1. Leveraging Omics Biomarker in Early Clinical Trials - Concept, Utility and Impact on Decision Making
Weidong Zhang
Pfizer Inc.
July 30, 2018

2. What are we looking for in early clinical trials?
Types of early clinical trials
First in human (FIH)/Proof of mechanism (PoM)
Early signal of efficacy (ESoE)
Proof of concept (PoC)
Primary objectives
FIH/POM
Safety and tolerability
PK profile
Target engagement (3 pillars)
ESoE and POC
Clinical efficacy

3. POM Success = Totality of Data
Biomarkers are essential for assessment of 3 pillars
POC
Success
Pillar 1
Pillar 2
Pillar 3
Adequate
Exposure
Adequate
Binding
Adequate
Pharm. Eff
Proximal mechanism biomarker with clear quantitative linkage to target activity
High quantifiability
High dynamic range
High sensitivity, specificity and reproducibility
Reasonable inter- and intra subject variability
Less invasive and easily accessible
POM Success = Totality of Data
Literature
Preclinical
Clinical

4. Successful PoM may significantly improve POS of POC studies
Morgan & Van der Graaf, 2012

5. Case study: Targeting TYK2/JAK1 with PF-06700841 in Psoriasis
Psoriasis pathogenesis
Psoriasis is an immune-mediated skin disease characterized by:
Inflammation and keratinocyte hyper-proliferation
marked infiltration of the skin by T lymphocytes and other immune cells.
TYK2/JAK1 and psoriasis
TYK2 and JAK1 mediate signal transduction of several pro-inflammatory cytokines implicated in psoriasis pathogenesis
TYK2i blocks Th17 cell differentiation and IL-17 production
JAK1i reduces resident T cells via suppression of gc cytokines.
Gene expression provide new opportunities for PD assessment
May provide proximal measurement of target activities
Mature and affordable technologies
Easy to access
High repeatability and reproducibility
Figure adapted from Riese RJ, et al. Best Pract Clin Res Rheumatol. 2010;24:

6. Investigation of Tyk2/Jak1 inhibitor : A 4-in-1 study
MAD
SAD
PoM/ESoE

7. Psoriasis study design
Placebo QD x 28 days
28 days follow-up
30mg QD x 28 days
28 days follow-up
100mg QD x 28 days
28 days follow-up
# subjects completed (# subjects discontinued)
Week
Placebo
30mg
100mg
Total 9 14 7 30 4
9 (0)
7 (7)
5 (2)
21 (9) 8
7 (2)
6 (8)
4 (3)
17 (13)
Elena
Key clinical endpoints
Psoriasis Area and Severity Index (PASI) change from baseline
Numeric Rating Scale (NRS) change from baseline

8. PASI = Psoriasis Area and Severity Index
Efficacy of PF
Elena
PASI = Psoriasis Area and Severity Index

9. POM of PF-06700841 using gene expression
Gene expression study using skin biopsy
Skin biopsies from Psoriasis patients
Lesional (baseline, week 2 and week 4)
Non-lesional (baseline)
Affymetrix Microarray
Three pathways defined
Psoriasis pathway
MAD3 pathway
IL17 pathway
Objectives
To identify genes/pathway modulated by PF
To declared PoM if 70% improvement in IL17 pathway is observed and statistical significance between the treated arms and placebo is achieved

10. Treatment effect on the psoriasis transcriptome
No major change
at D14 & D28
Improvement at D14
Further improvement at D28
Molecular phenotype at D14 & 28 approaches NL
Placebo
PF-30
PF-100 D0
D14
D28 LS NL
PASI75/Histology LOCF
PASI75 LOCF
Hist LOCF
@D28 NR R
3,222 Probes
2,962 Genes
(N = 9)
(N = 14)
(N = 7)
Karen
B transcriptome: DEG (LS vs NL with FCH>2 and FDR < 0.05)

11. Quantification of drug modulation using gene expression data
Pathway score (Lee 2008; Hanzelmann et al. 2013)
Gene-wise normalized Z score
𝑍 𝑖𝑗 ~𝑁(0,1)
Where 𝑖=𝑔𝑒𝑛𝑒 1, …, 𝐼;𝑗=𝑗𝑡ℎ 𝑠𝑎𝑚𝑝𝑙𝑒
Pathway activity score
𝑎 𝑝𝑗 = 𝑖=1 𝑘 𝑍 𝑖𝑗 𝑘
Improvement score
Bootstrap confidence interval
Weidong

12. Percent Improvement with 95% CIs: IL17 gene sig
KC IL17 Genes- differentially expressed in IL17-treated 1.5-FCH, FDR<0.1
61 genes UP regulated
Weidong

13. Percent improvement with 95% CIs: MAD3 gene sig
MAD3 Psoriasis Genes-differentially expressed in MAD3 Psoriasis Transcriptome
@ 2-FCH, FDR<0.05 (L vs. NL)
1116 genes UP
779 genes DOWN
Weidong

14. Summary
Gene expression biomarkers are useful for PoM studies to measure target engagement
Quantitative measurements provide objective assessment of PoM decision
Sophisticated statistical methods are needed for quantification of drug modulation with multiple gene expression biomarkers

15. Acknowledgement Pfizer Mount Sinai Hospital Rockefeller University
Elena Peeva
Matt Scaramozza
Karen Page
James Clark
David von Schack
Mount Sinai Hospital
Mayte Suarez-Farinas
Maria Suprun
Rockefeller University
James Krueger