Galapagos (Netherlands)

Patients with moderately to severely active ulcerative colitis have distinct filgotinib response trajectories. Evaluate factors associated with response to filgotinib over time. Patients from SELECTION (NCT02914522) receiving filgotinib 200 mg (FIL200) or 100 mg (FIL100), or placebo were included. Factors associated with partial Mayo Clinic Score (pMCS) were assessed post hoc using a mixed model for repeated measures (MMRM). The prognostic value of week 10 faecal calprotectin (FCP) was assessed versus week 58 outcomes; p values are nominal. The MMRM included 558 patients (FIL200, n = 199; FIL100, n = 172; placebo, n = 187). For filgotinib, factors associated with lower week 58 pMCS versus respective comparators (p < 0.05) included being biologic-naive, low baseline inflammatory burden (endoscopic subscore <3, C-reactive protein ≤3 mg/L), or week 10 histological remission, endoscopic subscore ≤1, rectal bleeding and stool frequency subscores of 0, Inflammatory Bowel Disease Questionnaire scores >170, and/or lower FCP concentration. The optimal prognostic week 10 FCP cut-off for a concurrent week 10 Mayo Clinic Score response was <250 µg/g; combined week 10 FCP <250 µg/g and pMCS remission had similar week 58 prognostic value for clinical remission as week 10 endoscopic response. Being biologic-naive, having low baseline inflammatory burden, or strong week 10 filgotinib responses were associated with lower pMCS over 1 year of treatment. FCP <250 µg/g and week 10 pMCS remission may reduce the need for follow-up endoscopy.

ObjectivesDARWIN 3 (ClinicalTrials.gov: NCT02065700) assessed the safety and efficacy of filgotinib in a long-term extension (LTE) of two phase II randomised controlled rheumatoid arthritis (RA) trials.MethodsEligible patients completing the 24-week DARWIN 1 (filgotinib plus methotrexate) and DARWIN 2 (filgotinib monotherapy) trials could enrol. Patients received filgotinib 200 mg/day, except 15 men who received filgotinib 100 mg/day. The primary endpoints were safety and tolerability, which were assessed by the incidence of treatment-emergent adverse events (TEAEs). Safety and efficacy analyses included all enrolled patients who received ≥1 dose of filgotinib in DARWIN 3.Results739 patients entered the LTE. The total patient-years of exposure (PYE) to filgotinib was 3706.3 years; the mean exposure duration was 259.8 weeks. 497 patients (67.3%) discontinued prematurely (including 266 TEAEs and 172 withdrawals due to the patient’s decision or ‘sponsor request’). Overall exposure-adjusted incidence rate (EAIR) was 67 (95% CI 62 to 72.2)/100 PYE for TEAEs and 3.8 (95% CI 3.2 to 4.5)/100 PYE for serious TEAEs. EAIR of infections was 23.3 (95% CI 21.2 to 25.6)/100 PYE, 1.3 (95% CI 0.9 to 1.7)/100 PYE for serious infections and 1.3 (95% CI 0.9 to 1.7)/100 PYE for herpes zoster. EAIRs of major adverse cardiovascular events (0.19 (95% CI 0.8 to 0.39)/100 PYE) and malignancies (0.6 (95% CI 0.4 to 0.9)/100 PYE) were low. Disease response assessed using non-responder imputation plateaued at LTE week 12 before slowly declining over time, with overall American College of Rheumatology (ACR)20/50/70 response rates of 26.9%/20.2%/14.7% at week 396.ConclusionFilgotinib was well tolerated in patients with RA for up to 8 years. Safety and efficacy profiles were maintained in patients previously receiving either filgotinib plus methotrexate or filgotinib monotherapy.

ObjectivesThe phase 2 MANTA and MANTA-RAy studies aimed to determine if the oral Janus kinase 1 preferential inhibitor filgotinib affects semen parameters and sex hormones in men with inflammatory diseases.MethodsMANTA (NCT03201445) and MANTA-RAy (NCT03926195) included men (21–65 years) with active inflammatory bowel disease (IBD) and rheumatic diseases (rheumatoid arthritis, spondyloarthritis or psoriatic arthritis), respectively. Eligible participants had semen parameters in the normal range per the WHO definition. In each study, participants were randomised 1:1 to receive once-daily, double-blind filgotinib 200 mg or placebo for 13 weeks for pooled analysis of the primary endpoint (proportion of participants with a ≥50% decrease from baseline in sperm concentration at week 13). Participants who met the primary endpoint were monitored over an additional 52 weeks for ‘reversibility’. Secondary endpoints included change from baseline to week 13 in: sperm concentration, total motility, normal morphology, total count and ejaculate volume. Sex hormones (luteinising hormone, follicle stimulating hormone, inhibin B and total testosterone) and reversibility were exploratory endpoints.ResultsAcross both studies, 631 patients were screened, and 248 were randomised to filgotinib 200 mg or placebo. Baseline demographics and characteristics were similar within indications between treatment groups. Numerically similar proportions of filgotinib-treated versus placebo-treated patients met the primary endpoint (8/120 (6.7%) vs 10/120 (8.3%)), Δ−1.7% (95% CI −9.3% to 5.8%)). There were no clinically relevant changes from baseline to week 13 in semen parameters or sex hormones, or patterns of reversibility between treatment groups. Filgotinib was well tolerated, with no new safety events.ConclusionsResults suggest that once daily filgotinib 200 mg for 13 weeks has no measurable impact on semen parameters or sex hormones in men with active IBD or inflammatory rheumatic diseases.

Abstract Background The once-daily, oral, Janus kinase 1 preferential inhibitor filgotinib (FIL) is approved for the treatment of moderately to severely active rheumatoid arthritis (RA) and ulcerative colitis (UC) in the UK, the EU and Japan.1 To further understand the safety profile of FIL across indications, we evaluated the risk of major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs) in patients treated with FIL 200 mg (FIL200) or FIL 100 mg (FIL100). Methods An integrated analysis was conducted with RA data from five phase 2/3 trials and two long-term extension (LTE) trials of FIL, and UC data from two phase 2/3 trials and one LTE trial of FIL (herein termed ‘overall’ data). Subgroup analyses by age and cardiovascular (CV) risk factors (excluding age) were conducted. Real-world data were extracted from a systematic literature review. Exposure-adjusted incidence rates (EAIRs) or incidence rates per 100 patient-years of exposure and 95% confidence intervals (CIs) were estimated for MACEs and VTEs. For clinical trial data, MACEs and VTEs included positively adjudicated events only. Results In pooled data, baseline characteristics were generally similar across treatment arms for RA and UC (Tables 1 and 2). In the RA data, MACE EAIRs were 0.29 and 0.41 for the overall FIL200 and FIL100 arms, respectively (Figure 1). MACE IRs were 0.45–0.77 for the general RA population. Higher MACE EAIRs were reported in the subgroup of patients with RA aged ≥65 years vs &amp;lt;65 years. In the RA subgroup with CV risk, MACE EAIRs were 0.53 for FIL200 and 0.64 for FIL100. VTE rates were 0.19 for both FIL200 and FIL100 overall in patients with RA, and 0.32–0.44 for the general RA population. Numerically higher VTE EAIRs with overlapping CIs were seen in patients with RA aged ≥65 years vs &amp;lt;65 years, and in those with vs without CV risk. In the UC data, MACE rates were 0.29, 0.35 and 0.87 in the overall FIL200 and FIL100 arms and in the general UC population, respectively (Figure 2). VTE rates were 0.08, 0.18 and 0.39 in the overall FIL200 and FIL100 arms and in the general UC population, respectively. For both MACE and VTE EAIRs, wide CIs were reported in patients with UC aged ≥65 years and in those with CV risk, owing to low numbers of events and/or patients in these subgroups. Conclusion No association was identified between FIL200 treatment and an increased risk of MACEs or VTEs compared with the general RA or UC population. Patients aged ≥65 years or with CV risk had slightly higher rates of MACEs and VTEs than those in other subgroups; however, overlapping CIs suggested no real difference. Further work should examine real-world data from FIL-treated patients and longer follow-up. 1. https://www.ema.europa.eu/en/medicines/human/EPAR/jyseleca

<h3>Introduction</h3> Filgotinib (FIL) is a once-daily, oral, JAK1 preferential inhibitor approved for UC. In the phase 2b/3 SELECTION trial, FIL 200 mg (FIL200) was well tolerated and effective in induction (IND) and maintenance (MNT) of clinical remission vs placebo (PBO). We assessed the efficacy and safety of continued FIL200 in its long-term extension (LTE) study. <h3>Methods</h3> The SELECTION programme comprised SELECTION (NCT02914522) and its ongoing LTE (NCT02914535). Adults with moderately to severely active UC received IND FIL200 or FIL100 or PBO for 11 weeks in SELECTION. Patients in clinical remission or Mayo Clinic Score (MCS) response at week 10 (responders) could enter the 47-week MNT study. Patients who completed IND and MNT (completers), IND non-responders and patients with disease worsening during MNT could enter the LTE. This interim analysis assessed the efficacy of open-label FIL200 among completers and non-responders up to LTE weeks 48 and 96, respectively. Partial MCS (pMCS) and minimal clinically important difference (MCID) in total HRQoL IBDQ score (≥16-point increase vs baseline) were assessed over time. Exposure-adjusted incidence rates per 100 PYE of adverse events (AEs) and AEs of interest were assessed in patients treated with open-label FIL200 in the LTE. <h3>Results</h3> Analyses included 147 completers and 372 non-responders (IND FIL200, n=160; IND FIL100, n=212). Data were available for 136 completers at LTEweek48 and for 97 IND FIL200 and 139 IND FIL100 non-responders at LTEweek96. Among completers, mean pMCS reductions observed in SELECTION were maintained up to LTE week 48 (<b>Figure 1a</b>). Among non-responders, mean pMCS decreased from LTE baseline to week 96 (<b>Figure 1b</b>). Proportions of patients achieving the MCID in total IBDQ score increased over time among completers (IND week 10, 90.4%; LTE week 48, 96.1%) and FIL200 non-responders (LTE week 48, 60.6%; LTE week 96, 66.7%). Safety events among patients on open-label FIL200 in the LTE (total PYE, 970.9) were as expected based on initial data. <h3>Conclusion</h3> FIL200 was effective in maintaining long-term improvements in UC symptoms and HRQoL among patients who completed SELECTION. In non-responders, initiating open-label FIL200 in the LTE study led to symptom and HRQoL improvements that were sustained over time.

<h3>Introduction</h3> For patients with UC, both subjectively and objectively reported measures are equally important treatment goals. We explored clinical, biological, HRQoL remission and endoscopic improvements as a combined endpoint (CE) from SELECTION (NCT02914522), a phase 2b/3 double-blind trial of filgotinib (FIL), a once-daily, oral, JAK1 preferential inhibitor, for the treatment of UC. <h3>Methods</h3> In SELECTION, patients with moderately to severely active UC were randomized 2:2:1 to FIL 200mg or 100mg (FIL200/100) or placebo (PBO) for an 11-week induction phase followed by a 47-week maintenance period in patients who achieved clinical remission or response. We defined a CE as achieving all of: 1) clinical remission defined as partial Mayo Score (excluding endoscopy domain) ≤2 and no subscore &gt;1, 2) biological remission defined as faecal calprotectin &lt;150 µg/g, 3) IBDQ remission defined as IBDQ &gt;170 and 4) endoscopic improvement defined as Mayo endoscopic subscore ≤1. We evaluated the CE in patients treated with FIL200 vs PBO at week 10 and 58. Among those achieving the CE, we analysed MCID improvement during induction and decline during maintenance on generic QoL instruments (SF-36 and EQ5D). <h3>Results</h3> Overall population included 381 biologic-naïve and 401 biologic-experienced patients undergoing induction, of whom 297 entered maintenance. A higher proportion of patients receiving FIL200 achieved CE than PBO by week 10 in the biologic-naïve cohort (17.6% vs 4.41%, p&lt;0.001) and by week 58 in the maintenance cohort (22.1% vs 7.14%, p=0.002) (<b>table 1</b>). Biologic-naïve CE achievers had higher MCID improvement across all generic QoL scales and domains. Patients achieving CE in maintenance experienced a lower proportion of MCID decline in EQ5D utility, and visual analogue scale. <h3>Conclusion</h3> Treatment with FIL resulted in a higher proportion of patients with combined clinical, biological, HRQoL remission and endoscopic improvements. Among patients achieving this combined composite endpoint, clinically meaningful improvements were observed in their overall QoL. Holistic assessment of several subjective and objective measures may help achieve better outcomes in UC.

IntroductionThe phase 2 MANTA and MANTA-RAy studies were developed in consultation with global regulatory authorities to investigate potential impacts of filgotinib, a Janus kinase 1 preferential inhibitor, on semen parameters in men with active inflammatory diseases. Here we describe the methods and rationale for these studies.Methods and RationaleThe MANTA and MANTA-RAy studies included men (aged 21–65 years) with active inflammatory bowel disease (IBD) and rheumatic diseases, respectively. Participants had no history of reproductive health issues, and the following semen parameter values (≥ 5th percentile of World Health Organization reference values) at baseline: semen volume ≥ 1.5 mL, total sperm/ejaculate ≥ 39 million, sperm concentration ≥ 15 million/mL, sperm total motility ≥ 40% and normal sperm morphology ≥ 30%. Each trial included a 13-week, randomized, double-blind, placebo-controlled period (filgotinib 200 mg vs placebo, up to N = 125 per arm), for pooled analysis of the week-13 primary endpoint (proportion of participants with ≥ 50% decrease from baseline in sperm concentration). All semen assessments were based on two samples (≤ 14 days apart) to minimize effects of physiological variation; stringent standardization processes were applied across assessment sites. From week 13, MANTA and MANTA-RAy study designs deviated owing to disease-specific considerations. All subjects with a ≥ 50% decrease in sperm parameters continued the study in the monitoring phase until reversibility, or up to a maximum of 52 weeks, with standard of care as treatment. Overall conclusions from MANTA and MANTA-RAy will be based on the totality of the data, including secondary/exploratory measures (e.g. sperm motility/morphology, sex hormones, reversibility of any effects on semen parameters).ConclusionsDespite the complexities, the MANTA and MANTA-RAy studies form a robust trial programme that is the first large-scale, placebo-controlled evaluation of potential impacts of an advanced IBD and rheumatic disease therapy on semen parameters.Trial RegistrationEudraCT numbers 2017-000402-38 and 2018-003933-14; ClinicalTrials.gov identifiers NCT03201445 and NCT03926195.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02168-4.