Zhao, Sally

Abstract Background Filgotinib (FIL) is a once-daily, oral, preferential Janus kinase 1 inhibitor in development for the treatment of inflammatory bowel disease. FIL for the treatment of moderately to severely active ulcerative colitis (UC) was evaluated in the phase 2b/3 randomized, double-blind, placebo (PBO)-controlled SELECTION study (NCT02914522). Long-term use of corticosteroids (CS) is associated with significant side effects. The aim of this post hoc analysis was to assess the CS-sparing effects of FIL in the SELECTION study. Methods Patients (18–75 years old) with moderately to severely active UC were randomized (2:2:1) to receive FIL 100 mg (n = 564), FIL 200 mg (n = 507) or PBO (n = 280) once daily orally for up to 11 weeks (induction study). At week 11, FIL induction responders were rerandomized 2:1 to continue their induction FIL dose or to receive PBO (maintenance study). CS use was kept stable up to week 14, at which point mandatory CS tapering occurred. CS could be resumed during the maintenance study; however, if the baseline CS dose was exceeded this was considered treatment failure. In this post hoc analysis, CS-free remission was defined as remission at week 58 (endoscopic subscore ≤ 1, rectal bleeding subscore = 0 and ≥ 1-point decrease in stool frequency subscore to achieve 0 or 1) without systemic or localized CS use that was indicated for UC in the previous 1, 3, 6 or 8 months. Results The baseline characteristics of patients in the maintenance study were similar across treatment groups (Table 1). Of the 92 patients receiving CS at maintenance baseline (week 11; maintenance week 0) who received FIL 200 mg during the maintenance study, 25 (27%) were in remission at week 58 and had been continuously CS-free for at least the previous 6 months (Table 2). The proportion of CS-free remitters in the FIL 200 mg group was consistently higher than with PBO (Table 2). In patients taking CS at maintenance baseline who had continued CS-use post baseline, lower median prednisone dosing was observed with FIL 200 mg than with PBO throughout the maintenance study (maximum difference at week 34 [maintenance week 23]: 5.0 mg vs 13.8 mg) (Figure 1). In SELECTION, a total of 199 patients received FIL 200 mg in the maintenance study, of whom 74 (37.2%) were in remission at week 58; of these 74 patients, 69 (93.2%) were continuously CS-free for at least the previous 6 months (Figure 2). Conclusion In this post hoc analysis of SELECTION maintenance study data, FIL 200 mg was effective in reducing and eliminating CS use through to week 58 in patients with moderately to severely active UC. The vast majority of patients taking FIL 200 mg who were in remission at week 58 had not taken CS in the previous 6 months.

Abstract Background Filgotinib (FIL), an oral preferential Janus kinase 1 inhibitor, was evaluated for the treatment of ulcerative colitis in the phase 2b/3 double-blind, placebo (PBO)-controlled SELECTION study (NCT02914522). Clinical, histological and endoscopic remission rates at week 58 were significantly greater with FIL 200 mg than with PBO (p < 0.025 for all comparisons). Here, we identify disease characteristics contributing to histo-endoscopic mucosal healing (HEMH; Geboes histological remission and endoscopic subscore ≤ 1) at week 58. FIL 100 mg data are excluded from by-treatment summaries because histological and endoscopic remission rates were not significantly different from PBO in SELECTION. Methods Eligible patients (18–75 years old) with moderately to severely active ulcerative colitis were enrolled in Induction Study A (biologic-naïve) or B (biologic-experienced) and randomized to receive FIL 200 mg, FIL 100 mg or PBO (2:2:1) once daily for up to 11 weeks, with response assessed at week 10. At week 11, FIL responders were re-randomized 2:1 to continue their induction FIL dose or to receive PBO for the 47-week maintenance study. PBO responders continued receiving PBO. For the maintenance study, univariate logistic regression was used to identify baseline and week 10 disease characteristics associated with HEMH (defined as achieving both Geboes histological remission [Grade 0 of ≤0.3, Grade 1 of ≤ 1.1, Grade 2a of ≤ 2A.3, Grade 2b of 2B.0, Grade 3 of 3.0, Grade 4 of 4.0, and Grade 5 of 5.0] and an endoscopic subscore of 0 or 1) at week 58 for patients receiving FIL 200 mg; variables with p < 0.05 in the univariate analysis were included in a multivariate analysis. Results Patients had similar characteristics across the treatment groups for both the induction (Table 1) and maintenance studies (Table 2). HEMH was achieved in a greater proportion of patients receiving FIL 200 mg than those receiving respective PBO at week 58 (32.7% vs 10.2%; p < 0.0001). No associations between disease characteristics (at baseline and week 11) and HEMH at week 58 were found (Table 3). Conclusion FIL 200 mg was effective at establishing HEMH compared with PBO at week 58; there were no baseline characteristics identified to be associated with HEMH at week 58.

Abstract Background Filgotinib (FIL) is an oral preferential Janus kinase (JAK) 1 inhibitor in development for the treatment of inflammatory diseases. FIL for the treatment of moderately to severely active ulcerative colitis (UC) was evaluated in the phase 2b/3, double-blind, placebo (PBO)-controlled SELECTION study (NCT02914522) and its long-term extension (LTE) study (NCT02914535). Here we report safety results from the FIL UC program. Methods Patients received FIL 100 mg, FIL 200 mg or PBO (2:2:1) once daily orally for up to 11 weeks for induction (cohort 1). At week 11, FIL induction responders were rerandomized 2:1 to continue FIL or receive PBO maintenance for 47 weeks (cohort 2). Week 10 non-responders and patients with worsening disease during the maintenance study were eligible for open-label FIL in the LTE. Patients completing the maintenance study could continue blinded dosing in the LTE. Cohort 3 comprised cohorts 1 and 2 and the LTE. Exposure-adjusted incidence rates (EAIRs) and exposure-adjusted event rates (EAERs) per 100 patient-years (PYs) were calculated for treatment-emergent adverse events (AEs) by treatment group in cohorts 1 and 2 (EAIR) and cohort 3 (EAER). Results In cohort 1, 1069 patients received FIL and 279 patients received PBO; baseline characteristics were generally similar across treatment groups (overall mean age, 43 years; mean UC duration, 8.4 years; mean Mayo Clinic Score, 9.0). EAIRs for AEs of interest were similar across treatment groups in cohorts 1 and 2 (Table 1). Treatment exposure for PBO, FIL 100 mg or FIL 200 mg in cohort 3 (i.e. cohorts 1 + 2 + the LTE) was 318, 360 and 1207 PYs, and median treatment duration was 12, 11 and 67 weeks, respectively. One case of pulmonary embolism occurred with FIL 200 mg induction and three venous thrombosis cases occurred with PBO maintenance/LTE (cohort 3) (Table 2). EAERs for all infections were similar across treatment groups, the most common being nasopharyngitis (Table 2). Opportunistic infections were rare. EAERs for serious infections were low across treatment groups (2.2 [PBO], 3.5 [FIL 100 mg], 2.2 [FIL 200 mg]), the most common being appendicitis (Table 2). EAERs for herpes zoster (HZ) were low in all treatment groups (0.3 [PBO], 0.3 [FIL 100 mg], 1.8 [FIL 200 mg]) (Table 2). HZ infections were cutaneous only and only one was serious. EAIRs for all infections in cohorts 1 and 2 were generally numerically higher for both PBO and FIL in patients over (vs under) 65 years old and in those with (vs without) biologic treatment failure (Figure 1). Conclusion FIL was well tolerated in patients with UC. Aggregation of AEs typical for pan-JAK inhibition was not observed, consistent with preferential JAK-1 inhibition with FIL.

Abstract Background Filgotinib (FIL) is a preferential Janus kinase 1 inhibitor in development for the treatment of inflammatory bowel disease. SELECTION was a phase 2b/3 randomized, double-blind, placebo (PBO)-controlled trial to evaluate FIL for the treatment of moderately to severely active ulcerative colitis (UC) (NCT02914522). The aim of this post hoc analysis was to assess the speed of improvement in patient-reported outcomes (PROs) during FIL treatment. Methods Eligible patients who were biologic-naïve or -experienced were enrolled in induction study A or induction study B, respectively. In each study, patients were randomized 2:2:1 to receive FIL 100 mg, FIL 200 mg or PBO once daily orally for 10 weeks. In this post hoc analysis, data from daily patient diaries up to day 15 of induction, including Mayo stool frequency subscores (SF; range, 0 [normal] to 3 [≥5 stools/day more than normal]) and rectal bleeding subscores (RB; range, 0 [no blood] to 3 [passing blood alone]), were used to evaluate the proportion of patients achieving predefined subscores or subscore reductions. Results Induction studies A and B comprised 659 and 689 patients, respectively. Baseline characteristics were similar across treatment groups within induction study A and within induction study B. In induction study A, more patients treated with FIL 200 mg vs PBO reported a reduction in SF of ≥1 from baseline as early as day 6 (FIL 200 mg, 35.8%; PBO, 20.6%, p<0.01) and every day from day 10 (Figure 1), and a reduction in RB of ≥1 from baseline as early as day 4 (FIL 200 mg, 36.9%; PBO, 23.7%; p<0.01) and every day from day 7 (Figure 2). In induction study B, more patients treated with FIL 200 mg vs PBO reported a reduction in SF of ≥1 from baseline as early as day 2 (FIL 200 mg, 21.6%; PBO, 12.1%; p<0.05) (Figure 3) and a reduction in RB of ≥1 from baseline as early as day 3 (FIL 200 mg, 29.5%; PBO, 17.6%; p<0.01) (Figure 4). More patients receiving FIL 200 mg vs PBO achieved the composite score of RB=0 and SF≤1 as early as day 9 in induction study A (FIL 200 mg, 18.8%; PBO, 9.5%, p<0.05). More patients receiving FIL 200 mg vs PBO achieved the composite score of RB=0 and SF≤1 as early as day 7 in induction study B (FIL 200 mg, 10.7%; PBO, 4.2%, p<0.05). Conclusion In this post hoc analysis of induction study data from SELECTION, improvements in SF and RB were observed within the first week of therapy with FIL 200 mg, compared with PBO, in patients with moderately to severely active UC. These data demonstrate that FIL 200 mg has rapid onset of action, as assessed by PROs, in both biologic-naïve and biologic-experienced patients.

Abstract Aims SELECTION (NCT02914522) Maintenance evaluated filgotinib (FIL), a preferential JAK1 inhibitor, as maintenance therapy for patients (pts) with moderately to severely active ulcerative colitis (UC) who achieved clinical remission or Mayo Clinic Score (MCS) response after 10 weeks of FIL 200mg QD, FIL 100mg QD or placebo (PBO) induction. Methods Pts randomized to FIL induction were rerandomized 2:1 to their induction FIL dose or PBO; pts randomized to PBO induction continued PBO maintenance. Steroid tapering was mandatory. The primary endpoint was clinical remission at Week 58. Key secondary endpoints and exploratory endpoints were assessed at Week 58. Results 664 pts were treated in the Maintenance Study (n=93, 270, and 301 from induction with PBO, FIL 100mg and FIL 200mg); efficacy analyses included only FIL induction pts. Baseline demographics and disease characteristics were generally balanced across treatment arms; 40% were biologic experienced. Significantly higher proportion of pts on FIL 200mg or FIL 100mg were in clinical remission vs PBO. Significantly higher proportions of pts achieved key secondary endpoints with FIL 200mg vs PBO. More pts on FIL 200 mg or FIL 100mg achieved an MCS response and endoscopic improvement vs PBO. Incidences of adverse events (AEs), serious AEs and discontinuations due to AEs were similar across arms. Serious infection (<2%) and herpes zoster (<1%) were infrequent among FIL-treated patients. There were no venous thromboses, including pulmonary embolism, among FIL-treated pts. Two pts on FIL 200mg died, both AEs leading to death were considered unrelated to FIL. Conclusions FIL 200mg and FIL 100mg were effective as maintenance treatment for pts with moderately to severely active UC who had achieved clinical response to FIL induction treatment. FIL 200 mg met all key secondary endpoints including endoscopic, histologic and 6-month corticosteroid-free remission. FIL was well tolerated in pts with moderate to severely active UC. Funding Agencies None