A Van der Aa

Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1)

Objectives To evaluate the efficacy and safety of different doses and regimens of filgotinib, an oral Janus kinase 1 inhibitor, as add-on treatment to methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and inadequate response to MTX. Methods In this 24-week phase IIb study, patients with moderate-to-severe active RA receiving a stable dose of MTX were randomised (1:1:1:1:1:1:1) to receive placebo or 50, 100 or 200 mg filgotinib, administered once daily or twice daily. Primary end point was the percentage of patients achieving a week 12 American College of Rheumatology (ACR)20 response. Results Overall, 594 patients were randomised and treated. At week 12, significantly more patients receiving filgotinib 100 mg once daily or 200 mg daily (both regimens) achieved an ACR20 response versus placebo. For other key end points at week 12 (ACR50, ACR-N, Disease Activity Score based on 28 joints and C reactive protein value, Clinical Disease Activity Index, Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index), differences in favour of 100  or 200 mg filgotinib daily were seen versus placebo; responses were maintained or improved through to week 24. Rapid onset of action and dose-dependent responses were observed for most efficacy end points and were associated with an increased haemoglobin concentration. No significant differences between once-daily and twice-daily regimens were seen. Treatment-emergent adverse event rates were similar in placebo and filgotinib groups. Serious infections occurred in one and five patients in the placebo and filgotinib groups, respectively. No tuberculosis or opportunistic infections were reported. Conclusions Filgotinib as add-on to MTX improved the signs and symptoms of active RA over 24 weeks and was associated with a rapid onset of action. Filgotinib was generally well tolerated. Trial registration number: NCT01888874.

Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2)

Objectives To evaluate the efficacy and safety of different doses of filgotinib, an oral Janus kinase 1 inhibitor, as monotherapy in patients with active rheumatoid arthritis (RA) and previous inadequate response to methotrexate (MTX). Methods In this 24-week phase IIb study, patients with moderately to severely active RA were randomised (1:1:1:1) to receive 50, 100 or 200 mg filgotinib once daily, or placebo, after a ≥4-week washout from MTX. The primary end point was the percentage of patients achieving an American College of Rheumatology (ACR)20 response at week 12. Results Overall, 283 patients were randomised and treated. At week 12, significantly more patients receiving filgotinib at any dose achieved ACR20 responses versus placebo (≥65% vs 29%, p<0.001). For other key end points at week 12 (ACR50, ACR70, ACR-N, Disease Activity Score based on 28 joints and C reactive protein, Clinical Disease Activity Index, Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index) significant differences from baseline in favour of filgotinib 100 and 200 mg versus placebo were seen; responses were maintained or improved through week 24. Rapid onset of action was observed for most efficacy end points. Dose-dependent increases in haemoglobin were observed. The percentage of patients with treatment-emergent adverse events (TEAE) was similar in the placebo and filgotinib groups (∼40%). Eight patients on filgotinib and one on placebo had a serious TEAE, and four patients, all of whom received filgotinib, experienced a serious infection. No tuberculosis or opportunistic infections were reported. Conclusions Over 24 weeks, filgotinib as monotherapy was efficacious in treating the signs and symptoms of active RA, with a rapid onset of action. Filgotinib was generally well tolerated. Trial registration number NCT01894516.

OP0263 Efficacy and safety of GLPG0634, a selective JAK1 inhibitor, after short-term treatment of rheumatoid arthritis; results of a phase IIA trial

Background GLPG0634 is an orally-available, selective inhibitor of Janus kinase 1 (JAK1). JAKs are critical components in signaling pathways for a number of cytokines and growth factors, including those involved in the disease process of rheumatoid arthritis (RA). Other non-selective JAK inhibitors have shown long-term efficacy in RA trials with an early onset of action, but doses and thereby efficacy are limited by side effects. By specifically targeting JAK1, treatment with GLPG0634 is expected to result in a cleaner safety profile while maintaining the rapid onset of clinical efficacy. Objectives Evaluate the short-term efficacy and safety of GLPG0634 in RA patients with insufficient response to methotrexate (MTX) alone. Methods A double-blind, placebo-controlled Proof-of-Concept trial in patients with active RA, showing an insufficient response to MTX, was conducted. Twenty-four patients with moderate to severe disease received GLPG0634 200 mg daily, half as once-daily regimen (200 mg q.d.) and half as twice-daily regimen (100 mg b.i.d.), and 12 patients received a matching placebo for a period of four weeks, while continuing to take their stable background therapy of MTX. Results Patient and disease characteristics were comparable for all three dose groups, with DAS28 (CRP) disease activity scores between 6.3 and 6.6. In each dose group, 11 out of 12 patients were female. The patients were well exposed to GLPG0634, with the same pharmacokinetics as previously observed in healthy volunteers. GLPG0634 was found well tolerated and safe with a rapid onset and high level of efficacy. Considering the small sample size, no clinically relevant differences were observed among the 100 mg b.i.d. and the 200 mg q.d. dose regimens. GLPG0634 met the primary endpoint of significant improvement in ACR20 response rate. Overall ACR20 responses were observed in 83% of patients receiving GLPG0634 vs. 33% of patients receiving placebo (p<0.01). GLPG0634 showed impressive results in secondary efficacy endpoints, such as the DAS28 (-2.5), and in reductions of serum C-reactive protein levels (-24.4 mg/L), both significant changes vs. placebo (p<0.0001). All patients completed the trial and no treatment-emergent safety signals were reported. No severe adverse events were reported in patients receiving GLPG0634. Instead of anemia, a modest improvement in hemoglobin was observed. In contrast to observations with JAK inhibitors with other selectivity profiles, no increases in LDL/cholesterol and no liver effects (ALT/AST) were observed in this trial. Conclusions These early clinical results are the first to demonstrate that selective inhibition of JAK1 is efficacious and safe for the treatment of RA. Consistent with the lack of inhibition of JAK2, no anemia was observed. Remarkable results include the high level of response within 4 weeks and the absence of effects on LDL/lipid. An extended GLPG0634 dose-range finding trial is now being conducted to further define the optimal doses for efficacy and safety for longer term studies. Disclosure of Interest F. Vanhoutte Employee of: Galapagos, M. Mazur: None Declared, F. Namour Employee of: Galapagos, A. van der Aa Employee of: Galapagos, P. Wigerinck Employee of: Galapagos, G. Van ’t Klooster Employee of: Galapagos

THU0206 The jak1-selective inhibitor filgotinib reduces multiple markers of inflammation linked to various pathologic cell types and processes in rheumatoid arthritis patients

Background JAK1, 2, 3 and TYK2 are cytoplasmic tyrosine kinases that mediate intracellular signaling of many cytokines and growth factors. Filgotinib (GLPG0634, GS-6034) is a JAK inhibitor with high selectivity for JAK1 over other JAK family members. Filgotinib has a favorable safety and efficacy profile in two Phase 2B studies in active rheumatoid arthritis (RA) patients who were methotrexate (MTX) inadequate responders. Objectives To assess the effect of filgotinib on a background of MTX treatment on markers of inflammation in RA patients. Methods Serum samples from RA patients who were on a stable dose of MTX and received either placebo (PBO), filgotinib 100mg or 200mg once daily (QD), were collected at baseline, week 4 and week 12 and analyzed for 35 soluble serum biomarkers by validated single-plex or multiplex immunoassays. Median % changes from baseline for biomarkers are reported. Wilcoxon rank-sum test assessed the significance of difference between filgotinib treated groups and PBO. Results Filgotinib treatment induced a dose-dependent and significant decrease in a variety of biomarkers implicated in RA pathogenesis including inflammation (IL-1β, IL-6, TNFα and SAA), matrix degradation and cartilage destruction (MMP1 and MMP3), immune cell trafficking (CXCL10, ICAM-1 and VCAM-1) and angiogenesis (VEGF). Cytokines involved in TH1 (IFN-γ, IL-2, IL-12) and TH17 (IL-1β, IL-6, IL-21, IL-23) cell subset differentiation and activity were significantly decreased. Additionally, decrease in the B-cell chemoattractant CXCL13 and the myeloid growth factor GM-CSF supports the anti-inflammatory effects of filgotinib treatment.Table 1. Median percent change of biomarkers at week 12 from baseline for PBO and 200mg QD dose PBO Filgotinib PBO Filgotinib PBO (N=78) Filgotinib (N=78) 200mg QD (N=78) 200mg QD (N=78) 200mg QD (N=75) (N=75) (N=75) BAFF -2 -6NS IL-2 -7 -20** MIP-1β 0 -7* CRP -8 -78*** IL-21 0 -28** MMP-1 -6 -26*** CXCL-13 3 -40*** IL-23 -6 -25*** MMP-3 -9 -43*** EGF 0 0NS IL-4 0 0NS RESISTIN -1 -16*** GM-CSF 0 -26*** IL-5 2 -14** SAA 7 -67*** ICAM-1 0 -14*** IL-6 -20 -63*** sgp130 0 4NS IFN-γ -2 -21* IL-7 1 -17*** TNF-α 1 -15*** IL-10 -3 -17** IL-8 -2 -12NS TNF-RI 0 -15*** IL-12 0 -24*** IP-10 -2 -31** VCAM-1 0 -16*** IL-13 -1 -8** LEPTIN 6 23* VEGF -2 -26*** IL-17A 2 -18* MCP-1 4 -8NS YKL-40 -7 -33*** IL-1β -2 -26*** MIP-1α 1 -8** p-values comparing % changes between filgotinib and PBO groups: NS, p>0.05; *p<0.05; **p<0.01; ***p<0.001. Conclusions Treatment with filgotinib decreased several factors that have key roles in RA for matrix degradation, cartilage destruction, angiogenesis, leukocyte adhesion and recruitment. The changes were accompanied by decreases in cytokines that promote and activate TH1, TH17, B-cells and myeloid cells that are important in RA. These findings provide insights into filgotinib mechanism of action and are consistent with its efficacy observed in RA patients. Disclosure of Interest P. Taylor Consultant for: Galapagos NV, Pfizer, Eli Lilly, UCB, GSK, R. Westhovens: None declared, A. Van der Aa Employee of: Galapagos NV, C. Jamoul Employee of: Galapagos NV, W. Li Employee of: Gilead Sciences, L. Goyal Employee of: Gilead Sciences, Y. Pan Employee of: Gilead Sciences, P. Harrison Employee of: Galapagos NV, C. Tasset Employee of: Galapagos NV, J. Tarrant Employee of: Gilead Sciences, R. Galien Employee of: Galapagos SASU

AB0494 Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, Shows Similar PK and PD Profiles in Japanese and Caucasian Healthy Volunteers

Background Filgotinib is an oral, selective Janus kinase 1 (JAK1) inhibitor combining a favorable safety profile and clinical efficacy in patients after 4 weeks of dosing with rheumatoid arthritis (RA) with a rapid onset of action. Its once-daily oral administration is supported by the long half-life of an active metabolite with the same JAK1 selectivity profile as the parent compound. Given ethnicity may cause for differences in drug metabolism and pharmacokinetics (PK), and pharmacodynamics (PD) resulting in variability in clinical response, filgotinib was studied in Japanese healthy volunteers to evaluate the potential for different dosing requirements compared to Caucasians. Objectives Compare the PK, PD and safety of filgotinib in Japanese to Caucasian healthy volunteers at 200 mg filgotinib. Methods In a single-center Phase 1 study, 2 panels of 10 Japanese (1st and 2nd generation residing outside Japan for less than 5 years) and 10 Caucasian healthy volunteers received once daily 200 mg filgotinib or placebo for 10 days. The PK of filgotinib and its active metabolite were evaluated, and the overall PD of the two moieties was assessed in whole blood using ex vivo IL-6 induced phosphorylation of STAT1 (pSTAT1) as biomarker for JAK1 activity and GM-CSF induced phosphorylation of STAT5 (pSTAT5) for JAK2 activity. Standard safety assessments were performed throughout the study duration. Results Steady state in filgotinib plasma concentrations was reached in 2 days in both Japanese and Caucasian volunteers with half-lives of 6 and 11 hours, respectively. In both ethnic groups, the active metabolite showed plasma concentrations well exceeding those of filgotinib with half-life values ranging of 17-20 hours and overall exposures for filgotinib and its metabolite being the same between the populations. In both ethnic groups, IL-6 induced pSTAT1 was inhibited over the entire 24 hour post-dosing period, with maximum inhibition observed between 1 and 5 hours post dose. No relevant inhibition of JAK2 activity was observed in Japanese and Caucasian healthy volunteers confirming the JAK1 over JAK2 selectivity of filgotinib. In Japanese healthy volunteers, filgotinib was generally safe and well tolerated with no relevant differences in safety profile as compared to Caucasian healthy volunteers. Conclusions Filgotinib showed comparable PK, PD and safety profiles in Japanese and Caucasian healthy volunteers. The similarity in the PK and PD response suggests that there are no relevant differences among the groups in drug metabolism or sensitivity to selective inhibition of JAK1. Thus, these data support that filgotinib could be safely administered without dose adjustment to Japanese RA patients. Disclosure of Interest F. Namour Shareholder of: GALAPAGOS, Employee of: GALAPAGOS, B. Vayssière Employee of: GALAPAGOS, R. Galien Shareholder of: GALAPAGOS, Employee of: GALAPAGOS, L. Fagard Employee of: GALAPAGOS, A. Van der Aa Shareholder of: GALAPAGOS, Employee of: GALAPAGOS, P. Harrison Shareholder of: GALAPAGOS, Employee of: GALAPAGOS, C. Tasset Shareholder of: GALAPAGOS, Employee of: GALAPAGOS

SAT0231 Effects of the jak1-selective inhibitor filgotinib on gene expression profile in blood of patients with active rheumatoid arthritis

Background: Filgotinib (FIL), an oral selective JAK1 inhibitor, has shown good safety and efficacy in two phase 2b studies (background methotrexate (MTX, DARWIN 1) and as monotherapy (DARWIN 2)) in active rheumatoid arthritis (RA) patients with inadequate response to MTX1,2. We conducted a large-scale RNA sequencing study of genes expressed in blood samples from these studies. Objectives: Identify RA-associated gene transcripts that are altered in response to FIL treatment. Methods: PAXgene blood samples from 242 RA patients receiving either a stable dose of MTX and placebo (PBO) or FIL 200 mg once daily (QD, DARWIN 1); or PBO, FIL 100 mg, or 200 mg monotherapy QD (DARWIN 2), were collected and analyzed at baseline, week 1 and/or week 12. RNA in whole blood was sequenced (Illumina HiSeq 2500) after globin depletion. Differential gene expression analysis was performed on all time-paired data after subtracting gene expression changes in the PBO group. Spearman’s rank correlation of gene expression to time, dose, and disease activity score (DAS28) were calculated on samples without missing values. A false-discovery rate (FDR) of 10% was applied for all analyses Results: Top-ranked gene sets positively associated with DAS28 disease activity at baseline over both studies included interferon alpha (IFN-α) and IFN gamma (IFN-γ) response, IL6/JAK/STAT3 signaling, and toll-like receptor signaling pathways (FDR<10%). Of 197 genes that positively correlated with disease score (increased gene expression with increased DAS28, FDR<10%), 117 (59%) trended toward reduced expression at 12 weeks with FIL in both studies. These genes were enriched in pathways which included granulocyte and macrophage activation. Conversely, of 256 genes negatively correlated with disease score (FDR<10%), 169 (66%) trended toward increased expression post-FIL (figure 1). Of 14724 genes expressed at >1CPM in at least 5% of the samples, 607 were differentially expressed following FIL treatment in either DARWIN1 or DARWIN2 with 48 genes significant in both studies (FDR<10%). Genes reaching significance in at least one study showed consistent magnitude and direction of change in both studies and were enriched in JAK/STAT, innate and adaptive immunity, and autoimmune associated pathways. CISH, SOCS2, SOCS3, VWA5a, APCDD1, DNASE1L3, and PIM3 correlated with both duration of treatment and FIL dose (FDR<10%). CISH and SOCS confirm JAK pathway modulation. Figure 1 Heatmap of 453 DAS28-correlated genes and the corresponding change in gene expression with 12 wk FIL in Phase2b RA studies Conclusions: RA patients treated with FIL show reproducible changes in gene expression consistent with modulation of JAK/STAT signaling and innate and adaptive immunity. FIL was shown to partially reverse the dysregulated gene expression profile associated with baseline DAS28 score, consistent with the efficacy observed in RA patients. References [1]Kavanaugh A, et al. Ann Rheum Dis2017;76:1009–19. [2]Westhovens R, et al. Ann Rheum Dis2017;76:998–1008. Disclosure of Interest: P. Taylor Consultant for: AbbVie, Biogen, BMS, Galapagos, GSK, Janssen, Lilly, MSD, Novartis, Sandoz, UCB;, J. Tarrant Employee of: GSI Employee, L. Zhao Employee of: GSI Employee, Y. Gindin Employee of: GSI Employee, A. Mirza Employee of: GSI Employee, P. Harrison Employee of: GLPG Employee, C. Tasset Employee of: GLPG Employee, R. Galien Employee of: GLPG Employee, A. Van der Aa Employee of: GLPG Employee, B. Downie Employee of: GSI Employee

SAT0200 Long term safety of filgotinib in the treatment of rheumatoid arthritis: week 108 data from a phase 2b open-label extension study

Background: Filgotinib (FIL) is an orally administered, selective inhibitor of Janus Kinase 1 (JAK1) in Phase 3 development for the treatment of rheumatoid arthritis (RA). Objectives: Assess the long-term safety and efficacy of FIL in the DARWIN 3 open-label extension study. Methods: Two 24-week Phase 2b studies were completed in patients (pts) with moderately to severely active RA (DARWIN 1, DARWIN 2; Ref 1, 2). Following study completion, pts were offered FIL in the ongoing DARWIN 3 extension study: 100 mg QD (US males), 200 mg QD, or 100 mg BID. This report summarizes safety data from the first dose of FIL in the DARWIN program to 11 Oct 2017 and efficacy data from the DARWIN 3 baseline visit to Week 108, which all ongoing pts have completed. Results: Of 877 pts, 790 (90%) completed DARWIN 1/2, and 739 (84%) enrolled in DARWIN 3; 603 (82%) were female, mean age 53 years. At analysis, 491/739 (66%) were on study. Cumulative patient years of exposure (PYE) was 1931, median time on study drug was 1072 days. Key data are summarized in table 1. 87%, 68%, and 48% of pts achieved ACR20/50/70, respectively, and 72% achieved DAS28-CRP≤3.2 (by observed case analysis).Table 1 Key Safety Events and Lab Abnormalities per 100 PYE* * Treatment groups with fewer than 10 subjects were omitted for clarity; †Non-melanoma skin cancer; ‡Single patient DVT leading to PE Conclusions: Filgotinib long-term RA data demonstrates an acceptable safety and durable efficacy profile. References [1]Westhovens R, et al. Ann Rheum Dis2017;76:998–1008. [2]Kavanaugh A, et al. Ann Rheum Dis2017;76:1009–1019. Disclosure of Interest: R. Westhovens Grant/research support from: Galapagos and Celltrion, Roche and BMS, Consultant for: Galapagos and Celltrion, Roche and BMS, R. Alten Grant/research support from: Galapagos/Gilead, K. Winthrop Consultant for: Pfizer, Lilly, Galapagos, Gilead, AbbVie, M. Greenwald Grant/research support from: Gilead, L. Ponce: None declared, F. Enriquez-Sosa: None declared, M. Stanislavchuk: None declared, M. Mazur: None declared, A. Spindler: None declared, R. Cseuz: None declared, N. Nikulenkova: None declared, M. Glowacka-Kulesz: None declared, I. Szombati: None declared, A. Dudek: None declared, N. Mozaffarian Shareholder of: Gilead, Employee of: Gilead, J. Greer Shareholder of: Gilead, Employee of: Gilead, R. Kunder Shareholder of: Gilead, Employee of: Gilead, D. An Shareholder of: Gilead, Employee of: Gilead, P. Harrison Shareholder of: Galapagos, Employee of: Galapagos, A. Van der Aa Shareholder of: Galapagos, Employee of: Galapagos, A. Kavanaugh Consultant for: Galapagos, M. Genovese Consultant for: Gilead, Galapagos, Abbvie, Lilly, Pfizer

THU0182 Monotherapy with the jak1-selective inhibitor filgotinib displays an anti-inflammatory biomarker profile in rheumatoid arthritis patients

Background Janus kinases (JAKs) are key proteins in the signal transduction of many cytokines and growth factors. The selective JAK1 inhibitor filgotinib (GLPG0634, GS-6034) has been evaluated in a 24-week phase 2B study (DARWIN 2) as monotherapy in active rheumatoid arthritis (RA) patients with inadequate response to methotrexate and has shown a good safety and efficacy profile1. Objectives To gain insight into filgotinib mode of action as monotherapy in RA patients by analysing the impact of filgotinib on a broad panel of immune modulators in the serum. Methods RA patients received either placebo (PBO), or filgotinib monotherapy at 50mg, 100mg or 200mg once daily (QD). Serum samples were collected at baseline, week 4 and week 12 and analysed using the 18-plex bead-based immunoassay (HSTCMAG-28SK Merck-Millipore) on BioPLEX-200 instrument to measure cytokine concentration. Median % change from baseline for biomarkers are reported for week 4 and 12. Wilcoxon rank-sum test assessed the significance of difference between filgotinib treated groups and PBO. Results Following treatment with filgotinib at 100 mg QD and 200mg QD, there were significant reductions in cytokines important in expansion and activity of multiple T cell subsets and innate immunity compared to PBO (see Table). These changes include decreases in proinflammatory cytokines (IL-6, IL-1β, and TNFα), TH1-related (IL-2, IFN-γ and IL-12), TH2-related (IL-4, IL-5, and IL-13) and TH17-related cytokines (IL-1β, IL-6, IL-17A, IL-21 and IL-23). All doses of filgotinib also reduced the B- and T-cell development cytokine IL-7. In contrast, IL-8 was not affected by filgotinib. Reductions in MIP1α, MIP1β and GM-CSF are in line with a down modulation of innate immune activity.Table 1. Median percent change of biomarkers from baseline Week 4 Week 12 PBO Filgotinib Filgotinib PBO Filgotinib Filgotinib (N=61) 100mg QD 200mg QD (N=61) 100mg QD 200mg QD QD (N=62) (N=65) (N=63) QD (N=65) GM-CSF 0 -11*** -9*** 6 -11*** -21*** IFN-γ 13 -15*** -13*** 6 -21*** -23*** IL-1β 6 -10** -13*** 8 -24*** -16*** IL-2 4 -9** -13*** 10 -22*** -21*** IL-4 10 -8*** -8*** 21 -17*** -22*** IL-5 2 -10** -3* 3 -20*** -14*** IL-6 17 -20** -35*** -13 -34* -52*** IL-7 2 -10*** -1NS 0 -22*** -21** IL-8 1 -1NS -1NS -7 -4NS -8NS IL-10 6 -12*** -17*** 13 -18*** -26*** IL-12 8 -7*** -14*** 6 -20*** -23*** IL-13 1 -10** -13** 13 -8*** -20*** IL-17A 7 -9*** -12*** 1 -21*** -16** IL-21 11 -14*** -10*** 4 -26*** -23*** IL-23 3 -12*** -12*** -4 -24*** -31*** MIP-1α 5 -5*** -8*** 3 -7*** -6** MIP-1β 3 -6** -6* 3 -5NS 3NS TNF-α 5 -7*** -12*** 5 -11** -14** P values comparing % changes between filgotinib and PBO groups: NS p>0.05; *p<0.05; **p<0.01; ***p<0.001. Conclusions Treatment of RA patients with filgotinib monotherapy resulted in significant reduction in the levels of a broad range of cytokines related to TH1, TH2, TH17 and potentially B cells, as well as innate immunity. This observed anti-inflammatory activity of filgotinib is consistent with its efficacy in RA patients. References Kavanaugh A et al. Ann Rheum Dis 2016;0:1–11.doi:10.1136/annrheumdis-2016–210105. Disclosure of Interest A. Kavanaugh Consultant for: Galapagos, Pfizer, Abbvie, Amgen, Celgene, Janssen, Novartis, Eli Lilly, UCB, A. Van der Aa Employee of: Galapagos NV, C. Jamoul Employee of: Galapagos NV, W. Li Employee of: Gilead Sciences, L. Goyal Employee of: Gilead Sciences, Y. Pan Employee of: Gilead Sciences, P. Harrison Employee of: Galapagos NV, C. Tasset Employee of: Galapagos NV, J. Tarrant Employee of: Gilead Sciences, R. Galien Employee of: Galapagos SASU

THU0205 Effects of the jak1-selective inhibitor filgotinib on multibiomarker disease activity scores in patients with active rheumatoid arthritis and an inadequate response to methotrexate

Background Filgotinib (GLPG0634, GS-6034) is an oral selective JAK1 inhibitor that has been evaluated in a 24-week phase 2B study (DARWIN 1) on the background of methotrexate (MTX) treatment in active rheumatoid arthritis (RA) patients who were MTX inadequate responders1. Objectives To evaluate the effect of filgotinib compared to placebo on a multi-biomarker disease activity (MBDA) score that measures 12 disease-related biomarkers of inflammation and joint injury in RA patients taking background MTX. Methods Serum samples of RA patients who were on a stable dose of MTX and received either placebo (PBO) or filgotinib 100mg or 200mg once daily (QD), were tested for MBDA components (Crescendo Biosciences, CA, US) at baseline, week 4 and week 12. Median % change from baseline for MBDA score and individual components are reported for week 4 and week 12. Wilcoxon rank-sum test assessed the significance of difference between filgotinib treated groups vs. PBO. Results Baseline MBDA scores and component values (median; interquartile range) were similar in PBO (55; 45–64), 100mg QD (58; 42–66), and 200mg QD (59; 50–67.5) treatment groups. Filgotinib treated patients had reductions in the MBDA score from baseline at both the 100mg and 200mg QD dose levels, but not in the PBO group. At both weeks 4 and 12, these reductions in the filgotinib treated groups were significantly different from the PBO group. Most of the individual components contributed to the decrease in MBDA score, but the largest reductions were observed for serum amyloid A (SAA), C-reactive protein (CRP), and IL-6, and the biomarkers of joint-damage, matrix metalloproteinase 3 (MMP3), MMP1, vascular endothelial growth factor (VEGF), and YKL40 (human cartilage glycoprotein 39). There was an increase in leptin and no change in epidermal growth factor (EGF) concentrations.Table 1. Median percent change from baseline of MBDA score and component concentrations Week 4 Week 12 PBO Filgotinib Filgotinib ) PBO Filgotinib Filgotinib (N=62) 100mg QD 200mg QD (N=65) 100mg QD par 200mg QD (N=63) (N=68) (N=62) (N=68) MBDA SCORE -1 -20*** -24*** -5 -19*** -24*** CRP 15 -57*** -71*** -8 -66*** -78*** EGF 14 -18NS -8NS 0 -10NS 0NS IL-6 -15 -34** -60*** -20 -41** -63*** LEPTIN 0 8NS 18NS 6 14NS 23* MMP-1 10 -16*** -24*** -6 -18** -26*** MMP-3 0 -24** -33*** -9 -25*** -43*** RESISTIN 1 -12** -22*** -1 -15* -16*** SAA 8 -45*** -65*** 7 -49*** -67*** TNF-RI 0 -11*** -26*** 0 -11*** -15*** VCAM-1 5 -10*** -15*** 0 -8** -16*** VEGF 3 -16*** -25*** -2 -16*** -26*** YKL-40 2 -12* -32*** -7 -17NS -33*** p-values comparing % changes between filgotinib and PBO groups NS, p>0.05; *p<0.05; **p<0.01; ***p<0.001. Conclusions RA patients treated with filgotinib in combination with MTX had significant reductions in the MBDA score that was driven by key RA biomarkers encompassing both inflammation and joint injury. These findings are consistent with the filgotinib efficacy observed in RA patients over 12 weeks. References Westhovens R, et al. Ann Rheum Dis 2016;0:1–11. doi:10.1136/annrheumdis-2016–210104. Disclosure of Interest M. Genovese Grant/research support from: Abbvie, Eli Lilly, Pfizer, Astellas, Vertex, Consultant for: Galapagos, Gilead, Abbvie, Eli Lilly, Pfizer, Astellas, Vertex, W. Li Employee of: Gilead Sciences, L. Goyal Employee of: Gilead Sciences, Y. Pan Employee of: Gilead Sciences, A. Van der Aa Employee of: Galapagos NV, C. Jamoul Employee of: Galapagos NV, P. Harrison Employee of: Galapagos NV, C. Tasset Employee of: Galapagos NV, R. Galien Employee of: Galapagos SASU, J. Tarrant Employee of: Gilead Sciences

THU0173 Long term safety and efficacy of filgotinib in a phase 2B open label extension study in patients with rheumatoid arthritis: results up to 144 weeks

Background Filgotinib (GLPG0634, GS-6034) is an oral JAK1 selective inhibitor with a favorable safety and efficacy profile in two 24-week Phase 2b studies as add-on to methotrexate (DARWIN 1) or as monotherapy (DARWIN 2) in patients with active rheumatoid arthritis (RA). Three daily doses were tested (50mg, 100mg or 200mg) in comparison to placebo. Objectives To assess long term safety and efficacy of filgotinib 200mg daily in patients from the DARWIN 3 Phase 2 open-label extension study. Methods Patients who completed DARWIN 1 or 2 and enrolled in DARWIN 3 received filgotinib 200mg once daily or 100mg twice daily, depending on prior treatment assignment. The DARWIN 3 data cut off was when the last patient reached extension Week 60. For safety, all data from the first intake of filgotinib in DARWIN 1/2/3 were analysed (up to 144 weeks). Results 877 patients participated in DARWIN 1 or 2, 790 completed and 739 entered DARWIN 3 from 22 countries (82% females, mean age 53y). 559 patients (75.6%) completed Week 60, 9.3% discontinued due to positive Quantiferon, 7.8% due to other adverse events, 6.8% for other reasons and 0.3% due to insufficient response. Overall exposure to filgotinib was 1314 patient-years (PYE). Treatment-emergent adverse events (157.7/100PYE), serious adverse events (5.3/100PYE) and serious infections (1.9/100PYE) occurred at similar rates compared to the core studies, however infections decreased on a percentage basis from 15% (109/739, W0–12) to 5% (25/549, W85–96). 16 cases of Herpes zoster were reported (1.2/100PYE), 6 cases of malignancy (excl. NMSC) (0.5/100PYE) and 1 case of MACE (0.1/100PYE). There was no active case of tuberculosis. Three fatalities were reported (0.2/100PYE). Mean change from baseline (CFB) at Week 96 and CTCAE toxicity grading in lab parameters of special interest are shown in table 1.Table 1. Mean CFB at Week 96 and CTCAE toxicity grading of selected lab parameters Mean CFB CTCAE Grade 3–4 (%) Hb +6.5 g/L 0.4 Neutrophils −1.73 giga/L 1 Lymphocytes −0.19 giga/L 2 Creatinine +8.2 μmol/L 0 ALT +6.1 U/L 0.4 LDL +13% – HDL +23% – Tot chol/HDL −4% – NK cells −0.02 giga/L – Based on an observed case analysis 84% (505/601), 65% (389/601), 44% (267/601) and 51% (299/587) of patients reached ACR20, ACR50, ACR70 and DAS28(CRP) remission at Week 60 respectively. Conclusions With 1314 patient-years of exposure, the safety profile of filgotinib appears consistent with that of previously reported double-blind studies and the clinical response appears durable. References Westhovens R et al. Ann Rheum Dis 2016;0:1–11. Kavanaugh A et al. Ann Rheum Dis 2016;0:1–11. Disclosure of Interest R. Alten Grant/research support from: Galapagos, R. Westhovens Grant/research support from: Roche, Consultant for: Galapagos, Speakers bureau: BMS, A. Kavanaugh Consultant for: Galapagos, Pfizer, AbbVie, Amgen, Celgene, Janssen, Novartis, Eli Lilly, UCB, M. Genovese Grant/research support from: Abbvie, Eli Lilly, Pfizer, Astellas, Vertex, Consultant for: Galapagos, Gilead, Abbvie, Eli Lilly, Pfizer, Astellas, Vertex, K. Winthrop Grant/research support from: BMS, Pfizer, Consultant for: pfizer, BMS, lilly, Abbvie, Roche, UCB, Galapagos, Amgen, M. Greenwald Grant/research support from: Abbvie,Amgen, Bristol Myers Squibb, Celgene, Galapagos, Gilead, Lilly, Merck, Pfizer, UCB, Consultant for: Lilly, Pfizer, L. Ponce: None declared, F. Enriquez: None declared, M. Stanislavchuk: None declared, M. Mazur: None declared, A. Spindler: None declared, R. Cseuz: None declared, N. Nikulenkova: None declared, M. Glowacka-Kulesz: None declared, I. Szombati: None declared, A. Dudek: None declared, L. Meuleners Employee of: Galapagos NV, C. Tasset Employee of: Galapagos NV, P. Harrison Employee of: Galapagos NV, A. Van der Aa Employee of: Galapagos NV