Objectives DARWIN 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.Methods Eligible 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.Results 739 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.Conclusion Filgotinib 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.

Abstract Background/Aims DARWIN 3 (NCT02065700) is a long-term extension (LTE) study assessing the safety and efficacy of filgotinib (FIL) in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). In the DARWIN 1 (NCT01888874) and DARWIN 2 (NCT01894516) parent studies, patients received FIL in combination with MTX or FIL monotherapy, respectively. To provide an update on the safety and efficacy of FIL 200 mg (FIL200) in patients with RA, with or without MTX, with a maximum of 8.2 years of exposure. Methods Patients completing the DARWIN 1 and DARWIN 2 phase 2 studies could enter DARWIN 3, receiving FIL200[PE1] +/-MTX. The proportion of patients experiencing treatment-emergent adverse events (TEAEs) were reported, comprising data from both the parent and LTE studies. Efficacy was assessed from LTE baseline using the American College of Rheumatology (ACR) 20/50/70 criteria and DAS28-CRP, up to 264 weeks. Low disease activity and remission were defined as DAS28-CRP ≤3.2 and <2.6, respectively. Results In total, 739 patients were enrolled in DARWIN 3. In the FIL + MTX vs FIL monotherapy groups, TEAEs were reported for 90.9% and 92.1% of patients, respectively (Table). The most common TEAE was infection. In both treatment groups, eight patients had a TEAE leading to death (1.6% and 3.3%, respectively). Exposure-adjusted incidence rates, censored at time of first event for major adverse cardiovascular event, venous thromboembolism, herpes zoster, infections, serious infections, non-melanoma skin cancer (NMSC), malignancies excluding NMSC, gastrointestinal perforations and TEAEs leading to death, will be reported. Through five years, ACR20/50/70 responses were maintained in 86.3%/66.7%/50.7% of the FIL + MTX group and 90.8%/74.8%/51.4% of the FIL monotherapy group, respectively (observed data). DAS28-CRP low disease activity and remission rates (non-responder imputation) at DARWIN 3 baseline were 46.1%/40.1% (FIL + MTX) and 29.6%/24.8% (FIL monotherapy). At Week 264, the proportion of patients achieving low disease activity and remission were 34.0%/34.3% (FIL + MTX) and 27.0%/24.8% (FIL monotherapy). Conclusion With a maximum of 8.2 years of exposure in patients with RA, the FIL safety profile is similar between the background MTX and monotherapy treatment arms. Both arms show sustained efficacy over time. Disclosure P. Emery: Consultancies; Consultant of: AbbVie, AstraZeneca, BMS, Boehringer-Ingelheim, Galapagos, Gilead, Lilly, Novartis, Pfizer, Roche, and Samsung. Member of speakers’ bureau; y Speakers bureau: AbbVie, AstraZeneca, BMS, Boehringer-Ingelheim, Galapagos, Gilead, Lilly, Novartis, Pfizer, and Samsung. Grants/research support; Grant/research support from: AbbVie, BMS, Lilly, Novartis, Pfizer, Roche, and Samsung. R. Westhovens: Consultancies; Celltrion, Galapagos, and Gilead,. Member of speakers’ bureau; Celltrion, Galapagos, and Gilead. R.H.E. Alten: Consultancies; AbbVie, Amgen, Biogen, BMS, Celltrion, Gilead, Janssen, Lilly, Medac, MSD, Mylan, Novartis, Pfizer, Roche, Sandoz, SanofiGenzyme, UCB, and VIATRIS. L. Dagna: Consultancies; AbbVie, Amgen, AstraZeneca, Biogen, Boehringer-Ingelheim, BMS, Celltrion, Eli Lilly & Company, Galapagos, GlaxoSmithKline, Janssen, Kiniksa Pharmaceuticals, Novartis, Pfizer, Roche, Sanofi-Genzyme,. Grants/research support; AbbVie, BMS, Celgene, GlaxoSmithKline, Janssen, Kiniksa, Merck Sharp & Dohme, Mundipharma Pharmaceuticals, Novartis, Pfizer, Roche, Sanofi-Genzyme, and SOBI,. A. Kavanaugh: Consultancies; Amgen, AbbVie, BMS, Pfizer, UCB, Janssen, Novartis, and Pfizer. K.L. Winthrop: Consultancies; AbbVie, AstraZeneca, BMS, Eli Lilly & Company, Galapagos, Gilead, GlaxoSmithKline, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB. Grants/research support; BMS and Pfizer. J. Barry: Corporate appointments; Galapagos. Shareholder/stock ownership; Galapagos. R. Besuyen: Corporate appointments; Galapagos. Shareholder/stock ownership; Galapagos. C. Corallo: Corporate appointments; Galapagos. Shareholder/stock ownership; Galapagos. C. Watson: Corporate appointments; Galapagos. Shareholder/stock ownership; Galapagos. N. Martin: Consultancies; Galapagos. M. Genovese: Corporate appointments; Gilead Sciences. Shareholder/stock ownership; Gilead Sciences. A.J. Spindler: None. M. Stanislavchuk: Grants/research support; Amgen, AstraZeneca, Celgene, Eli Lilly, Galapagos, Gilead, Human Genome, Janssen, MSD, Nichi-Iko, Pfizer, and Roche. M. Greenwald: Grants/research support; AbbVie, Aclaris, Galapagos, Janssen, Lilly, and Nimbus.

Importance:Noninfectious uveitis is a leading cause of visual impairment with an unmet need for additional treatment options. Objective:To assess the efficacy and safety of filgotinib, a Janus kinase 1 (JAK1) preferential inhibitor, for the treatment of noninfectious uveitis. Design, Setting, and Participants:The HUMBOLDT trial was a double-masked, placebo-controlled, phase 2, randomized clinical trial conducted from July 2017 to April 2021 at 26 centers in 7 countries. Eligible participants (aged ≥18 years) had active noninfectious intermediate uveitis, posterior uveitis, or panuveitis despite at least 2 weeks of treatment with oral prednisone (10-60 mg per day). Interventions:Participants were randomly assigned 1:1 to receive filgotinib, 200 mg, or placebo orally once daily for up to 52 weeks. Main Outcomes and Measures:The primary end point was the proportion of participants experiencing treatment failure by week 24. Treatment failure was a composite end point represented by assessment of the presence of chorioretinal and/or retinal vascular lesions, best-corrected visual acuity, and anterior chamber cell and vitreous haze grades. Safety was assessed in participants who received at least 1 dose of study drug or placebo. Results:Between July 26, 2017, and April 22, 2021, 116 participants were screened, and 74 (mean [SD] age, 46 [16] years; 43 female [59.7%] of 72 participants, as 2 participants did not receive treatment doses) were randomly assigned to receive filgotinib (n = 38) or placebo (n = 36). Despite early termination of the trial for business reasons ahead of meeting enrollment targets, a significantly reduced proportion of participants who received filgotinib experienced treatment failure by week 24 vs placebo (12 of 32 participants [37.5%] vs 23 of 34 participants [67.6%]; difference vs placebo -30.1%; 95% CI, -56.2% to -4.1%; P = .006). Business reasons were unrelated to efficacy or safety. Adverse events were reported in 30 of 37 participants (81.1%) who received filgotinib and in 24 of 35 participants (68.6%) who received placebo. Serious adverse events were reported in 5 of 37 participants (13.5%) in the filgotinib group and in 2 of 35 participants (5.7%) in the placebo group. No deaths were reported during the trial. Conclusions and Relevance:Results of this randomized clinical trial show that filgotinib lowered the risk of treatment failure in participants with active noninfectious intermediate uveitis, posterior uveitis, or panuveitis vs placebo. Although the HUMBOLDT trial provided evidence supporting the efficacy of filgotinib in patients with active noninfectious uveitis, the premature termination of the trial prevented collection of additional safety or efficacy information of this JAK1 preferential inhibitor. Trial Registration:ClinicalTrials.gov Identifier: NCT03207815.

Background/Aims DARWIN 3 (NCT02065700) is a long-term extension (LTE) study assessing the safety and efficacy of filgotinib (FIL) in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). In the DARWIN 1 (NCT01888874) and DARWIN 2 (NCT01894516) parent studies, patients received FIL in combination with MTX or FIL monotherapy, respectively. To provide an update on the safety and efficacy of FIL 200 mg (FIL200) in patients with RA, with or without MTX, with a maximum of 8.2 years of exposure. Methods Patients completing the DARWIN 1 and DARWIN 2 phase 2 studies could enter DARWIN 3, receiving FIL200[PE1] +/-MTX. The proportion of patients experiencing treatment-emergent adverse events (TEAEs) were reported, comprising data from both the parent and LTE studies. Efficacy was assessed from LTE baseline using the American College of Rheumatology (ACR) 20/50/70 criteria and DAS28-CRP, up to 264 weeks. Low disease activity and remission were defined as DAS28-CRP <= 3.2 and <2.6, respectively. Results In total, 739 patients were enrolled in DARWIN 3. In the FIL + MTX vs FIL monotherapy groups, TEAEs were reported for 90.9% and 92.1% of patients, respectively (Table). The most common TEAE was infection. In both treatment groups, eight patients had a TEAE leading to death (1.6% and 3.3%, respectively). Exposure-adjusted incidence rates, censored at time of first event for major adverse cardiovascular event, venous thromboembolism, herpes zoster, infections, serious infections, non-melanoma skin cancer (NMSC), malignancies excluding NMSC, gastrointestinal perforations and TEAEs leading to death, will be reported. Through five years, ACR20/50/70 responses were maintained in 86.3%/66.7%/50.7% of the FIL + MTX group and 90.8%/74.8%/51.4% of the FIL monotherapy group, respectively (observed data). DAS28-CRP low disease activity and remission rates (non-responder imputation) at DARWIN 3 baseline were 46.1%/40.1% (FIL + MTX) and 29.6%/24.8% (FIL monotherapy). At Week 264, the proportion of patients achieving low disease activity and remission were 34.0%/34.3% (FIL + MTX) and 27.0%/24.8% (FIL monotherapy). Conclusion With a maximum of 8.2 years of exposure in patients with RA, the FIL safety profile is similar between the background MTX and monotherapy treatment arms. Both arms show sustained efficacy over time.

Importance Noninfectious uveitis is a leading cause of visual impairment with an unmet need for additional treatment options. Objective To assess the efficacy and safety of filgotinib, a Janus kinase 1 (JAK1) preferential inhibitor, for the treatment of noninfectious uveitis. Design, Setting, and Participants The HUMBOLDT trial was a double-masked, placebo-controlled, phase 2, randomized clinical trial conducted from July 2017 to April 2021 at 26 centers in 7 countries. Eligible participants (aged ≥18 years) had active noninfectious intermediate uveitis, posterior uveitis, or panuveitis despite at least 2 weeks of treatment with oral prednisone (10-60 mg per day). Interventions Participants were randomly assigned 1:1 to receive filgotinib, 200 mg, or placebo orally once daily for up to 52 weeks. Main Outcomes and Measures The primary end point was the proportion of participants experiencing treatment failure by week 24. Treatment failure was a composite end point represented by assessment of the presence of chorioretinal and/or retinal vascular lesions, best-corrected visual acuity, and anterior chamber cell and vitreous haze grades. Safety was assessed in participants who received at least 1 dose of study drug or placebo. Results Between July 26, 2017, and April 22, 2021, 116 participants were screened, and 74 (mean [SD] age, 46 [16] years; 43 female [59.7%] of 72 participants, as 2 participants did not receive treatment doses) were randomly assigned to receive filgotinib (n = 38) or placebo (n = 36). Despite early termination of the trial for business reasons ahead of meeting enrollment targets, a significantly reduced proportion of participants who received filgotinib experienced treatment failure by week 24 vs placebo (12 of 32 participants [37.5%] vs 23 of 34 participants [67.6%]; difference vs placebo −30.1%; 95% CI, −56.2% to −4.1%; P = .006). Business reasons were unrelated to efficacy or safety. Adverse events were reported in 30 of 37 participants (81.1%) who received filgotinib and in 24 of 35 participants (68.6%) who received placebo. Serious adverse events were reported in 5 of 37 participants (13.5%) in the filgotinib group and in 2 of 35 participants (5.7%) in the placebo group. No deaths were reported during the trial. Conclusions and Relevance Results of this randomized clinical trial show that filgotinib lowered the risk of treatment failure in participants with active noninfectious intermediate uveitis, posterior uveitis, or panuveitis vs placebo. Although the HUMBOLDT trial provided evidence supporting the efficacy of filgotinib in patients with active noninfectious uveitis, the premature termination of the trial prevented collection of additional safety or efficacy information of this JAK1 preferential inhibitor. Trial Registration ClinicalTrials.gov Identifier: NCT03207815

Objectives The aim of this article is to describe the safety and efficacy of filgotinib 200 mg (FIL200) or FIL 100 mg (FIL100) in Japanese patients with rheumatoid arthritis in a long-term extension (NCT03025308).Methods Patients who completed any of three parent studies (NCT02889796: inadequate response to methotrexate; NCT02873936: inadequate response to biologic disease-modifying antirheumatic drugs; NCT02886728: methotrexate-na & iuml;ve) without rescue therapy could enter the long-term extension; patients taking FIL continued their dosage, and those who received comparators were rerandomised to FIL200 or FIL100. This analysis includes Week 156 interim results.Results Among Japanese patients, 110 received FIL200, and 97 received FIL100. Mean (SD) FIL200 and FIL100 exposure was 157.0 (51.49) and 156.0 (52.45) weeks. The exposure-adjusted incidence rates (95% confidence interval) for FIL200/FIL100 were 2.7 (1.4, 5.2)/2.4 (1.2, 5.1) for herpes zoster, 0.9 (0.3, 2.8)/1.0 (0.3, 3.2) for malignancy (excluding nonmelanoma skin cancer), and 0.6 (0.2, 2.4)/0.3 (0.0, 2.4) for major adverse cardiovascular events. More patients receiving FIL200 with prior FIL200 exposure achieved clinical remission vs other groups (including Clinical Disease Activity Index remission in 40% vs <= 27% at Week 156).Conclusions FIL200 and FIL100 were generally well tolerated by Japanese patients, without new, unexpected adverse events.

BACKGROUND:There is a need for efficacious therapies for patients with Crohn's disease that are better tolerated and more durable than available treatments. We aimed to evaluate the efficacy and safety of filgotinib, an oral Janus kinase 1 preferential inhibitor, for treating Crohn's disease. METHODS:This phase 3, double-blind, randomised, placebo-controlled trial was conducted in 371 centres in 39 countries. Eligible patients were aged 18-75 years with moderately to severely active Crohn's disease for at least 3 months before enrolment. Patients were enrolled into one of two induction studies on the basis of their experience with biological agents (induction study A included biologic-naive and later biologic-experienced patients and induction study B included biologic-experienced patients). In both induction studies, patients were randomly assigned (1:1:1), using an interactive web response system, to receive oral filgotinib 200 mg, filgotinib 100 mg, or placebo once daily for 11 weeks. Patients who received filgotinib and had two-item patient-reported outcome (PRO2) clinical remission or an endoscopic response at week 10 were re-randomised (2:1) to receive their induction dose or placebo orally, once daily to the end of week 58 in the maintenance study. Co-primary endpoints were PRO2 clinical remission and an endoscopic response at week 10 (induction studies) and week 58 (maintenance study). PRO2 clinical remission was defined as an abdominal pain subscore of not more than 1 and a liquid or very soft stool frequency subscore of not more than 3 (from eDiary data) and endoscopic response was defined as a reduction of at least 50% in Simple Endoscopic Score for Crohn's disease from induction baseline (from central reading of endoscopy). For the induction studies, efficacy was assessed in all randomly assigned patients who received at least one dose of study drug. For the maintenance study, efficacy was assessed in all patients from either filgotinib treatment group in the induction studies who reached PRO2 clinical remission or an endoscopic response at week 10, and who were re-randomised and received at least one dose of study drug in the maintenance study. Patients who received placebo throughout the induction and maintenance studies were not included in the full analysis set for the maintenance study. Safety was assessed in all patients who received at least one dose of study drug. This trial is complete and is registered with ClinicalTrials.gov, NCT02914561. FINDINGS:Between Oct 31, 2016, and Nov 11, 2022, 2634 patients were screened, of whom 1372 were enrolled (induction study A: n=707, induction study B: n=665, and maintenance study: n=481). There were 346 (49%) women and 358 (51%) men in induction study A, 356 (54%) women and 303 (46%) men in induction study B, and 242 women (51%) and 236 men (49%) in the maintenance study. Significantly more patients had PRO2 clinical remission at week 10 with filgotinib 200 mg than with placebo in induction study B (29·7% vs 17·9%, difference 11·9%; 95% CI 3·7 to 20·2, p=0·0039) but not induction study A (32·9% vs 25·7%, 6·9%; -1·4 to 15·2, p=0·0963); there was no significant difference for endoscopic response (induction study A: 23·9% vs 18·1%, difference 5·5%; 95% CI -2·0 to 12·9, p=0·1365; induction study B: 11·9% vs 11·4%, 0·1%; -6·5 to 6·6, p=0·9797). At week 58, both co-primary endpoints were reported in greater proportions of patients who received filgotinib 200 mg than in those who received placebo (PRO2 clinical remission: 43·8% vs 26·4%, difference 16·8%; 95% CI 2·0 to 31·6, p=0·0382; endoscopic response: 30·4% vs 9·4%, difference 20·6%; 95% CI 8·2 to 33·1, p=0·0038). Co-primary endpoints were not met for filgotinib 100 mg in any study. In the induction studies, the most frequently reported treatment-emergent adverse events (TEAEs; ≥5% of patients in any group) were abdominal pain; arthralgia; an exacerbation, flare, or worsening of Crohn's disease; headache; nasopharyngitis; nausea; and pyrexia. In the maintenance study, the most frequently reported TEAEs (≥5% of patients in any filgotinib or associated placebo group) were those reported in the induction studies (except for headache) and abdominal distension, upper abdominal pain, anaemia, and flatulence. Serious TEAEs were reported in 49 patients in induction study A (18 [8%]) of 222 patients in the filgotinib 200 mg group, 16 [7%] of 245 patients in the filgotinib 100 mg group, and 15 [6%] of 237 patients in the placebo group), 81 patients in induction study B (19 [9%] of 202 patients in the filgotinib 200 mg group, 36 [16%] of 228 patients in the filgotinib 100 mg group, and 26 [11%] of 229 patients in the placebo group), and 49 patients in the maintenance study (13 [11%] of 118 patients in the filgotinib 200 mg-filgotinib 200 mg group, five [9%] of 56 patients in the filgotinib 200 mg-placebo group, 14 [13%] of 104 patients in the filgotinib 100 mg-filgotinib 100 mg group, three [5%] of 55 patients in the filgotinib 100 mg-placebo group, and 14 [10%] of 145 patients in the placebo-placebo group). No deaths were reported during the induction and maintenance studies. INTERPRETATION:Filgotinib 200 mg did not meet the co-primary endpoints of clinical remission and an endoscopic response at week 10, but did meet the co-primary endpoints at week 58. Filgotinib treatment was well tolerated, and no new safety signals were reported. FUNDING:Galapagos.

Background The inflammatory reflex is a centrally integrated physiological mechanism whereby vagus nerve signaling regulates the production of proinflammatory cytokines that mediate systemic inflammation. The safety and efficacy of a neuroimmune modulation device were assessed in a first-in-human, double-blind pilot study in subjects with multi-drug refractory rheumatoid arthritis (RA). Previously reported data showed that vagus nerve stimulation (VNS) for 12 weeks using the neuroimmune modulation device, a miniature, leadless neurostimulator that is surgically implanted in the neck on the left vagus nerve, improved clinical outcomes, was safe and well-tolerated.[1] We now report 36-month long-term data from this pilot study. Objectives Determine the long-term safety and efficacy of neuroimmune modulation using a novel neuroimmune modulation device. Methods Subjects (N=14) with active RA and prior insufficient response to ≥2 biological or targeted synthetic (b/ts) DMARDs with ≥2 modes of action were implanted with the neuroimmune modulation device.[1] All subjects who completed Week 12 (N=14) were enrolled in an open-label, long-term extension study where subjects continued or if assigned to the sham group, began to receive treatment. Of these subjects, 11 completed 36 months of treatment as follows: VNS for 1 minute either once per day (QD, N=4) or four times per day (QID, N=3); subjects randomized to sham treatment during the first 12 weeks were crossed over to active VNS for 1 minute, randomized to either QD (N=3) or QID (N=1). The addition of a concomitant b/tsDMARD to study treatment was allowed at the discretion of the investigator and the subject. The safety and clinical effectiveness of VNS using the Clinical Disease Activity Index (CDAI) were evaluated. Results The 11 subjects completing the Month 36 visit had previously failed, on average, five different agents, with 73% (8/11) having failed a tsDMARD. The average CDAI change from baseline (i.e., initiation of stimulation) for the 11 subjects completing Month 36 was -17.8 (SD 16.3). At Month 36, 64% (7/11) of subjects achieved a CDAI MCID response from baseline (by the 12pt/6pt/1pt criteria[1]), of whom two (2) were treated with VNS monotherapy and five (5) were on continuous VNS with concomitant b/tsDMARD. The number of subjects in low disease activity (LDA) increased from 9% (1/11) at baseline to 45% (5/11) at Month 36, while the number of subjects in high disease activity (HDA) decreased from 64% (7/11) at baseline to 36% (4/11) at Month 36. Through Month 36, 81% (9/11) subjects elected to combine VNS with a b/tsDMARD, with 8/11 continuing concomitant b/tsDMARD at Month 36. Two adverse events related to VNS therapy occurred during the long-term follow-up period. These events were non-serious, anticipated, and reported by the same subject. One event was a mild sore throat, and the other was moderate tenderness near the implant site. Both events resolved without sequelae following a reduction in stimulation strength. There were no related infections, surgical revisions, or device explantations. Conclusion Despite small numbers, data demonstrate long term use of VNS was safe and effective treatment for RA to maintain or lower disease activity including when added to a b/tsDMARD. Reference [1]Genovese MC, et al. The Lancet Rheumatology. 2020 Sep 1;2(9):e527-38. Acknowledgements: NIL. Disclosure of Interests Norman Gaylis: None declared, David Sikes: None declared, Alan Kivitz: None declared, Diane M Horowitz: None declared, Melissa Evangelista Shareholder of: SetPoint Medical, Employee of: SetPoint Medical, Yaakov Levine Shareholder of: SetPoint Medical, Employee of: SetPoint Medical, David Chernoff Shareholder of: SetPoint Medical, Employee of: SetPoint Medical, Mark C. Genovese: None declared.

ABSTRACT Objectives To present safety and efficacy of the JAK1 preferential inhibitor filgotinib in Japanese patients with prior inadequate response (IR) to methotrexate (MTX) from a 52-week randomised controlled parent study (PS) and long-term extension (LTE) through June 2020. Methods The PS (NCT02889796) randomised MTX-IR patients to filgotinib 200 (FIL200) or 100 mg (FIL100), adalimumab (ADA) 40 mg, or placebo; all took stable background MTX. At week (W) 24, placebo patients were rerandomised to FIL200 or FIL100. The primary endpoint was W12 American College of Rheumatology 20% improvement; safety was assessed by adverse event (AE) reporting. For the LTE (NCT03025308), eligible filgotinib patients continued FIL200/FIL100; ADA patients were rerandomised (blinded) to FIL200 or FIL100; all continued MTX. Results In all, 114/147 Japanese patients completed the PS, 115 enrolled in LTE, and 103 remained on study in June 2020. In the PS, AEs were consistent with the overall population, and W24 efficacy was maintained or improved through W52, comparable with the overall population. LTE AE incidences were similar between doses; filgotinib efficacy was consistent from baseline to W48 and similar between PS ADA and filgotinib patients. Conclusions Among MTX-IR Japanese patients, filgotinib maintained efficacy over 1 year; LTE safety was consistent with the PS.

What is this summary about? This summary explains the findings from a recent investigation that combined the results of over 1000 people from three clinical studies to understand the safety of evobrutinib. Evobrutinib is an oral medication (taken by mouth), being researched as a potential treatment for multiple sclerosis (MS). This medication was also investigated in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Over 1000 people have taken evobrutinib as part of three separate phase 2 clinical studies. These studies looked at how much of the drug should be taken, how safe the drug is, and how well it might work for treating a certain medical condition. What were the results? Evobrutinib was well-tolerated by participants in all three studies. The number of side effects reported by participants taking the medication was very similar to those reported by participants taking the placebo (a ‘dummy’ treatment without a real drug). The most common side effects in clinical studies were urinary tract infections, headache, swelling of the nose and throat, diarrhoea and blood markers of potential liver damage (these returned to normal once the treatment was stopped). What do the results mean? The safety data from all three clinical studies are encouraging and can be used to inform further research into using evobrutinib in MS. Clinical Trial Registration: NCT02975349 (multiple sclerosis), NCT03233230 (rheumatoid arthritis), NCT02975336 (systemic lupus erythematosus) ( ClinicalTrials.gov )

Filgotinib is an orally administered, preferential Janus kinase (JAK) inhibitor indicated for the treatment of moderate-tosevere rheumatoid arthritis (RA).The short-term safety, efficacy, and patient-reported outcomes (PROs) with filgotinib from Phase 2b/ 3 clinical trials (DARWIN 1 and 2; FINCH 1, 2, and 3) are described in patients who inadequately responded to methotrexate (MTX) and biologic disease-modifying antirheumatic drugs or who were naïve to MTX.This article reviews the safety and efficacy from the long-term extension (LTE) trials, DARWIN 3 (N=739) and FINCH 4 (N=2731), and PROs across the filgotinib development program in RA.Overall, in the DARWIN clinical trials (conducted from 2013-2023), patients received their LTE treatment for ≤8 years, while in the FINCH trials (ongoing from 2016-2025), patients received filgotinib treatment for ≤6 years in the LTE.The longer-term safety profile and consistent, sustained efficacy (American College of Rheumatology 20/50/70, Clinical Disease Activity Index, and Disease Activity Scale in 28 joints with C-reactive protein response rates) of filgotinib were largely similar to those observed in the shorterterm parent trials ≤52 weeks.PRO results from the parent trials showed improvements in patients' quality of life with filgotinib treatment, which compared to or exceeded improvements seen with placebo and active comparators (adalimumab, MTX).Filgotinib has a higher specificity for JAK1 compared with other therapeutic treatments, leading to reduced inhibition of JAK2/3-dependent pathways, potentially providing a distinct safety profile.Filgotinib is approved in Europe and Japan for treatment of people with moderate-to-severe RA, though it has not been approved by the US Food and Drug Administration, due to concerns around the benefit/ risk profile of the filgotinib 200-mg dosage and the potential impact on semen parameters.

OBJECTIVE:Preliminary evidence suggests that vagus nerve stimulation (VNS) may have some benefit in patients with rheumatoid arthritis (RA); however, prior studies have been small and/or uncontrolled; this study aimed to address that gap.METHODS:This randomized, double-blind, sham-controlled trial enrolled patients aged 18 to 75 years with active RA who had failed conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and were naïve to biologic and/or targeted synthetic DMARDs. All patients received an auricular vagus nerve stimulator and were randomized 1:1 to active stimulation or sham. The primary endpoint was the proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Secondary endpoints included mean changes in disease activity score of 28 joints with C-reactive protein (DAS28-CRP) and Health Assessment Questionnaire-Disability Index (HAQ-DI).RESULTS:A total of 113 patients (mean age 54 years; 82% female) enrolled, and 101 patients (89.4%) completed week 12. ACR20 response at week 12 was 25.0% for active stimulation versus 26.9% for sham (difference vs. sham, -1.9; 95% CI, -18.8, 14.9, P = 0.823). The least square mean ± SE change in DAS28-CRP was -0.95 ± 0.16 for active stimulation and -0.66 ± 0.16 for sham (P = 0.201); in HAQ-DI it was -0.19 ± 0.06 for active stimulation and -0.02 ± 0.06 for sham (P = 0.044). Adverse events occurred in 17 patients (15%); all were mild or moderate.CONCLUSION:Auricular VNS did not meaningfully improve RA disease activity. If VNS with other modalities is pursued in the future for the treatment of RA, larger, controlled studies will be needed to understand its utility.

Introduction: We evaluated the efficacy and safety of filgotinib (FIL), an oral, once-daily, Janus kinase 1 preferential inhibitor, for the treatment of Crohn’s disease (CD). Methods: DIVERSITY1 (NCT02914561) was a phase 3 double-blind, placebo (PBO)-controlled trial in adults aged 18–75 years with moderately to severely active CD. Patients were randomized 1:1:1 to FIL 200 mg (FIL200), FIL 100 mg (FIL100) or PBO once daily for 10 weeks in Induction (IND) Study A (biologic [bio]-naive and bio-experienced) or B (bio-experienced). Non-EU-specific co-primary endpoints at IND Study W10 and Maintenance (MNT) Study W58 were CDAI clinical remission (score < 150) and endoscopic response assessed by SES-CD score (≥ 50% reduction from baseline). FIL-treated patients were rerandomized 2:1 to their IND dose or PBO in the MNT Study if at W10 they had endoscopic response or were in PRO2 clinical remission (the EU-specific co-primary endpoint). Results: In IND Studies A and B, 707 and 665 patients were randomized to FIL200 (n=223; n=204), FIL100 (n=245; n=230) or PBO (n=239; n=231), respectively. In the MNT Study, 481 patients were rerandomized to continue FIL or PBO treatment (FIL200–FIL200, n=118; FIL200–PBO, n=56; FIL100–FIL100, n=105; FIL100–PBO, n=56; PBO–PBO, n=146). Among treated patients, 89.3% (629/704), 83.8% (552/659) and 48.1% (230/478) completed the IND A, IND B and MNT studies, respectively. In the IND Studies at W10, a significantly higher proportion of patients in the FIL200 group vs PBO group were in CDAI clinical remission (IND A: 32.9% vs 19.8%; IND B: 26.7% vs 14.8%; both p < 0.05). The proportions of patients who had endoscopic response at W10 were not statistically significantly different for either FIL dose vs PBO (Figure 1). In the MNT Study at W58, the proportions of patients in CDAI clinical remission were not statistically significantly different for either FIL dose vs PBO. A significantly greater proportion of patients in the FIL200–FIL200 group vs FIL200–PBO group had endoscopic response at W58 (30.4% vs 9.4%; p = 0.0038). Secondary endpoints are summarized in the Table 1. FIL had a safety profile in CD that was consistent with that in UC. Conclusion: In the DIVERSITY1 study in CD, FIL200 was not superior to PBO based on both co-primary endpoints in IND. Nonetheless, FIL200 was efficacious in inducing CDAI clinical remission at W10. Among patients who had endoscopic response or were in PRO2 clinical remission at W10, FIL200 was efficacious in achieving endoscopic response at W58 in MNT.Figure 1.: Co-primary Endpoints (CDAI Clinical Remission and Endoscopic Response) at W10 of A) IND Study A and B) IND Study B, and at W58 of C) MNT Study of FIL in CD (Full Analysis Sets). a: The Full Analysis Set for the MNT study includes all rerandomized patients who met the protocol definition of PRO2 clinical remission or endoscopic response at W10 and received at least one dose of FIL or PBO during the MNT study. The Full Analysis Set for the MNT study excluded 19 rerandomized patients (FIL200–FIL200, n=6; FIL200–PBO, n=3; FIL100–FIL100, n =7; FIL100–PBO, n=3). Each co-primary endpoint comparison of FIL200 vs PBO was tested at the 2-sided 0.05 significance level first. If the difference was statistically significant for both co-primary endpoints, the secondary endpoints and comparing FIL100 vs PBO for the co-primary endpoints were tested at the 2-sided 0.025 significance level using hierarchical testing within each sequence. CDAI clinical remission was defined as a CDAI score of less than 150. Endoscopic response was defined as a reduction of at least 50% in Simple Endoscopic Score for CD from IND baseline. CD, Crohn’s Disease; CDAI, Crohn’s Disease Activity Index; CI, confidence interval; FIL, filgotinib; FIL100, filgotinib 100 mg; FIL200, filgotinib 200 mg; IND, Induction; MNT, Maintenance; PBO, placebo; PRO2, 2-item patient-reported outcomes; W10, week 10; W58, week 58. Table 1. - Selected Secondary Endpoints in IND and MNT Studies of FIL in CD (Full Analysis Sets) IND Study, A or B (W10) AFIL200n=222 AFIL100n=245 APBOn=237 A∆% FIL200 vs PBO (95% CI); P valueand∆% FIL100 vs PBO (95% CI); P value BFIL200n=202 BFIL100n=228 BPBOn=229 B∆% FIL200 vs PBO (95% CI); P valueand∆% FIL100 vs PBO (95% CI); P value PRO2 clinical remission, n (%) 73/222 (32.9) 75/245 (30.6) 61/237 (25.7) 6.9 (−1.4, 15.2); 0.0963and4.2 (−3.9, 12.2); 0.3050 60/202 (29.7) 43/228 (18.9) 41/229 (17.9) 11.9 (3.7, 20.2); 0.0039and1.1 (−6.2, 8.5); 0.7556 CDAI clinical response, n (%) 116/222 (52.3) 113/245 (46.1) 94/237 (39.7) 12.0 (3.2, 20.8); 0.0074and5.5 (−3.2, 14.1); 0.2159 78/202 (38.6) 81/228 (35.5) 63/229 (27.5) 11.6 (2.6, 20.6); 0.0110and8.2 (−0.4, 16.7); 0.0593 MNT Study (W58) FIL200–FIL200n=112 FIL200–PBOn=53 ∆% FIL200–FIL200 vs FIL200–PBO (95% CI); P value FIL100–FIL100 n=98 FIL100–PBOn=53 ∆% FIL100–FIL100 vs FIL100–PBO (95% CI); P value PRO2 clinical remission, n (%) 49/112 (43.8) 14/53 (26.4) 16.8 (2.0, 31.6); 0.0382 29/98 (29.6) 13/53 (24.5) 5.8 (−8.5, 20.0); 0.4263 CDAI clinical response, n (%) 51/112 (45.5) 18/53 (34.0) 10.9 (−4.7, 26.4); 0.1827 33/98 (33.7) 16/53 (30.2) 4.0 (−11.1, 19.2); 0.5944 6-month CS-free CDAI clinical remission, n (%) 17/50 (34.0) 5/25 (20.0) 14.0 (−5.1, 33.1); 0.1900 2/41 (4.9) 3/25 (12.0) −5.5 (−22.6, 11.6); 0.4248 In line with the hierarchical testing strategy, any statistical significance for the secondary endpoints is nominal owing to the co-primary endpoints not being met in IND Study A, IND Study B or MNT Study. Therefore, no conclusions about the statistical significance of the secondary endpoints can be made. PRO2 clinical remission was defined as an abdominal pain score of not more than 1 and a stool frequency score of not more than 3. CDAI clinical response was defined as a reduction from IND baseline by at least 100 points or a CDAI score of less than 150. Six-month CS-free CDAI clinical remission was defined as a CDAI score of less than 150, with no use of CS indicated for CD for at least 6 months prior to MNT Study W58 among patients with CS use at MNT baseline. CD, Crohn’s Disease; CDAI, Crohn’s Disease Activity Index; CI, confidence interval; CS, corticosteroid; FIL, filgotinib; FIL100, filgotinib 100 mg; FIL200, filgotinib 200 mg; IND, Induction; MNT, Maintenance; PBO, placebo; PRO2, 2-item patient reported outcome; W10, week 10; W58, week 58.

Objective: Characterize safety of the Janus kinase-1 preferential inhibitor filgotinib (FIL) in Japanese patients with moderately to severely active rheumatoid arthritis (RA). Methods: Data from three Phase 3 trials (NCT02889796, NCT02873936, and NCT02886728) and a long-term extension (NCT03025308) through September 2019 were integrated; patients received >= 1 dose of FIL 200 (FIL200) or 100 mg (FIL100) daily, or placebo (PBO). We calculated exposure-adjusted incidence rates (EAIRs) per 100 patient-years FIL exposure (100PYE) for treatment-emergent adverse events (TEAEs) and adverse events of special interest. Results: Among 3691 total patients and 6080.7 PYE, 229 Japanese patients received FIL for 311.4 PYE (median 1.5, maximum 2.5 years). During the 12-week PBO-controlled period, serious TEAEs and TEAEs leading to study drug disruption were comparable between FIL and PBO. Serious infection rates were 1.9%, 0%, and 2% for FIL200, FIL100, and PBO during the PBO-controlled period; long-term FIL200 and FIL100 EAIRs were 3.8 and 2.1/100PYE. No herpes zoster (HZ) or major adverse cardiovascular events (MACEs) occurred during the PBO-controlled period; long-term FIL200 and FIL100 EAIRs were 3.0 and 2.1/100PYE (HZ) and 0.6 and 0/100PYE (MACE). Conclusion: Long-term FIL treatment (median 1.5, maximum 2.5 years exposure) was well tolerated at 100- and 200-mg doses in Japanese patients with RA.

Objectives: Effective steroid-sparing therapies for the treatment of sarcoidosis are lacking; IL-6 antagonists may reduce sarcoidosis disease activity. This study assessed the safety and efficacy of the IL-6 receptor antagonist, sarilumab, in subjects with glucocorticoid-dependent sarcoidosis. Methods: This phase II, double-blind, placebo-controlled, randomized withdrawal trial enrolled 15 subjects with biopsy-proven sarcoidosis at Stanford University from November 2019 to September 2022. In period 1, subjects were treated with open-label s.c. sarilumab 200 mg every 2 weeks for 16 weeks, with predefined tapering of prednisone. Subjects who completed period 1 without a sarcoidosis flare entered period 2 and were randomized to continue sarilumab or to receive matching placebo for 12 weeks. The end points included flare-free survival, as well as changes in pulmonary function tests, chest imaging, patient-reported outcomes, and laboratory values. Results: Fifteen subjects were enrolled in the study (median age 57 years, 80% male, 73.3% White), and 10 subjects successfully completed period 1. During period 1, 4 of the 15 subjects (26.7%) discontinued due to worsening of their sarcoidosis, and CT chest imaging worsened in 5 of the 15 subjects (35.7%). During period 2, 0 of 2 subjects in the sarilumab group and 1 of 8 subjects (12.5%) in the placebo group had a flare. Treatment with sarilumab 200 mg was generally well tolerated in subjects with sarcoidosis. Conclusion: In this double-blind, placebo-controlled, randomized withdrawal trial, a meaningful signal of improvement in subjects with sarcoidosis treated with sarilumab was not observed. Given the small numbers in this study, no definitive conclusions can be drawn.

Two studies were conducted to assess the effects of buspirone and alprazolam on a three-choice working memory water escape task. Both studies involved giving rats three daily trials, each trial consisting of an information run during which guillotine doors forced the rats to swim into the correct escape alley and a test run during which the rats could enter any of the three alleys but escape only on entering the same alley to which they had been forced on the information run. In the first experiment, rats were trained to a 70% correct choice criterion with 5-min interrun intervals and then tested for performance with 5, 20, 20 with distraction and 60-min interrun intervals. In the second experiment, rats in each of the drug groups were tested after receiving one of three different doses of their respective drug. Results suggest that 1.0, 3.0, and 10.0 mg/kg buspirone but not 0.5, 1.0, and 2.0 mg/kg alprazolam impaired performance of rats on a three-choice working memory water escape task.