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R.s. Martin - One of the best experts on this subject based on the ideXlab platform.

  • Phase III trial results with Blisibimod, a selective inhibitor of B-cell activating factor, in subjects with systemic lupus erythematosus (SLE): results from a randomised, double-blind, placebo-controlled trial
    Annals of the rheumatic diseases, 2018
    Co-Authors: Joan T. Merrill, Morton Scheinberg, William R Shanahan, Kenneth C. Kalunian, David Wofsy, R.s. Martin
    Abstract:

    Background Targeted inhibitors of B-cell activating factor (BAFF) have been evaluated in phase III trials in over 4000 patients with systemic lupus erythematosus (SLE). Post hoc analyses of these studies identify greater treatment effect in patients entering with higher disease activity, greater corticosteroid doses, anti double-stranded DNA (dsDNA) and low complement C3 or C4. Objectives To evaluate the efficacy and safety of Blisibimod, a BAFF inhibitor, in a population of patients with SLE enriched for high disease activity. Methods 442 patients with SLE with antinuclear antibodies or anti-dsDNA and Safety of Estrogen in Lupus Erythematosus National Assessment – Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score ≥10 on standard-of-care medications were randomised to receive weekly subcutaneous Blisibimod (200 mg) or placebo. Corticosteroid taper was encouraged from week 8. The primary end point was the week 52 SLE Responder Index-6 (SRI-6). Results The SRI-6 primary end point was not met. There was a statistically significant steroid-sparing effect, and significantly more Blisibimod-treated subjects achieved corticosteroid taper. Increased Blisibimod treatment effect on SRI-6 was observed in subjects who achieved a concomitant decrease in corticosteroid dose from baseline. In subjects with baseline urinary protein:creatinine ratio (UPCR) ≥56.5 mg/mmol, significantly higher proportions of Blisibimod subjects achieved >50% reduction in UPCR and/or UPCR Blisibimod was well-tolerated. The most common adverse events were upper respiratory tract infection, urinary tract infection, injection site erythema/reaction and diarrhoea. Conclusions Although the SRI-6 end point was not met, Blisibimod was associated with successful steroid reduction, decreased proteinuria and biomarker responses. Trial registration number NCT01395745.

  • SAT0240 Phase 3 trial results with Blisibimod, a selective inhibitor of B-cell activating factor, in subjects with systemic lupus erythematosus (SLE)
    Poster Presentations, 2017
    Co-Authors: Joan T. Merrill, Morton Scheinberg, R.s. Martin, William R Shanahan, Kenneth C. Kalunian, David Wofsy
    Abstract:

    Background Targeted, biologic inhibitors of B-cell Activating Factor (BAFF) have been evaluated in Phase 3 trials in over 5000 patients with SLE. Post hoc analyses of these studies identify lower placebo response and greater treatment effect using more stringent endpoints in patients entering with higher disease activity, greater corticosteroid doses, and/or anti-double-stranded DNA (dsDNA) and low complement C3 or C41,2. Objectives The Phase 3 CHABLIS-SC1 trial evaluated Blisibimod, an inhibitor of B-cell activating factor (BAFF), in a “responder population” identified from prior studies with this drug class. Methods 442 SLE patients with anti-nuclear antibodies or anti-dsDNA, SELENA-SLEDAI score ≥10 on standard of care medications were randomized to receive weekly subcutaneous Blisibimod (200 mg) or placebo. Corticosteroid taper was encouraged from Week 8 with the goal to reach ≤7.5 mg prednisone/day. The primary endpoint at Week 52 was the SLE Responder Index-6 (SRI-6): ≥6-point improvement in SELENA-SLEDAI, no new BILAG 1A or 2B domain scores, and Results This study did not meet its primary endpoint at Week 52. Response rates to Blisibimod were equivalent to past trials of BAFF inhibitors, but the placebo response was greater. A slightly higher proportion of subjects on Blisibimod met the SRI-6 and SRI-4 criteria at most timepoints and more Blisibimod-treated subjects achieved corticosteroid taper to prednisone ≤7.5 mg/day from Week 40 through Week 52 (p=0.04 at Week 44). Reductions in peripheral B cell lineages, anti-dsDNA, anti-phospholipid antibodies, and serum immunoglobulins, and increases in complement C3 and C4 were observed with Blisibimod (see Table). Blisibimod was well-tolerated. The most common adverse events were upper respiratory tract infection (10.6% vs 14.3% on placebo), urinary tract infection (6.9% vs 10.7%), injection site erythema (7.8% vs 2.0%), injection site reaction (7.3% vs 2.6%), and diarrhea (7.3% vs 2.6%). Conclusions With a deliberate focus on a “responder population” for whom lower placebo rates were observed in previous trials, much higher placebo response rates were observed in the CHABLIS-SC1 trial. Modest benefits of Blisibimod were observed on serological effects and corticosteroid tapering. References van Vollenhoven RF et al. Ann Rheum Dis. 2012;71:1343. Merrill JT et al. Ann Rheum Dis. 2016;75(2):332–40. Disclosure of Interest J. Merrill Grant/research support from: BMS, GSK, Consultant for: Anthera, GSK, EMD Serono, Lilly, Astra Zeneca, BMS, UCB, Celgene, Biogen, R. Martin Shareholder of: Anthera, Employee of: Anthera, W. Shanahan Shareholder of: Anthera, Employee of: Anthera, M. Scheinberg Consultant for: GSK,Pfizer, Janssen, Genzyme,Anthera, Novartis, Speakers bureau: GSK,Pfizer, Janssen, Genzyme,Anthera, Novartis, K. Kalunian Grant/research support from: GSK, Celgene, UCB, Consultant for: Anthera, Genentech, BMS, Lilly, Biogen, Shire, Exagen, D. Wofsy Consultant for: Anthera, Genentech, Amgen, GSK

  • Assessments of Fatigue and Disease Activity in Patients With Systemic Lupus Erythematosus Enrolled in the Phase 2 Clinical Trial With Blisibimod
    Lupus, 2016
    Co-Authors: Michelle Petri, Morton Scheinberg, R.s. Martin, Richard Furie
    Abstract:

    This report evaluates the effects of Blisibimod (A-623, AMG 623), a potent and selective inhibitor of B-cell activating factor (BAFF), on patient-reported fatigue and disease activity in the Phase 2b PEARL-SC clinical trial in patients with systemic lupus erythematosus (SLE). A total of 547 individuals who met the American College of Rheumatology (ACR) classification criteria for SLE, were positive for anti-double-stranded DNA or antinuclear antibodies, and had a Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score ≥6 at baseline, were randomized to receive placebo or Blisibimod for at least 24 weeks. Patient self-reported fatigue was evaluated using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and disease activity was evaluated using Physician's Global Assessment, SELENA-SLEDAI, and British Isles Lupus Assessment Group Score. Statistically significant improvements in FACIT-Fatigue score were observed among individuals randomized to Blisibimod, especially in the 200 mg QW group where favorable effects on disease activity with Blisibimod compared to placebo were observed as early as Week 8. The mean improvement from baseline of 6.9 points at Week 24, compared with 4.4 points with placebo, met the criteria for minimal clinically important improvement difference defined for patients with SLE. Despite concomitant improvements in FACIT-Fatigue, SLE Responder Index (SRI) and SLE biomarkers (reported previously), FACIT-Fatigue score correlated only weakly with disease activity. While poor correlation between fatigue and disease activity is not new, the observation that correlation remains poor despite concurrent population improvements in disease and fatigue brings a new facet to our understanding of SLE.

  • ab0412 exploratory results from the bliss and illuminate trials support the design of the chablis sc1 trial a randomized double blind placebo controlled phase 3 study to evaluate the efficacy and safety of Blisibimod administration in subjects with s
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Joan T. Merrill, C. Hislop, R.s. Martin, Vibeke Strand, M Gangal, Kenneth C. Kalunian
    Abstract:

    Background Targeted, biologic inhibitors of B-cell Activating Factor (BAFF) have been evaluated in 4 large Phase 3 clinical trials in nearly 4000 patients with Systemic Lupus Erythematosus (SLE). Data from these studies identify that greatest treatment effect is discernable using more stringent endpoints in patients who enter with higher disease activity scores, taking more corticosteroids, and/or have anti-double-stranded DNA (dsDNA) and low complement C3 or C4 1,2,3 . Objectives The CHABLIS-SC1 study (NCT01395745) has completed enrollment and will be the first trial to prospectively evaluate the impact of treatment on the above “responder populations” using the BAFF inhibitor, Blisibimod. Methods CHABLIS-SC1 enrolled subjects positive for anti-nuclear and/or anti-dsDNA antibodies with SELENA-SLEDAI≥10 despite corticosteroid therapy. Subjects were randomized to have Blisibimod or placebo added to their background medications. Efficacy will be evaluated using the SLE Responder Index-6 (SRI-6) at Week 52, defined as: ≥6 point reduction in SELENA-SLEDAI; no new BILAG A or 2 new BILAG B organ domain scores; and no worsening in Physician9s Global Assessment. Results Table 1 identifies that the baseline characteristics of the 442 subjects enrolled into the CHABLIS-SC1 study more frequently meet all descriptions of “responder populations” identified previously 2–7 . In previous studies, the SRI-6 was associated with lower placebo responder rates and greater benefit of BAFF inhibitors over placebo. Conclusions BAFF inhibitors are known to be at least modestly effective in SLE and impact B Cell-driven immunopathology such as autoantibodies. The CHABLIS-SC1 study design will determine whether enrichment for the hypothesized “responder population,” patients with more severe, immunologically active SLE, will robustly discriminate treatment impact of Blisibimod when background therapy is maintained. References van Vollenhoven RF et al. Ann Rheum Dis. 2012;71:1343. Isenberg DA, et al. Ann Rheum Dis. 2015 Sep. Merrill JT et al. Ann Rheum Dis. 2015 Aug. Dooley MA et al Lupus, 2013;22(1):63, Manzi et al Ann Rheum Dis. 2012;71(11):1833, Merrill et al 2015 (EULAR abstract); Benlysta FDA Drug Approval Package. Acknowledgement We wish to thank all of the patients, Investigators and study personnel participating in this trial. Disclosure of Interest J. Merrill Consultant for: Anthera Pharmaceuticals Inc, V. Strand Consultant for: Anthera, C. Hislop Shareholder of: Anthera, Employee of: Anthera, M. Gangal Shareholder of: Anthera, Employee of: Anthera, R. Martin Shareholder of: Anthera, Employee of: Anthera, K. Kalunian Consultant for: Anthera

  • Blisibimod for treatment of systemic lupus erythematosus with trials you become wiser
    Expert Opinion on Biological Therapy, 2016
    Co-Authors: Morton Scheinberg, C. Hislop, R.s. Martin
    Abstract:

    ABSTRACTIntroduction: Blisibimod is a potent and selective inhibitor of B cell activating factor (BAFF), a mediator of differentiation, maturation and survival of B cells. It has a unique tetravalent, ‘peptibody’ structure and resulting high potency, and is currently in clinical evaluation for the treatment of SLE. The importance of BAFF in the pathogenesis of systemic lupus erythematosus (SLE) is under intense investigation. The anti BAFF monoclonal antibody belimumab was approved by the FDA for the treatment of SLE.Areas covered: The general properties of Blisibimod are reviewed including pharmacokinetic and pharmacodynamic properties in patients with SLE, efficacy and safety in the phase 2 PEARL-SC and open-label extension trials, and the focus in the ongoing phase 3 trial (CHABLIS-SC1) on the hypothesized ‘responder’ population. In addition, the rationale for evaluating Blisibimod in patients with IgA nephropathy, a common nephritic disease for which there is no approved therapy, is presented.Expert O...

Morton Scheinberg - One of the best experts on this subject based on the ideXlab platform.

  • Phase III trial results with Blisibimod, a selective inhibitor of B-cell activating factor, in subjects with systemic lupus erythematosus (SLE): results from a randomised, double-blind, placebo-controlled trial
    Annals of the rheumatic diseases, 2018
    Co-Authors: Joan T. Merrill, Morton Scheinberg, William R Shanahan, Kenneth C. Kalunian, David Wofsy, R.s. Martin
    Abstract:

    Background Targeted inhibitors of B-cell activating factor (BAFF) have been evaluated in phase III trials in over 4000 patients with systemic lupus erythematosus (SLE). Post hoc analyses of these studies identify greater treatment effect in patients entering with higher disease activity, greater corticosteroid doses, anti double-stranded DNA (dsDNA) and low complement C3 or C4. Objectives To evaluate the efficacy and safety of Blisibimod, a BAFF inhibitor, in a population of patients with SLE enriched for high disease activity. Methods 442 patients with SLE with antinuclear antibodies or anti-dsDNA and Safety of Estrogen in Lupus Erythematosus National Assessment – Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score ≥10 on standard-of-care medications were randomised to receive weekly subcutaneous Blisibimod (200 mg) or placebo. Corticosteroid taper was encouraged from week 8. The primary end point was the week 52 SLE Responder Index-6 (SRI-6). Results The SRI-6 primary end point was not met. There was a statistically significant steroid-sparing effect, and significantly more Blisibimod-treated subjects achieved corticosteroid taper. Increased Blisibimod treatment effect on SRI-6 was observed in subjects who achieved a concomitant decrease in corticosteroid dose from baseline. In subjects with baseline urinary protein:creatinine ratio (UPCR) ≥56.5 mg/mmol, significantly higher proportions of Blisibimod subjects achieved >50% reduction in UPCR and/or UPCR Blisibimod was well-tolerated. The most common adverse events were upper respiratory tract infection, urinary tract infection, injection site erythema/reaction and diarrhoea. Conclusions Although the SRI-6 end point was not met, Blisibimod was associated with successful steroid reduction, decreased proteinuria and biomarker responses. Trial registration number NCT01395745.

  • SAT0240 Phase 3 trial results with Blisibimod, a selective inhibitor of B-cell activating factor, in subjects with systemic lupus erythematosus (SLE)
    Poster Presentations, 2017
    Co-Authors: Joan T. Merrill, Morton Scheinberg, R.s. Martin, William R Shanahan, Kenneth C. Kalunian, David Wofsy
    Abstract:

    Background Targeted, biologic inhibitors of B-cell Activating Factor (BAFF) have been evaluated in Phase 3 trials in over 5000 patients with SLE. Post hoc analyses of these studies identify lower placebo response and greater treatment effect using more stringent endpoints in patients entering with higher disease activity, greater corticosteroid doses, and/or anti-double-stranded DNA (dsDNA) and low complement C3 or C41,2. Objectives The Phase 3 CHABLIS-SC1 trial evaluated Blisibimod, an inhibitor of B-cell activating factor (BAFF), in a “responder population” identified from prior studies with this drug class. Methods 442 SLE patients with anti-nuclear antibodies or anti-dsDNA, SELENA-SLEDAI score ≥10 on standard of care medications were randomized to receive weekly subcutaneous Blisibimod (200 mg) or placebo. Corticosteroid taper was encouraged from Week 8 with the goal to reach ≤7.5 mg prednisone/day. The primary endpoint at Week 52 was the SLE Responder Index-6 (SRI-6): ≥6-point improvement in SELENA-SLEDAI, no new BILAG 1A or 2B domain scores, and Results This study did not meet its primary endpoint at Week 52. Response rates to Blisibimod were equivalent to past trials of BAFF inhibitors, but the placebo response was greater. A slightly higher proportion of subjects on Blisibimod met the SRI-6 and SRI-4 criteria at most timepoints and more Blisibimod-treated subjects achieved corticosteroid taper to prednisone ≤7.5 mg/day from Week 40 through Week 52 (p=0.04 at Week 44). Reductions in peripheral B cell lineages, anti-dsDNA, anti-phospholipid antibodies, and serum immunoglobulins, and increases in complement C3 and C4 were observed with Blisibimod (see Table). Blisibimod was well-tolerated. The most common adverse events were upper respiratory tract infection (10.6% vs 14.3% on placebo), urinary tract infection (6.9% vs 10.7%), injection site erythema (7.8% vs 2.0%), injection site reaction (7.3% vs 2.6%), and diarrhea (7.3% vs 2.6%). Conclusions With a deliberate focus on a “responder population” for whom lower placebo rates were observed in previous trials, much higher placebo response rates were observed in the CHABLIS-SC1 trial. Modest benefits of Blisibimod were observed on serological effects and corticosteroid tapering. References van Vollenhoven RF et al. Ann Rheum Dis. 2012;71:1343. Merrill JT et al. Ann Rheum Dis. 2016;75(2):332–40. Disclosure of Interest J. Merrill Grant/research support from: BMS, GSK, Consultant for: Anthera, GSK, EMD Serono, Lilly, Astra Zeneca, BMS, UCB, Celgene, Biogen, R. Martin Shareholder of: Anthera, Employee of: Anthera, W. Shanahan Shareholder of: Anthera, Employee of: Anthera, M. Scheinberg Consultant for: GSK,Pfizer, Janssen, Genzyme,Anthera, Novartis, Speakers bureau: GSK,Pfizer, Janssen, Genzyme,Anthera, Novartis, K. Kalunian Grant/research support from: GSK, Celgene, UCB, Consultant for: Anthera, Genentech, BMS, Lilly, Biogen, Shire, Exagen, D. Wofsy Consultant for: Anthera, Genentech, Amgen, GSK

  • Assessments of Fatigue and Disease Activity in Patients With Systemic Lupus Erythematosus Enrolled in the Phase 2 Clinical Trial With Blisibimod
    Lupus, 2016
    Co-Authors: Michelle Petri, Morton Scheinberg, R.s. Martin, Richard Furie
    Abstract:

    This report evaluates the effects of Blisibimod (A-623, AMG 623), a potent and selective inhibitor of B-cell activating factor (BAFF), on patient-reported fatigue and disease activity in the Phase 2b PEARL-SC clinical trial in patients with systemic lupus erythematosus (SLE). A total of 547 individuals who met the American College of Rheumatology (ACR) classification criteria for SLE, were positive for anti-double-stranded DNA or antinuclear antibodies, and had a Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score ≥6 at baseline, were randomized to receive placebo or Blisibimod for at least 24 weeks. Patient self-reported fatigue was evaluated using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and disease activity was evaluated using Physician's Global Assessment, SELENA-SLEDAI, and British Isles Lupus Assessment Group Score. Statistically significant improvements in FACIT-Fatigue score were observed among individuals randomized to Blisibimod, especially in the 200 mg QW group where favorable effects on disease activity with Blisibimod compared to placebo were observed as early as Week 8. The mean improvement from baseline of 6.9 points at Week 24, compared with 4.4 points with placebo, met the criteria for minimal clinically important improvement difference defined for patients with SLE. Despite concomitant improvements in FACIT-Fatigue, SLE Responder Index (SRI) and SLE biomarkers (reported previously), FACIT-Fatigue score correlated only weakly with disease activity. While poor correlation between fatigue and disease activity is not new, the observation that correlation remains poor despite concurrent population improvements in disease and fatigue brings a new facet to our understanding of SLE.

  • Blisibimod for treatment of systemic lupus erythematosus with trials you become wiser
    Expert Opinion on Biological Therapy, 2016
    Co-Authors: Morton Scheinberg, C. Hislop, R.s. Martin
    Abstract:

    ABSTRACTIntroduction: Blisibimod is a potent and selective inhibitor of B cell activating factor (BAFF), a mediator of differentiation, maturation and survival of B cells. It has a unique tetravalent, ‘peptibody’ structure and resulting high potency, and is currently in clinical evaluation for the treatment of SLE. The importance of BAFF in the pathogenesis of systemic lupus erythematosus (SLE) is under intense investigation. The anti BAFF monoclonal antibody belimumab was approved by the FDA for the treatment of SLE.Areas covered: The general properties of Blisibimod are reviewed including pharmacokinetic and pharmacodynamic properties in patients with SLE, efficacy and safety in the phase 2 PEARL-SC and open-label extension trials, and the focus in the ongoing phase 3 trial (CHABLIS-SC1) on the hypothesized ‘responder’ population. In addition, the rationale for evaluating Blisibimod in patients with IgA nephropathy, a common nephritic disease for which there is no approved therapy, is presented.Expert O...

  • THU0387 Effects of Blisibimod, An Inhibitor of B Cell Activating Factor, On Patient Reported Outcomes and Disease Activity in Patients with Systemic Lupus Erythematosus
    Annals of the Rheumatic Diseases, 2015
    Co-Authors: Michelle Petri, Morton Scheinberg, C. Hislop, R.s. Martin, Richard Furie
    Abstract:

    Background Blisibimod (A-623, AMG 623), a potent and selective inhibitor of B-cell activating factor (BAFF), was evaluated in the phase 2b clinical trial PEARL-SC (NCT01162681) in patients with systemic lupus erythematosus (SLE). Effects of Blisibimod on disease activity and safety were reported previously [1]. Objectives To conduct secondary endpoint analyses of the effects of subcutaneously-administered Blisibimod on patient-reported outcomes from the PEARL-SC trial. Methods 547 SLE patients who met the ACR classification criteria, had anti-double-stranded DNA or anti-nuclear antibodies, and SELENA-SLEDAI score ≥6 at baseline, were randomized in the PEARL-SC study 1:1 to receive placebo or Blisibimod administered at 1 of 3 dose levels, 100 mg weekly (QW), 200 mg QW, or 200 mg every 4 weeks for up to 52 weeks (with a median of 37 weeks) or until the last subject completed 6 months of study drug therapy. Patient self-reported outcomes were evaluated using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and disease activity was evaluated utilizing both SELENA-SLEDAI and BILAG. Results Significant improvements in measures of disease activity in subjects with severe disease (defined as baseline SELENA-SLEDAI score≥10 and receiving steroids), especially at the highest Blisibimod dose of 200mg QW, were reported previously [1]. Approximately 76% of subjects had SELENA-SLEDAI musculoskeletal involvement at enrollment, and 89% of subjects had mucocutaneous involvement. At Week 24, approximately 12% and 39% of subjects randomized to the 200mg QW Blisibimod arm had musculoskeletal or mucocutaneous organ involvement, compared with approximately 15% and 42% respectively in the placebo arm (p Conclusions Fatigue remains a debilitating manifestation of lupus. In this trial, Blisibimod showed a tendency toward improved mucocutaneous and musculoskeletal disease activity as well as patient self-reported fatigue. These data support further evaluation of Blisibimod in patients with SLE. References Furie RA, Leon G, Thomas M, Petri MA, et al. A phase 2, randomised, placebo-controlled clinical trial of Blisibimod, an inhibitor of B cell activating factor, in patients with moderate-to-severe systemic lupus erythematosus, the PEARL-SC study. Ann Rheum Dis. 2014. Goligher EC, Pouchot J, Brant R, Kherani RB et al. Minimal clinically important difference for 7 measures of fatigue in patients with systemic lupus erythematosus. J Rheumatol. 2008;35(4):635-42. Acknowledgements We wish to thank all of the patients, Investigators and clinical teams involved in the PEARl-SC trial. Disclosure of Interest M. Petri Consultant for: Anthera Pharmaceuticals, R. Martin Shareholder of: Anthera Pharmaceuticals, Employee of: Anthera Pharmaceuticals, C. Hislop Shareholder of: Anthera Pharmaceuticals, Employee of: Anthera Pharmaceuticals, M. Scheinberg: None declared, R. Furie Consultant for: Anthera Pharmaceuticals

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

  • Assessments of Fatigue and Disease Activity in Patients With Systemic Lupus Erythematosus Enrolled in the Phase 2 Clinical Trial With Blisibimod
    Lupus, 2016
    Co-Authors: Michelle Petri, Morton Scheinberg, R.s. Martin, Richard Furie
    Abstract:

    This report evaluates the effects of Blisibimod (A-623, AMG 623), a potent and selective inhibitor of B-cell activating factor (BAFF), on patient-reported fatigue and disease activity in the Phase 2b PEARL-SC clinical trial in patients with systemic lupus erythematosus (SLE). A total of 547 individuals who met the American College of Rheumatology (ACR) classification criteria for SLE, were positive for anti-double-stranded DNA or antinuclear antibodies, and had a Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score ≥6 at baseline, were randomized to receive placebo or Blisibimod for at least 24 weeks. Patient self-reported fatigue was evaluated using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and disease activity was evaluated using Physician's Global Assessment, SELENA-SLEDAI, and British Isles Lupus Assessment Group Score. Statistically significant improvements in FACIT-Fatigue score were observed among individuals randomized to Blisibimod, especially in the 200 mg QW group where favorable effects on disease activity with Blisibimod compared to placebo were observed as early as Week 8. The mean improvement from baseline of 6.9 points at Week 24, compared with 4.4 points with placebo, met the criteria for minimal clinically important improvement difference defined for patients with SLE. Despite concomitant improvements in FACIT-Fatigue, SLE Responder Index (SRI) and SLE biomarkers (reported previously), FACIT-Fatigue score correlated only weakly with disease activity. While poor correlation between fatigue and disease activity is not new, the observation that correlation remains poor despite concurrent population improvements in disease and fatigue brings a new facet to our understanding of SLE.

  • THU0387 Effects of Blisibimod, An Inhibitor of B Cell Activating Factor, On Patient Reported Outcomes and Disease Activity in Patients with Systemic Lupus Erythematosus
    Annals of the Rheumatic Diseases, 2015
    Co-Authors: Michelle Petri, Morton Scheinberg, C. Hislop, R.s. Martin, Richard Furie
    Abstract:

    Background Blisibimod (A-623, AMG 623), a potent and selective inhibitor of B-cell activating factor (BAFF), was evaluated in the phase 2b clinical trial PEARL-SC (NCT01162681) in patients with systemic lupus erythematosus (SLE). Effects of Blisibimod on disease activity and safety were reported previously [1]. Objectives To conduct secondary endpoint analyses of the effects of subcutaneously-administered Blisibimod on patient-reported outcomes from the PEARL-SC trial. Methods 547 SLE patients who met the ACR classification criteria, had anti-double-stranded DNA or anti-nuclear antibodies, and SELENA-SLEDAI score ≥6 at baseline, were randomized in the PEARL-SC study 1:1 to receive placebo or Blisibimod administered at 1 of 3 dose levels, 100 mg weekly (QW), 200 mg QW, or 200 mg every 4 weeks for up to 52 weeks (with a median of 37 weeks) or until the last subject completed 6 months of study drug therapy. Patient self-reported outcomes were evaluated using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and disease activity was evaluated utilizing both SELENA-SLEDAI and BILAG. Results Significant improvements in measures of disease activity in subjects with severe disease (defined as baseline SELENA-SLEDAI score≥10 and receiving steroids), especially at the highest Blisibimod dose of 200mg QW, were reported previously [1]. Approximately 76% of subjects had SELENA-SLEDAI musculoskeletal involvement at enrollment, and 89% of subjects had mucocutaneous involvement. At Week 24, approximately 12% and 39% of subjects randomized to the 200mg QW Blisibimod arm had musculoskeletal or mucocutaneous organ involvement, compared with approximately 15% and 42% respectively in the placebo arm (p Conclusions Fatigue remains a debilitating manifestation of lupus. In this trial, Blisibimod showed a tendency toward improved mucocutaneous and musculoskeletal disease activity as well as patient self-reported fatigue. These data support further evaluation of Blisibimod in patients with SLE. References Furie RA, Leon G, Thomas M, Petri MA, et al. A phase 2, randomised, placebo-controlled clinical trial of Blisibimod, an inhibitor of B cell activating factor, in patients with moderate-to-severe systemic lupus erythematosus, the PEARL-SC study. Ann Rheum Dis. 2014. Goligher EC, Pouchot J, Brant R, Kherani RB et al. Minimal clinically important difference for 7 measures of fatigue in patients with systemic lupus erythematosus. J Rheumatol. 2008;35(4):635-42. Acknowledgements We wish to thank all of the patients, Investigators and clinical teams involved in the PEARl-SC trial. Disclosure of Interest M. Petri Consultant for: Anthera Pharmaceuticals, R. Martin Shareholder of: Anthera Pharmaceuticals, Employee of: Anthera Pharmaceuticals, C. Hislop Shareholder of: Anthera Pharmaceuticals, Employee of: Anthera Pharmaceuticals, M. Scheinberg: None declared, R. Furie Consultant for: Anthera Pharmaceuticals

  • FRI0389 Effects of Chronic Treatment with Subcutaneous Blisibimod on Renal and Inflammation Biomarkers in Subjects with Systemic Lupus Erythematosus in Phase 2 PEARL-SC and Open-Label Extension Studies
    Annals of the Rheumatic Diseases, 2014
    Co-Authors: F.a. Richard, Morton Scheinberg, M. Thomas, Alvina D. Chu, C. Hislop, R.s. Martin, Michelle Petri
    Abstract:

    Background Blisibimod is a peptibody that inhibits B-cell activating factor (BAFF). Significant improvements in secondary evaluations of SLE disease activity including proteinuria were reported previously[1] from the Phase 2 randomized, double-blind, placebo-controlled trial with subcutaneous Blisibimod in patients with SLE, PEARL-SC (Phase 2b, NCT01162681). Objectives To evaluate whether the effects on renal biomarkers, observed in patients who received Blisibimod in the PEARL-SC study were durable through continued dosing in the open-label extension trial (OLE, NCT01305746). Methods 547 subjects with serologically-active SLE and SELENA SLEDAI ≥6 were randomized to self-administer Blisibimod (200 mg monthly SC, 100 mg weekly SC, 200 mg weekly SC) or regimen-matched placebo in the PEARL-SC study. The subjects received drugs for up to 52 weeks (median 37 weeks). At baseline 76 subjects had renal involvement using SELENA-SLEDAI definitions. A total of 382 subjects enrolled in the OLE study and received Blisibimod. Here we report the effects of Blisibimod on inflammation biomarkers in the PEARL-SC study and in those subjects in the OLE study who had initiated Blisibimod therapy in the PEARL study (N=277) and continued through the interim analysis of the OLE study in March 2013. In addition, we report treatment effects on renal biomarkers in 2 renal subgroups defined as (i) baseline proteinuria ≥0.5 g (determined from random urines, N=41), or (ii) baseline proteinuria ≥1g (N=25). Results Significant reductions in proteinuria reported in the PEARL-SC study reductions in proteinuria were observed with Blisibimod, compared to baseline, from Week 12 through Week 52 in the subgroup of subjects with baseline protein/creatinine ratio (Pr/Cr) ≥1 (Figure 1A) and through Week 44 in those with baseline Pr/Cr ≥0.5. These effects were durable through 52 weeks of open label treatment. When compared with response in the patients randomized to placebo in PEARL-SC, there was a tendency toward increases in mean GFR in the patients receiving Blisibimod at Week 24 in both renal subgroups with mean ΔGFR =1.4 and -3.0 mL/min [N=36,37], for Blisibimod and placebo respectively, in the subgroup with baseline Pr/Cr ≥0.5. Reductions in titers of anti-double-stranded DNA (dsDNA) antibodies and increases in complement C3 and C4 compared with baseline were observed through 52 weeks of Blisibimod therapy (Figure 1B, C and D). Blisibimod was safe and well-tolerated at all dose levels with no meaningful imbalances in serious adverse events or infections between Blisibimod and placebo in the PEARL-SC study, and continued to be well-tolerated through the OLE study. Conclusions These data demonstrate that Blisibimod induces durable effects on proteinuria and renal biomarkers. Clinical studies are ongoing to evaluate the effects of Blisibimod in patients with SLE (including renal manifestations) and IgA nephropathy. References Furie RA, Scheinberg MA, Leon G, et al. Arthritis Rheum. 2012;64(12):4169. Disclosure of Interest F. Richard Consultant for: Anthera Pharmaceuticals, M. Scheinberg: None declared, M. Thomas: None declared, A. Chu: None declared, C. Hislop Employee of: Anthera Pharmaceuticals, R. Martin: None declared, M. Petri Consultant for: Anthera Pharmaceuticals DOI 10.1136/annrheumdis-2014-eular.5593

  • FRI0388 Effects of Blisibimod on Serum Immunoglobulins and Infection Risk in Patients with Systemic Lupus Erythematosus from the Placebo-Controlled PEARL-SC and Open-Label Extension Studies
    Annals of the Rheumatic Diseases, 2014
    Co-Authors: F.a. Richard, Morton Scheinberg, M. Thomas, Alvina D. Chu, C. Hislop, R.s. Martin, Michelle Petri
    Abstract:

    Background Blisibimod, a peptibody that inhibits B-cell activating factor (BAFF), was previously found [1] to be safe, efficacious and well-tolerated in patients with systemic lupus erythematosus (SLE) that participated in a Phase 2 randomized, double-blind, placebo-controlled trial (PEARL-SC, NCT01162681). Objectives To evaluate the effects of long-term exposure to Blisibimod on IgG, IgM and infection risk and white blood cell counts in patients with SLE during the PEARL-SC and the ensuing open-label extension (OLE) study (NCT01305746). Methods 547 SLE patients with anti-double-stranded DNA or anti-nuclear antibodies >1:80 and SELENA-SLEDAI score ≥6 at baseline were enrolled into the PEARL-SC study, and randomized 1:1 to receive placebo or Blisibimod administered at 1 of 3 dose levels. In the PEARL-SC study, subjects received blinded study drug for 24 to 52 weeks (with a median of 37 weeks). A total of 382 subjects enrolled in the OLE study and received Blisibimod. The efficacy, safety and tolerability of Blisibimod in the combined studies are reported here upto the time of the interim analysis of the OLE study in March 2013. Results Significant reductions in peripheral B cells, IgG and IgM occured in patients in the pooled Blisibimod group compared with placebo from Week 8 through Week 52 in the PEARL-SC study (percent changes with Blisibimod vs placebo in IgG= -14.1% vs -3.9%, and IgM= -34.6% vs -9.3%, p≤0.003, N=94 at Week 52). IgG and IgM levels continued to be lower compared with pre-treatment levels through Week 80 (changes in IgG= -10.7%, IgM= -34.6%, N=31). There was no difference between treatments in the numbers of subjects reporting infections: placebo 62.0% and Blisibimod 58.2%. Furthermore, the mean concentrations of IgG in patients who reported infections were similar between the pooled placebo group (14.6-16.2 g/L) and the pooled Blisibimod group (12.9-16.6 g/L). Finally, no effects of Blisibimod were observed on peripheral counts of white blood cells including monocytes, lymphocytes, and neutrophils compared with placebo in the PEARL-SC study or over the course of longer-term open-label dosing. Blisibimod was safe and well-tolerated at all dose levels with no meaningful imbalances in serious adverse events in the PEARL-SC study with the exception of injection site reactions (200mg QW Blisibimod=15%, matched placebo=7%). During the placebo-controlled study, critically low IgG levels ( Conclusions In patients with SLE, Blisibimod induces pharmacological effects on immunoglobulin production that are consistent with a BAFF-mediated inhibition without adversely impacting the risk of infection. Clinical studies with Blisibimod in patients with SLE and IgA nephropathy are currently enrolling. References Furie RA, Scheinberg MA, Leon G, et al. Arthritis Rheum. 2012;64(12):4169. Disclosure of Interest F. Richard Consultant for: Anthera Pharmaceuticals, M. Scheinberg: None declared, M. Thomas: None declared, A. Chu: None declared, R. Martin Shareholder of: Anthera Pharmaceuticals, Employee of: Anthera Pharmaceuticals, C. Hislop Shareholder of: Anthera Pharmaceuticals, Employee of: Anthera Pharmaceuticals, M. Petri Consultant for: Anthera Pharmaceuticals DOI 10.1136/annrheumdis-2014-eular.2261

  • A phase 2, randomised, placebo-controlled clinical trial of Blisibimod, an inhibitor of B cell activating factor, in patients with moderate-to-severe systemic lupus erythematosus, the PEARL-SC study
    Annals of the rheumatic diseases, 2014
    Co-Authors: Richard Furie, M. Thomas, Alvina D. Chu, C. Hislop, R.s. Martin, Michelle Petri, G. Leon, Morton Scheinberg
    Abstract:

    Objective To evaluate the efficacy and safety of subcutaneous Blisibimod, an inhibitor of B cell activating factor, in patients with systemic lupus erythematosus (SLE) in a dose-ranging Phase 2b clinical trial. Methods 547 patients with SLE with anti-double stranded DNA or antinuclear antibodies and Safety of Estrogens in Lupus Erythematosus National Assessment–SLE Disease Activity Index (SELENA-SLEDAI) score ≥6 at baseline were randomised to receive placebo or Blisibimod at one of 3 dose levels. The primary end point, measured at Week 24, was the SLE Responder Index-5 (SRI-5, meeting established SRI criteria but with ≥5 point improvement in SELENA-SLEDAI). Results Although SRI-5 response rates were not significantly improved in the pooled Blisibimod groups compared with placebo, they were higher in subjects randomised to the highest dose of Blisibimod (200 mg once-weekly (QW)) compared with pooled placebo, from Week 16 to Week 24, reaching statistical significance at Week 20 (p=0.02). SRI response rates compared with placebo were higher still in subjects who attained SELENA-SLEDAI improvements of ≥8, and in a subgroup of patients with severe disease (SELENA-SLEDAI ≥10 and receiving corticosteroids at baseline). In subjects with protein:creatine ratios of 1–6 at baseline, significant reductions in proteinuria were observed with Blisibimod. Significant (p No imbalances in serious adverse events or infections (4/280 and 3/266), deaths (4/280 and 3/266) and malignancies (2/280 and 2/266) were reported for Blisibimod compared with placebo. Conclusions This study successfully identified a safe, effective and convenient dose, study population and end point for evaluation of Blisibimod effect in Phase 3. Trial registration number NCT01162681.

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  • ab0412 exploratory results from the bliss and illuminate trials support the design of the chablis sc1 trial a randomized double blind placebo controlled phase 3 study to evaluate the efficacy and safety of Blisibimod administration in subjects with s
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Joan T. Merrill, C. Hislop, R.s. Martin, Vibeke Strand, M Gangal, Kenneth C. Kalunian
    Abstract:

    Background Targeted, biologic inhibitors of B-cell Activating Factor (BAFF) have been evaluated in 4 large Phase 3 clinical trials in nearly 4000 patients with Systemic Lupus Erythematosus (SLE). Data from these studies identify that greatest treatment effect is discernable using more stringent endpoints in patients who enter with higher disease activity scores, taking more corticosteroids, and/or have anti-double-stranded DNA (dsDNA) and low complement C3 or C4 1,2,3 . Objectives The CHABLIS-SC1 study (NCT01395745) has completed enrollment and will be the first trial to prospectively evaluate the impact of treatment on the above “responder populations” using the BAFF inhibitor, Blisibimod. Methods CHABLIS-SC1 enrolled subjects positive for anti-nuclear and/or anti-dsDNA antibodies with SELENA-SLEDAI≥10 despite corticosteroid therapy. Subjects were randomized to have Blisibimod or placebo added to their background medications. Efficacy will be evaluated using the SLE Responder Index-6 (SRI-6) at Week 52, defined as: ≥6 point reduction in SELENA-SLEDAI; no new BILAG A or 2 new BILAG B organ domain scores; and no worsening in Physician9s Global Assessment. Results Table 1 identifies that the baseline characteristics of the 442 subjects enrolled into the CHABLIS-SC1 study more frequently meet all descriptions of “responder populations” identified previously 2–7 . In previous studies, the SRI-6 was associated with lower placebo responder rates and greater benefit of BAFF inhibitors over placebo. Conclusions BAFF inhibitors are known to be at least modestly effective in SLE and impact B Cell-driven immunopathology such as autoantibodies. The CHABLIS-SC1 study design will determine whether enrichment for the hypothesized “responder population,” patients with more severe, immunologically active SLE, will robustly discriminate treatment impact of Blisibimod when background therapy is maintained. References van Vollenhoven RF et al. Ann Rheum Dis. 2012;71:1343. Isenberg DA, et al. Ann Rheum Dis. 2015 Sep. Merrill JT et al. Ann Rheum Dis. 2015 Aug. Dooley MA et al Lupus, 2013;22(1):63, Manzi et al Ann Rheum Dis. 2012;71(11):1833, Merrill et al 2015 (EULAR abstract); Benlysta FDA Drug Approval Package. Acknowledgement We wish to thank all of the patients, Investigators and study personnel participating in this trial. Disclosure of Interest J. Merrill Consultant for: Anthera Pharmaceuticals Inc, V. Strand Consultant for: Anthera, C. Hislop Shareholder of: Anthera, Employee of: Anthera, M. Gangal Shareholder of: Anthera, Employee of: Anthera, R. Martin Shareholder of: Anthera, Employee of: Anthera, K. Kalunian Consultant for: Anthera

  • Blisibimod for treatment of systemic lupus erythematosus with trials you become wiser
    Expert Opinion on Biological Therapy, 2016
    Co-Authors: Morton Scheinberg, C. Hislop, R.s. Martin
    Abstract:

    ABSTRACTIntroduction: Blisibimod is a potent and selective inhibitor of B cell activating factor (BAFF), a mediator of differentiation, maturation and survival of B cells. It has a unique tetravalent, ‘peptibody’ structure and resulting high potency, and is currently in clinical evaluation for the treatment of SLE. The importance of BAFF in the pathogenesis of systemic lupus erythematosus (SLE) is under intense investigation. The anti BAFF monoclonal antibody belimumab was approved by the FDA for the treatment of SLE.Areas covered: The general properties of Blisibimod are reviewed including pharmacokinetic and pharmacodynamic properties in patients with SLE, efficacy and safety in the phase 2 PEARL-SC and open-label extension trials, and the focus in the ongoing phase 3 trial (CHABLIS-SC1) on the hypothesized ‘responder’ population. In addition, the rationale for evaluating Blisibimod in patients with IgA nephropathy, a common nephritic disease for which there is no approved therapy, is presented.Expert O...

  • THU0387 Effects of Blisibimod, An Inhibitor of B Cell Activating Factor, On Patient Reported Outcomes and Disease Activity in Patients with Systemic Lupus Erythematosus
    Annals of the Rheumatic Diseases, 2015
    Co-Authors: Michelle Petri, Morton Scheinberg, C. Hislop, R.s. Martin, Richard Furie
    Abstract:

    Background Blisibimod (A-623, AMG 623), a potent and selective inhibitor of B-cell activating factor (BAFF), was evaluated in the phase 2b clinical trial PEARL-SC (NCT01162681) in patients with systemic lupus erythematosus (SLE). Effects of Blisibimod on disease activity and safety were reported previously [1]. Objectives To conduct secondary endpoint analyses of the effects of subcutaneously-administered Blisibimod on patient-reported outcomes from the PEARL-SC trial. Methods 547 SLE patients who met the ACR classification criteria, had anti-double-stranded DNA or anti-nuclear antibodies, and SELENA-SLEDAI score ≥6 at baseline, were randomized in the PEARL-SC study 1:1 to receive placebo or Blisibimod administered at 1 of 3 dose levels, 100 mg weekly (QW), 200 mg QW, or 200 mg every 4 weeks for up to 52 weeks (with a median of 37 weeks) or until the last subject completed 6 months of study drug therapy. Patient self-reported outcomes were evaluated using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and disease activity was evaluated utilizing both SELENA-SLEDAI and BILAG. Results Significant improvements in measures of disease activity in subjects with severe disease (defined as baseline SELENA-SLEDAI score≥10 and receiving steroids), especially at the highest Blisibimod dose of 200mg QW, were reported previously [1]. Approximately 76% of subjects had SELENA-SLEDAI musculoskeletal involvement at enrollment, and 89% of subjects had mucocutaneous involvement. At Week 24, approximately 12% and 39% of subjects randomized to the 200mg QW Blisibimod arm had musculoskeletal or mucocutaneous organ involvement, compared with approximately 15% and 42% respectively in the placebo arm (p Conclusions Fatigue remains a debilitating manifestation of lupus. In this trial, Blisibimod showed a tendency toward improved mucocutaneous and musculoskeletal disease activity as well as patient self-reported fatigue. These data support further evaluation of Blisibimod in patients with SLE. References Furie RA, Leon G, Thomas M, Petri MA, et al. A phase 2, randomised, placebo-controlled clinical trial of Blisibimod, an inhibitor of B cell activating factor, in patients with moderate-to-severe systemic lupus erythematosus, the PEARL-SC study. Ann Rheum Dis. 2014. Goligher EC, Pouchot J, Brant R, Kherani RB et al. Minimal clinically important difference for 7 measures of fatigue in patients with systemic lupus erythematosus. J Rheumatol. 2008;35(4):635-42. Acknowledgements We wish to thank all of the patients, Investigators and clinical teams involved in the PEARl-SC trial. Disclosure of Interest M. Petri Consultant for: Anthera Pharmaceuticals, R. Martin Shareholder of: Anthera Pharmaceuticals, Employee of: Anthera Pharmaceuticals, C. Hislop Shareholder of: Anthera Pharmaceuticals, Employee of: Anthera Pharmaceuticals, M. Scheinberg: None declared, R. Furie Consultant for: Anthera Pharmaceuticals

  • FRI0389 Effects of Chronic Treatment with Subcutaneous Blisibimod on Renal and Inflammation Biomarkers in Subjects with Systemic Lupus Erythematosus in Phase 2 PEARL-SC and Open-Label Extension Studies
    Annals of the Rheumatic Diseases, 2014
    Co-Authors: F.a. Richard, Morton Scheinberg, M. Thomas, Alvina D. Chu, C. Hislop, R.s. Martin, Michelle Petri
    Abstract:

    Background Blisibimod is a peptibody that inhibits B-cell activating factor (BAFF). Significant improvements in secondary evaluations of SLE disease activity including proteinuria were reported previously[1] from the Phase 2 randomized, double-blind, placebo-controlled trial with subcutaneous Blisibimod in patients with SLE, PEARL-SC (Phase 2b, NCT01162681). Objectives To evaluate whether the effects on renal biomarkers, observed in patients who received Blisibimod in the PEARL-SC study were durable through continued dosing in the open-label extension trial (OLE, NCT01305746). Methods 547 subjects with serologically-active SLE and SELENA SLEDAI ≥6 were randomized to self-administer Blisibimod (200 mg monthly SC, 100 mg weekly SC, 200 mg weekly SC) or regimen-matched placebo in the PEARL-SC study. The subjects received drugs for up to 52 weeks (median 37 weeks). At baseline 76 subjects had renal involvement using SELENA-SLEDAI definitions. A total of 382 subjects enrolled in the OLE study and received Blisibimod. Here we report the effects of Blisibimod on inflammation biomarkers in the PEARL-SC study and in those subjects in the OLE study who had initiated Blisibimod therapy in the PEARL study (N=277) and continued through the interim analysis of the OLE study in March 2013. In addition, we report treatment effects on renal biomarkers in 2 renal subgroups defined as (i) baseline proteinuria ≥0.5 g (determined from random urines, N=41), or (ii) baseline proteinuria ≥1g (N=25). Results Significant reductions in proteinuria reported in the PEARL-SC study reductions in proteinuria were observed with Blisibimod, compared to baseline, from Week 12 through Week 52 in the subgroup of subjects with baseline protein/creatinine ratio (Pr/Cr) ≥1 (Figure 1A) and through Week 44 in those with baseline Pr/Cr ≥0.5. These effects were durable through 52 weeks of open label treatment. When compared with response in the patients randomized to placebo in PEARL-SC, there was a tendency toward increases in mean GFR in the patients receiving Blisibimod at Week 24 in both renal subgroups with mean ΔGFR =1.4 and -3.0 mL/min [N=36,37], for Blisibimod and placebo respectively, in the subgroup with baseline Pr/Cr ≥0.5. Reductions in titers of anti-double-stranded DNA (dsDNA) antibodies and increases in complement C3 and C4 compared with baseline were observed through 52 weeks of Blisibimod therapy (Figure 1B, C and D). Blisibimod was safe and well-tolerated at all dose levels with no meaningful imbalances in serious adverse events or infections between Blisibimod and placebo in the PEARL-SC study, and continued to be well-tolerated through the OLE study. Conclusions These data demonstrate that Blisibimod induces durable effects on proteinuria and renal biomarkers. Clinical studies are ongoing to evaluate the effects of Blisibimod in patients with SLE (including renal manifestations) and IgA nephropathy. References Furie RA, Scheinberg MA, Leon G, et al. Arthritis Rheum. 2012;64(12):4169. Disclosure of Interest F. Richard Consultant for: Anthera Pharmaceuticals, M. Scheinberg: None declared, M. Thomas: None declared, A. Chu: None declared, C. Hislop Employee of: Anthera Pharmaceuticals, R. Martin: None declared, M. Petri Consultant for: Anthera Pharmaceuticals DOI 10.1136/annrheumdis-2014-eular.5593

  • FRI0388 Effects of Blisibimod on Serum Immunoglobulins and Infection Risk in Patients with Systemic Lupus Erythematosus from the Placebo-Controlled PEARL-SC and Open-Label Extension Studies
    Annals of the Rheumatic Diseases, 2014
    Co-Authors: F.a. Richard, Morton Scheinberg, M. Thomas, Alvina D. Chu, C. Hislop, R.s. Martin, Michelle Petri
    Abstract:

    Background Blisibimod, a peptibody that inhibits B-cell activating factor (BAFF), was previously found [1] to be safe, efficacious and well-tolerated in patients with systemic lupus erythematosus (SLE) that participated in a Phase 2 randomized, double-blind, placebo-controlled trial (PEARL-SC, NCT01162681). Objectives To evaluate the effects of long-term exposure to Blisibimod on IgG, IgM and infection risk and white blood cell counts in patients with SLE during the PEARL-SC and the ensuing open-label extension (OLE) study (NCT01305746). Methods 547 SLE patients with anti-double-stranded DNA or anti-nuclear antibodies >1:80 and SELENA-SLEDAI score ≥6 at baseline were enrolled into the PEARL-SC study, and randomized 1:1 to receive placebo or Blisibimod administered at 1 of 3 dose levels. In the PEARL-SC study, subjects received blinded study drug for 24 to 52 weeks (with a median of 37 weeks). A total of 382 subjects enrolled in the OLE study and received Blisibimod. The efficacy, safety and tolerability of Blisibimod in the combined studies are reported here upto the time of the interim analysis of the OLE study in March 2013. Results Significant reductions in peripheral B cells, IgG and IgM occured in patients in the pooled Blisibimod group compared with placebo from Week 8 through Week 52 in the PEARL-SC study (percent changes with Blisibimod vs placebo in IgG= -14.1% vs -3.9%, and IgM= -34.6% vs -9.3%, p≤0.003, N=94 at Week 52). IgG and IgM levels continued to be lower compared with pre-treatment levels through Week 80 (changes in IgG= -10.7%, IgM= -34.6%, N=31). There was no difference between treatments in the numbers of subjects reporting infections: placebo 62.0% and Blisibimod 58.2%. Furthermore, the mean concentrations of IgG in patients who reported infections were similar between the pooled placebo group (14.6-16.2 g/L) and the pooled Blisibimod group (12.9-16.6 g/L). Finally, no effects of Blisibimod were observed on peripheral counts of white blood cells including monocytes, lymphocytes, and neutrophils compared with placebo in the PEARL-SC study or over the course of longer-term open-label dosing. Blisibimod was safe and well-tolerated at all dose levels with no meaningful imbalances in serious adverse events in the PEARL-SC study with the exception of injection site reactions (200mg QW Blisibimod=15%, matched placebo=7%). During the placebo-controlled study, critically low IgG levels ( Conclusions In patients with SLE, Blisibimod induces pharmacological effects on immunoglobulin production that are consistent with a BAFF-mediated inhibition without adversely impacting the risk of infection. Clinical studies with Blisibimod in patients with SLE and IgA nephropathy are currently enrolling. References Furie RA, Scheinberg MA, Leon G, et al. Arthritis Rheum. 2012;64(12):4169. Disclosure of Interest F. Richard Consultant for: Anthera Pharmaceuticals, M. Scheinberg: None declared, M. Thomas: None declared, A. Chu: None declared, R. Martin Shareholder of: Anthera Pharmaceuticals, Employee of: Anthera Pharmaceuticals, C. Hislop Shareholder of: Anthera Pharmaceuticals, Employee of: Anthera Pharmaceuticals, M. Petri Consultant for: Anthera Pharmaceuticals DOI 10.1136/annrheumdis-2014-eular.2261

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

  • Assessments of Fatigue and Disease Activity in Patients With Systemic Lupus Erythematosus Enrolled in the Phase 2 Clinical Trial With Blisibimod
    Lupus, 2016
    Co-Authors: Michelle Petri, Morton Scheinberg, R.s. Martin, Richard Furie
    Abstract:

    This report evaluates the effects of Blisibimod (A-623, AMG 623), a potent and selective inhibitor of B-cell activating factor (BAFF), on patient-reported fatigue and disease activity in the Phase 2b PEARL-SC clinical trial in patients with systemic lupus erythematosus (SLE). A total of 547 individuals who met the American College of Rheumatology (ACR) classification criteria for SLE, were positive for anti-double-stranded DNA or antinuclear antibodies, and had a Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score ≥6 at baseline, were randomized to receive placebo or Blisibimod for at least 24 weeks. Patient self-reported fatigue was evaluated using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and disease activity was evaluated using Physician's Global Assessment, SELENA-SLEDAI, and British Isles Lupus Assessment Group Score. Statistically significant improvements in FACIT-Fatigue score were observed among individuals randomized to Blisibimod, especially in the 200 mg QW group where favorable effects on disease activity with Blisibimod compared to placebo were observed as early as Week 8. The mean improvement from baseline of 6.9 points at Week 24, compared with 4.4 points with placebo, met the criteria for minimal clinically important improvement difference defined for patients with SLE. Despite concomitant improvements in FACIT-Fatigue, SLE Responder Index (SRI) and SLE biomarkers (reported previously), FACIT-Fatigue score correlated only weakly with disease activity. While poor correlation between fatigue and disease activity is not new, the observation that correlation remains poor despite concurrent population improvements in disease and fatigue brings a new facet to our understanding of SLE.

  • THU0387 Effects of Blisibimod, An Inhibitor of B Cell Activating Factor, On Patient Reported Outcomes and Disease Activity in Patients with Systemic Lupus Erythematosus
    Annals of the Rheumatic Diseases, 2015
    Co-Authors: Michelle Petri, Morton Scheinberg, C. Hislop, R.s. Martin, Richard Furie
    Abstract:

    Background Blisibimod (A-623, AMG 623), a potent and selective inhibitor of B-cell activating factor (BAFF), was evaluated in the phase 2b clinical trial PEARL-SC (NCT01162681) in patients with systemic lupus erythematosus (SLE). Effects of Blisibimod on disease activity and safety were reported previously [1]. Objectives To conduct secondary endpoint analyses of the effects of subcutaneously-administered Blisibimod on patient-reported outcomes from the PEARL-SC trial. Methods 547 SLE patients who met the ACR classification criteria, had anti-double-stranded DNA or anti-nuclear antibodies, and SELENA-SLEDAI score ≥6 at baseline, were randomized in the PEARL-SC study 1:1 to receive placebo or Blisibimod administered at 1 of 3 dose levels, 100 mg weekly (QW), 200 mg QW, or 200 mg every 4 weeks for up to 52 weeks (with a median of 37 weeks) or until the last subject completed 6 months of study drug therapy. Patient self-reported outcomes were evaluated using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and disease activity was evaluated utilizing both SELENA-SLEDAI and BILAG. Results Significant improvements in measures of disease activity in subjects with severe disease (defined as baseline SELENA-SLEDAI score≥10 and receiving steroids), especially at the highest Blisibimod dose of 200mg QW, were reported previously [1]. Approximately 76% of subjects had SELENA-SLEDAI musculoskeletal involvement at enrollment, and 89% of subjects had mucocutaneous involvement. At Week 24, approximately 12% and 39% of subjects randomized to the 200mg QW Blisibimod arm had musculoskeletal or mucocutaneous organ involvement, compared with approximately 15% and 42% respectively in the placebo arm (p Conclusions Fatigue remains a debilitating manifestation of lupus. In this trial, Blisibimod showed a tendency toward improved mucocutaneous and musculoskeletal disease activity as well as patient self-reported fatigue. These data support further evaluation of Blisibimod in patients with SLE. References Furie RA, Leon G, Thomas M, Petri MA, et al. A phase 2, randomised, placebo-controlled clinical trial of Blisibimod, an inhibitor of B cell activating factor, in patients with moderate-to-severe systemic lupus erythematosus, the PEARL-SC study. Ann Rheum Dis. 2014. Goligher EC, Pouchot J, Brant R, Kherani RB et al. Minimal clinically important difference for 7 measures of fatigue in patients with systemic lupus erythematosus. J Rheumatol. 2008;35(4):635-42. Acknowledgements We wish to thank all of the patients, Investigators and clinical teams involved in the PEARl-SC trial. Disclosure of Interest M. Petri Consultant for: Anthera Pharmaceuticals, R. Martin Shareholder of: Anthera Pharmaceuticals, Employee of: Anthera Pharmaceuticals, C. Hislop Shareholder of: Anthera Pharmaceuticals, Employee of: Anthera Pharmaceuticals, M. Scheinberg: None declared, R. Furie Consultant for: Anthera Pharmaceuticals

  • A phase 2, randomised, placebo-controlled clinical trial of Blisibimod, an inhibitor of B cell activating factor, in patients with moderate-to-severe systemic lupus erythematosus, the PEARL-SC study
    Annals of the rheumatic diseases, 2014
    Co-Authors: Richard Furie, M. Thomas, Alvina D. Chu, C. Hislop, R.s. Martin, Michelle Petri, G. Leon, Morton Scheinberg
    Abstract:

    Objective To evaluate the efficacy and safety of subcutaneous Blisibimod, an inhibitor of B cell activating factor, in patients with systemic lupus erythematosus (SLE) in a dose-ranging Phase 2b clinical trial. Methods 547 patients with SLE with anti-double stranded DNA or antinuclear antibodies and Safety of Estrogens in Lupus Erythematosus National Assessment–SLE Disease Activity Index (SELENA-SLEDAI) score ≥6 at baseline were randomised to receive placebo or Blisibimod at one of 3 dose levels. The primary end point, measured at Week 24, was the SLE Responder Index-5 (SRI-5, meeting established SRI criteria but with ≥5 point improvement in SELENA-SLEDAI). Results Although SRI-5 response rates were not significantly improved in the pooled Blisibimod groups compared with placebo, they were higher in subjects randomised to the highest dose of Blisibimod (200 mg once-weekly (QW)) compared with pooled placebo, from Week 16 to Week 24, reaching statistical significance at Week 20 (p=0.02). SRI response rates compared with placebo were higher still in subjects who attained SELENA-SLEDAI improvements of ≥8, and in a subgroup of patients with severe disease (SELENA-SLEDAI ≥10 and receiving corticosteroids at baseline). In subjects with protein:creatine ratios of 1–6 at baseline, significant reductions in proteinuria were observed with Blisibimod. Significant (p No imbalances in serious adverse events or infections (4/280 and 3/266), deaths (4/280 and 3/266) and malignancies (2/280 and 2/266) were reported for Blisibimod compared with placebo. Conclusions This study successfully identified a safe, effective and convenient dose, study population and end point for evaluation of Blisibimod effect in Phase 3. Trial registration number NCT01162681.

  • OP0116 Effects of Blisibimod, a Subcutaneous Inhibitor of B Cell Activating Factor, in Patients with SLE
    Annals of the Rheumatic Diseases, 2013
    Co-Authors: Richard Furie, Morton Scheinberg, M. Thomas, Alvina D. Chu, C. Hislop, R.s. Martin, G. Leon, Edgar Ramiterre, Michelle Petri
    Abstract:

    Background Blisibimod, a potent inhibitor of B cell activating factor (BAFF), was evaluated in a Phase 2b clinical trial in patients with SLE. Objectives To determine the effect of subcutaneous Blisibimod on SLE disease activity, including rate of response to the SLE responder index (SRI). Methods 547 serologically-active SLE patients with baseline SELENA-SLEDAI ≥6 were randomized to receive Blisibimod (100mg weekly (QW), 200mg QW, or 200mg Q4W) or placebo in matchin dosing regimens. The primary endpoint was a comparison at Week 24 of the percentage of subjects in the pooled Blisibimod and placebo groups who achieved an SRI-5 response (SRI with ≥5 point improvement in SELENA–SLEDAI). Results The primary endpoint was not met due to the lack of efficacy in the two lower doses. However, SRI-5 response was higher in subjects receiving Blisibimod 200mg QW compared with placebo (p=0.02 at Week 20). SRI improvements compared with placebo were higher still in subjects who attained SELENA–SLEDAI improvements of ≥8, and in patients with severe disease (SELENA–SLEDAI≥10 and receiving corticosteroids, n=278, figure 1 ). Despite declining patient numbers, response to Blisibimod remained higher than placebo beyond Week 24 while N>30 subjects per cohort. Numerically higher response was also observed with Blisibimod in all components of the SRI. Blisibimod was safe and well-tolerated at all dose levels with no meaningful imbalances in serious adverse events or infections compared with placebo. Image/graph Conclusions These are the first evidence that SLE disease activity may be improved with subcutaneous injections of a novel biologic therapy. Disclosure of Interest R. Furie Consultant for: Anthera Pharmaceuticals, M. Scheinberg: None Declared, G. Leon: None Declared, E. Ramiterre: None Declared, M. Thomas: None Declared, A. Chu: None Declared, C. Hislop Employee of: Anthera Pharmaceuticals, R. Martin: None Declared, M. Petri Employee of: Anthera Pharmaceuticals

  • OP0129 Effects of Blisibimod, an Inhibitor of B-Cell Activating Factor, on Markers of Renal Disease in Patients with SLE
    Annals of the Rheumatic Diseases, 2013
    Co-Authors: Richard Furie, Morton Scheinberg, M. Thomas, Alvina D. Chu, C. Hislop, R.s. Martin, G. Leon, Edgar Ramiterre, Michelle Petri
    Abstract:

    Background Elevations of BAFF are observed in patients with SLE. Here we report renal findings from a Phase 2b clinical trial in patients with SLE treated with the subcutaneous BAFF inhibitor, Blisibimod. Objectives To evaluate the effect of 24-week therapy with Blisibimod on markers of renal disease in patients with proteinuria or active inflammation. Methods 547 patients with serologically-active SLE and SELENA SLEDAI ≥6 were randomized to receive placebo or Blisibimod. 13.9% of patients had renal involvement at baseline per SELENA-SLEDAI. Proteinuria and inflammation biomarkers were evaluated throughout the study. Results In a subgroup of subjects with baseline urinary protein equivalent to 1–6g/24hr (n=49), significantly greater reductions in proteinuria were observed with Blisibimod compared to placebo from Weeks 8 through 24 (respective mean reductions of 0.73g/24hr (-35.0%) and 0.24g/24hr (-5.1%) at Week 24, p=0.045). Similarly, significantly greater reductions in proteinuria were observed in a subgroup of subjects with active inflammation ie low C3 and high anti-dsDNA (n=195, figure 1 ). Treatment with Blisibimod was also associated with significant improvements in markers of B-cell inflammation: anti–dsDNA antibodies, C3 and C4, and B-cell counts. Image/graph Conclusions These data confirm and extend the established role of BAFF in SLE by demonstrating that BAFF inhibition is associated with decreased renal inflammation. The findings support further evaluation of Blisibimod in SLE, and other autoimmune kidney diseases such as lupus nephritis, IgA nephropathy and idiopathic membranous glomerulonephritis. Disclosure of Interest R. Furie Consultant for: Anthera Pharmaceuticals, M. Scheinberg: None Declared, G. Leon: None Declared, E. Ramiterre: None Declared, M. Thomas: None Declared, A. Chu: None Declared, C. Hislop Employee of: Anthera Pharmaceuticals, R. Martin Employee of: Anthera Pharmaceuticals, M. Petri Consultant for: Anthera Pharmaceuticals