Biomarker: Clinical Validation for Intended Use - … · Biomarker: Clinical Validation for Intended Use Joop van Gerven professor of clinical neuropsychopharmacology. Centre for

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


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



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



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


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


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


VAS

Aler

tnes

s: c

hang

e fro

m b

asel

ine

-40

-30

-20

-10

0

10


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


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


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


Log

Body

Sw

ay: c

hang

e fro

m b

asel

ine

-0.2

0.0

0.2

0.4

0.6

0.8


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


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

Documents

Biomarker: Clinical Validation for Intended Use - … · Biomarker: Clinical Validation for Intended Use Joop van Gerven professor of clinical neuropsychopharmacology. Centre for