using biomarkers for early phase dose selection with protein antagonist drugs ivan nestorov...

USING BIOMARKERSUSING BIOMARKERS

FORFOR

EARLY PHASE DOSE SELECTIONEARLY PHASE DOSE SELECTIONWITHWITH

PROTEIN ANTAGONIST DRUGSPROTEIN ANTAGONIST DRUGS

Ivan Nestorovivan.nestorov@biogenidec.com

TALK FRAMEWORKTALK FRAMEWORK

• Setting the stage: introductions and definitions

• PK and binding as major early markers

• Biological activity as validation for binding

• Walk-through example

• Regulatory implications

THERAPEUTIC PROTEINSTHERAPEUTIC PROTEINSafter B.M. Rao, D.A. Laufenburger, K.D. Wittrup. Integrating cell-level kinetic modeling into after B.M. Rao, D.A. Laufenburger, K.D. Wittrup. Integrating cell-level kinetic modeling into the design of engineered protein therapeutics. Nature Biotechnology. 23: 191-194, 2005.the design of engineered protein therapeutics. Nature Biotechnology. 23: 191-194, 2005.

• Antagonists (e.g. antibodies, soluble receptors) - block native protein interactions by binding to target protein(s)– Examples – anti-TNF, anti-VEGF, anti-BLyS/APRIL

• Agonists (e.g. cytokines, growth factors) - stimulate cell surface receptors– Examples – erythropoietin, rhGH, G-CSF, IL-2

• Targeting agents (e.g. antibodies, immunotoxins) – target specific cell surface antigens or deliver therapeutic agents– Examples – anti-CD20

BAFF-R

BCMA

TACI

B-Cell

APRIL

BLyS (BAFF)

Heterotrimer

B cell differentiation

B cell survivalAntibody

productionIg class switch

EXAMPLES:BLYS/APRIL antagonist (atacicept)

THE RESPONSE CASCADEM Danhof, G Alvan, SG Dahl, J Kuhlmann, G Paintaud. Mechanism-based pharmacokinetic-

pharmacodynamic modeling-a new classification of biomarkers. Pharm Res. 2005; 22:1432-1437.

PHASE 1 DATA

HOW TO USE THIS INFORMATION FOR DOSAGE REGIMEN DESIGN IN PHASE 2/3?

Atacicept exposure–response cascade (RA)

BLyS/APRILInhibition

DOSE & Freq.

MoABiomarkers

DiseaseBiomarkers

ClinicalMarkers

ClinicalEndpoints

FREE DRUGFREE TARGET

COMPLEX

Binding &Inhibition

Biological activity

Disease related activity

Clinical activity

Clinical efficacy

IgXFACS

IgX RFACPA

ESR, CRPJOINT CNTS

ACRXX%DAS28

THERAPEUTIC PROTEINSTHERAPEUTIC PROTEINS• Large molecules, slow PK and PD

• Specific binding to targets dominant (by engineering)

• Target load often:– Significant (in molar concentration terms)– Distributed across various tissues– Constantly renewed by endogenous production of targets– Endogenous production may be boosted by depletion

• Nonspecific binding sometimes negligible (!!! check)

• No P450 metabolism, but Ab’s to drug possible

• Protein drug metabolism often capacity limited

PK & TARGET BINDING: PK & TARGET BINDING: MAJOR EARLY MARKERSMAJOR EARLY MARKERS

• Free drug PK is expected to be nonlinear– Unless nonlinearity is overwhelmed– Or unless total drug is measured– PK Assays are critical

• Dosing should be targeted at the saturation– Below saturation – sub-therapeutic regimen– Above saturation – waste of drug and/or potential

over-inhibition– Saturation – both in blood and tissues– Saturation is a dynamic process – at all times

FREEDRUG PK

TISSUES, SoA

ABSORPTIONSITE

BLOOD

L1 KIN

ETICS

BIN

DIN

G T

OL

1 &

L2

TISSUES,

SoA

BLOOD

L2 KIN

ETICS

TISSUES,

SoA

BLOODen

dogenous

product

ion

BINDING EQUILIBRIUM:

• Binding affinity

• Drug & ligand concentrations– Systemically

– In tissues

• Dosing schedule

• Endogenous ligand production– Systemically

– In tissues

PK & BINDING

FREEDRUG PK

TISSUES, SoA

ABSORPTIONSITE

BLOOD

L1 KIN

ETICS

BIN

DIN

G T

OL

1 &

L2

TISSUES,

SoA

BLOOD

L2 KIN

ETICS

TISSUES,

SoA

BLOODen

dogenous

product

ion

PK, BINDING & DOSINGOBJECTIVE:

• Adequate binding– Process in time– At Sites of Action

– Not necessarily complete binding of ligand

• Markers of PK/binding– Free drug– Total drug– Complex concentration

– Free ligand concentration

• Means to achieve goal:– Type of dosing regimen– Dosing levels– Dosing frequency– Mode of administration

0

200

400

600

800

1000

0 14 28 42 56 70 84 98 112 126

Time [days]

Ata

cice

pt/B

LyS

Com

plex

[U

/mL]

ACCUMULATION OF COMPLEX P.P. Tak, et al. Atacicept in patients with rheumatoid arthritis: an exploratory, multicenter, double-blind, placebo-controlled,

dose – escalating, single and repeat dose phase 1b study. Accepted Arthr. & Rheum. ar-06-1723, 2007.

BLyS Concentration after Rituximab in RAG. Cambridge et al. Circulating Levels of B Lymphocyte Stimulator in Patients With Rheumatoid Arthritis

Following Rituximab Treatment. Arthritis and Rheumatism 54: 723-732 (2006).

BLyS accummulation rate in serum: ~0.08 ng/mL/day

DESIGN SO FAR:DESIGN SO FAR:

• Type of dosage: Loading - Maintenance– Eliminate initial target ligand load– Boost the redistribution of target ligand – Compensate endogenous ligand production

• Dose levels and dosing frequency ???

• Mode of administration: ???

RECEPTOR MEDIATED PKA. Munafo, A. Priestley, I. Nestorov, J. Visich, M. Rogge. Safety, pharmacokinetics and

pharmacodynamics of atacicept in healthy volunteers. Eur. J. Clin. Pharm. 63:647-656 (2007).

1

10

100

1000

10000

100000

0 7 14 21 28 35 42 49

Time [days]

Fre

e at

acic

ept

[ng

/mL

]

2.1 mg

70 mg

210 mg

630 mg

0

50

100

150

200

250

300

0 50 100 150 200 250 300

Time [days]

Ata

cice

pt:B

LyS

Com

plex

[U/m

L]

Atacicept/BLyS ComplexFree Atacicept

QUIZ:DOSING FREQUENCY?

1

10

100

1000

0 7 14 21 28 35 42 49 56 63 70 77 84Time [days]

Fre

e d

rug

[n

g/m

L]

0

40

80

120

160

Dru

g/T

arg

et c

om

ple

x [U

/mL

]

Free drug

Drug/Target Complex

Terminal Halflife:20-30 days

1

10

100

1000

0 7 14 21 28 35 42 49 56 63 70 77 84Time [days]

Fre

e d

rug

[n

g/m

L]

0

40

80

120

160

Dru

g/T

arg

et c

om

ple

x [U

/mL

]

Free drug

Drug/Target Complex

30-40% incompleteinhibition

Next dose?

QUIZ:DOSING FREQUENCY?

Biological activity tracks target ligand binding

20

40

60

80

100

120

0 7 14 21 28 35 42 49 56 63

Time [days]

IgM

[%

of

Bas

elin

e]

18 mg/kg IV

4x3 mg/kg SC

4x1 mg/kg SC0

150

300

450

600

750

0 7 14 21 28 35 42 49 56 63 70 77 84

Time [days]

Ata

cice

pt:

BL

yS C

om

ple

x [U

/mL

]

More frequent dosing at smaller doses yields better effect

Biological Activity Drug-Ligand Complex

DESIGN SO FAR:DESIGN SO FAR:• Biological activity tracks binding

• Type of dosage: Loading - Maintenance– Eliminate initial ligand load– Boost the redistribution of ligand – Compensate endogenous ligand production

• Dose levels and dosing frequency– More frequent smaller doses yield higher biological activity

compared to less frequent higher doses– Single dose saturation – between 75 and 210 mg– Dosing interval to maximize inhibition – 7 – 14 days– What doses / dosing intervals???

• Mode of administration: ???

S.C. ADMINISTRATION of PROTEIN DRUGS

• Uptake by lymphatic system

• Poorly quantified

• Dependent on MW

• Lymphatic & blood circulation closely interwined

• Consider kinetic vs dynamic rates

• Lymph can be SoAS.C. injection

10

100

1000

10000

100000

1000000

0 7 14 21 28 35 42

Time [days]

Free

ata

cice

pt [n

g/m

L]

9 mg/kg S.C.

9 mg/kg I.V.

20

40

60

80

100

120

0 7 14 21 28 35 42Time [days]

IgM

[%

of

Ba

se

line

]

… but biological activity is the same …

S.c. Atacicept systemic bioavailability is ~ 35 - 40% …

COMPARING S.C. COMPARING S.C. && I.V. ADMINISTRATION I.V. ADMINISTRATION

10

100

1000

10000

100000

1000000

0 7 14 21 28 35 42

Time [days]

Fre

e a

tac

ice

pt

[ng

/mL

]

9 mg/kg S.C.

9 mg/kg I.V.

0

100

200

300

400

0 7 14 21 28 35 42

Time [days]

Ata

cice

pt:

BL

yS C

om

ple

x [U

/mL

]

… because target binding is the same!

COMPARING S.C. COMPARING S.C. && I.V. ADMINISTRATION I.V. ADMINISTRATION

DESIGN SO FAR:DESIGN SO FAR:

• Biological activity tracks binding

• Type of dosage: Loading - Maintenance– Eliminate initial ligand load– Boost the redistribution of ligand – Compensate endogenous ligand production

• Dose levels and dosing frequency– More frequent smaller doses yield higher biological

activity compared to less frequent higher doses– Single dose saturation – between 75 and 210 mg– Dosing interval to maximize inhibition – 7 – 14 days– What doses / dosing intervals???

• Mode of administration: SC

TIME TO BECOME QUANTITATIVE…

ATACICEPT PATACICEPT Pop PK/PD MODELop PK/PD MODELI. Nestorov et al. Population modeling of the relationship between TACI‑Ig exposure and biomarker response in patients with

rheumatoid arthritis (RA). Population Analysis Group in Europe meeting PAGE 2006, June 14-16, 2006.

Abs.Site

Central Peripheral

IgM, IgG, IgA

CIC

CIK syn 50

1 max

offK

CL

QKa

Vc Vp

DOSE

0

20

40

60

80

100

0 14 28 42 56 70 84 98 112 126 140 154 168

Time [days]

25 mg

50 mg

75 mg

150 mg

500 mg

Varying doses, same dosing frequency (QW)

Simulations: Dose saturation of effect

Going beyond 150 mg

for QW not justified

IgM

[%

of

bas

elin

e]

DESIGN COMPLETEDESIGN COMPLETE• Biological activity tracks binding

• Type of dosage: Loading - Maintenance– Eliminate initial ligand load– Boost the redistribution of ligand – Compensate endogenous ligand production

• Dose levels and dosing frequency– More frequent smaller doses yield higher biological activity

compared to less frequent higher doses– Single dose saturation – between 75 and 210 mg– Dosing interval to maximize inhibition – 7 – 14 days– Dosing frequency – once weekly (QW)– Dose levels for Phase 2/3 study: 25, 75 and 150 mg

• Mode of administration: SC

REGULATORY ACTIONREGULATORY ACTION

PHASE 1

CONCLUSIONSCONCLUSIONS

• PK and target binding are major early biomarkers for protein antagonists

• Saturation of binding can be used for early phase dosage regimen design

• Population PK/PD modeling helps quantify saturation

• Mechanistic validation should be implemented as much as possible