Reduction of Tissue pstat3 in Crohn s Disease Patients Treated with Filgotinib (GLPG0634, GS- 6034), a JAK1-Selective Inhibitor

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1 Reduction of Tissue pstat3 in Crohn s Disease Patients Treated with Filgotinib (GLPG0634, GS- 6034), a JAK1-Selective Inhibitor Gert De Hertogh, MD, PhD S. Vermeire, G. De Hertogh, G. Chen, D. French, E. Huntzicker, A. Van der Aa, T. Van Kaem, P. Harrison, C. Tasset, R. Galien, Y. Pan, B. Feagan, W. Sandborn Barcelona, 18 February 2017

2 2 Disclosures: Gert De Hertogh, MD, PhD Lectures: Falk symposium Fees for central pathology review: Genentech Inc., Novartis Pharma AG, Janssen R&D, Denys Research Consultants, Galapagos NV

3 3 Participating countries and investigators Belgium: Dr. Vijverman, Dr. Muls, Dr. De Vos, Dr. Vermeire, Dr. Dewit, Dr. Colard Czech Republic: Dr. Vanasek, Dr. Drastich, Dr. Tichy, Dr. Kozeluhova, Dr. Konecny, Dr. Knoflicek France: Dr. Hebuterne, Dr. Bouhnik, Dr. Michiels, Dr. Bommelaer, Dr. Desreumaux, Dr. Grimaud, Dr. Roblin Germany: Dr. Kuehbacher, Dr. Stallmach, Dr. Malfertheiner, Dr. Schreiber, Dr. Bokemeyer, Dr. Helwig, Dr. Stein, Dr. Sturm Hungary: Dr. Gurzo, Dr. Lakatos, Dr. Sike, Dr. Salamon, Dr. Csiki, Dr. Peterfai, Dr. Heringh Poland: Dr. Klopocka, Dr. Wisniewska-Jarosinska, Dr. Petryka, Dr. Romanczyk, Dr. Wasko-Czopnik, Dr. Kierkus Romania: Dr. Mateescu, Dr. Goldis, Dr. Gheorghe, Dr. Tantau Russia: Dr. Osipenko, Dr. Yurkov, Dr. Abdulkhakov, Dr. Tkachenko, Dr. Belousova, Dr. Alekseeva, Dr. Pershko, Dr. Pesegova, Dr. Baranovsky, Dr. Ovchinnikova, Dr. Popova, Dr. Parfenov, Dr. Khalif UK: Dr. Levison, Dr. Goh, Dr. Hart, Dr. McLaughlin

4 4 Filgotinib is a JAK1 selective inhibitor Janus kinases (JAK) are a family of tyrosine kinases that play a key role in cytokine signalling Many of these cytokines are proinflammatory in Crohn s Disease The selective JAK1 inhibitor filgotinib blocks cytokine signalling through the inhibition of STAT phosphorylation STAT3 activation has been previously associated with Inflammatory Bowel Disease (Musso et al., Inflamm Bowel Dis, 2005) Filgotinib Yamaoka et al., Genome Biology, 2004

5 % responders Filgotinib Demonstrated Efficacy in a Phase 2 Study in Crohn s Patients (FITZROY) Filgotinib induced clinical remission and response at week 10 in significantly more patients with active Crohn s disease compared to placebo % P< % 41% (60/128) (18/44) P< % (76/128) Placebo 200 mg filgotinib 0 (10/44) Clinical remission (CDAI<150 points) Clinical response ( 100-points decrease in CDAI) Vermeire et al., Lancet, 2017 OPO23 & DOP075, ECCO

6 Subset of Patients Selected for Tissue Based pstat3 Analysis 60 subjects from filgotinib and placebo arms with a complete set of paired biopsies at pretreatment and week 10 from each of the 6 predefined segments of the lower GI tract selected pstat3 was evaluated by IHC using a py705 specific antibody H-score was correlated with clinical remission status (CDAI<150) Most affected areas Least affected areas Rectum H-Score: 1(%cells 1+) + 2(%cells 2+) + 3(%cells 3+) Where, 1+, 2+, 3+ indicate nuclear staining intensity Range is from 0 to 300 6

7 Variable Segmental Distribution of pstat3 in Crohn s Disease Example of pstat3 staining from a patient at pretreatment (CDAI = 283) Ileum Ascending (Right) Colon Transverse Colon H-score: 34 H-score: 54 H-score: µm 100 µm 100 µm Descending (Left) Colon Sigmoid Colon Rectum H-Score: 22 H-Score: 8.6 H-Score: µm 100 µm 100 µm 7

8 8 Pretreatment pstat3 Level is Comparable Between the Two Treatment Arms H-Score Geometric Mean (95% CI) Treatment Filgotinib Placebo Most affected area (12.33, 19.38) N = (14.57, 29.11) N = 18 Least affected area (9.50, 15.11) N = (9.50, 19.27) N = 18 ANOVA for repeated measurement model was used for the estimation and comparison H-Scores are based on averaging pstat3 level over 6 segments for both most and least affected areas

9 9 Decrease in pstat3 Level Comparable Between Most and Least Affected Areas for all Subjects Pretreatment Week 10 Ratio to Pretreatment Most Least Most Least Most Least H-Score Geometric Mean (95% CI)* (19.5,26.8) N = (13.9,19.2) N = (14.4,22.5) N = (10.2,15.9) N = (0.6,0.9) N = (0.6,0.9) N = 59 p-value < < *Average pstat3 level over 6 biopsy segments Despite overall higher pstat3 level in the most affected samples, no significant difference in ratio to pretreatment at week 10 between most and least affected areas

10 10 pstat3 Levels are Significantly Reduced Following Filgotinib Treatment at Week 10 Most affected region in colon H-Score %Change in Most Affected Region Treatment Clinical Remission N Geometric Mean %Change 95% LCL 95% UCL % Change Decrease Increase Filgotinib N Y Overall Placebo N Y Overall Filgotinib decreases pstat3 levels in remitters (CDAI<150) and non-remitters In placebo subjects, only remitters have decreased pstat3 levels

11 Filgotinib Treatment Reduces pstat3 Levels in Both Epithelial and Immune Cell Compartments CDAI: 293 H-Score: 33 Pretreatment CDAI: 121 H-Score: 3.3 Week 10 Remitter (Ileum) Crypt epithelium Immune infiltrate 10 µm 10 µm CDAI: 268 H-Score: 35.8 CDAI: 189 H-Score: 12.1 Non-remitter (Ileum) 10 µm 10 µm 11

12 Clinical Remission is Associated with Reduced pstat3 Levels Pretreatment Week 10 Placebo Remitter (Ileum) CDAI: 269 H-Score: 36 CDAI: 84 H-Score: 19 Low power images 100 µm 100 µm Neutrophils High power images Lymphocytes 10 µm 10 µm 12

13 13 Conclusions As previously reported, STAT3 activation was observed in Crohn s patient biopsies in the FITZROY study Clinical remission status was associated with a decrease in pstat3 In non-remitters, the observed pstat3 reduction with filgotinib compared to placebo illustrates its pharmacodynamic effect through JAK1 inhibition