Moerch, Ulrik

Summary Background Filgotinib 200 mg (FIL200) is an approved treatment for adults with moderately to severely active ulcerative colitis (UC). Aim To report integrated safety data from the phase 2b/3 SELECTION study (NCT02914522) and its ongoing long‐term extension study SELECTIONLTE (NCT02914535). Methods Safety outcomes were analysed in adults with moderately to severely active UC who received FIL200, filgotinib 100 mg (FIL100) or placebo once daily throughout the 11‐week SELECTION induction study, the 47‐week SELECTION maintenance study (if applicable) and SELECTIONLTE (if applicable). Exposure‐adjusted incidence rates (EAIRs) per 100 censored patient‐years of exposure with 95% confidence intervals were reported for treatment‐emergent adverse events (AEs). Certain AE data were presented in subgroups, including age and prior biologic exposure status. Results This interim analysis included 1348 patients representing 3326.2 patient‐years of exposure. Baseline characteristics of patients entering SELECTION were similar across treatment groups. EAIRs for serious infection, thromboembolic events and major adverse cardiovascular events (MACE) were consistently low across treatment groups. Most patients with MACE had cardiovascular risk factors. The EAIR for herpes zoster was numerically higher for FIL200 than for placebo. Infection incidences were numerically higher in biologic‐experienced than biologic‐naive patients. Higher incidences of certain AEs in patients 65 years of age or older were as expected. Four deaths occurred, including three cardiovascular deaths, none of which was considered related to filgotinib. Conclusion FIL200 and FIL100 were well tolerated with no unexpected safety signals in patients with moderately to severely active UC, regardless of previous biologic exposure or age. ClinicalTrials.gov Identifiers (NCT numbers) NCT02914522, NCT02914535.

Abstract Background and Aims Corticosteroid-free remission is an important treatment goal for patients with ulcerative colitis [UC]. The corticosteroid-sparing effects of filgotinib, an oral, Janus kinase 1 preferential inhibitor, were assessed in SELECTION, a placebo-controlled, phase 2b/3 trial in moderately to severely active UC. Methods These post hoc analyses assessed 1-, 3-, 6-, and 8-month rates of corticosteroid-free clinical remission at Week 58 and change in median daily prednisone-equivalent dose over time. A matching-adjusted indirect comparison [MAIC] of maintenance studies assessed corticosteroid-free remission with filgotinib 200 mg, intravenous vedolizumab, subcutaneous vedolizumab, and oral tofacitinib. Results The Maintenance Study full analysis set included 199 patients receiving filgotinib 200 mg and 98 receiving placebo. Among patients receiving corticosteroids at Maintenance Study baseline, at Week 58, 30.4%, 29.3%, 27.2%, and 21.7% receiving filgotinib had been in corticosteroid-free remission for ≥1, ≥3, ≥6, or ≥8 months, respectively, versus 6.4% receiving placebo across thresholds [p <0.05]. Median daily prednisone-equivalent dose decreased from 17.5 mg/day to 10.0 mg/day with filgotinib treatment during the Maintenance Study. Based upon the MAIC, filgotinib was associated with greater likelihood of corticosteroid-free clinical remission versus intravenous vedolizumab (odds ratio [OR], 15.2; 95% confidence interval [CI], 1.6–139.9; p <0.05]) and similar odds to subcutaneous vedolizumab [OR, 3.8; CI, 0.2–63.8; p = 0.36] in biologic-naïve patients, and similar odds to tofacitinib overall [OR, 2.0; 0.4–9.1; p = 0.39]. Conclusions Filgotinib 200 mg demonstrated corticosteroid-sparing effects and maintained corticosteroid-free clinical remission in patients with UC. MAIC results should be interpreted cautiously given the large CIs and differences in study design and patient populations. [ClinicalTrials.gov: NCT02914522].

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) 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.