypnoticOrexin antagonist vs zolpidem
Question-Based Development: Pharmacology benchmarking biomarkers vs positive controls
a) Adapative tracking performance
0 2 4 6 8 10 12-15
-10
-5
0
5
10
PlaceboZolpidem1000 mg400 mg
100 mg200 mg
Time after administration (h)
Mea
n ch
ange
from
bas
elin
e (%
)
b) Saccadic peak velocity
0 2 4 6 8 10 12-140
-120
-100
-80
-60
-40
-20
0
20
40
PlaceboZolpidem1000 mg400 mg200 mg100 mg
Time after administration (h)
Mea
n ch
ange
from
bas
elin
e (d
egre
e/s)
c) Body sway
0 2 4 6 8 10 12-360
-240
-120
0
120
240
360
480
600
720
PlaceboZolpidem1000 mg400 mg200 mg100 mg
Time after administration (h)
Mea
n ch
ange
from
bas
elin
e (m
m)
d) Smooth pursuit
0 2 4 6 8 10 12-20
-10
0
10
20
PlaceboZolpidem1000 mg400 mg200 mg100 mg
Time after administration (h)
Mea
n ch
ange
from
bas
elin
e (%
)
e) Delta Pz−Oz
0 2 4 6 8 10 12-1.0
-0.5
0.0
0.5
1.0
1.5PlaceboZolpidem1000 mg400 mg200 mg100 mg
Time after administration (h)
Mea
n ch
ange
from
bas
elin
e (u
V)
f) Theta Pz−Oz
0 2 4 6 8 10 12-1.0
-0.5
0.0
0.5
1.0
1.5PlaceboZolpidem1000 mg400 mg200 mg100 mg
Time after administration (h)
Mea
n ch
ange
from
bas
elin
e (u
V)
first-in-man of orexinantagonistsingle-ascending doseNeuroCart batteryzolpidem as positive control
almorexant 200-400 mg similar to zolpidem 10 mgsomewhat less postural instabilityalmorexant effects lasted longerno signs of narcolepsy
Question-Based Development: Pharmacology biomarkers can show competitive advantages
Question-Based Development: Effects 3: does the drug affect (patho)physiology?
Serotonergic5HT2 cortisol
temperatureCholinergic
M1 pupil diametermemory
Norepinephrinemetabolism MHPG
DopaminergicD2 prolactin
Hypertensionblood pressure
Diabetes Mellitusoral glucose toleranceglucose clamping
Hypercholesterolaemiacholesterol
HyperthyroidismTSH, FT4
Cardiac arrhythmiasQTc
Examples of (Patho)physiological Biomarkers
Example 3
Early phase I studiesNew anxiolyticsPartial subtype selective GABAA-agonists vs lorazepam
α2,3 subtype selective compounds:
TPA023, MK-0343, SL65.1498
83
45
21
α3
4811545SL65.1498
182318MK-0343
5110TPA023
α5α2α1
83
45
21
α3
4811545SL65.1498
182318MK-0343
5110TPA023
α5α2α1
in vitro efficacies relative to full agonist
sedation,postural instability
memorydisturbanceanxiolysis
Early Development of New Class of Anxiolytics: Partial Subtype Selective GABAA
-agonists
Saccadic Peak Velocity sensitive biomarker for anxiolytic
GABAA
-agonists
Saccadic Peak Velocity vs VAS Calmness for different anxiolytics
and sedatives -
shock threat
-1 0 1 2 3 4 5 6 7
SPV (deg/sec)
-100
-75
-50
-25
0
VA
S C
alm
ness
(mm
)
diphenhydramineR2 = 0.09
pregabalinR2 = 0.83
alprazolamR2 = 0.83
Saccadic Peak Velocity, Binding Affinity and Anxiolytic
Dose
0 2 4 6 8 10 12
SPV dose equivalence (10 mg Temazepam)
0
10
20
30
40
50
60
70
80
Kd a
t ben
zodi
azep
ine
bind
ing
site
(nM
)
Midazolam
Quazepam
Temazepam
Bromazepam
Diazepam
Lorazepam
Alprazolam
0 2 4 6 8 10 12
SPV dose equivalence (10 mg Temazepam)
0
2
4
6
8
10
12
14
16
Low
est m
aint
enan
ce d
ose
(mg
po/d
aily
)
Midazolam
Quazepam
Temazepam
Bromazepam
Diazepam
LorazepamAlprazolam
0 10 20 30 40
Dose Temazepam (mg)
0
50
100
150
200
250
Cha
nge
in S
PV
(deg
/sec
)
0 120 240 360 480 600
Time (minutes)
-150
-100
-50
0
50
Sacc
adic
Pea
k Ve
loci
ty; c
hang
e fro
m b
asel
ine
(deg
/sec
)
Saccadic Peak Velocity (SPV)
0 600-150
50
∆ lorazepam○ TPA023 1.5 mg□ TPA023 0.5 mg● placebo
Question-Based Development: Effects 3: biomarkers can show physiological selectivity
Body Sway postural instability
0 120 240 360 480 600
Time (minutes)
-0.50
0.00
0.50
1.00
log
Bod
y S
way
Eye
s C
lose
d; c
hang
e fro
m b
asel
ine
(log
mm
)
0 300 600-0.50
1.00
Body sway∆ lorazepam○ TPA023 1.5 mg□ TPA023 0.5 mg● placebo
Question-Based Development: Effects 3: biomarkers can show physiological selectivity
Visual Analogue Scales for alertness, mood and calmness
(English original version) VISUAL ANALOGUE SCALES
(As described in : Bond A, Lader M. The use of analogue scales in rating subjective feelings.
Br J Med Psychol 1974;47:211-18) 1. Please rate the way you feel in terms of the dimensions given below. 2. Regard the line as representing the full range of each dimension. 3. Rate your feelings as they are at the moment. 4. Mark clearly and perpendicularly across each line. 1 Alert ________________________________________________ Drowsy 2 Calm ________________________________________________ Excited 3 Strong ________________________________________________ Feeble 4 Confused ________________________________________________ Clear-headed 5 Well-coordinated________________________________________________ Clumsy 6 Lethargic ________________________________________________ Energetic 7 Contented ________________________________________________ Discontented 8 Troubled ________________________________________________ Tranquil 9 Mentally slow ________________________________________________ Quick-witted 10 Tense ________________________________________________ Relaxed 11 Attentive ________________________________________________ Dreamy 12 Incompetent ________________________________________________ Proficient 13 Happy ________________________________________________ Sad 14 Antagonistic ________________________________________________ Amicable 15 Interested ________________________________________________ Bored 16 Withdrawn ________________________________________________ Gregarious (*Line numbers refer to VAS-item definition in the ProMaSys study database)
alertness
VAS sedation
∆ lorazepam○ TPA023 1.5 mg□ TPA023 0.5 mg● placebo
0 120 240 360 480 600
Time (minutes)
-5
0
5
10
ln V
AS
Ale
rtnes
s ab
ove
base
line
(ln m
m)
Question-Based Development: Effects 3: biomarkers can show physiological differences
diff vs PLAC 95%CI p TPA 0.5 mg 1.35 (-0.37 / 3.08) 0.119 TPA 1.5 mg -0.33 (-2.05 / 1.39) 0.698 LOR 2 mg -1.8 (-3.52 /-0.08) 0.041
Question-Based Development: Pharmacology 3: less sedation with partial GABAA
-Agonists
VAS
Aler
tnes
s: c
hang
e fro
m b
asel
ine
-40
-30
-20
-10
0
10
SPV: change from baseline-120 -100 -80 -60 -40 -20 0 20
VAS
Aler
tnes
s: c
hang
e fro
m b
asel
ine
-40
-30
-20
-10
0
10
SPV: change from baseline-120 -100 -80 -60 -40 -20 0 20
VAS
Aler
tnes
s: c
hang
e fro
m b
asel
ine
-40
-30
-20
-10
0
10
SPV: change from baseline-120 -100 -80 -60 -40 -20 0 20
TPA023
MK-0343
SL65.1498
VAS alertness vs SPV
VAS
Aler
tnes
s: c
hang
e fro
m b
asel
ine
-40
-30
-20
-10
0
10
SPV: change from baseline-120 -100 -80 -60 -40 -20 0 20
zolpidem
● lorazepam 2 mg□ TPA023 1.5 mg
● lorazepam 2 mg□ SL65.1498 25 mg
● lorazepam 2 mg□ MK-0343 0.75 mg
● lorazepam 2 mg□ zolpidem 10 mg
Log
Body
Sw
ay: c
hang
e fro
m b
asel
ine
-0.2
0.0
0.2
0.4
0.6
0.8
SPV: change from baseline-120 -100 -80 -60 -40 -20 0 20
T t t L TPACMP2
Log
Body
Sw
ay: c
hang
e fro
m b
asel
ine
-0.2
0.0
0.2
0.4
0.6
0.8
SPV: change from baseline-120 -100 -80 -60 -40 -20 0 20
Log
Body
Sw
ay: c
hang
e fro
m b
asel
ine
-0.2
0.0
0.2
0.4
0.6
0.8
SPV: change from baseline-120 -100 -80 -60 -40 -20 0 20
MK-0343
TPA023
SL65.1498
Body sway vs SPV
Log
Body
Sw
ay: c
hang
e fro
m b
asel
ine
-0.2
0.0
0.2
0.4
0.6
0.8
SPV: change from baseline-120 -100 -80 -60 -40 -20 0 20
Zolpidem
● lorazepam 2 mg□ TPA023 1.5 mg
● lorazepam 2 mg□ SL65.1498 25 mg
● lorazepam 2 mg□ MK-0343 0.75 mg
● lorazepam 2 mg□ zolpidem 10 mg
Question-Based Development: Effects 3: less postural instability with partial GABAA
-Agonists
Question-Based Development: Window 4: biomarkers predict improved adverse effect profile
RFSE RFSI RWSE RWSI0
10
20
30
RFSE RFSI RWSE RWSI0
1
2
3
4
5
6
7
Placebo
TPA023 0.5mg
TPA023 1.5mg
Lorazepam 2mg
‡
‡
‡
‡
† †
Number correct Reaction time correct
‡
• less sedation• less postural stability• less memory impairment
Question-Based Development: Window 4: biomarkers predict anxiolytic
efficacy
1 2 3 4
-5
-4
-3
-2
-1
0PBO/Drug60/61
48/43 45/37 36/33
*** * *
Week of study
Cha
nge
in H
AM-A
,TP
A023
vs.
pla
cebo
Atack JR. Subtype-selective GABAA receptor modulation yields a novel pharmacological profile: the design and development of TPA023. Adv Pharmacol. 2009;57:137-85.
Conclusions (1)
Biomarkers are essential tools to answer questions during drug development
‘proof-of-action-site penetration’‘proof-of-pharmacological activity’
Best answers are obtained with biomarkers that:have well-established relationships with mechanism of drug action and/or pathophysiologyshow good concentration/effect relationshipshave excellent test characteristics including frequent repeatability
Conclusions (2)
Combinations of biomarkers can create informative effect profiles:
drug-class specific ‘fingerprints’relationships with underlying mechanisms of actionpotential competitive advantage(duration of action, window etc)
Positive controls can provideclinical benchmarks for effects of new drugindications for pharmacological selectivityimpression of functional (adverse) effects