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Yoshiya Tanaka - One of the best experts on this subject based on the ideXlab platform.

  • interleukin 23 drives expansion of thelper 17 cells through epigenetic regulation by signal transducer and activators of transcription 3 in lupus patients
    Rheumatology, 2020
    Co-Authors: Seunghyun Lee, Kaoru Yamagata, Shingo Nakayamada, Satoshi Kubo, Hiroko Yoshinari, Yoshiya Tanaka
    Abstract:

    OBJECTIVES To elucidate the molecular mechanisms underlying pathogenic Th17 cells, we investigated the modulation of epigenetic modifications and its association with SLE. METHODS Naive CD4+ T cells were cultured in Th17 polarizing conditions for 5 days and then treated with various cytokines, including IL-23. Expression of Th17 cell-related markers and phosphorylation of signal transducers and activators of transcription (pSTATs) were analysed using flow cytometry and quantitative PCR. Histone modifications were assessed using chromatin immunoprecipitation PCR. T cell phenotypes and pSTATs were analysed in blood samples of patients with SLE (n = 28). Finally, the effects of Baricitinib on memory Th17 cells were investigated in SLE patients (n = 12). RESULTS Stimulation of resting Th17 cells with IL-23 promoted maturation of these cells (P < 0.0001). IL-23 induced pSTAT3, but not pSTAT4, during Th17 cell maturation (P < 0.05). IL-23-induced STAT3 directly bound the RORγT gene locus. This was accompanied by induction of the H3H4me3 permissive mark and reduction of the H3K27me3 repressive mark, leading to enhanced RORγT gene expression. IL-23-induced expansion of Th17 cells and pSTAT3 were suppressed by the addition of Baricitinib in a concentration-dependent manner (P < 0.05). In memory Th17 cells from SLE patients, pSTAT3 was hypersensitized by IL-23 stimulation and inhibited by Baricitinib (P < 0.05). CONCLUSION The results of this study indicate that IL-23/STAT3 signalling plays a fundamental role in Th17 cell maturation through transcriptional and epigenetic modifications in patients with SLE. This mechanism may underlie pathogenic Th17 cell expansion and may lead to identification of novel therapeutic targets for SLE.

  • Temporary interruption of Baricitinib: characterization of interruptions and effect on clinical outcomes in patients with rheumatoid arthritis.
    Arthritis Research & Therapy, 2020
    Co-Authors: Paul Emery, Yoshiya Tanaka, Douglas E Schlichting, Terence Rooney, Scott D. Beattie, Tracy E. Cardillo, Cameron Helt, Josef S. Smolen
    Abstract:

    Background In clinical practice, temporary interruption of rheumatoid arthritis (RA) therapy is common for various reasons including side effects, non-compliance, or necessity for surgery. To characterize temporary interruptions of Baricitinib and placebo-matched tablets in phase 3 studies of patients with moderate-to-severe rheumatoid arthritis (RA) and describe their impact on efficacy and safety. Methods During 4 Baricitinib phase 3 studies, investigators documented timing, reason, and duration of investigator-initiated temporary interruptions of study drug. In 2 studies, patients recorded RA symptoms in daily diaries for 12 weeks. Post hoc analyses investigated changes in symptom scores during interruptions and resumption of treatment. Interruptions were evaluated for reoccurrence of adverse events or laboratory abnormalities after retreatment. Results Across the placebo-controlled studies, interruptions occurred in larger proportions of Baricitinib- (2 mg, 18%; 4 mg, 18%) vs placebo-treated (9%) patients in only one study (bDMARD-inadequate responder patients, RA-BEACON). In the active comparator-controlled studies, the lowest rates of interruption were in the Baricitinib monotherapy arm (9%) of RA-BEGIN (vs methotrexate monotherapy or combination therapy), and proportions were similar for Baricitinib (10%) and adalimumab (9%) in RA-BEAM. Adverse events were the most common reason for interruption, but their reoccurrence after drug restart was infrequent. Most interruptions lasted ≤ 2 weeks. Daily diaries indicated modest symptom increases during interruption with return to pre-interruption levels or better after resumption. Interruptions had no impact on long-term efficacy outcomes. Conclusions Consistent with its pharmacologic properties, brief interruptions of Baricitinib during phase 3 studies were associated with minor increases in RA symptoms that resolved following retreatment. This analysis provides useful information for clinicians, as temporary interruption of antirheumatic therapy is common in the care of patients with RA. Trial registration ClinicalTrials.gov; NCT01710358, NCT01711359, NCT01721057, NCT01721044.

  • Low rates of radiographic progression of structural joint damage over 2 years of Baricitinib treatment in patients with rheumatoid arthritis.
    RMD Open, 2019
    Co-Authors: Désirée Van Der Heijde, Yoshiya Tanaka, Michael Schiff, Taeko Ishii, R Ortmann, L. Xie, Gabriella Meszaros, Marta Casillas, Paul Emery
    Abstract:

    Objectives To evaluate radiographic progression of structural joint damage over 2 years in patients with rheumatoid arthritis from Baricitinib clinical trials who were disease-modifying antirheumatic drug (DMARD)–naive or had an inadequate response to conventional synthetic DMARDs (csDMARD-IR). Methods Patients had completed one of three phase III studies and entered a long-term extension (LTE) study, continuing on the same Baricitinib dose as at originating study completion. At 52 weeks, DMARD-naive patients receiving methotrexate (MTX) or combination therapy (Baricitinib 4 mg+MTX) were switched to Baricitinib 4 mg monotherapy (±MTX per investigator opinion); MTX-IR patients receiving adalimumab were switched to Baricitinib 4 mg on background MTX. At 24 weeks, csDMARD-IR patients receiving placebo were switched to Baricitinib 4 mg on background csDMARD. Radiographs at baseline, year 1 and year 2 were scored using the van der Heijde modified Total Sharp Score. Linear extrapolation was used for missing data. Results Of 2573 randomised patients, 2125 (82.6%) entered the LTE, of whom 1893 (89.1%) entered this analysis. At year 2, progression was significantly lower with initial Baricitinib (monotherapy or combination therapy) versus initial MTX in DMARD-naive patients (proportion with non-progression defined by ≤smallest detectable change (SDC): 87.3% Baricitinib 4 mg+MTX; 70.6% MTX; p≤ 0.001). In MTX-IR patients, progression with initial Baricitinib was significantly lower than with initial placebo and similar to initial adalimumab (≤SDC: 82.7% Baricitinib 4 mg; 83.5% adalimumab; 70.6% placebo; p≤0.001). In csDMARD-IR patients, significant benefit was seen with Baricitinib 4 mg (≤SDC: 87.2% vs 73.2% placebo; p≤0.01). Conclusions Treatment with once-daily Baricitinib resulted in low rates of radiographic progression for up to 2 years.

  • clinical outcomes in patients switched from adalimumab to Baricitinib due to non response and or study design phase iii data in patients with rheumatoid arthritis
    Annals of the Rheumatic Diseases, 2019
    Co-Authors: Yoshiya Tanaka, Edward C. Keystone, Bruno Fautrel, R Ortmann, L. Xie, B Zhu, Maher Issa, Himanshu Patel, Carol L. Gaich
    Abstract:

    Objective To evaluate clinical outcomes in patients who changed treatment from adalimumab to Baricitinib, an oral Janus kinase (JAK)1/JAK2 inhibitor, during a phase III programme. Methods In phase III RA-BEAM, patients were randomised 3:3:2 to placebo, Baricitinib 4 mg once daily, or adalimumab 40 mg biweekly. At week 16 or subsequent visits, non-responders were rescued to open-label Baricitinib 4 mg. At week 52, patients could enter a long-term extension (LTE) and continue on Baricitinib or switch from adalimumab to Baricitinib 4 mg with no adalimumab washout period. Percentage of patients achieving low disease activity and remission were assessed, along with physical function, patient’s assessment of pain, and safety. Results Thirty-five (7%) Baricitinib-treated and 40 (12%) adalimumab-treated patients were rescued to Baricitinib in RA-BEAM; 78% (381/487) of Baricitinib-treated and 72% (238/330) of adalimumab-treated patients who were not rescued in RA-BEAM, entered the LTE and continued/were switched to Baricitinib. In both Baricitinib-rescued and adalimumab-rescued patients, there were significant improvements in all measures up to 12 weeks after rescue compared with the time of rescue. Patients who switched from adalimumab to Baricitinib showed improvements in disease control through 12 weeks in the LTE. Exposure-adjusted incidence rates for treatment-emergent adverse events (TEAEs) and infections, including serious events, were similar for patients who switched from adalimumab to Baricitinib and those who continued on Baricitinib. Conclusions Switching from adalimumab to Baricitinib (without adalimumab washout) was associated with improvements in disease control, physical function and pain during the initial 12 weeks postswitch, without an increase in TEAEs, serious adverse events or infections. Trial registration numbers NCT01710358, NCT01885078.

  • jak1 jak2 inhibition by Baricitinib in diabetic kidney disease results from a phase 2 randomized controlled clinical trial
    Nephrology Dialysis Transplantation, 2018
    Co-Authors: Yoshiya Tanaka, Katherine R. Tuttle, Frank C. Brosius, Sharon G. Adler, Matthias Kretzler, Ravindra L. Mehta, James A. Tumlin, Masakazu Haneda
    Abstract:

    Background Inflammation signaled by Janus kinases (JAKs) promotes progression of diabetic kidney disease (DKD). Baricitinib is an oral, reversible, selective inhibitor of JAK1 and JAK2. This study tested the efficacy of Baricitinib versus placebo on albuminuria in adults with Type 2 diabetes at high risk for progressive DKD. Methods In this Phase 2, double-blind, dose-ranging study, participants were randomized 1:1:1:1:1 to receive placebo or Baricitinib (0.75 mg daily; 0.75 mg twice daily; 1.5 mg daily; or 4 mg daily), for 24 weeks followed by 4-8 weeks of washout. Results Participants (N = 129) were 63±9.1 (mean±standard deviation) years of age, 27.1% (35/129) women and 11.6% (15/129) African-American race. Baseline hemoglobin A1c (HbA1c) was 7.3±1% and estimated glomerular filtration rate was 45.0±12.1 mL/min/1.73 m2 with first morning urine albumin-creatinine ratio (UACR) of 820 (407-1632) (median; interquartile range) mg/g. Baricitinib, 4 mg daily, decreased morning UACR by 41% at Week 24 compared with placebo (ratio to baseline 0.59, 95% confidence interval 0.38-0.93, P = 0.022). UACR was decreased at Weeks 12 and 24 and after 4-8 weeks of washout. Baricitinib 4 mg decreased inflammatory biomarkers over 24 weeks (urine C-X-C motif chemokine 10 and urine C-C motif ligand 2, plasma soluble tumor necrosis factor receptors 1 and 2, intercellular adhesion molecule 1 and serum amyloid A). The only adverse event rate that differed between groups was anemia at 32.0% (8/25) for Baricitinib 4 mg daily versus 3.7% (1/27) for placebo. Conclusions Baricitinib decreased albuminuria in participants with Type 2 diabetes and DKD. Further research is required to determine if Baricitinib reduces DKD progression.

Terence Rooney - One of the best experts on this subject based on the ideXlab platform.

  • Temporary interruption of Baricitinib: characterization of interruptions and effect on clinical outcomes in patients with rheumatoid arthritis.
    Arthritis Research & Therapy, 2020
    Co-Authors: Paul Emery, Yoshiya Tanaka, Douglas E Schlichting, Terence Rooney, Scott D. Beattie, Tracy E. Cardillo, Cameron Helt, Josef S. Smolen
    Abstract:

    Background In clinical practice, temporary interruption of rheumatoid arthritis (RA) therapy is common for various reasons including side effects, non-compliance, or necessity for surgery. To characterize temporary interruptions of Baricitinib and placebo-matched tablets in phase 3 studies of patients with moderate-to-severe rheumatoid arthritis (RA) and describe their impact on efficacy and safety. Methods During 4 Baricitinib phase 3 studies, investigators documented timing, reason, and duration of investigator-initiated temporary interruptions of study drug. In 2 studies, patients recorded RA symptoms in daily diaries for 12 weeks. Post hoc analyses investigated changes in symptom scores during interruptions and resumption of treatment. Interruptions were evaluated for reoccurrence of adverse events or laboratory abnormalities after retreatment. Results Across the placebo-controlled studies, interruptions occurred in larger proportions of Baricitinib- (2 mg, 18%; 4 mg, 18%) vs placebo-treated (9%) patients in only one study (bDMARD-inadequate responder patients, RA-BEACON). In the active comparator-controlled studies, the lowest rates of interruption were in the Baricitinib monotherapy arm (9%) of RA-BEGIN (vs methotrexate monotherapy or combination therapy), and proportions were similar for Baricitinib (10%) and adalimumab (9%) in RA-BEAM. Adverse events were the most common reason for interruption, but their reoccurrence after drug restart was infrequent. Most interruptions lasted ≤ 2 weeks. Daily diaries indicated modest symptom increases during interruption with return to pre-interruption levels or better after resumption. Interruptions had no impact on long-term efficacy outcomes. Conclusions Consistent with its pharmacologic properties, brief interruptions of Baricitinib during phase 3 studies were associated with minor increases in RA symptoms that resolved following retreatment. This analysis provides useful information for clinicians, as temporary interruption of antirheumatic therapy is common in the care of patients with RA. Trial registration ClinicalTrials.gov; NCT01710358, NCT01711359, NCT01721057, NCT01721044.

  • safety profile of Baricitinib in japanese patients with active rheumatoid arthritis with over 1 6 years median time in treatment an integrated analysis of phases 2 and 3 trials
    Modern Rheumatology, 2020
    Co-Authors: Masayoshi Harigai, Tsutomu Takeuchi, Maher Issa, Terence Rooney, Josef S. Smolen, Chadi Saifan, Kevin L. Winthrop, Atsushi Nishikawa, Yoshitaka Isaka, Naotsugu Akashi
    Abstract:

    Objectives: Baricitinib is a selective oral inhibitor of JAK1/JAK2 for patients with moderately-to-severely active rheumatoid arthritis (RA). Baricitinib’s safety profile in Japanese patients was e...

  • comparison of Baricitinib upadacitinib and tofacitinib mediated regulation of cytokine signaling in human leukocyte subpopulations
    Arthritis Research & Therapy, 2019
    Co-Authors: Iain B. Mcinnes, R Ortmann, Terence Rooney, Nicole L Byers, William L. Macias, Richard E Higgs, Jonathan A Lee, Guilherme Rocha, Thomas Wehrman, X Zhang
    Abstract:

    The in vitro pharmacology of Baricitinib, upadacitinib, and tofacitinib was evaluated to understand differences among these JAK inhibitors (JAKis) at the cellular level. Peripheral blood mononuclear cells from healthy donors were incubated with different JAKis, levels of phosphorylated signal transducer and activator of transcription (pSTAT) were measured following cytokine stimulation, and half maximum inhibitory concentration (IC50) values were calculated in phenotypically gated leukocyte subpopulations. Therapeutic dose relevance of the in vitro analysis was assessed using calculated mean concentration-time profiles over 24 h obtained from JAKi-treated subjects. Time above IC50 and average daily percent inhibition of pSTAT formation were calculated for each JAKi, cytokine, and cell type. Distinct JAKis displayed different in vitro pharmacologic profiles. For example, tofacitinib and upadacitinib were the most potent inhibitors of the JAK1/3-dependent cytokines tested (interleukin [IL]-2, IL-4, IL-15, and IL-21) with lower IC50 values and increased time above IC50 translating to a greater overall inhibition of STAT signaling during the dosing interval. All JAKis tested inhibited JAK1/2-dependent cytokines (e.g., IL-6 and interferon [IFN]-γ), the JAK1/tyrosine kinase 2 (TYK2)-dependent cytokines IL-10 and IFN-α, the JAK2/2-dependent cytokines IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), and the JAK2/TYK2-dependent cytokine granulocyte colony-stimulating factor (G-CSF), but often to significantly differing degrees. Different JAKis modulated distinct cytokine pathways to varying degrees, and no agent potently or continuously inhibited an individual cytokine signaling pathway throughout the dosing interval. Notably, Baricitinib inhibited JAK1/3 signaling to a lesser extent than upadacitinib and tofacitinib, while upadacitinib, Baricitinib, and tofacitinib inhibited the signaling of JAK2/2-dependent cytokines, including GM-CSF and IL-3, as well as the signaling of the JAK2/TYK2-dependent cytokine G-CSF.

  • Cardiovascular Safety During Treatment With Baricitinib in Rheumatoid Arthritis.
    Arthritis & Rheumatology, 2019
    Co-Authors: Peter C Taylor, Michael E Weinblatt, Maher Issa, Terence Rooney, Gerd R. Burmester, Chadi Saifan, Sarah Witt, Cd Walls, Claudia A. Salinas, Xin Zhang
    Abstract:

    Objective To assess the frequency of cardiovascular and venous thromboembolic events in clinical studies of Baricitinib, an oral, selective JAK1 and JAK2 inhibitor approved in more than 50 countries for the treatment of moderately-to-severely active rheumatoid arthritis (RA). Methods Data were pooled from 9 RA studies. Placebo comparison up to 24 weeks included data from 6 studies. Randomized dose comparison between Baricitinib doses of 2 mg and 4 mg used data from 4 studies and from the associated long-term extension study. The data analysis set designated "All-bari-RA" included all Baricitinib exposures at any dose. Results Overall, 3,492 RA patients received Baricitinib (7,860 patient-years of exposure). No imbalance compared to the placebo group was seen in the incidence of major adverse cardiovascular events (MACE) (incidence rates [IRs] of 0.5 per 100 patient-years for placebo and 0.8 per 100 patient-years for 4 mg Baricitinib), arterial thrombotic events (ATE) (IRs of 0.5 per 100 patient-years for placebo and 0.5 per 100 patient-years for 4 mg Baricitinib), or congestive heart failure (CHF) broad term (IRs of 4.3 per 100 patient-years for placebo and 2.4 per 100 patient-years for 4 mg Baricitinib). Deep vein thrombosis (DVT)/pulmonary embolism (PE) were reported in 0 of 1,070 patients treated with placebo and 6 of 997 patients treated with 4 mg Baricitinib during the placebo-controlled period; these events were serious in 2 of 6 patients, while all 6 had risk factors and 1 patient developed DVT/PE after discontinuation of the study drug. In the 2 mg-4 mg-extended data analysis set, IRs of DVT/PE were comparable between the doses across event types (IRs of 0.5 per 100 patient-years in those receiving 2 mg Baricitinib and 0.6 per 100 patient-years in those receiving 4 mg Baricitinib). In the All-bari-RA data analysis set, the rates were stable over time, with an IR of DVT/PE of 0.5 per 100 patient-years. Conclusion In RA clinical trials, no association was found between Baricitinib treatment and the incidence of MACE, ATE, or CHF. With regard to incidence of DVT/PE, 6 events occurred in patients treated with 4 mg Baricitinib, but no cases of DVT/PE were reported in the placebo group. During longer-term evaluation, the incidence of DVT/PE was similar between the Baricitinib dose groups, with consistent IR values over time, and this was similar to the rates previously reported in patients with RA.

  • safety profile of Baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment
    The Journal of Rheumatology, 2019
    Co-Authors: Josef S. Smolen, Tsutomu Takeuchi, Terence Rooney, C. Dickson, L Chen, William L. Macias, Mark C. Genovese, David L. Hyslop, Jennifer Riddle Camp, Tracy E. Cardillo
    Abstract:

    Objective. Baricitinib is an oral, once-daily selective Janus kinase (JAK1/JAK2) inhibitor for adults with moderately to severely active rheumatoid arthritis (RA). We evaluated Baricitinib’s safety profile through 288 weeks (up to September 1, 2016) with an integrated database [8 phase III/II/Ib trials, 1 longterm extension (LTE)]. Methods. The “all-bari-RA” group included patients who received any Baricitinib dose. Placebo comparison was based on the 6 studies with 4 mg and placebo up to Week 24 (“placebo-4 mg” dataset). Dose response assessment was based on 4 studies with 2 mg and 4 mg including LTE data (“2 mg-4 mg–extended”). The uncommon events description used the non-controlled all-bari-RA. Results. There were 3492 patients who received Baricitinib for 6637 total patient-years (PY) of exposure (median 2.1 yrs, maximum 5.5 yrs). No differences in rates of death, adverse events leading to drug discontinuation, malignancies, major adverse cardiovascular event (MACE), or serious infections were seen for 4 mg versus placebo or for 4 mg versus 2 mg. Infections including herpes zoster were significantly more frequent for 4 mg versus placebo. Deep vein thrombosis/pulmonary embolism were reported with 4 mg but not placebo [all-bari-RA incidence rate (IR) 0.5/100 PY]; the IR did not differ between doses (0.5 vs 0.6/100 PY, 2 mg vs 4 mg, respectively) or compared to published RA rates. All-bari-RA had 6 cases of lymphoma (IR 0.09/100 PY), 3 gastrointestinal perforations (0.05/100 PY), 10 cases of tuberculosis (all in endemic areas; 0.15/100 PY), and 22 all-cause deaths (0.33/100 PY). IR for malignancies (0.8/100 PY) and MACE (0.5/100 PY) were low and did not increase with prolonged exposure. Conclusion. In this integrated analysis of patients with moderate to severe active RA with exposure up to 5.5 years, Baricitinib has an acceptable safety profile in the context of demonstrated efficacy. Trial registration numbers: NCT01185353, NCT00902486, NCT01469013, NCT01710358, NCT01721044, NCT01721057, NCT01711359, and NCT01885078 at clinicaltrials.gov.

William L. Macias - One of the best experts on this subject based on the ideXlab platform.

  • comparison of Baricitinib upadacitinib and tofacitinib mediated regulation of cytokine signaling in human leukocyte subpopulations
    Arthritis Research & Therapy, 2019
    Co-Authors: Iain B. Mcinnes, R Ortmann, Terence Rooney, Nicole L Byers, William L. Macias, Richard E Higgs, Jonathan A Lee, Guilherme Rocha, Thomas Wehrman, X Zhang
    Abstract:

    The in vitro pharmacology of Baricitinib, upadacitinib, and tofacitinib was evaluated to understand differences among these JAK inhibitors (JAKis) at the cellular level. Peripheral blood mononuclear cells from healthy donors were incubated with different JAKis, levels of phosphorylated signal transducer and activator of transcription (pSTAT) were measured following cytokine stimulation, and half maximum inhibitory concentration (IC50) values were calculated in phenotypically gated leukocyte subpopulations. Therapeutic dose relevance of the in vitro analysis was assessed using calculated mean concentration-time profiles over 24 h obtained from JAKi-treated subjects. Time above IC50 and average daily percent inhibition of pSTAT formation were calculated for each JAKi, cytokine, and cell type. Distinct JAKis displayed different in vitro pharmacologic profiles. For example, tofacitinib and upadacitinib were the most potent inhibitors of the JAK1/3-dependent cytokines tested (interleukin [IL]-2, IL-4, IL-15, and IL-21) with lower IC50 values and increased time above IC50 translating to a greater overall inhibition of STAT signaling during the dosing interval. All JAKis tested inhibited JAK1/2-dependent cytokines (e.g., IL-6 and interferon [IFN]-γ), the JAK1/tyrosine kinase 2 (TYK2)-dependent cytokines IL-10 and IFN-α, the JAK2/2-dependent cytokines IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), and the JAK2/TYK2-dependent cytokine granulocyte colony-stimulating factor (G-CSF), but often to significantly differing degrees. Different JAKis modulated distinct cytokine pathways to varying degrees, and no agent potently or continuously inhibited an individual cytokine signaling pathway throughout the dosing interval. Notably, Baricitinib inhibited JAK1/3 signaling to a lesser extent than upadacitinib and tofacitinib, while upadacitinib, Baricitinib, and tofacitinib inhibited the signaling of JAK2/2-dependent cytokines, including GM-CSF and IL-3, as well as the signaling of the JAK2/TYK2-dependent cytokine G-CSF.

  • MRI and Dose Selection in a Phase II Trial of Baricitinib with Conventional Synthetic Disease-modifying Antirheumatic Drugs in Rheumatoid Arthritis.
    The Journal of Rheumatology, 2019
    Co-Authors: Charles Peterfy, Edward C. Keystone, Peter C Taylor, Douglas E Schlichting, Paul Emery, Scott D. Beattie, Monica E. Luchi, Mark C. Genovese, Julie Dicarlo, William L. Macias
    Abstract:

    Objective Magnetic resonance imaging (MRI) was used in a Phase IIb study (NCT01185353) of Baricitinib in patients with RA to support dose selection for the Phase III program. Methods 301 patients with active RA on stable methotrexate were randomized 2:1:1:1:1 to placebo or once-daily Baricitinib (1-, 2-, 4-, or 8-mg) for up to 24 weeks. 154 patients with definitive radiographic erosion had MRI of the hand/wrist at baseline and weeks 12 and 24. Two expert radiologists, blinded to treatment and visit order, scored images for synovitis, osteitis, bone erosion, and cartilage loss. Combined inflammation (osteitis + 3x synovitis score) and total joint damage (erosion + 2.5x cartilage loss score) scores were calculated. Treatment groups were compared using analysis of covariance adjusting for baseline scores. Results Mean changes from baseline to week 12 for synovitis were -0.10, -1.50, and -1.60 for patients treated with placebo, Baricitinib 4-mg, and Baricitinib 8-mg, respectively (P=0.003 vs placebo for Baricitinib 4- and 8-mg); mean changes for osteitis were 0.00, -3.20, and -2.10 (P=0.001 vs placebo for Baricitinib 4-mg and P=0.037 for 8-mg) and mean changes for bone erosion were 0.90, 0.10, and 0.40 (P=0.089 for 4-mg and P=0.275 for 8 mg), respectively in these treatment groups. Conclusion Using MRI findings in this subgroup of patients suggest suppression of synovitis, osteitis, and combined inflammation by Baricitinib 4- and 8-mg, which corroborate previously demonstrated clinical efficacy of Baricitinib and increase confidence that Baricitinib 4-mg could positively effect reduction of the radiographic progression in Phase III studies.

  • safety profile of Baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment
    The Journal of Rheumatology, 2019
    Co-Authors: Josef S. Smolen, Tsutomu Takeuchi, Terence Rooney, C. Dickson, L Chen, William L. Macias, Mark C. Genovese, David L. Hyslop, Jennifer Riddle Camp, Tracy E. Cardillo
    Abstract:

    Objective. Baricitinib is an oral, once-daily selective Janus kinase (JAK1/JAK2) inhibitor for adults with moderately to severely active rheumatoid arthritis (RA). We evaluated Baricitinib’s safety profile through 288 weeks (up to September 1, 2016) with an integrated database [8 phase III/II/Ib trials, 1 longterm extension (LTE)]. Methods. The “all-bari-RA” group included patients who received any Baricitinib dose. Placebo comparison was based on the 6 studies with 4 mg and placebo up to Week 24 (“placebo-4 mg” dataset). Dose response assessment was based on 4 studies with 2 mg and 4 mg including LTE data (“2 mg-4 mg–extended”). The uncommon events description used the non-controlled all-bari-RA. Results. There were 3492 patients who received Baricitinib for 6637 total patient-years (PY) of exposure (median 2.1 yrs, maximum 5.5 yrs). No differences in rates of death, adverse events leading to drug discontinuation, malignancies, major adverse cardiovascular event (MACE), or serious infections were seen for 4 mg versus placebo or for 4 mg versus 2 mg. Infections including herpes zoster were significantly more frequent for 4 mg versus placebo. Deep vein thrombosis/pulmonary embolism were reported with 4 mg but not placebo [all-bari-RA incidence rate (IR) 0.5/100 PY]; the IR did not differ between doses (0.5 vs 0.6/100 PY, 2 mg vs 4 mg, respectively) or compared to published RA rates. All-bari-RA had 6 cases of lymphoma (IR 0.09/100 PY), 3 gastrointestinal perforations (0.05/100 PY), 10 cases of tuberculosis (all in endemic areas; 0.15/100 PY), and 22 all-cause deaths (0.33/100 PY). IR for malignancies (0.8/100 PY) and MACE (0.5/100 PY) were low and did not increase with prolonged exposure. Conclusion. In this integrated analysis of patients with moderate to severe active RA with exposure up to 5.5 years, Baricitinib has an acceptable safety profile in the context of demonstrated efficacy. Trial registration numbers: NCT01185353, NCT00902486, NCT01469013, NCT01710358, NCT01721044, NCT01721057, NCT01711359, and NCT01885078 at clinicaltrials.gov.

  • Characterization and Changes of Lymphocyte Subsets in Baricitinib-Treated Patients With Rheumatoid Arthritis: An Integrated Analysis.
    Arthritis & Rheumatology, 2018
    Co-Authors: Yoshiya Tanaka, Peter C Taylor, Maher Issa, Stephanie De Bono, Iain B. Mcinnes, Nicole L Byers, L Chen, William L. Macias, Veronica Rogai, Terence Rooney
    Abstract:

    OBJECTIVE Baricitinib is an orally administered inhibitor of JAK1 and JAK2 that has been shown to be effective in treating rheumatoid arthritis (RA). This study was undertaken to analyze changes in lymphocyte cell subsets during Baricitinib treatment and to correlate these changes with clinical outcomes. METHODS An integrated analysis was conducted by pooling data from 3 completed phase III trials comparing placebo with Baricitinib treatment (RA-BEAM, RA-BUILD, and RA-BEACON) and 1 ongoing long-term extension study (RA-BEYOND) in patients with active RA (n = 2,186). RESULTS Baricitinib treatment was associated with an early transient increase in total lymphocyte count at week 4, which returned to baseline by week 12. Transient changes within normal reference ranges in T cells and subsets were observed with Baricitinib treatment, up to week 104. B cells and relevant subpopulations increased after 4 weeks of Baricitinib treatment, with no further increases noted through 104 weeks of treatment. Natural killer (NK) cells temporarily increased after 4 weeks of Baricitinib treatment, before decreasing below baseline levels and then stabilizing over time. With Baricitinib treatment, few correlations were observed between changes in lymphocyte subsets and clinical end points, and most correlations were also observed within the placebo group. A modest potential association between low NK cell numbers and treatment-emergent infections was observed in the Baricitinib 4 mg/day treatment group, but not for serious infections or herpes zoster. CONCLUSION Overall, these findings demonstrate that changes in lymphocyte subsets were largely within normal reference ranges across the Baricitinib phase III RA clinical program and were not associated with increased risk of serious infections.

  • Response to Baricitinib based on prior biologic use in patients with refractory rheumatoid arthritis.
    Rheumatology, 2018
    Co-Authors: Mark C. Genovese, L. Xie, Douglas E Schlichting, Joel M. Kremer, Juan Sanchez Burson, Tara Carmack, Hanspeter Tony, Cynthia E. Kartman, Carlos Pantojas, William L. Macias
    Abstract:

    Objective RA patients who have failed biologic DMARDs (bDMARDs) represent an unmet medical need. We evaluated the effects of baseline characteristics, including prior bDMARD exposure, on Baricitinib efficacy and safety. Methods RA-BEACON patients (previously reported) had moderate to severe RA with insufficient response to one or more TNF inhibitor and were randomized 1:1:1 to once-daily placebo or 2 or 4 mg Baricitinib. Prior bDMARD use was allowed. The primary endpoint was a 20% improvement in ACR criteria (ACR20) at week 12 for 4 mg vs placebo. An exploratory, primarily post hoc, subgroup analysis evaluated efficacy at weeks 12 and 24 by ACR20 and Clinical Disease Activity Index (CDAI) ⩽10. An interaction P-value ⩽0.10 was considered significant, with significance at both weeks 12 and 24 given more weight. Results The odds ratios predominantly favored Baricitinib over placebo and were generally similar to those in the overall study (3.4, 2.4 for ACR20 weeks 12 and 24, respectively). Significant quantitative interactions were observed for Baricitinib 4 mg vs placebo at weeks 12 and 24: ACR20 by region (larger effect Europe) and CDAI ⩽10 by disease duration (larger effect ⩾10 years). No significant interactions were consistently observed for ACR20 by age; weight; disease duration; seropositivity; corticosteroid use; number of prior bDMARDs, TNF inhibitors or non-TNF inhibitors; or a specific prior TNF inhibitor. Treatment-emergent adverse event rates, including infections, appeared somewhat higher across groups with greater prior bDMARD use. Conclusion Baricitinib demonstrated a consistent, beneficial treatment effect in bDMARD-refractory patients across subgroups based on baseline characteristics and prior bDMARD use. Trial registration ClinicalTrials.gov (https://clinicaltrials.gov/), NCT01721044.

Douglas E Schlichting - One of the best experts on this subject based on the ideXlab platform.

  • Temporary interruption of Baricitinib: characterization of interruptions and effect on clinical outcomes in patients with rheumatoid arthritis.
    Arthritis Research & Therapy, 2020
    Co-Authors: Paul Emery, Yoshiya Tanaka, Douglas E Schlichting, Terence Rooney, Scott D. Beattie, Tracy E. Cardillo, Cameron Helt, Josef S. Smolen
    Abstract:

    Background In clinical practice, temporary interruption of rheumatoid arthritis (RA) therapy is common for various reasons including side effects, non-compliance, or necessity for surgery. To characterize temporary interruptions of Baricitinib and placebo-matched tablets in phase 3 studies of patients with moderate-to-severe rheumatoid arthritis (RA) and describe their impact on efficacy and safety. Methods During 4 Baricitinib phase 3 studies, investigators documented timing, reason, and duration of investigator-initiated temporary interruptions of study drug. In 2 studies, patients recorded RA symptoms in daily diaries for 12 weeks. Post hoc analyses investigated changes in symptom scores during interruptions and resumption of treatment. Interruptions were evaluated for reoccurrence of adverse events or laboratory abnormalities after retreatment. Results Across the placebo-controlled studies, interruptions occurred in larger proportions of Baricitinib- (2 mg, 18%; 4 mg, 18%) vs placebo-treated (9%) patients in only one study (bDMARD-inadequate responder patients, RA-BEACON). In the active comparator-controlled studies, the lowest rates of interruption were in the Baricitinib monotherapy arm (9%) of RA-BEGIN (vs methotrexate monotherapy or combination therapy), and proportions were similar for Baricitinib (10%) and adalimumab (9%) in RA-BEAM. Adverse events were the most common reason for interruption, but their reoccurrence after drug restart was infrequent. Most interruptions lasted ≤ 2 weeks. Daily diaries indicated modest symptom increases during interruption with return to pre-interruption levels or better after resumption. Interruptions had no impact on long-term efficacy outcomes. Conclusions Consistent with its pharmacologic properties, brief interruptions of Baricitinib during phase 3 studies were associated with minor increases in RA symptoms that resolved following retreatment. This analysis provides useful information for clinicians, as temporary interruption of antirheumatic therapy is common in the care of patients with RA. Trial registration ClinicalTrials.gov; NCT01710358, NCT01711359, NCT01721057, NCT01721044.

  • Use of magnetic resonance imaging to support dose selection in a phase II trial of Baricitinib combined with conventional synthetic disease-modifying antirheumatic drugs in rheumatoid arthritis
    'The Journal of Rheumatology', 2019
    Co-Authors: Peterfy C, Douglas E Schlichting, Pc Taylor, Dicarlo J, Emery P, Mc Genovese, Ec Keystone, Sd Beattie, Luchi M, Macias W
    Abstract:

    Objective Magnetic resonance imaging (MRI) was used in a Phase IIb study (NCT01185353) of Baricitinib in patients with RA to support dose selection for the Phase III program. Methods 301 patients with active RA on stable methotrexate were randomized 2:1:1:1:1 to placebo or once-daily Baricitinib (1-, 2-, 4-, or 8-mg) for up to 24 weeks. 154 patients with definitive radiographic erosion had MRI of the hand/wrist at baseline and weeks 12 and 24. Two expert radiologists, blinded to treatment and visit order, scored images for synovitis, osteitis, bone erosion, and cartilage loss. Combined inflammation (osteitis + 3x synovitis score) and total joint damage (erosion + 2.5x cartilage loss score) scores were calculated. Treatment groups were compared using analysis of covariance adjusting for baseline scores. Results Mean changes from baseline to week 12 for synovitis were -0.10, -1.50, and -1.60 for patients treated with placebo, Baricitinib 4-mg, and Baricitinib 8-mg, respectively (P=0.003 vs placebo for Baricitinib 4- and 8-mg); mean changes for osteitis were 0.00, -3.20, and -2.10 (P=0.001 vs placebo for Baricitinib 4-mg and P=0.037 for 8-mg) and mean changes for bone erosion were 0.90, 0.10, and 0.40 (P=0.089 for 4-mg and P=0.275 for 8 mg), respectively in these treatment groups. Conclusion Using MRI findings in this subgroup of patients suggest suppression of synovitis, osteitis, and combined inflammation by Baricitinib 4- and 8-mg, which corroborate previously demonstrated clinical efficacy of Baricitinib and increase confidence that Baricitinib 4-mg could positively effect reduction of the radiographic progression in Phase III studies

  • MRI and Dose Selection in a Phase II Trial of Baricitinib with Conventional Synthetic Disease-modifying Antirheumatic Drugs in Rheumatoid Arthritis.
    The Journal of Rheumatology, 2019
    Co-Authors: Charles Peterfy, Edward C. Keystone, Peter C Taylor, Douglas E Schlichting, Paul Emery, Scott D. Beattie, Monica E. Luchi, Mark C. Genovese, Julie Dicarlo, William L. Macias
    Abstract:

    Objective Magnetic resonance imaging (MRI) was used in a Phase IIb study (NCT01185353) of Baricitinib in patients with RA to support dose selection for the Phase III program. Methods 301 patients with active RA on stable methotrexate were randomized 2:1:1:1:1 to placebo or once-daily Baricitinib (1-, 2-, 4-, or 8-mg) for up to 24 weeks. 154 patients with definitive radiographic erosion had MRI of the hand/wrist at baseline and weeks 12 and 24. Two expert radiologists, blinded to treatment and visit order, scored images for synovitis, osteitis, bone erosion, and cartilage loss. Combined inflammation (osteitis + 3x synovitis score) and total joint damage (erosion + 2.5x cartilage loss score) scores were calculated. Treatment groups were compared using analysis of covariance adjusting for baseline scores. Results Mean changes from baseline to week 12 for synovitis were -0.10, -1.50, and -1.60 for patients treated with placebo, Baricitinib 4-mg, and Baricitinib 8-mg, respectively (P=0.003 vs placebo for Baricitinib 4- and 8-mg); mean changes for osteitis were 0.00, -3.20, and -2.10 (P=0.001 vs placebo for Baricitinib 4-mg and P=0.037 for 8-mg) and mean changes for bone erosion were 0.90, 0.10, and 0.40 (P=0.089 for 4-mg and P=0.275 for 8 mg), respectively in these treatment groups. Conclusion Using MRI findings in this subgroup of patients suggest suppression of synovitis, osteitis, and combined inflammation by Baricitinib 4- and 8-mg, which corroborate previously demonstrated clinical efficacy of Baricitinib and increase confidence that Baricitinib 4-mg could positively effect reduction of the radiographic progression in Phase III studies.

  • Response to Baricitinib based on prior biologic use in patients with refractory rheumatoid arthritis.
    Rheumatology, 2018
    Co-Authors: Mark C. Genovese, L. Xie, Douglas E Schlichting, Joel M. Kremer, Juan Sanchez Burson, Tara Carmack, Hanspeter Tony, Cynthia E. Kartman, Carlos Pantojas, William L. Macias
    Abstract:

    Objective RA patients who have failed biologic DMARDs (bDMARDs) represent an unmet medical need. We evaluated the effects of baseline characteristics, including prior bDMARD exposure, on Baricitinib efficacy and safety. Methods RA-BEACON patients (previously reported) had moderate to severe RA with insufficient response to one or more TNF inhibitor and were randomized 1:1:1 to once-daily placebo or 2 or 4 mg Baricitinib. Prior bDMARD use was allowed. The primary endpoint was a 20% improvement in ACR criteria (ACR20) at week 12 for 4 mg vs placebo. An exploratory, primarily post hoc, subgroup analysis evaluated efficacy at weeks 12 and 24 by ACR20 and Clinical Disease Activity Index (CDAI) ⩽10. An interaction P-value ⩽0.10 was considered significant, with significance at both weeks 12 and 24 given more weight. Results The odds ratios predominantly favored Baricitinib over placebo and were generally similar to those in the overall study (3.4, 2.4 for ACR20 weeks 12 and 24, respectively). Significant quantitative interactions were observed for Baricitinib 4 mg vs placebo at weeks 12 and 24: ACR20 by region (larger effect Europe) and CDAI ⩽10 by disease duration (larger effect ⩾10 years). No significant interactions were consistently observed for ACR20 by age; weight; disease duration; seropositivity; corticosteroid use; number of prior bDMARDs, TNF inhibitors or non-TNF inhibitors; or a specific prior TNF inhibitor. Treatment-emergent adverse event rates, including infections, appeared somewhat higher across groups with greater prior bDMARD use. Conclusion Baricitinib demonstrated a consistent, beneficial treatment effect in bDMARD-refractory patients across subgroups based on baseline characteristics and prior bDMARD use. Trial registration ClinicalTrials.gov (https://clinicaltrials.gov/), NCT01721044.

  • Patient-reported outcomes of Baricitinib in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment
    Arthritis Research & Therapy, 2017
    Co-Authors: Michael Schiff, Tsutomu Takeuchi, Carol L. Gaich, Roy Fleischmann, Douglas E Schlichting, Amy M. Delozier, Wen Ling Kuo, Ji Eon Won, Tara Carmack, Terence Rooney
    Abstract:

    This study evaluates patient-reported outcomes (PROs) in a double-blind, phase III study of Baricitinib as monotherapy or combined with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) with no or minimal prior conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and naive to biological DMARDs. Patients were randomized 4:3:4 to MTX administered once weekly (N = 210), Baricitinib monotherapy (4 mg once daily (QD), N = 159), or combination of Baricitinib (4 mg QD) and MTX (Baricitinib + MTX, N = 215). PROs included the Patient’s Global Assessment of Disease Activity (PtGA), patient's assessment of pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), duration of morning joint stiffness (MJS), worst joint pain, worst tiredness, Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA), Short Form 36 version 2, Acute (SF-36); and EuroQol 5-Dimensions (EQ-5D) Health State Profile. Comparisons were assessed with analysis of covariance (ANCOVA) and logistic regression models. Compared to MTX, patients in both Baricitinib groups reported greater improvement (p ≤ 0.01) in HAQ-DI, PtGA, pain, fatigue, worst join pain, SF-36 physical component score, and EQ-5D at weeks 24 and 52. For the SF-36 mental component score, patients in both Baricitinib groups reported statistically significant improvements (p ≤ 0.01) at week 52 compared to MTX-treated patients. Statistically significant improvements (p ≤ 0.05) were observed with the WPAI-RA for the Baricitinib groups vs. MTX at week 24 and for the WPAI-RA daily activity and work productivity measures for Baricitinib + MTX at week 52. In this study, Baricitinib alone or in combination with MTX, when used as initial therapy, resulted in significant improvement compared to MTX in the majority of the pre-specified PRO measures. ClinicalTrials.gov, NCT01711359 . Registered on 18 October 2012.

Peter C Taylor - One of the best experts on this subject based on the ideXlab platform.

  • comparative effectiveness of improvement in pain and physical function for Baricitinib versus adalimumab tocilizumab and tofacitinib monotherapies in rheumatoid arthritis patients who are naive to treatment with biologic or conventional synthetic dis
    RMD Open, 2020
    Co-Authors: Bruno Fautrel, Peter C Taylor, B Zhu, Paul Emery, M A F J Van De Laar, F De Leonardis, C L Kannowski, Claudia Nicolay, Z Kadziola, I De La Torre
    Abstract:

    OBJECTIVE: To compare improvement in pain and physical function for patients treated with Baricitinib, adalimumab, tocilizumab and tofacitinib monotherapy from randomised, methotrexate (MTX)-controlled trials in conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)/biologic (bDMARD)-naive RA patients using matching-adjusted indirect comparisons (MAICs). METHODS: Data were from Phase III trials on patients receiving monotherapy Baricitinib, tocilizumab, adalimumab, tofacitinib or MTX. Pain was assessed using a visual analogue scale (0-100 mm) and physical function using the Health Assessment Questionnaire-Disability Index (HAQ-DI). An MAIC based on treatment-arm matching, an MAIC with study-level matching and Bucher's method without matching compared change in outcomes between therapies. Matching variables included age, gender, baseline disease activity and baseline value of outcome measure. RESULTS: With all methods, greater improvements were observed in pain and HAQ-DI at 6 months for Baricitinib compared with adalimumab and tocilizumab (p<0.05). Differences in treatment effects (TEs) favouring Baricitinib for pain VAS for treatment-arm matching, study-level matching and Bucher's method, respectively, were -12, -12 and -12 for Baricitinib versus adalimumab and -7, -7 and -9 for Baricitinib versus tocilizumab; the difference in TEs for HAQ-DI was -0.28, -0.28 and -0.30 for adalimumab and -0.23, -0.23 and -0.26 for tocilizumab. For Baricitinib versus tofacitinib, no statistically significant differences for pain improvement were observed except with one of the three methods (Bucher method) and none for HAQ-DI. CONCLUSIONS: Results suggest greater pain reduction and improved physical function for Baricitinib monotherapy compared with tocilizumab and adalimumab monotherapy. No statistically significant differences in pain reduction and improved physical function were observed between Baricitinib and tofacitinib with the MAIC analyses.

  • Achieving Pain Control in Rheumatoid Arthritis with Baricitinib or Adalimumab Plus Methotrexate: Results from the RA-BEAM Trial
    Journal of Clinical Medicine, 2019
    Co-Authors: Peter C Taylor, Bruno Fautrel, B Zhu, Carol L. Gaich, Roy Fleischmann, Yvonne C. Lee, Elizabeth L. Perkins, Amanda Quebe, Xiang Zhang
    Abstract:

    The purpose of the study was to assess the proportion of patients who achieve pain relief thresholds, the time needed to reach the thresholds, and the relationship between pain and inflammation among patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate in RA-BEAM (NCT0170358). A randomized, double-blind trial was conducted, comparing Baricitinib (N = 487), adalimumab (N = 330), and placebo (N = 488) plus methotrexate. Pain was evaluated by patient’s assessment on a 0–100 mm visual analog scale (VAS). The following were assessed through a 24-week placebo-controlled period: the proportion of patients who achieved ≥30%, ≥50%, and ≥70% pain relief, the time to achieve these pain relief thresholds, remaining pain (VAS ≤ 10 mm, ≤20 mm, or ≤40 mm), and the relationship between inflammation markers and pain relief. Baricitinib-treated patients were more likely (p < 0.05) to achieve ≥30%, ≥50%, and ≥70% pain relief than placebo- and adalimumab-treated patients, as early as Week 1 vs. placebo and at Week 4 vs. adalimumab. A greater proportion of Baricitinib-treated patients achieved ≤20 mm or ≤40 mm remaining pain vs. placebo- and adalimumab-treated patients. Baricitinib-treated patients tended to demonstrate consistent pain relief independent of levels of inflammation control. In RA patients with an inadequate response to methotrexate, Baricitinib provided greater and more rapid pain relief than adalimumab and placebo. Analyses suggest the relationship between inflammation and pain may be different for Baricitinib and adalimumab treatments.

  • Cardiovascular Safety During Treatment With Baricitinib in Rheumatoid Arthritis.
    Arthritis & Rheumatology, 2019
    Co-Authors: Peter C Taylor, Michael E Weinblatt, Maher Issa, Terence Rooney, Gerd R. Burmester, Chadi Saifan, Sarah Witt, Cd Walls, Claudia A. Salinas, Xin Zhang
    Abstract:

    Objective To assess the frequency of cardiovascular and venous thromboembolic events in clinical studies of Baricitinib, an oral, selective JAK1 and JAK2 inhibitor approved in more than 50 countries for the treatment of moderately-to-severely active rheumatoid arthritis (RA). Methods Data were pooled from 9 RA studies. Placebo comparison up to 24 weeks included data from 6 studies. Randomized dose comparison between Baricitinib doses of 2 mg and 4 mg used data from 4 studies and from the associated long-term extension study. The data analysis set designated "All-bari-RA" included all Baricitinib exposures at any dose. Results Overall, 3,492 RA patients received Baricitinib (7,860 patient-years of exposure). No imbalance compared to the placebo group was seen in the incidence of major adverse cardiovascular events (MACE) (incidence rates [IRs] of 0.5 per 100 patient-years for placebo and 0.8 per 100 patient-years for 4 mg Baricitinib), arterial thrombotic events (ATE) (IRs of 0.5 per 100 patient-years for placebo and 0.5 per 100 patient-years for 4 mg Baricitinib), or congestive heart failure (CHF) broad term (IRs of 4.3 per 100 patient-years for placebo and 2.4 per 100 patient-years for 4 mg Baricitinib). Deep vein thrombosis (DVT)/pulmonary embolism (PE) were reported in 0 of 1,070 patients treated with placebo and 6 of 997 patients treated with 4 mg Baricitinib during the placebo-controlled period; these events were serious in 2 of 6 patients, while all 6 had risk factors and 1 patient developed DVT/PE after discontinuation of the study drug. In the 2 mg-4 mg-extended data analysis set, IRs of DVT/PE were comparable between the doses across event types (IRs of 0.5 per 100 patient-years in those receiving 2 mg Baricitinib and 0.6 per 100 patient-years in those receiving 4 mg Baricitinib). In the All-bari-RA data analysis set, the rates were stable over time, with an IR of DVT/PE of 0.5 per 100 patient-years. Conclusion In RA clinical trials, no association was found between Baricitinib treatment and the incidence of MACE, ATE, or CHF. With regard to incidence of DVT/PE, 6 events occurred in patients treated with 4 mg Baricitinib, but no cases of DVT/PE were reported in the placebo group. During longer-term evaluation, the incidence of DVT/PE was similar between the Baricitinib dose groups, with consistent IR values over time, and this was similar to the rates previously reported in patients with RA.

  • MRI and Dose Selection in a Phase II Trial of Baricitinib with Conventional Synthetic Disease-modifying Antirheumatic Drugs in Rheumatoid Arthritis.
    The Journal of Rheumatology, 2019
    Co-Authors: Charles Peterfy, Edward C. Keystone, Peter C Taylor, Douglas E Schlichting, Paul Emery, Scott D. Beattie, Monica E. Luchi, Mark C. Genovese, Julie Dicarlo, William L. Macias
    Abstract:

    Objective Magnetic resonance imaging (MRI) was used in a Phase IIb study (NCT01185353) of Baricitinib in patients with RA to support dose selection for the Phase III program. Methods 301 patients with active RA on stable methotrexate were randomized 2:1:1:1:1 to placebo or once-daily Baricitinib (1-, 2-, 4-, or 8-mg) for up to 24 weeks. 154 patients with definitive radiographic erosion had MRI of the hand/wrist at baseline and weeks 12 and 24. Two expert radiologists, blinded to treatment and visit order, scored images for synovitis, osteitis, bone erosion, and cartilage loss. Combined inflammation (osteitis + 3x synovitis score) and total joint damage (erosion + 2.5x cartilage loss score) scores were calculated. Treatment groups were compared using analysis of covariance adjusting for baseline scores. Results Mean changes from baseline to week 12 for synovitis were -0.10, -1.50, and -1.60 for patients treated with placebo, Baricitinib 4-mg, and Baricitinib 8-mg, respectively (P=0.003 vs placebo for Baricitinib 4- and 8-mg); mean changes for osteitis were 0.00, -3.20, and -2.10 (P=0.001 vs placebo for Baricitinib 4-mg and P=0.037 for 8-mg) and mean changes for bone erosion were 0.90, 0.10, and 0.40 (P=0.089 for 4-mg and P=0.275 for 8 mg), respectively in these treatment groups. Conclusion Using MRI findings in this subgroup of patients suggest suppression of synovitis, osteitis, and combined inflammation by Baricitinib 4- and 8-mg, which corroborate previously demonstrated clinical efficacy of Baricitinib and increase confidence that Baricitinib 4-mg could positively effect reduction of the radiographic progression in Phase III studies.

  • Characterization and Changes of Lymphocyte Subsets in Baricitinib-Treated Patients With Rheumatoid Arthritis: An Integrated Analysis.
    Arthritis & Rheumatology, 2018
    Co-Authors: Yoshiya Tanaka, Peter C Taylor, Maher Issa, Stephanie De Bono, Iain B. Mcinnes, Nicole L Byers, L Chen, William L. Macias, Veronica Rogai, Terence Rooney
    Abstract:

    OBJECTIVE Baricitinib is an orally administered inhibitor of JAK1 and JAK2 that has been shown to be effective in treating rheumatoid arthritis (RA). This study was undertaken to analyze changes in lymphocyte cell subsets during Baricitinib treatment and to correlate these changes with clinical outcomes. METHODS An integrated analysis was conducted by pooling data from 3 completed phase III trials comparing placebo with Baricitinib treatment (RA-BEAM, RA-BUILD, and RA-BEACON) and 1 ongoing long-term extension study (RA-BEYOND) in patients with active RA (n = 2,186). RESULTS Baricitinib treatment was associated with an early transient increase in total lymphocyte count at week 4, which returned to baseline by week 12. Transient changes within normal reference ranges in T cells and subsets were observed with Baricitinib treatment, up to week 104. B cells and relevant subpopulations increased after 4 weeks of Baricitinib treatment, with no further increases noted through 104 weeks of treatment. Natural killer (NK) cells temporarily increased after 4 weeks of Baricitinib treatment, before decreasing below baseline levels and then stabilizing over time. With Baricitinib treatment, few correlations were observed between changes in lymphocyte subsets and clinical end points, and most correlations were also observed within the placebo group. A modest potential association between low NK cell numbers and treatment-emergent infections was observed in the Baricitinib 4 mg/day treatment group, but not for serious infections or herpes zoster. CONCLUSION Overall, these findings demonstrate that changes in lymphocyte subsets were largely within normal reference ranges across the Baricitinib phase III RA clinical program and were not associated with increased risk of serious infections.