Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis.

BACKGROUND: Baricitinib is an oral, reversible inhibitor of the Janus kinases JAK1 and JAK2 that may have therapeutic value in patients with rheumatoid arthritis. METHODS: We conducted a 52-week, phase 3, double-blind, placebo- and active-controlled trial in which 1307 patients with active rheumatoid arthritis who were receiving background therapy with methotrexate were randomly assigned to one of three regimens in a 3:3:2 ratio: placebo (switched to baricitinib after 24 weeks), 4 mg of baricitinib once daily, or 40 mg of adalimumab (an anti-tumor necrosis factor α monoclonal antibody) every other week. End-point measures evaluated after adjustment for multiplicity included 20% improvement according to the criteria of the American College of Rheumatology (ACR20 response) (the primary end point), the Disease Activity Score for 28 joints (DAS28), the Health Assessment Questionnaire-Disability Index, and the Simplified Disease Activity Index at week 12, as well as radiographic progression of joint damage as measured by the van der Heijde modification of the total Sharp score (mTSS) (range, 0 to 448, with higher scores indicating greater structural joint damage) at week 24. RESULTS: More patients had an ACR20 response at week 12 with baricitinib than with placebo (primary end point, 70% vs. 40%, P<0.001). All major secondary objectives were met, including inhibition of radiographic progression of joint damage, according to the mTSS at week 24 with baricitinib versus placebo (mean change from baseline, 0.41 vs. 0.90; P<0.001) and an increased ACR20 response rate at week 12 with baricitinib versus adalimumab (70% vs. 61%, P=0.014). Adverse events, including infections, were more frequent through week 24 with baricitinib and adalimumab than with placebo. Cancers were reported in five patients (two who received baricitinib and three who received placebo). Baricitinib was associated with reductions in neutrophil counts and increases in levels of creatinine and low-density lipoprotein cholesterol. CONCLUSIONS: In patients with rheumatoid arthritis who had had an inadequate response to methotrexate, baricitinib was associated with significant clinical improvements as compared with placebo and adalimumab. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01710358 .).

Prevalence, disease burden, and treatment reality of patients with severe, uncontrolled asthma in Japan.

BACKGROUND: The severe asthma and severe, uncontrolled asthma (SUA) populations in Japan are not well-studied. We investigated the prevalence of continuously treated severe asthma and SUA patients, their disease burden, and the treatment reality via a Japanese health insurance claims database. METHODS: Continuously treated asthma patients (patients prescribed inhaled corticosteroids for asthma ≥4 times in the past year) aged ≥17 years at the index date (latest visit between April 2014 and March 2015 for asthma treatment) were included in this analysis (KEIFU study, UMIN000027695). Asthma severity and control status at the index date were defined using modified criteria of ERS/ATS guidelines. Asthma hospitalization, oral corticosteroid (OCS) use, and total medical expenses were calculated using data up to 12 months post-index date. RESULTS: We identified 10,579 patients as continuously treated asthma patients. Of these, 823 (7.8%) had severe asthma; 267 (2.5%) and 556 (5.3%) patients had SUA and severe, controlled asthma (SCA), respectively. Compared with SCA and mild to moderate asthma patients, a greater percentage of SUA patients required hospitalization (13.7%, 6.2%, and 3.0%, respectively) and were prescribed OCSs (67.4%, 45.9%, and 16.2%, respectively). Yearly total medical expenses were also greater for SUA patients (mean [standard deviation]: 8346 [12,280], vs 5989 [10,483] and 3422 [8800] USD, respectively). CONCLUSIONS: The percentages of severe asthma and SUA patients continuously treated in Japan were obtained through this large-scale analysis using a health insurance claims database. SUA patients had greater medical and economic burdens, suggesting more appropriate treatment is required according to the treatment guidelines.

Benefit of Filgotinib, a JAK1 Preferential Inhibitor, in Rheumatoid Arthritis Patients with Previous Rapid Radiographic Progression: Post Hoc Analysis of Two Trials.

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.

Filgotinib Modulates Inflammation-Associated Peripheral Blood Protein Biomarkers in Adults with Active Rheumatoid Arthritis and Prior Inadequate Response to Methotrexate.

INTRODUCTION: Our aim was to evaluate protein biomarker changes related to the administration of filgotinib, a Janus kinase (JAK) 1 preferential inhibitor, in patients with moderately to severely active rheumatoid arthritis (RA) with inadequate response to methotrexate. METHODS: Plasma and serum samples were collected from patients enrolled in FINCH 1 (NCT02889796), a Phase 3 trial. Patients with stable backgrounds of methotrexate were randomly assigned once-daily oral filgotinib 200 or 100 mg, subcutaneous adalimumab 40 mg every 2 weeks (W), or placebo. Up to 35 biomarkers were analyzed at baseline, W4, and W12 with enzyme-linked immunosorbent assays and chemiluminescence and electrochemiluminescence assays. RESULTS: At baseline, four distinct biomarker clusters were identified. The strongest intragroup correlations were in bone-cartilage resorption/inflammation and JAK/signal transducer and activator of transcription (STAT) signaling activity. At baseline, significant positive correlations were identified for cytokines with patient-reported pain and with patient measures of fatigue. Filgotinib reduced levels of cytokines associated with inflammation and cell migration as early as W4 and through W12. Compared to adalimumab, filgotinib induced significant reductions in bone-related turnover biomarkers, N-telopeptide of type 1 collagen and C-telopeptide 1, as well as biomarkers associated with baseline disease activity. No baseline predictors of therapeutic response to filgotinib were identified. CONCLUSIONS: Filgotinib reduced peripheral protein biomarkers associated with JAK/STAT signaling, inflammatory signaling, immune cell migration, and bone resorption as soon as W4 in FINCH 1. Effects were dose-dependent and consistent with the clinical efficacy of filgotinib observed in FINCH 1. The changes in peripheral biomarkers associated with filgotinib treatment in methotrexate-experienced patients are consistent with changes observed in both methotrexate-naïve and biologic disease-modifying antirheumatic drug-experienced RA populations. These data demonstrate dose-dependent effects of preferential JAK1 inhibition by filgotinib on peripheral blood protein biomarkers in methotrexate-experienced patients with RA. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02889796.

Efficacy and Safety of Filgotinib in Patients with High Risk of Poor Prognosis Who Showed Inadequate Response to MTX: A Post Hoc Analysis of the FINCH 1 Study.

INTRODUCTION: This exploratory analysis of FINCH 1 (NCT02889796) examined filgotinib (FIL) efficacy and safety in a subgroup of patients with rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX; MTX-IR) who had four poor prognostic factors (PPFs). METHODS: Patients with MTX-IR received placebo up to week (W)24 or FIL200 mg, FIL100 mg, or adalimumab up to W52; all received MTX. Efficacy and safety data were stratified by four PPFs versus fewer than four PPFs: seropositivity, high-sensitivity C-reactive protein (CRP) ≥ 6 mg/L, Disease Activity Score in 28 joints with CRP > 5.1, and erosions on X-rays. RESULTS: At baseline, 687/1755 patients had four PPFs. At W12, whether with four PPFs or fewer than four PPFs, response rates on all American College of Rheumatology (ACR) measures were significantly greater with FIL200 and FIL100 versus placebo. At W52, FIL200 ACR20/50/70 response rates remained at least numerically higher versus adalimumab in both subgroups. At W52, FIL200 reduced modified total Sharp score (mTSS) change versus adalimumab in patients with four or fewer than four PPFs. CONCLUSIONS: In high-risk (four PPFs) patients with MTX-IR RA, FIL200 and FIL100 showed similar reductions in disease activity versus placebo at W12 as in patients with fewer than four PPFs. mTSS in patients receiving FIL200 changed little from W24 to W52, while that in patients receiving FIL100 progressed comparably to patients who received adalimumab. Tolerability was comparable across treatment arms and subgroups.

Efficacy and Safety of Baricitinib in Japanese Patients with Active Rheumatoid Arthritis Receiving Background Methotrexate Therapy: A 12-week, Double-blind, Randomized Placebo-controlled Study.

OBJECTIVE: To evaluate efficacy and safety, baricitinib [Janus kinase (JAK) 1/JAK2 inhibitor] was compared with placebo in Japanese patients with active rheumatoid arthritis (RA) despite background treatment with methotrexate (MTX). METHODS: This was a phase IIB, double-blind, randomized, placebo-controlled study (clinicaltrials.gov: NCT01469013). Patients had moderate to severe active adult-onset RA despite stable treatment with MTX. Patients (n = 145) were randomized in a 2:1:1:1:1 ratio to placebo or 1 mg, 2 mg, 4 mg, or 8 mg oral baricitinib daily for 12 weeks. The primary analysis compared the combined 4/8-mg dose groups with placebo for the American College of Rheumatology (ACR) 20 response rate at 12 weeks. Other outcomes included additional measures of disease activity, physical function, laboratory abnormalities, and adverse events. RESULTS: A significantly higher proportion of patients in the combined 4/8-mg baricitinib group (37/48, 77%) compared with the placebo group (15/49, 31%) had at least an ACR20 response after 12 weeks of treatment (p < 0.001). Significant improvements in disease activity, remission, and physical function were observed as early as Week 2 of treatment with baricitinib, particularly with daily doses of ≥ 4 mg. Only 1 patient receiving baricitinib discontinued because of an adverse event. Adverse event rates with baricitinib doses ≤ 4 mg daily were similar to placebo, but there was a higher incidence of adverse events and laboratory abnormalities in the 8-mg group. CONCLUSION: In this phase II study, baricitinib was well tolerated and rapidly improved the signs, symptoms, and physical function of Japanese patients with active RA, supporting continued development of baricitinib (clinicaltrials.gov NCT01469013).