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Michelle Petri - One of the best experts on this subject based on the ideXlab platform.

  • Safety and Efficacy of Belimumab Plus Standard Therapy for Up to Thirteen Years in Patients With Systemic Lupus Erythematosus
    Arthritis & rheumatology (Hoboken N.J.), 2019
    Co-Authors: Daniel J Wallace, Richard Furie, Joan T Merrill, William Stohl, James D Mckay, Ellen M Ginzler, Arthur Weinstein, W. Winn Chatham, W. Joseph Mccune, Michelle Petri
    Abstract:

    Objective To investigate the long-term safety and efficacy of intravenous (IV) Belimumab plus standard of care (SOC) therapy for systemic lupus erythematosus (SLE) in patients with active, autoantibody-positive SLE. Methods The study was designed as a multicenter, open-label, continuation study of IV Belimumab given every 4 weeks in conjunction with SOC therapy in patients with SLE who completed a phase II, double-blind study. Adverse events (AEs) and laboratory data were monitored from the first Belimumab dose (in either study) until 24 weeks after the final dose. Efficacy assessments included SLE Responder Index (SRI) and flare index scores (each assessed at 16-week intervals) and glucocorticoid use (assessed at 4-week intervals). Results Of the 476 patients in the parent study, 298 (62.6%) entered the continuation study, of whom 96 (32.2%) remained in the study. Patients received Belimumab for up to 13 years (median duration of exposure 3,334.0 days [range 260-4,332 days], total Belimumab exposure 2,294 patient-years, median number of infusions 115.5 [range 7-155]). The percentage of patients with AEs each year remained stable or decreased. Normal serum IgG levels were maintained in the majority of patients over the study, and the rate of infections remained stable. The percentage of patients who achieved an SRI response increased from 32.8% (year 1) to 75.6% of those remaining on treatment at year 12. The glucocorticoid dose was decreased in patients who had been receiving >7.5 mg/day at baseline. Conclusion This study is the longest to date to assess Belimumab treatment in patients with SLE in clinical trials. Belimumab was well tolerated with no new safety concerns, and efficacy was maintained in patients who continued the study. For patients who initially exhibited a satisfactory response to Belimumab, the treatment continues to be well tolerated and provides long-term disease control.

  • cumulative corticosteroid dose over fifty two weeks in patients with systemic lupus erythematosus pooled analyses from the phase iii Belimumab trials
    Arthritis & Rheumatism, 2016
    Co-Authors: Ronald F Van Vollenhoven, Michelle Petri, Daniel J Wallace, Anne E Hammer, C. Molta, David A Roth, Yongqiang Tang, A Thompson
    Abstract:

    Objective To examine the effects of treatment with Belimumab on corticosteroid dose in patients with systemic lupus erythematosus (SLE) over 52 weeks in 2 randomized, controlled trials. Methods Data on patients who were taking corticosteroids at baseline in the Study of Belimumab in Subjects with SLE trials were pooled post hoc to compare patients who received Belimumab 10 mg/kg plus standard therapy with those who received placebo plus standard therapy. The primary end point was cumulative change from baseline in corticosteroid dose (prednisone equivalent) through week 52. Further analyses specifically examined oral corticosteroid dose. Results At baseline, 966 of 1,125 patients (86%) were receiving corticosteroids (478 Belimumab 10 mg/kg and 488 placebo). Most were women (94%), their mean age was 37.1 years, mean Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index score was 9.8, and mean corticosteroid dosage was 12.5 mg/day. Over 52 weeks, there was a smaller increase in mean cumulative corticosteroid dose for the Belimumab group than for the placebo group (531.2 mg versus 916.3 mg; P < 0.0001). Compared with placebo, the mean of all decreases in cumulative corticosteroid dose was higher with Belimumab (P = 0.0165), and the mean of all increases was lower (P = 0.0005). More patients in the Belimumab group had decreases in oral corticosteroid dose (38.5% versus 30.9%), and fewer had increases in dose (18.4% versus 30.7%), compared with placebo. Adverse events were comparable across groups. Conclusion Our findings show a significantly smaller increase in cumulative corticosteroid dose over 1 year, more patients with decreases in oral corticosteroid dose, and fewer patients with increases in oral corticosteroid dose in the Belimumab group compared with the placebo group. These data suggest that Belimumab may be steroid sparing.

  • op0041 pregnancy outcomes for systemic lupus erythematosus sle subjects with conception during Belimumab intravenous iv and subcutaneous sc placebo controlled clinical trials and long term extension trials
    Annals of the Rheumatic Diseases, 2014
    Co-Authors: M Powell, Amanda M Eudy, D Hill, H Landy, Michelle Petri
    Abstract:

    Background SLE is an autoimmune disease typically affecting women of childbearing age that can be associated with significant maternal and fetal morbidity. Belimumab is a biologic approved as adjunctive therapy for SLE. Although pregnant women were excluded from Belimumab clinical trials and treatment was discontinued if a pregnancy occurred, pregnancy outcomes were collected when a pregnancy was identified. Objectives To describe pregnancy outcomes of women who conceived while participating in Belimumab phase 2-4 clinical trial studies. Methods Cumulative pregnancy outcome data with autoantibody status (when available) were collected from women who conceived while participating in Belimumab SLE phase 2-4 clinical trials. Results As of 08 March 2013, 66 pregnancies with known outcomes in subjects who received Belimumab and 6 who received placebo had been reported in the IV and SC SLE studies (Table). A lower frequency of fetal loss was noted in subjects treated with Belimumab (27%; 18 of 66) compared to the placebo group (50%; 3 of 6). Live births were noted in 33 of 66 pregnancies (50%) in the Belimumab group, 3 of which were associated with congenital anomalies (1 case of Dandy Walker syndrome, 1 case of bilateral enlarged kidneys in a pregnancy also exposed to a known teratogenic drug, and an unbalanced translocation involving chromosomes 11 and 13 that was linked to the mother). In the group receiving Belimumab, anticardiolipin antibodies were present at baseline in 21% (7 of 33) of subjects who had live births and in 44% (8 of 18) of subjects with fetal loss. Conclusions Total fetal loss in Belimumab-treated subjects was similar to background estimates in SLE patients (∼25%), although data remain limited. Valuable clinical information can be obtained through the Belimumab Pregnancy Registry (BPR), an international, prospective cohort study with voluntary participation. The BPR will add to current clinical experience with Belimumab and assist clinicians and patients regarding potential risks and benefits of treating SLE patients who are contemplating pregnancy or are pregnant. GSK1550188; eTrack Study #201182 References Andrade R, Sanchez ML, Alarcon GS, et al. Adverse pregnancy outcomes in women with systemic lupus erythematosus from a multiethnic US cohort: LUMINA (LU1). Clin Exp Rheumatol. 2008;26:268-74. Clowse ME, Magder LS, Witter F et al. The impact of increased lupus activity on obstetric outcomes. Arthritis Rheum. 2005;52:514-21. Rahman P, Gladman DD, Urowitz MB. Clinical predictors of fetal outcome in systemic lupus erythematosus. J Rheumatol. 1998; 25.8:1526-30. Disclosure of Interest M. Powell Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, D. Hill Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, A. Eudy Employee of: GlaxoSmithKline, H. Landy Consultant for: GlaxoSmithKline, M. Petri Consultant for: GlaxoSmithKline DOI 10.1136/annrheumdis-2014-eular.4484

  • safety profile of Belimumab pooled data from placebo controlled phase 2 and 3 studies in patients with systemic lupus erythematosus
    Lupus, 2013
    Co-Authors: Daniel J Wallace, Richard Furie, Michelle Petri, Ronald F Van Vollenhoven, Sandra V Navarra, Roger A Levy, Mathew Thomas, S Cooper, A Gallacher, Zj Zhong
    Abstract:

    Safety data were pooled and analyzed from one phase 2 and two phase 3 double-blind, placebo-controlled, repeat-dose systemic lupus erythematosus (SLE) trials of Belimumab 1, 4 (phase 2 only), and 10 mg/kg. Types and rates of adverse events (AEs) were similar across treatment groups. Rates of patients experiencing any serious AE were 16.6%, 19.5%, 13.5%, and 18.0% with placebo, and Belimumab 1, 4, and 10 mg/kg, respectively; rates of serious infusion reactions (including hypersensitivity reactions) occurring on the same days as infusions were 0.4%, 0.9%, 0%, and 0.9%, and rates of serious infections were 5.5%, 7.1%, 6.3%, and 5.3%. Malignancy rates/100 patient-years (excluding non-melanoma skin cancer) were 0.29 with placebo vs. 0.20 with all Belimumab doses combined; mortality rates/100 patient-years were 0.43 vs. 0.73. These data support the conclusion that Belimumab in combination with standard SLE therapy was generally well tolerated in a predominantly autoantibody-positive population with active SLE. ...

  • a phase iii randomized placebo controlled study of Belimumab a monoclonal antibody that inhibits b lymphocyte stimulator in patients with systemic lupus erythematosus
    Arthritis & Rheumatism, 2011
    Co-Authors: Richard Furie, Andreas Schwarting, Michelle Petri, Omid Zamani, Ricard Cervera, Daniel J Wallace, D Tegzova, Jorge Sanchezguerrero, Joan T Merrill, Winn W Chatham
    Abstract:

    Objective To assess the efficacy/safety of the B lymphocyte stimulator inhibitor Belimumab plus standard therapy compared with placebo plus standard therapy in active systemic lupus erythematosus (SLE). Methods In a phase III, multicenter, randomized, placebo-controlled trial, 819 antinuclear antibody-positive or anti-double-stranded DNA-positive SLE patients with scores ≥6 on the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) were randomized in a 1:1:1 ratio to receive 1 mg/kg Belimumab, 10 mg/kg Belimumab, or placebo intravenously on days 0, 14, and 28 and then every 28 days for 72 weeks. The primary efficacy end point was the SLE Responder Index (SRI) response rate at week 52 (an SRI response was defined as a ≥4-point reduction in SELENA-SLEDAI score, no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new BILAG B score, and no worsening in physician's global assessment score versus baseline). Results Belimumab at 10 mg/kg plus standard therapy met the primary efficacy end point, generating a significantly greater SRI response at week 52 compared with placebo (43.2% versus 33.5%; P = 0.017). The rate with 1 mg/kg Belimumab was 40.6% (P = 0.089). Response rates at week 76 were 32.4%, 39.1%, and 38.5% with placebo, 1 mg/kg Belimumab, and 10 mg/kg Belimumab, respectively. In post hoc sensitivity analyses evaluating higher SELENA-SLEDAI score thresholds, 10 mg/kg Belimumab achieved better discrimination at weeks 52 and 76. Risk of severe flares over 76 weeks (based on the modified SLE Flare Index) was reduced with 1 mg/kg Belimumab (34%) (P = 0.023) and 10 mg/kg Belimumab (23%) (P = 0.13). Serious and severe adverse events, including infections, laboratory abnormalities, malignancies, and deaths, were comparable across groups. Conclusion Belimumab plus standard therapy significantly improved SRI response rate, reduced SLE disease activity and severe flares, and was generally well tolerated in SLE.

Daniel J Wallace - One of the best experts on this subject based on the ideXlab platform.

  • Safety and Efficacy of Belimumab Plus Standard Therapy for Up to Thirteen Years in Patients With Systemic Lupus Erythematosus
    Arthritis & rheumatology (Hoboken N.J.), 2019
    Co-Authors: Daniel J Wallace, Richard Furie, Joan T Merrill, William Stohl, James D Mckay, Ellen M Ginzler, Arthur Weinstein, W. Winn Chatham, W. Joseph Mccune, Michelle Petri
    Abstract:

    Objective To investigate the long-term safety and efficacy of intravenous (IV) Belimumab plus standard of care (SOC) therapy for systemic lupus erythematosus (SLE) in patients with active, autoantibody-positive SLE. Methods The study was designed as a multicenter, open-label, continuation study of IV Belimumab given every 4 weeks in conjunction with SOC therapy in patients with SLE who completed a phase II, double-blind study. Adverse events (AEs) and laboratory data were monitored from the first Belimumab dose (in either study) until 24 weeks after the final dose. Efficacy assessments included SLE Responder Index (SRI) and flare index scores (each assessed at 16-week intervals) and glucocorticoid use (assessed at 4-week intervals). Results Of the 476 patients in the parent study, 298 (62.6%) entered the continuation study, of whom 96 (32.2%) remained in the study. Patients received Belimumab for up to 13 years (median duration of exposure 3,334.0 days [range 260-4,332 days], total Belimumab exposure 2,294 patient-years, median number of infusions 115.5 [range 7-155]). The percentage of patients with AEs each year remained stable or decreased. Normal serum IgG levels were maintained in the majority of patients over the study, and the rate of infections remained stable. The percentage of patients who achieved an SRI response increased from 32.8% (year 1) to 75.6% of those remaining on treatment at year 12. The glucocorticoid dose was decreased in patients who had been receiving >7.5 mg/day at baseline. Conclusion This study is the longest to date to assess Belimumab treatment in patients with SLE in clinical trials. Belimumab was well tolerated with no new safety concerns, and efficacy was maintained in patients who continued the study. For patients who initially exhibited a satisfactory response to Belimumab, the treatment continues to be well tolerated and provides long-term disease control.

  • cumulative corticosteroid dose over fifty two weeks in patients with systemic lupus erythematosus pooled analyses from the phase iii Belimumab trials
    Arthritis & Rheumatism, 2016
    Co-Authors: Ronald F Van Vollenhoven, Michelle Petri, Daniel J Wallace, Anne E Hammer, C. Molta, David A Roth, Yongqiang Tang, A Thompson
    Abstract:

    Objective To examine the effects of treatment with Belimumab on corticosteroid dose in patients with systemic lupus erythematosus (SLE) over 52 weeks in 2 randomized, controlled trials. Methods Data on patients who were taking corticosteroids at baseline in the Study of Belimumab in Subjects with SLE trials were pooled post hoc to compare patients who received Belimumab 10 mg/kg plus standard therapy with those who received placebo plus standard therapy. The primary end point was cumulative change from baseline in corticosteroid dose (prednisone equivalent) through week 52. Further analyses specifically examined oral corticosteroid dose. Results At baseline, 966 of 1,125 patients (86%) were receiving corticosteroids (478 Belimumab 10 mg/kg and 488 placebo). Most were women (94%), their mean age was 37.1 years, mean Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index score was 9.8, and mean corticosteroid dosage was 12.5 mg/day. Over 52 weeks, there was a smaller increase in mean cumulative corticosteroid dose for the Belimumab group than for the placebo group (531.2 mg versus 916.3 mg; P < 0.0001). Compared with placebo, the mean of all decreases in cumulative corticosteroid dose was higher with Belimumab (P = 0.0165), and the mean of all increases was lower (P = 0.0005). More patients in the Belimumab group had decreases in oral corticosteroid dose (38.5% versus 30.9%), and fewer had increases in dose (18.4% versus 30.7%), compared with placebo. Adverse events were comparable across groups. Conclusion Our findings show a significantly smaller increase in cumulative corticosteroid dose over 1 year, more patients with decreases in oral corticosteroid dose, and fewer patients with increases in oral corticosteroid dose in the Belimumab group compared with the placebo group. These data suggest that Belimumab may be steroid sparing.

  • disease control and safety of Belimumab plus standard therapy over 7 years in patients with systemic lupus erythematosus
    The Journal of Rheumatology, 2014
    Co-Authors: Ellen M Ginzler, Richard Furie, Daniel J Wallace, Joan T Merrill, Winn W Chatham, William Stohl, James D Mckay, Joseph W Mccune, Arthur Weinstein, John Z Zhong
    Abstract:

    Objective. To evaluate the efficacy/safety of Belimumab plus standard therapy in patients (n = 449) with active systemic lupus erythematosus (SLE) treated up to 7 years (n = 177 currently ongoing). Methods. Patients (n = 345) who completed a double-blind, placebo-controlled, 52-week study of Belimumab 1, 4, or 10 mg/kg and 24-week extension of Belimumab (placebo switched to 10 mg/kg; Belimumab same dose or switched to 10 mg/kg) could receive Belimumab 10 mg/kg in an open-label continuation study (n = 296). Disease activity was analyzed in patients with active SLE at baseline of the initial study. Biomarker and SLE medication changes were evaluated, and adverse events (AE) were monitored throughout the study. Results. Total Belimumab exposure over 7 years (double-blind and open-label periods): 1746 patient-years. SLE Responder Index (SRI) response rates at Week 52 in autoantibody-positive patients: placebo, 29%; Belimumab, 46% (p < 0.05). In the continuation study, 57% of auto-antibody-positive patients had an SRI response by Year 2 and 65% by Year 7; severe flares occurred in 19% with placebo and 17% with Belimumab during the first year, with the annual rate declining to 2%–9% during years 2–7. Anti-dsDNA autoantibodies in patients positive for them at baseline had a progressive decline of 40%–60% from baseline over 2–7 years with Belimumab. Corticosteroid use decreased over time with ≥ 50–55% reduction in median dose during years 5–7. Serious and overall annual AE rates, including infections, were generally stable or decreased during 7-year treatment. Conclusion. Disease control and safety profile were maintained in patients with active SLE taking Belimumab plus standard therapy for up to 7 years. [[ClinicalTrials.gov][1] numbers: [NCT00071487][2] and [NCT00583362][3]] [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00071487&atom=%2Fjrheum%2F41%2F2%2F300.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00583362&atom=%2Fjrheum%2F41%2F2%2F300.atom

  • safety profile of Belimumab pooled data from placebo controlled phase 2 and 3 studies in patients with systemic lupus erythematosus
    Lupus, 2013
    Co-Authors: Daniel J Wallace, Richard Furie, Michelle Petri, Ronald F Van Vollenhoven, Sandra V Navarra, Roger A Levy, Mathew Thomas, S Cooper, A Gallacher, Zj Zhong
    Abstract:

    Safety data were pooled and analyzed from one phase 2 and two phase 3 double-blind, placebo-controlled, repeat-dose systemic lupus erythematosus (SLE) trials of Belimumab 1, 4 (phase 2 only), and 10 mg/kg. Types and rates of adverse events (AEs) were similar across treatment groups. Rates of patients experiencing any serious AE were 16.6%, 19.5%, 13.5%, and 18.0% with placebo, and Belimumab 1, 4, and 10 mg/kg, respectively; rates of serious infusion reactions (including hypersensitivity reactions) occurring on the same days as infusions were 0.4%, 0.9%, 0%, and 0.9%, and rates of serious infections were 5.5%, 7.1%, 6.3%, and 5.3%. Malignancy rates/100 patient-years (excluding non-melanoma skin cancer) were 0.29 with placebo vs. 0.20 with all Belimumab doses combined; mortality rates/100 patient-years were 0.43 vs. 0.73. These data support the conclusion that Belimumab in combination with standard SLE therapy was generally well tolerated in a predominantly autoantibody-positive population with active SLE. ...

  • Long-term safety profile of Belimumab plus standard therapy in patients with systemic lupus erythematosus.
    Arthritis and rheumatism, 2012
    Co-Authors: Joan T Merrill, Daniel J Wallace, Jeffrey R Lisse, James D Mckay, Ellen M Ginzler, Cynthia Aranow, Frank R. Wellborne, Michael Burnette, John J. Condemi, Z. John Zhong
    Abstract:

    Objective To evaluate the safety profile of long-term Belimumab therapy combined with standard therapy for systemic lupus erythematosus (SLE) in patients with active disease. Methods Patients who were randomized to receive intravenous placebo or Belimumab 1, 4, or 10 mg/kg, plus standard therapy, and completed the initial 52-week double-blind treatment period were then allowed to enter a 24-week open-label extension phase. During the extension period, patients in the Belimumab group either received the same dose or were switched to 10 mg/kg and patients in the placebo group were switched to Belimumab 10 mg/kg. Patients who achieved a satisfactory response during the 24-week extension period were allowed to participate in the long-term continuation study of monthly Belimumab 10 mg/kg. Adverse events (AEs) and abnormal laboratory results were analyzed per 100 patient-years in 1-year intervals. Results Of the 364 patients who completed the 52-week double-blind treatment period, 345 entered the 24-week extension, and 296 continued treatment with Belimumab in the long-term continuation study. Safety data through 4 years of Belimumab exposure (1,165 cumulative patient-years) are reported. Incidence rates of AEs, severe/serious AEs, infusion reactions, infections, malignancies, grades 3/4 laboratory abnormalities, and discontinuations due to AEs were stable or declined during 4-year Belimumab exposure. The most common AEs included arthralgia, upper respiratory tract infection, headache, fatigue, and nausea. Serious infusion reactions were rare: only 1 occurred during the 4-year followup period. Rates of serious infection decreased from 5.9/100 patient-years to 3.4/100 patient-years, and no specific type of infection predominated. Conclusion Belimumab added to standard therapy was generally well-tolerated over the 4-year treatment period in patients with SLE, which suggests that Belimumab can be administered long term with an acceptable safety profile.

Richard Furie - One of the best experts on this subject based on the ideXlab platform.

  • Safety and Efficacy of Belimumab Plus Standard Therapy for Up to Thirteen Years in Patients With Systemic Lupus Erythematosus
    Arthritis & rheumatology (Hoboken N.J.), 2019
    Co-Authors: Daniel J Wallace, Richard Furie, Joan T Merrill, William Stohl, James D Mckay, Ellen M Ginzler, Arthur Weinstein, W. Winn Chatham, W. Joseph Mccune, Michelle Petri
    Abstract:

    Objective To investigate the long-term safety and efficacy of intravenous (IV) Belimumab plus standard of care (SOC) therapy for systemic lupus erythematosus (SLE) in patients with active, autoantibody-positive SLE. Methods The study was designed as a multicenter, open-label, continuation study of IV Belimumab given every 4 weeks in conjunction with SOC therapy in patients with SLE who completed a phase II, double-blind study. Adverse events (AEs) and laboratory data were monitored from the first Belimumab dose (in either study) until 24 weeks after the final dose. Efficacy assessments included SLE Responder Index (SRI) and flare index scores (each assessed at 16-week intervals) and glucocorticoid use (assessed at 4-week intervals). Results Of the 476 patients in the parent study, 298 (62.6%) entered the continuation study, of whom 96 (32.2%) remained in the study. Patients received Belimumab for up to 13 years (median duration of exposure 3,334.0 days [range 260-4,332 days], total Belimumab exposure 2,294 patient-years, median number of infusions 115.5 [range 7-155]). The percentage of patients with AEs each year remained stable or decreased. Normal serum IgG levels were maintained in the majority of patients over the study, and the rate of infections remained stable. The percentage of patients who achieved an SRI response increased from 32.8% (year 1) to 75.6% of those remaining on treatment at year 12. The glucocorticoid dose was decreased in patients who had been receiving >7.5 mg/day at baseline. Conclusion This study is the longest to date to assess Belimumab treatment in patients with SLE in clinical trials. Belimumab was well tolerated with no new safety concerns, and efficacy was maintained in patients who continued the study. For patients who initially exhibited a satisfactory response to Belimumab, the treatment continues to be well tolerated and provides long-term disease control.

  • AI-18 The effect of Belimumab on B cell selection in human SLE
    Lupus science & medicine, 2018
    Co-Authors: Weiqing Huang, Tam Quach, Cosmin Dascalu, Tungming Leung, Thomas L. Rothstein, Martin Lesser, Richard Furie, Meggan Mackay
    Abstract:

    Background Belimumab has a therapeutic benefit in active SLE, especially in patients with high titers of anti-dsDNA antibodies. The current study was designed to address whether the profound loss of naive B cells in Belimumab treated patients is accompanied by a shift in the immunoglobulin repertoire of either mature B cells or plasma cells. Methods 15 SLE patients who had been continuously treated with Belimumab 10 mg/kg monthly for >5 years were matched with 17 SLE controls. 5 SLE patients newly starting on Belimumab were studied before and 6 months after drug initiation. B cell phenotyping was performed using flow cytometry. Mature B cells and plasmablasts were sort purified, VH libraries were generated using barcoded primers (iRepertoire) and pooled libraries were sequenced using miSeq. Analyses of unmutated and mutated IgM sequences from mature B cells and all sequences from plasmablasts were performed using customized Perl and R scripts. Results Phenotyping – novel findings: BAFF regulates the transitional B cell checkpoint with conservation of transitional type 1 cells and ≈90% loss of transitional type 3 and naive B cells after chronic Belimumab treatment. Neither ‘naive activated’ B cells nor CD21lo B cells subset are preferentially depleted by Belimumab. The early increase in CD27+ class switched cells after Belimumab treatment is due to an increase in memory B cells rather than B1 cells. After >5 years of treatment, class switched memory B cells, B1 B cells and plasmablasts are also substantially depleted. Next Generation Sequencing of VH genes: There was no redistribution of V, D or J family usage among unmutated IgM sequences. There was no effect of Belimumab on the frequency of the autoreactive VH4–34 gene or on CDR3 length or composition in unmutated IgM sequences. There was a significantly greater loss of VH4–34 among mutated IgM sequences and plasmablast sequences compared with unmutated sequences in subjects treated with chronic Belimumab than in lupus controls. Conclusions Although BAFF highly regulates survival of naive B cells past the T1 stage in humans, we were unable to identify an effect of Belimumab on VH distribution or CDR3 composition of naive B cells, suggesting a minimal effect on selection of the naive B cell repertoire. By contrast Belimumab may promote negative selection of autoreactive activated naive B cells and plasmblasts.

  • Safety and Efficacy of Belimumab to Treat Systemic Lupus Erythematosus in Academic Clinical Practices
    The Journal of rheumatology, 2015
    Co-Authors: Joyce Hui-yuen, Andrew H. Eichenfield, Amy J. Starr, Lisa F. Imundo, Arthi Reddy, Jennifer Taylor, Liza M. Bermudez, Jill P. Buyon, Richard Furie
    Abstract:

    Objective. To evaluate the use and efficacy of Belimumab in academic practices. Belimumab is a human monoclonal antibody that inhibits soluble B lymphocyte stimulator and has been approved for the treatment of adults with systemic lupus erythematosus (SLE). Methods. Invitations to participate and complete a 1-page questionnaire for each patient prescribed Belimumab were sent to 16 physicians experienced in SLE phase III clinical trials. The outcome was defined as the physician’s impression of improvement in the initial manifestation(s) being treated without worsening in other organ systems. Results. Of 195 patients treated with Belimumab at 10 academic centers, 96% were taking background medications for SLE at initiation of Belimumab, with 74% taking corticosteroids. The main indications for initiation of Belimumab were arthritis, rash, and/or worsening serologic activity, with 30% of patients unable to taper corticosteroids. Of the 120 patients taking Belimumab for at least 6 months, 51% responded clinically and 67% had ≥ 25% improvement in laboratory values. While numbers are limited, black patients showed improvement at 6 months. In a subset of 39 patients with childhood-onset SLE, 65% responded favorably at 6 months, and 35% discontinued corticosteroids. Conclusion. Our data demonstrate favorable clinical and laboratory outcomes in patients with SLE at 6 months across all racial and ethnic groups, with similar improvement seen among patients with childhood-onset SLE.

  • disease control and safety of Belimumab plus standard therapy over 7 years in patients with systemic lupus erythematosus
    The Journal of Rheumatology, 2014
    Co-Authors: Ellen M Ginzler, Richard Furie, Daniel J Wallace, Joan T Merrill, Winn W Chatham, William Stohl, James D Mckay, Joseph W Mccune, Arthur Weinstein, John Z Zhong
    Abstract:

    Objective. To evaluate the efficacy/safety of Belimumab plus standard therapy in patients (n = 449) with active systemic lupus erythematosus (SLE) treated up to 7 years (n = 177 currently ongoing). Methods. Patients (n = 345) who completed a double-blind, placebo-controlled, 52-week study of Belimumab 1, 4, or 10 mg/kg and 24-week extension of Belimumab (placebo switched to 10 mg/kg; Belimumab same dose or switched to 10 mg/kg) could receive Belimumab 10 mg/kg in an open-label continuation study (n = 296). Disease activity was analyzed in patients with active SLE at baseline of the initial study. Biomarker and SLE medication changes were evaluated, and adverse events (AE) were monitored throughout the study. Results. Total Belimumab exposure over 7 years (double-blind and open-label periods): 1746 patient-years. SLE Responder Index (SRI) response rates at Week 52 in autoantibody-positive patients: placebo, 29%; Belimumab, 46% (p < 0.05). In the continuation study, 57% of auto-antibody-positive patients had an SRI response by Year 2 and 65% by Year 7; severe flares occurred in 19% with placebo and 17% with Belimumab during the first year, with the annual rate declining to 2%–9% during years 2–7. Anti-dsDNA autoantibodies in patients positive for them at baseline had a progressive decline of 40%–60% from baseline over 2–7 years with Belimumab. Corticosteroid use decreased over time with ≥ 50–55% reduction in median dose during years 5–7. Serious and overall annual AE rates, including infections, were generally stable or decreased during 7-year treatment. Conclusion. Disease control and safety profile were maintained in patients with active SLE taking Belimumab plus standard therapy for up to 7 years. [[ClinicalTrials.gov][1] numbers: [NCT00071487][2] and [NCT00583362][3]] [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00071487&atom=%2Fjrheum%2F41%2F2%2F300.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00583362&atom=%2Fjrheum%2F41%2F2%2F300.atom

  • safety profile of Belimumab pooled data from placebo controlled phase 2 and 3 studies in patients with systemic lupus erythematosus
    Lupus, 2013
    Co-Authors: Daniel J Wallace, Richard Furie, Michelle Petri, Ronald F Van Vollenhoven, Sandra V Navarra, Roger A Levy, Mathew Thomas, S Cooper, A Gallacher, Zj Zhong
    Abstract:

    Safety data were pooled and analyzed from one phase 2 and two phase 3 double-blind, placebo-controlled, repeat-dose systemic lupus erythematosus (SLE) trials of Belimumab 1, 4 (phase 2 only), and 10 mg/kg. Types and rates of adverse events (AEs) were similar across treatment groups. Rates of patients experiencing any serious AE were 16.6%, 19.5%, 13.5%, and 18.0% with placebo, and Belimumab 1, 4, and 10 mg/kg, respectively; rates of serious infusion reactions (including hypersensitivity reactions) occurring on the same days as infusions were 0.4%, 0.9%, 0%, and 0.9%, and rates of serious infections were 5.5%, 7.1%, 6.3%, and 5.3%. Malignancy rates/100 patient-years (excluding non-melanoma skin cancer) were 0.29 with placebo vs. 0.20 with all Belimumab doses combined; mortality rates/100 patient-years were 0.43 vs. 0.73. These data support the conclusion that Belimumab in combination with standard SLE therapy was generally well tolerated in a predominantly autoantibody-positive population with active SLE. ...

David D'cruz - One of the best experts on this subject based on the ideXlab platform.

  • Efficacy, pharmacokinetic and pharmacodynamic profile of Belimumab for systemic lupus erythematosus
    Expert opinion on drug metabolism & toxicology, 2015
    Co-Authors: Natasha Jordan, David D'cruz
    Abstract:

    Introduction: Systemic lupus erythematosus (SLE) is a severe autoimmune disease and a sizeable proportion of patients remain refractory to currently available immunosuppressive agents. The burden of uncontrolled disease is significant as disease flare and persistent inflammation lead to long-term damage accrual and increased morbidity. Belimumab, a humanized monoclonal antibody that inhibits B-lymphocyte stimulator (BLyS), is the first drug to be approved by the US FDA for the treatment of SLE in 50 years.Areas covered: In this review, we provide an overview of novel therapeutic agents under development for the treatment of SLE, a description of the pharmacodynamic and pharmacokinetic properties of Belimumab, evidence of efficacy of Belimumab as demonstrated in clinical trials, safety and tolerability data and a summary of ongoing clinical trials of Belimumab in SLE. This information was amassed following a comprehensive MEDLINE and Cochrane library search. Ongoing clinical trial information was obtained ...

  • Belimumab for the treatment of systemic lupus erythematosus.
    Expert review of clinical immunology, 2014
    Co-Authors: Natasha Jordan, David D'cruz
    Abstract:

    Given their pivotal role in autoantibody production, B-cells have become an attractive therapeutic target in systemic lupus erythematosus (SLE). Belimumab, a fully human monoclonal antibody against B lymphocyte stimulator (BLyS), a B-cell survival factor, was licensed in 2011 for the treatment of autoantibody-positive SLE. The BLISS-52 and BLISS-76 Phase III trials successfully demonstrated that Belimumab (10 mg/kg) with standard therapy significantly decreased disease activity in SLE patients compared to placebo with standard therapy. Overall, Belimumab has been found to be safe and well tolerated. While the BLISS-52 and BLISS-76 studies are the largest clinical trials in SLE to date, they mainly focused on musculoskeletal, mucocutaneous, hematologic and general constitutional features of the disease. Patients with severe lupus nephritis and severe central nervous system disease were excluded from these trials. Studies of Belimumab in lupus nephritis are ongoing that may clarify the role of this agent in the clinical management of SLE.

  • Update on Belimumab for the management of systemic lupus erythematosus.
    Expert opinion on biological therapy, 2014
    Co-Authors: Pamela M. K. Lutalo, David D'cruz
    Abstract:

    Introduction: Belimumab is a fully humanised mAb against B lymphocyte stimulator (B-LyS). It is the first biological drug to be licensed and approved by the US FDA and the European Medicines Evaluation Agency for use in combination with standard immunosuppressants in autoantibody-positive systemic lupus erythematosus (SLE). The clinical effectiveness and impact of this drug on lupus morbidity and mortality is evaluated in this review.Areas covered: An overview of the efficacy and safety of Belimumab based on 7-year longitudinal continuation study data from SLE patients enrolled in the Phase II double-blind, randomised, placebo-controlled, 52-week study of Belimumab 1, 4 and 10 mg/kg doses and an overview of the open-label 24-week extension of Belimumab plus standard immunosuppressant therapy. A review of the current Belimumab clinical trials, the experience of Belimumab in real-world settings and a description of the impact that Belimumab has had on the healthcare quality of life of SLE patients.Expert op...

  • Belimumab for the management of systemic lupus erythematosus
    Expert opinion on biological therapy, 2012
    Co-Authors: Pamela M. K. Lutalo, David D'cruz
    Abstract:

    Introduction: In 2011, Belimumab, a fully humanized monoclonal antibody against B lymphocyte stimulator, became the first biological agent to be licensed by the United States Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) for the use in auto-antibody positive adult Systemic Lupus Erythematosus (SLE). Areas covered: An overview of the clinical trial data, review of the medical and scientific literature following a MEDLINE search forms the basis of this expert opinion on biological therapy review. The Belimumab International SLE Study Phase III randomized placebo-controlled trials, BLISS-52 and BLISS-76, met the primary endpoint based on the SLE responder index (SRI) at week 52. The trials reported that Belimumab 10 mg/kg infusions with standard therapy significantly reduced SLE disease activity compared with placebo with standard therapy. Expert opinion: The clinical efficacy, safety and tolerability of Belimumab indicates a potential role for this drug in achieving ...

Joan T Merrill - One of the best experts on this subject based on the ideXlab platform.

  • Safety and Efficacy of Belimumab Plus Standard Therapy for Up to Thirteen Years in Patients With Systemic Lupus Erythematosus
    Arthritis & rheumatology (Hoboken N.J.), 2019
    Co-Authors: Daniel J Wallace, Richard Furie, Joan T Merrill, William Stohl, James D Mckay, Ellen M Ginzler, Arthur Weinstein, W. Winn Chatham, W. Joseph Mccune, Michelle Petri
    Abstract:

    Objective To investigate the long-term safety and efficacy of intravenous (IV) Belimumab plus standard of care (SOC) therapy for systemic lupus erythematosus (SLE) in patients with active, autoantibody-positive SLE. Methods The study was designed as a multicenter, open-label, continuation study of IV Belimumab given every 4 weeks in conjunction with SOC therapy in patients with SLE who completed a phase II, double-blind study. Adverse events (AEs) and laboratory data were monitored from the first Belimumab dose (in either study) until 24 weeks after the final dose. Efficacy assessments included SLE Responder Index (SRI) and flare index scores (each assessed at 16-week intervals) and glucocorticoid use (assessed at 4-week intervals). Results Of the 476 patients in the parent study, 298 (62.6%) entered the continuation study, of whom 96 (32.2%) remained in the study. Patients received Belimumab for up to 13 years (median duration of exposure 3,334.0 days [range 260-4,332 days], total Belimumab exposure 2,294 patient-years, median number of infusions 115.5 [range 7-155]). The percentage of patients with AEs each year remained stable or decreased. Normal serum IgG levels were maintained in the majority of patients over the study, and the rate of infections remained stable. The percentage of patients who achieved an SRI response increased from 32.8% (year 1) to 75.6% of those remaining on treatment at year 12. The glucocorticoid dose was decreased in patients who had been receiving >7.5 mg/day at baseline. Conclusion This study is the longest to date to assess Belimumab treatment in patients with SLE in clinical trials. Belimumab was well tolerated with no new safety concerns, and efficacy was maintained in patients who continued the study. For patients who initially exhibited a satisfactory response to Belimumab, the treatment continues to be well tolerated and provides long-term disease control.

  • disease control and safety of Belimumab plus standard therapy over 7 years in patients with systemic lupus erythematosus
    The Journal of Rheumatology, 2014
    Co-Authors: Ellen M Ginzler, Richard Furie, Daniel J Wallace, Joan T Merrill, Winn W Chatham, William Stohl, James D Mckay, Joseph W Mccune, Arthur Weinstein, John Z Zhong
    Abstract:

    Objective. To evaluate the efficacy/safety of Belimumab plus standard therapy in patients (n = 449) with active systemic lupus erythematosus (SLE) treated up to 7 years (n = 177 currently ongoing). Methods. Patients (n = 345) who completed a double-blind, placebo-controlled, 52-week study of Belimumab 1, 4, or 10 mg/kg and 24-week extension of Belimumab (placebo switched to 10 mg/kg; Belimumab same dose or switched to 10 mg/kg) could receive Belimumab 10 mg/kg in an open-label continuation study (n = 296). Disease activity was analyzed in patients with active SLE at baseline of the initial study. Biomarker and SLE medication changes were evaluated, and adverse events (AE) were monitored throughout the study. Results. Total Belimumab exposure over 7 years (double-blind and open-label periods): 1746 patient-years. SLE Responder Index (SRI) response rates at Week 52 in autoantibody-positive patients: placebo, 29%; Belimumab, 46% (p < 0.05). In the continuation study, 57% of auto-antibody-positive patients had an SRI response by Year 2 and 65% by Year 7; severe flares occurred in 19% with placebo and 17% with Belimumab during the first year, with the annual rate declining to 2%–9% during years 2–7. Anti-dsDNA autoantibodies in patients positive for them at baseline had a progressive decline of 40%–60% from baseline over 2–7 years with Belimumab. Corticosteroid use decreased over time with ≥ 50–55% reduction in median dose during years 5–7. Serious and overall annual AE rates, including infections, were generally stable or decreased during 7-year treatment. Conclusion. Disease control and safety profile were maintained in patients with active SLE taking Belimumab plus standard therapy for up to 7 years. [[ClinicalTrials.gov][1] numbers: [NCT00071487][2] and [NCT00583362][3]] [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00071487&atom=%2Fjrheum%2F41%2F2%2F300.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00583362&atom=%2Fjrheum%2F41%2F2%2F300.atom

  • efficacy and safety of Belimumab in patients with rheumatoid arthritis a phase ii randomized double blind placebo controlled dose ranging study
    The Journal of Rheumatology, 2013
    Co-Authors: William Stohl, Joan T Merrill, Jeffrey R Lisse, James D Mckay, John Z Zhong, William W Freimuth, Mark C Genovese
    Abstract:

    Objective. To evaluate the efficacy/safety of Belimumab in patients with rheumatoid arthritis (RA). Methods. Patients fulfilling American College of Rheumatology (ACR) criteria for RA for ≥ 1 year who had at least moderate disease activity while receiving stable disease-modifying antirheumatic drug (DMARD) therapy and failed ≥ 1 DMARD were randomly assigned to placebo or Belimumab 1, 4, or 10 mg/kg, administered intravenously on Days 1, 14, and 28, and then every 4 weeks for 24 weeks (n = 283). This was followed by an optional 24-week extension (n = 237) in which all patients received Belimumab. Primary efficacy endpoint was the Week 24 ACR20 response. Results. Week 24 ACR20 responses with placebo and Belimumab 1, 4, and 10 mg/kg were 15.9%, 34.7% (p = 0.010), 25.4% (p = 0.168), and 28.2% (p = 0.080), respectively. Patients taking any Belimumab dose who continued with Belimumab in the open-label extension had an ACR20 response of 41% at 48 weeks. A similar ACR20 response (42%) at 48 weeks was seen in patients taking placebo who switched in the extension to Belimumab 10 mg/kg. Greater response rates were observed in patients who at baseline were rheumatoid factor-positive, anticitrullinated protein antibody-positive, or tumor necrosis factor inhibitor-naive, or had elevated C-reactive protein levels, Disease Activity Score 28 > 5.1, or low B lymphocyte stimulator levels ( Conclusion. In this phase II trial, Belimumab demonstrated efficacy and was generally well tolerated in patients with RA who had failed previous therapies. [ClinicalTrials.gov identifier NCT00071812]

  • Long-term safety profile of Belimumab plus standard therapy in patients with systemic lupus erythematosus.
    Arthritis and rheumatism, 2012
    Co-Authors: Joan T Merrill, Daniel J Wallace, Jeffrey R Lisse, James D Mckay, Ellen M Ginzler, Cynthia Aranow, Frank R. Wellborne, Michael Burnette, John J. Condemi, Z. John Zhong
    Abstract:

    Objective To evaluate the safety profile of long-term Belimumab therapy combined with standard therapy for systemic lupus erythematosus (SLE) in patients with active disease. Methods Patients who were randomized to receive intravenous placebo or Belimumab 1, 4, or 10 mg/kg, plus standard therapy, and completed the initial 52-week double-blind treatment period were then allowed to enter a 24-week open-label extension phase. During the extension period, patients in the Belimumab group either received the same dose or were switched to 10 mg/kg and patients in the placebo group were switched to Belimumab 10 mg/kg. Patients who achieved a satisfactory response during the 24-week extension period were allowed to participate in the long-term continuation study of monthly Belimumab 10 mg/kg. Adverse events (AEs) and abnormal laboratory results were analyzed per 100 patient-years in 1-year intervals. Results Of the 364 patients who completed the 52-week double-blind treatment period, 345 entered the 24-week extension, and 296 continued treatment with Belimumab in the long-term continuation study. Safety data through 4 years of Belimumab exposure (1,165 cumulative patient-years) are reported. Incidence rates of AEs, severe/serious AEs, infusion reactions, infections, malignancies, grades 3/4 laboratory abnormalities, and discontinuations due to AEs were stable or declined during 4-year Belimumab exposure. The most common AEs included arthralgia, upper respiratory tract infection, headache, fatigue, and nausea. Serious infusion reactions were rare: only 1 occurred during the 4-year followup period. Rates of serious infection decreased from 5.9/100 patient-years to 3.4/100 patient-years, and no specific type of infection predominated. Conclusion Belimumab added to standard therapy was generally well-tolerated over the 4-year treatment period in patients with SLE, which suggests that Belimumab can be administered long term with an acceptable safety profile.

  • a phase iii randomized placebo controlled study of Belimumab a monoclonal antibody that inhibits b lymphocyte stimulator in patients with systemic lupus erythematosus
    Arthritis & Rheumatism, 2011
    Co-Authors: Richard Furie, Andreas Schwarting, Michelle Petri, Omid Zamani, Ricard Cervera, Daniel J Wallace, D Tegzova, Jorge Sanchezguerrero, Joan T Merrill, Winn W Chatham
    Abstract:

    Objective To assess the efficacy/safety of the B lymphocyte stimulator inhibitor Belimumab plus standard therapy compared with placebo plus standard therapy in active systemic lupus erythematosus (SLE). Methods In a phase III, multicenter, randomized, placebo-controlled trial, 819 antinuclear antibody-positive or anti-double-stranded DNA-positive SLE patients with scores ≥6 on the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) were randomized in a 1:1:1 ratio to receive 1 mg/kg Belimumab, 10 mg/kg Belimumab, or placebo intravenously on days 0, 14, and 28 and then every 28 days for 72 weeks. The primary efficacy end point was the SLE Responder Index (SRI) response rate at week 52 (an SRI response was defined as a ≥4-point reduction in SELENA-SLEDAI score, no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new BILAG B score, and no worsening in physician's global assessment score versus baseline). Results Belimumab at 10 mg/kg plus standard therapy met the primary efficacy end point, generating a significantly greater SRI response at week 52 compared with placebo (43.2% versus 33.5%; P = 0.017). The rate with 1 mg/kg Belimumab was 40.6% (P = 0.089). Response rates at week 76 were 32.4%, 39.1%, and 38.5% with placebo, 1 mg/kg Belimumab, and 10 mg/kg Belimumab, respectively. In post hoc sensitivity analyses evaluating higher SELENA-SLEDAI score thresholds, 10 mg/kg Belimumab achieved better discrimination at weeks 52 and 76. Risk of severe flares over 76 weeks (based on the modified SLE Flare Index) was reduced with 1 mg/kg Belimumab (34%) (P = 0.023) and 10 mg/kg Belimumab (23%) (P = 0.13). Serious and severe adverse events, including infections, laboratory abnormalities, malignancies, and deaths, were comparable across groups. Conclusion Belimumab plus standard therapy significantly improved SRI response rate, reduced SLE disease activity and severe flares, and was generally well tolerated in SLE.