Background/Aims The preferential Janus kinase-1 inhibitor filgotinib (FIL) is approved to treat RA in Europe. We assessed FIL efficacy/safety in patients (pts) with inadequate response (IR) to biologic DMARDs (bDMARDs) in a long-term extension trial (LTE; NCT03025308) enrolled from a Phase 3 parent study (PS; NCT02873936). Methods bDMARD-IR pts received FIL 200mg (FIL200), 100mg (FIL100), or placebo (PBO) and stable conventional synthetic (cs)DMARDs up to 24 weeks (W). At W14 of the PS, pts with IR to FIL or PBO (<20% improvement in swollen and tender joint counts) switched to standard of care (SOC). Pts completing PS on FIL, PBO, or SOC could enter LTE. PS FIL pts were maintained, blinded, on their FIL dose; PS PBO and SOC pts were rerandomized, blinded, to FIL200 or FIL100. We report efficacy up to LTE W48 for ACR20/50/70 improvement, DAS28[CRP] ≤3.2 and <2.6, and CDAI ≤10 and ≤2.8. Exposure-adjusted incidence rates (EAIR)/100 pt-years of exposure of treatment-emergent adverse events (TEAEs) and AEs of special interest (AESIs) are summarized up to data cutoff of June 1, 2020. Results The PS included 147, 153, and 148 pts on FIL200, FIL100, and PBO. Of the FIL200 pts who entered LTE, 80/121 continued study drug at June 1, 2020, as did 76/110 FIL100 pts. Pts still on LTE FIL from PBO were 35/47 FIL200 and 32/46 FIL100 pts; from SOC: 13/23 FIL200 and 13/22 FIL100 pts. LTE baseline (BL) characteristics were similar in FIL200 and FIL100 pts (mean RA duration: 13.2 and 12.8 years, DAS28[CRP]: 3.5 and 3.7). During LTE, PS FIL ACR20/50/70 response rates decreased modestly by W48. Among PS PBO pts, response rates were lower at LTE BL but reached similar levels as PS FIL pts by W48; rates increased up to W48 in SOC/FIL pts (either dose) but not to levels of other groups. Percentages of pts attaining DAS28(CRP) ≤3.2, DAS28(CRP) <2.6, CDAI ≤10, and CDAI ≤2.8 were maintained up to W48 for FIL/FIL pts, while PBO/FIL and SOC/FIL pts showed similar patterns as for ACR responses. TEAE, serious AE, and serious infection EAIRs were higher in SOC/FIL pts vs FIL/FIL or PBO/FIL pts but samples were small, and confidence intervals overlapped. Five pts died: FIL200/FIL200, n = 3; PBO/FIL200, n = 1; FIL100/FIL100, n = 1. There were no opportunistic infections. EAIRs of MACE were low DVT/PE occurred in two FIL200/FIL200, one FIL100/FIL100, and one SOC/FIL200 pts. Conclusion Efficacy was mostly maintained in PS FIL pts up to W48. Response among PS PBO and SOC pts increased from BL to W48, but response in PS SOC pts continued to be lower than in other groups; these pts may represent a refractory population. FIL safety was largely consistent between PS and LTE. Disclosure M. Buch: Honoraria; reports research support, consulting, speaker or personal fees from AbbVie; Eli Lilly and Co.; Gilead Sciences, Inc.; Merck-Serono; Pfizer; Roche; Sanofi; and UCB. Grants/research support; received funding (paid to her host institution) for research from Gilead Gilead Sciences, Inc. T. Takeuchi: Consultancies; serving as a consultant for Astellas, Chugai, and Eli Lilly Japan. Member of speakers’ bureau; Speaker’s bureau AbbVie, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Gilead Sciences, Mitsubishi-Tanabe, Novartis, Pfizer Japan, Sanofi, and Dainippon Sumitomo. Grants/research support; reports receiving grant/research support from AbbVie, Asahi Kasei, Astellas, Chugai, Daiichi Sankyo, Eisai, Mitsubishi-Tanabe, Shionogi, Takeda, and UCB Japan. V. Rajendran: Shareholder/stock ownership; employee of and shareholder in Galapagos NV. J. Gottenberg: Consultancies; serving as a consultant for Bristol-Myers Squibb, Sanofi Genzyme, and UCB. Member of speakers’ bureau; serving on a speaker’s bureau for Gilead Sciences, Inc., Galapagos, AbbVie, Eli Lilly and Co., Roche, Sanofi Genzyme, and UCB. Grants/research support; reports receiving grant/research support from Bristol-Myers Squibb and Pfizer. A. Pechonkina: Other; employee of Gilead Sciences, Inc. and may own stock in Gilead Sciences, Inc. Y. Tan: Other; employee of Gilead Sciences, Inc. and may own stock in Gilead Sciences, Inc. Q. Gong: Other; employee of Gilead Sciences, Inc. and may own stock in Gilead Sciences, Inc. K. Van Beneden: Other; employee of and shareholder in Galapagos NV. R. Caporali: Honoraria; reports receiving speaker’s fees and consultation grants from AbbVie, BMS, Celltrion, Fresenius-Kabi, Gilead-Galapagos, Lilly, MSD, Pfizer, Roche, Samsung-Bioepis, Sanofi and UCB.
Background/Aims The preferential Janus kinase (JAK)-1 inhibitor filgotinib (FIL) is approved for treatment of moderately to severely active RA in Europe and Japan. We assessed efficacy and safety of FIL in patients (pts) with inadequate response to MTX (MTX-IR) who completed a Phase 3 trial (NCT02889796) and went on to enroll in a long-term extension (LTE; NCT03025308). Methods Pts who completed the parent study (PS) on study drug were eligible to enter the LTE. LTE data cutoff was June 1, 2020, and safety data are reported to that date, with median exposure 2.2 years. Efficacy data to W48 are reported for 4 treatment groups (all with background MTX): pts who received FIL 200mg (FIL200) or FIL 100mg (FIL100) in the PS and continued their dose in LTE (FIL200/FIL200, FIL100/FIL100) and ADA pts who were re-randomized, double blind, to FIL200 or FIL100 for LTE (ADA/FIL200, ADA/FIL100). ACR20/50/70 response rates, DAS28[CRP] ≤3.2 and <2.6, and CDAI ≤10 and ≤2.8 are reported. Exposure-adjusted incidence rates (EAIR)/100 pt-years of exposure of treatment-emergent adverse events (TEAEs) and AEs of special interest (AESIs) are summarized. Results As of June 1, 2020, 522/571 (91%) FIL200/FIL200, 502/570 (88%) FIL100/FIL100, 118/128 (92%) ADA/FIL200, and 115/130 (89%) ADA/FIL100 pts were still on study drug. LTE baseline (BL) disease characteristics were similar between groups: mean duration of RA was approximately 8.7 years; DAS28(CRP) was 2.55 and mean MTX dosage was 15.0 mg/week. Proportions of pts achieving ACR20/50/70, DAS28(CRP) ≤3.2, <2.6, and CDAI ≤10, ≤2.8 were maintained in all 4 LTE groups through W48. Numerically greater proportions of pts met response criteria at W48 in the FIL200 groups vs FIL100, regardless of PS treatment. TEAEs, serious AEs, and AEs Grade ≥3 were largely comparable between groups and lowest in ADA/FIL100 pts. There were 3 deaths in each PS FIL group and 2 in each PS ADA group; EAIRs for deaths were lower for FIL/FIL groups compared with ADA/FIL groups. Opportunistic infections occurred only in FIL/FIL pts (2 in each group). Nonmelanoma skin cancer (NMSC; n = 5) occurred only in FIL/FIL groups, and malignancies excluding NMSC occurred in all groups except ADA/FIL100. Conclusion During the LTE through W48, response rates were maintained for FIL/FIL and ADA/FIL pts. Though there were differences between LTE groups, safety was largely comparable and consistent with that observed in the PS and in previously reported results of safety data from 7 trials: rates of AESIs were low, and all confidence intervals were overlapping. Limitation: the LTE was not formally randomized for comparison between FIL/FIL and ADA/FIL treatment groups, the groups were of unequal size, and the switch from ADA to FIL for LTE was by design, rather than based on disease activity. Disclosure B. Combe: Consultancies; AbbVie; Eli Lilly & Co.; Gilead Sciences, Inc.; Janssen; Pfizer; Roche-Chugai; and Sanofi. Member of speakers’ bureau; for BMS; Eli Lilly & Co.; Gilead Sciences, Inc.; MSD; Pfizer; Roche- Chugai; and UCB. Grants/research support; Novartis, Pfizer, and Roche-Chugai. Y. Tanaka: Consultancies; Eli Lilly, Daiichi- Sankyo, Taisho, Ayumi, Sanofi, GSK, Abbvie. Member of speakers’ bureau; Daiichi- Sankyo, Eli Lilly, Novartis, YL Biologics, Bristol-Myers, Eisai, Chugai, Abbvie, Astellas, Pfizer, Sanofi, Asahi-kasei, GSK, Mitsubishi-Tanabe, Gilead, Janssen. Grants/research support; Abbvie, Mitsubishi-Tanabe, Chugai, Asahi-Kasei, Eisai, Takeda, Daiichi-Sankyo. P. Emery: Consultancies; AbbVie, BMS, Celltrion, Gilead, Lilly, Novartis, Roche, Samsung, and Sandoz. Grants/research support; AbbVie, BMS, Lilly, and Samsung. A. Pechonkina: Shareholder/stock ownership; employee and shareholder in Gilead Sciences, Inc. A. Kuo: Shareholder/stock ownership; employee and shareholder in Gilead Sciences, Inc. Q. Gong: Shareholder/stock ownership; employee and shareholder in Gilead Sciences, Inc. K. Van Beneden: Shareholder/stock ownership; employee of and shareholder in Galapagos, NV. V. Rajendran: Shareholder/stock ownership; employee of and shareholder in Galapagos, NV. H. Schulze-Koops: Consultancies; from AbbVie, Amgen, BMS, Celgene, Celltrion, Chugai, Gilead, Janssen, Eli Lilly and Company, Merck Sharp & Dohme, Novartis- Sandoz, Pfizer, Roche, Sanofi. Grants/research support; AbbVie and Novartis.
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.
Introduction We conducted a post hoc analysis of efficacy and safety of filgotinib stratified by estimated radiographic progression rate before baseline (BL) in patients with rheumatoid arthritis (RA) who had inadequate response to methotrexate (MTX; FINCH 1; NCT02889796) or were naïve to it (FINCH 3; NCT02886728). Methods Radiographic progression rate was BL-Modified Total Sharp Score (mTSS) divided by RA duration (BL mTSS/year); estimated rapid radiographic progression (e-RRP) was BL change in mTSS/year ≥ 5; and estimated nonrapid radiographic progression (e-NRRP) was BL mTSS/year < 5. Efficacy and safety were compared between subgroups. All p -values are nominal. Results In FINCH 1 and FINCH 3, 558/1755 (31.8%) and 787/1249 (63.0%) patients, respectively, had BL e-RRP. BL characteristics were generally similar between subgroups within each trial. At week (W) 24, in FINCH 1, proportions achieving a Disease Activity Score 28 for rheumatoid arthritis with C-reactive protein < 2.6 were significantly greater with filgotinib 200 (FIL200) and 100 mg (FIL100) versus placebo among e-RRP and e-NRRP subgroups. In each study, proportions of FIL-treated patients achieving Clinical Disease Activity Index ≤ 2.8 and Simple Disease Activity Index ≤ 3.3 were similar between subgroups. In FINCH 3, disease activity measures were at least numerically improved among patients receiving FIL versus MTX monotherapy. At W24, mTSS changes from BL (CFB) were greater among patients with e-RRP in FINCH 1 and FINCH 3 versus e-NRRP (0.81 versus 0.19, p = 0.001; 0.67 versus 0.25, p = 0.31, respectively). At W52, in FINCH 1, mTSS CFBs were smaller among e-RRP patients treated with FIL200 (0.40; p < 0.001) and FIL100 (0.77; p = 0.024) versus adalimumab (ADA; 1.46). In FINCH 3 at W52, mTSS CFBs were significantly smaller with FIL200 versus MTX among e-RRP patients. Rates of treatment-emergent adverse events (AEs) were comparable between subgroups and across treatment arms. Conclusions Patients with previous e-RRP who received standard care tended to progress radiographically. FIL200 demonstrated persistent, consistent benefit for disease activity control among e-RRP and e-NRRP subgroups, and AE profiles were similar between subgroups. Although filgotinib efficacy was somewhat reduced among patients with e-RRP, filgotinib treatment slowed radiographic progression in both subgroups. Trial Registration Clinicaltrials.gov NCT02889796, NCT02886728. Supplementary Information The online version contains supplementary material available at 10.1007/s40744-022-00503-3.
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