EMA-EFPIA Workshop Dose Selection and Dose-Exposure-Response Characterisation

London 4-12-2014

A Systems Pharmacology Perspective on the Clinical Development of Fatty Acid Amide Hydrolase Inhibitors

for Pain Piet van der Graaf

Editor-in-Chief Leiden Academic Centre for Drug Research (LACDR) CPT: Pharmacometrics & Systems Pharmacology Leiden University, The Netherlands www.nature.com/psp p.vandergraaf@lacdr.leidenuniv.nl

Systems Pharmacology: Picking the right target

•Target Selection •Generate hypotheses for novel drug targets

•Target Validation

•Further assess the potential of a novel drug target

•Target Authorisation

•Assessment of novel therapeutic intervention against product concept

2

When not to use Systems Pharmacology for dose selection?

?

DOSE

RESPONSE

Compound A with unknown mechanism of action showed a dose-independent efficacy in the rat model of infra-red-light induced schizophrenia

3

Opportunity/Feasibility

Need

MOA quantitatively understood

Uncertainty of dose

prediction

NO Pharmacology YES Precedented

Unprecedented

X

V

X Waste of time

Academic interest

Low-hanging fruit

The Challenge

4

Opportunity/Feasibility

Need

MOA quantitatively understood

Uncertainty of dose

prediction

NO Pharmacology YES Precedented

Unprecedented

PTH(1-84)

TRK-A

FAAH

5

6

7

8

• NGF mAbs clinically-precedented efficacy

• Use Systems Pharmacology model to dose predict for novel targets in NGF pathway (TRK-A)

• High need: balance efficacy – potential CNS side effects TRK-A inhibitors

Known efficacious dose (exposure) NGF mAb

Predicted Systems Pharmacology pathway

response (dpERK)

Equivalent TRK-A dose (exposure)

Clinical Efficacy

Dose Prediction for a TrkA Kinase Inhibitor versus a Compound that Binds NGF

Impact of a compound that binds NGF (green) versus TrkA kinase inhibitor with different pharmacological properties (red and blue) on the dppERK response Inset panel shows the drug PK in the interstitial fluid compartment

10

0 50 100 150 200 250 300 350Time after dose (h)

0

5

10

15

20

25

CB1

rece

ptor

occ

upan

cy (%

)

0.10.313102040

PF-04457845 (mg)

Systems-pharmacology-model predicted elevations of CNS CB1 receptor occupancy by AEA following a single dose of PF-04457845

www.xenologiq.com Quantitative drug discovery solutions

Opportunity/Feasibility

Need

MOA quantitatively understood

Uncertainty of dose

prediction

NO Pharmacology YES Precedented

Unprecedented

PTH(1-84)

TRK-A

FAAH

13

www.nature.com/psp

14