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Gabriel Robbie - One of the best experts on this subject based on the ideXlab platform.

  • Targeting the interferon pathway with Sifalimumab for the treatment of systemic lupus erythematosus
    Immunotherapy, 2017
    Co-Authors: Warren Greth, Philip Brohawn, Gabriel Robbie, Micki Hultquist, Bing Yao
    Abstract:

    Dysregulation of the type I interferon (IFN) system is associated with various immunologic diseases, such as systemic lupus erythematosus (SLE). Targeting this dysregulation presents an attractive approach for SLE therapy. Sifalimumab, a fully human immunoglobulin G1 κ monoclonal antibody that binds to and neutralizes most IFN-α subtypes, has been recently evaluated in a Phase IIb study in patients with moderate to severe SLE. Insights gained from earlier studies were used to inform design of the Phase IIb study, to provide a more comprehensive evaluation of Sifalimumab. Sifalimumab demonstrated broad efficacy across composite and organ-specific end points, suggesting that targeting of IFN-α is a promising treatment option for SLE, particularly for those patients whose disease is refractory to current standard of care.

  • population pharmacokinetic analysis of Sifalimumab from a clinical phase iib trial in systemic lupus erythematosus patients
    British Journal of Clinical Pharmacology, 2016
    Co-Authors: Bo Zheng, Warren Greth, Gabriel Robbie
    Abstract:

    Aims Sifalimumab, a human immunoglobulin (Ig) G1 monoclonal antibody against INF-alpha, is being studied as a treatment for systemic lupus erythematosus (SLE). This analysis characterized population pharmacokinetics (PK) of Sifalimumab following repeat fixed dose and evaluated the utility of fixed dosing vs. body weight normalized dosing in SLE patients. Methods PK data were collected in a phase IIb study where 298 patients received multiple intravenous doses (200–1200 mg) of Sifalimumab every 4 weeks for 52 weeks. A population pharmacokinetic model was developed using 3961 quantifiable serum concentrations and the impact of patient demographics, clinical indices and biomarkers on pharmacokinetic parameters was evaluated. The appropriateness of the final model was evaluated using visual predictive check and bootstrap. Results A two compartment model with first order elimination adequately described Sifalimumab serum PK. The estimated typical clearance (CL) and central volume of distribution (V1) were 184 ml day–1 and 2.82 l with 24% and 16% between-subject variability (BSV), respectively. Body weight, dose, 21 INF gene signature baseline and concomitant steroid use were identified as statistically significant covariates for CL and V1 and accounted for <10% of PK variability in the final model. Typical values and BSV of PK parameters from the current analysis with fixed dosing were similar to previous population PK results with body weight normalized dosing. Conclusions The transition from body weight normalized dosing to fixed dosing did not impact Sifalimumab PK. These findings support the use of fixed dosing for Sifalimumab in future clinical studies evaluating it as a potential treatment for SLE.

  • Population pharmacokinetic analysis of Sifalimumab from a clinical phase IIb trial in systemic lupus erythematosus patients
    British journal of clinical pharmacology, 2016
    Co-Authors: Bo Zheng, Warren Greth, Gabriel Robbie
    Abstract:

    Aims Sifalimumab, a human immunoglobulin (Ig) G1 monoclonal antibody against INF-alpha, is being studied as a treatment for systemic lupus erythematosus (SLE). This analysis characterized population pharmacokinetics (PK) of Sifalimumab following repeat fixed dose and evaluated the utility of fixed dosing vs. body weight normalized dosing in SLE patients. Methods PK data were collected in a phase IIb study where 298 patients received multiple intravenous doses (200–1200 mg) of Sifalimumab every 4 weeks for 52 weeks. A population pharmacokinetic model was developed using 3961 quantifiable serum concentrations and the impact of patient demographics, clinical indices and biomarkers on pharmacokinetic parameters was evaluated. The appropriateness of the final model was evaluated using visual predictive check and bootstrap. Results A two compartment model with first order elimination adequately described Sifalimumab serum PK. The estimated typical clearance (CL) and central volume of distribution (V1) were 184 ml day–1 and 2.82 l with 24% and 16% between-subject variability (BSV), respectively. Body weight, dose, 21 INF gene signature baseline and concomitant steroid use were identified as statistically significant covariates for CL and V1 and accounted for

  • ab0167 pharmacokinetics of Sifalimumab and target modulation of a type i interferon gene signature in patients with moderate to severe systemic lupus erythematosus
    Annals of the Rheumatic Diseases, 2015
    Co-Authors: Chris Morehouse, Brandon W Higgs, Philip Brohawn, B Zheng, Lorin Roskos, Gabriel Robbie
    Abstract:

    Background Sifalimumab is a fully human, IgG 1 κ monoclonal antibody in Phase IIb clinical development for systemic lupus erythematosus (SLE). Sifalimumab binds to and neutralizes the majority of IFN-α subtypes. Objectives We assessed the pharmacokinetic and pharmacodynamic effects of Sifalimumab through analysis of the blood of adult patients with moderate to severe SLE enrolled in a Phase IIb study. Methods Adult patients who satisfied ACR classification criteria for SLE were enrolled in a Phase IIb randomized controlled trial 1 and received Sifalimumab 200, 600, or 1,200 mg intravenously every 4 weeks, or placebo (following starting doses at Days 1, 15, and 29). Blood specimens were collected for PK and PD assessments at several time points from pre-dosage to 516 days after initial administration. Sifalimumab drug concentrations were measured via a validated electrochemiluminescence assay, and PK parameters were determined by noncompartmental analysis. Transcript profiling was conducted through real-time quantitative reverse transcription–polymerase chain reaction (qRT–PCR) on a type I IFN-inducible gene signature (IFNGS). Results Sifalimumab serum concentrations exhibited linear and dose-proportional PK over the 200 to 1,200 mg every 4 weeks dosage range. Mean maximum concentration (C max ) and trough concentrations (C trough ), respectively, ranged from 117 to 562 ug/mL and 19.9 to 150 ug/mL, respectively, at steady state. Mean clearance and half-life ranged from 0.11 to 0.14 L/day and 24 to 26 days. A total of 349 of 431 patients (81%) were positive for the IFNGS in whole blood at baseline. Expression of IFNGS in whole blood decreased following Sifalimumab administration for all dosages in patients positive for the IFNGS at baseline. Neutralization scores were calculated for each available time point (Days 15 to 365), based on patients9 Day-1 baseline expression IFNGS values. Percentage neutralization scores for each dosage arm were summarized (mean ± SE) for all available time points. In the 200-mg every 4 week dosage arm, a moderate mean signature neutralization (6.1–21.8%) was observed at Day 15 and maintained through Day 365. Maximum mean neutralization (21.8%) was observed at Day 15. In the 600-mg every 4 week dosage arm, moderate mean signature neutralization (8.3–27%) was observed at Day 15 and maintained through Day 365. Maximum mean neutralization (27%) was observed at Day 15. Finally, in the 1,200 mg every 4 week dosage arm, slightly more substantial mean signature neutralization (17.7–25.3%) was observed at Day 15 and maintained through Day 365. Maximum mean neutralization (25.3%) was observed at Day 15. IFNGS induction was noted for the placebo at each time point assessed. For all patients who received Sifalimumab, maximum mean signature neutralization was observed at the first time point assessed (Day 15), while near-equivalent to sub-maximal neutralization magnitudes were noted at subsequent time points. Conclusions Sifalimumab PK was linear and dose-proportional. Sifalimumab demonstrated expected mechanism of action in SLE. Target engagement of Sifalimumab was confirmed with inhibition of the IFNGS. As expected, inhibition of IFN signature was less than complete over the dosage range tested. References Khamashta M, et al. Arthritis Rheumatol. 2014;66:3530–31 (Abs L4). Acknowledgements Funded by MedImmune. Disclosure of Interest C. Morehouse Shareholder of: AstraZeneca, Employee of: MedImmune, P. Brohawn Shareholder of: AstraZeneca, Employee of: MedImmune, B. Higgs Shareholder of: AstraZeneca, Employee of: MedImmune, B. Zheng Employee of: MedImmune, Y. Yao Shareholder of: AstraZeneca, Employee of: MedImmune, L. Roskos Shareholder of: AstraZeneca, Employee of: MedImmune, G. Robbie Shareholder of: AstraZeneca, Employee of: MedImmune

  • population pharmacokinetics of Sifalimumab an investigational anti interferon α monoclonal antibody in systemic lupus erythematosus
    Clinical Pharmacokinectics, 2013
    Co-Authors: Rajesh Narwal, Lorin K. Roskos, Gabriel Robbie
    Abstract:

    Background and Objectives Sifalimumab is a fully human immunoglobulin G1κ monoclonal antibody that binds to and neutralizes a majority of the subtypes of human interferon-α. Sifalimumab is being evaluated as a treatment for systemic lupus erythematosus (SLE). The primary objectives of this analysis were (a) to develop a population pharmacokinetic model for Sifalimumab in SLE; (b) to identify and quantitate the impact of patient/disease characteristics on pharmacokinetic variability; and (c) to evaluate fixed versus body weight (WT)-based dosing regimens.

Warren Greth - One of the best experts on this subject based on the ideXlab platform.

  • Targeting the interferon pathway with Sifalimumab for the treatment of systemic lupus erythematosus
    Immunotherapy, 2017
    Co-Authors: Warren Greth, Philip Brohawn, Gabriel Robbie, Micki Hultquist, Bing Yao
    Abstract:

    Dysregulation of the type I interferon (IFN) system is associated with various immunologic diseases, such as systemic lupus erythematosus (SLE). Targeting this dysregulation presents an attractive approach for SLE therapy. Sifalimumab, a fully human immunoglobulin G1 κ monoclonal antibody that binds to and neutralizes most IFN-α subtypes, has been recently evaluated in a Phase IIb study in patients with moderate to severe SLE. Insights gained from earlier studies were used to inform design of the Phase IIb study, to provide a more comprehensive evaluation of Sifalimumab. Sifalimumab demonstrated broad efficacy across composite and organ-specific end points, suggesting that targeting of IFN-α is a promising treatment option for SLE, particularly for those patients whose disease is refractory to current standard of care.

  • population pharmacokinetic analysis of Sifalimumab from a clinical phase iib trial in systemic lupus erythematosus patients
    British Journal of Clinical Pharmacology, 2016
    Co-Authors: Bo Zheng, Warren Greth, Gabriel Robbie
    Abstract:

    Aims Sifalimumab, a human immunoglobulin (Ig) G1 monoclonal antibody against INF-alpha, is being studied as a treatment for systemic lupus erythematosus (SLE). This analysis characterized population pharmacokinetics (PK) of Sifalimumab following repeat fixed dose and evaluated the utility of fixed dosing vs. body weight normalized dosing in SLE patients. Methods PK data were collected in a phase IIb study where 298 patients received multiple intravenous doses (200–1200 mg) of Sifalimumab every 4 weeks for 52 weeks. A population pharmacokinetic model was developed using 3961 quantifiable serum concentrations and the impact of patient demographics, clinical indices and biomarkers on pharmacokinetic parameters was evaluated. The appropriateness of the final model was evaluated using visual predictive check and bootstrap. Results A two compartment model with first order elimination adequately described Sifalimumab serum PK. The estimated typical clearance (CL) and central volume of distribution (V1) were 184 ml day–1 and 2.82 l with 24% and 16% between-subject variability (BSV), respectively. Body weight, dose, 21 INF gene signature baseline and concomitant steroid use were identified as statistically significant covariates for CL and V1 and accounted for <10% of PK variability in the final model. Typical values and BSV of PK parameters from the current analysis with fixed dosing were similar to previous population PK results with body weight normalized dosing. Conclusions The transition from body weight normalized dosing to fixed dosing did not impact Sifalimumab PK. These findings support the use of fixed dosing for Sifalimumab in future clinical studies evaluating it as a potential treatment for SLE.

  • Sifalimumab an anti interferon α monoclonal antibody in moderate to severe systemic lupus erythematosus a randomised double blind placebo controlled study
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Munther Khamashta, Jorn Drappa, Richard Furie, L. Wang, G. Illei, Joan T Merrill, Kenneth C Kalunian, Victoria P Werth, Warren Greth
    Abstract:

    Objectives The efficacy and safety of Sifalimumab were assessed in a phase IIb, randomised, double-blind, placebo-controlled study ([NCT01283139][1]) of adults with moderate to severe active systemic lupus erythematosus (SLE). Methods 431 patients were randomised and received monthly intravenous Sifalimumab (200 mg, 600 mg or 1200 mg) or placebo in addition to standard-of-care medications. Patients were stratified by disease activity, interferon gene-signature test (high vs low based on the expression of four genes) and geographical region. The primary efficacy end point was the percentage of patients achieving an SLE responder index response at week 52. Results Compared with placebo, a greater percentage of patients who received Sifalimumab (all dosages) met the primary end point (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg 59.8%). Other improvements were seen in Cutaneous Lupus Erythematosus Disease Area and Severity Index score (200 mg and 1200 mg monthly), Physician's Global Assessment (600 mg and 1200 mg monthly), British Isles Lupus Assessment Group-based Composite Lupus Assessment (1200 mg monthly), 4-point reductions in the SLE Disease Activity Index−2000 score and reductions in counts of swollen joints and tender joints. Serious adverse events occurred in 17.6% of patients on placebo and 18.3% of patients on Sifalimumab. Herpes zoster infections were more frequent with Sifalimumab treatment. Conclusions Sifalimumab is a promising treatment for adults with SLE. Improvement was consistent across various clinical end points, including global and organ-specific measures of disease activity. Trial registration number NCT01283139; Results. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01283139&atom=%2Fannrheumdis%2F75%2F11%2F1909.atom

  • Population pharmacokinetic analysis of Sifalimumab from a clinical phase IIb trial in systemic lupus erythematosus patients
    British journal of clinical pharmacology, 2016
    Co-Authors: Bo Zheng, Warren Greth, Gabriel Robbie
    Abstract:

    Aims Sifalimumab, a human immunoglobulin (Ig) G1 monoclonal antibody against INF-alpha, is being studied as a treatment for systemic lupus erythematosus (SLE). This analysis characterized population pharmacokinetics (PK) of Sifalimumab following repeat fixed dose and evaluated the utility of fixed dosing vs. body weight normalized dosing in SLE patients. Methods PK data were collected in a phase IIb study where 298 patients received multiple intravenous doses (200–1200 mg) of Sifalimumab every 4 weeks for 52 weeks. A population pharmacokinetic model was developed using 3961 quantifiable serum concentrations and the impact of patient demographics, clinical indices and biomarkers on pharmacokinetic parameters was evaluated. The appropriateness of the final model was evaluated using visual predictive check and bootstrap. Results A two compartment model with first order elimination adequately described Sifalimumab serum PK. The estimated typical clearance (CL) and central volume of distribution (V1) were 184 ml day–1 and 2.82 l with 24% and 16% between-subject variability (BSV), respectively. Body weight, dose, 21 INF gene signature baseline and concomitant steroid use were identified as statistically significant covariates for CL and V1 and accounted for

  • AB0189 Geographic Differences in Demographics, Clinical Characteristics, and Standard of Care in Multinational Studies of Patients with Moderate to Severe Sle
    Annals of the Rheumatic Diseases, 2015
    Co-Authors: Richard Furie, Jorn Drappa, Munther Khamashta, L. Wang, Warren Greth, G. Illei
    Abstract:

    Background Most randomized controlled clinical trials (RCTs) in systemic lupus erythematosus (SLE) include stratification factors to assure a balanced allocation of subgroups that might respond differently to therapeutic interventions. Strata could include baseline disease activity, baseline corticosteroid dosage, or race. Despite such stratification, geographic differences appear to impact responses in some studies. Sifalimumab and anifrolumab are fully human, IgG1 κ monoclonal antibodies in Phase IIb clinical development for SLE. Sifalimumab binds to and neutralizes the majority of IFN-α subtypes (Phase II study completed 1 ). Anifrolumab binds to and neutralizes the type I IFN receptor and thus prevents signaling by any of the type I IFNs (Phase II study ongoing). Objectives To assess geographic differences as potential confounders of efficacy analysis, we compared demographic data, baseline clinical characteristics, and standard of care (SOC) across geographic regions of 2 worldwide Sifalimumab and anifrolumab Phase IIb SLE RCTs. Methods This post-hoc analysis compared combined baseline data from the 2 RCTs between pre-specified geographic regions with an expected high placebo plus SOC response (Region 1 [R1]: Central America, South America, Eastern Europe, Asia) and low placebo plus SOC response (Region 2 [R2]: North America, Western Europe, South Africa). Eligibility criteria, similar for the 2 studies, resulted in enrollment of patients with moderate to severe SLE. Patients with active lupus nephritis or severe neuropsychiatric SLE were excluded. Results Of the 736 randomized patients, 507 (68.9%) were from R1, and 229 (31.1%) were from R2. There were no clinically meaningful differences between regions in mean scores of global measures of disease activity (SLEDAI-2K: 11.3 vs 10.8; BILAG-2004 composite: 19.3 vs 19.2; physician global assessment: 1.79 vs 1.83). However, differences were seen in mean values of several demographic characteristics: patients from R1 were younger (38.0 vs 43.0 years), had a lower BMI (25.2 vs 28.1 kg.m 2 ), a shorter duration of SLE (81.8 vs 131.2 months), and a lower SLICC/ACR damage index score (0.5 vs 1.1). In addition, higher percentages of R1 patients had elevated double-stranded DNA antibodies (85.0% vs 67.3%) and hypocomplementemia (C3: 44.8% vs 33.6%; C4: 29.0% vs 18.3%). Antimalarial use during the study was similar, but more R1 patients were treated with azathioprine (28.2%.vs 12.2%) and corticosteroids (94.1% vs 65.1%) and at higher corticosteroid dosages (≥10 mg/day: 66.9% vs 36.7%). In contrast, fewer patients received mycophenolate in R1 (5.1% vs 21.0%). Conclusions SLE patients enrolled in RCTs from different geographic regions had notable differences in some demographic and baseline clinical characteristics as well as prescribed SOC medications. These differences may impact the analysis of the treatment response with SOC and/or investigational drug. Therefore, an imbalance in patients from regions with expected high or low SOC response should be considered in the feasibility and statistical considerations in SLE RCTs. References Khamashta M et al. Arthritis Rheumatol. 2014;66:S10 (Abstract L4) Acknowledgements Funded: MedImmune. Editorial Assistance: Mark Hughes, PhD, QXV Communications, UK Disclosure of Interest R. Furie Consultant for: Medimmune, M. Khamashta Grant/research support from: Bayer, Consultant for: INOVA diagnostics, Medimmune, GSK, UCB, L. Wang Employee of: MedImmune, J. Drappa Employee of: MedImmune, W. Greth Shareholder of: AstraZeneca, Employee of: MedImmune/AstraZeneca, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune

Liangwei Wang - One of the best experts on this subject based on the ideXlab platform.

G. Illei - One of the best experts on this subject based on the ideXlab platform.

  • Systemic Lupus Erythematosus (SLE) Responder Index response is associated with global benefit for patients with SLE.
    Lupus, 2018
    Co-Authors: Richard Furie, L. Wang, G. Illei, Jorn Drappa
    Abstract:

    A post-hoc analysis of pooled data from two Phase IIb trials (Sifalimumab; NCT01283139, anifrolumab; NCT01438489) assessed the clinical significance of a Systemic Lupus Erythematosus (SLE) Responder Index (SRI(4)) response (Week 52) for 736 patients with moderate to severe SLE disease activity (study entry). SRI(4) responders achieved significantly greater improvements in clinical outcome measures (including percentages of patients with a ≥ 7-point reduction in SLE Disease Activity Index (SLEDAI)–2000 (2K), British Isles Lupus Assessment Group “A” or “2B” flare rate, and oral corticosteroid reduction to ≤7.5 mg/day; change from baseline in Physician’s Global Assessment; and numbers of SLEDAI–2K organ domains with improvement), as well as in patient-reported outcomes (Patient’s Global Assessment, Functional Assessment of Chronic Illness Therapy−Fatigue; Short-Form 36 Health Survey Physical Component Summary, Mental Component Summary, Vitality domain scores) vs. nonresponders. Of patients with abnormal sero...

  • OP0044 Systemic Lupus Erythematosus (SLE) Responder Index [SRI(4)] Response Is Associated with Global Benefit in Patients with Moderate To Severe SLE
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Richard Furie, Jorn Drappa, L. Wang, G. Illei
    Abstract:

    Background The SRI(4) is a composite endpoint used in SLE clinical trials. A post-hoc analysis of two Phase III studies of belimumab1 showed that the achievement of an SRI(4) response at 52 weeks is associated with clinically meaningful benefits, irrespective of the treatment assignments. Confirmation of these findings in independent cohorts will enhance the wider acceptance of SRI(4) as a measure of clinically meaningful improvement. Objectives We assessed the global clinical benefit represented by the achievement of an SRI(4) response in patients with moderate to severe SLE. Methods Changes from baseline in clinical, laboratory, and patient reported outcome measures at Day 365 were compared between SRI(4) responders (n=396) and non-responders (n=340) in the combined dataset of two Phase II studies that evaluated Sifalimumab and anifrolumab in moderate to severe SLE. Results (detailed in Table): Baseline demographics were similar between the two studies. At Day 365, a greater percentage of responders than non-responders had a ≥7-point reduction in SLE Disease Activity Index 2000 (SLEDAI-2K) and achieved a reduction of oral corticosteroid dose to ≤7.5 mg/day. Responders also had a greater percentage change from baseline in clinical SLEDAI scores, greater improvements in the Physician9s Global Assessment (PGA) score and the number of organ domains with improvement on SLEDAI-2K. The rates of British Isles Lupus Assessment Group (BILAG) “A” or “2B” flares were lower in SRI(4) responders compared with non-responders. Among patients with ≥8 swollen and ≥8 tender joints at baseline, a larger percentage of responders had a ≥50% improvement in swollen and tender joint counts. In patients with moderate to severe skin disease at baseline, defined as a Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity score ≥10, a greater percentage of responders had ≥50% improvement in CLASI. In patients with abnormal baseline serological parameters, responders had greater improvements in anti-double stranded DNA concentrations; however, the differences in complement C3 and C4 concentrations were not significant. Responders also had greater improvements in patient-reported outcomes: percentage change from baseline in Patient Global Assessment, and absolute change in Short Form 36 Health Survey (SF-36) [Physical Component Summary (PCS) score; Mental Component Summary (MCS) score; Vitality domain], and Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue scores. Conclusions SRI(4) response in patients with moderate to severe SLE was associated with broad improvements in clinical, laboratory, and patient reported outcome measures. These results confirm previous findings, indicating that SRI(4) response is associated with a global clinically important benefit. References Furie R, et al. Lupus Sci Med 2014;1:e000031 Acknowledgement Funded by MedImmune. Editorial assistance: K Alexander, QXV Comms, an Ashfield business, UK Disclosure of Interest R. Furie Consultant for: MedImmune, L. Wang Employee of: MedImmune, J. Drappa Shareholder of: AstraZeneca, Employee of: MedImmune, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune

  • Sifalimumab an anti interferon α monoclonal antibody in moderate to severe systemic lupus erythematosus a randomised double blind placebo controlled study
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Munther Khamashta, Jorn Drappa, Richard Furie, L. Wang, G. Illei, Joan T Merrill, Kenneth C Kalunian, Victoria P Werth, Warren Greth
    Abstract:

    Objectives The efficacy and safety of Sifalimumab were assessed in a phase IIb, randomised, double-blind, placebo-controlled study ([NCT01283139][1]) of adults with moderate to severe active systemic lupus erythematosus (SLE). Methods 431 patients were randomised and received monthly intravenous Sifalimumab (200 mg, 600 mg or 1200 mg) or placebo in addition to standard-of-care medications. Patients were stratified by disease activity, interferon gene-signature test (high vs low based on the expression of four genes) and geographical region. The primary efficacy end point was the percentage of patients achieving an SLE responder index response at week 52. Results Compared with placebo, a greater percentage of patients who received Sifalimumab (all dosages) met the primary end point (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg 59.8%). Other improvements were seen in Cutaneous Lupus Erythematosus Disease Area and Severity Index score (200 mg and 1200 mg monthly), Physician's Global Assessment (600 mg and 1200 mg monthly), British Isles Lupus Assessment Group-based Composite Lupus Assessment (1200 mg monthly), 4-point reductions in the SLE Disease Activity Index−2000 score and reductions in counts of swollen joints and tender joints. Serious adverse events occurred in 17.6% of patients on placebo and 18.3% of patients on Sifalimumab. Herpes zoster infections were more frequent with Sifalimumab treatment. Conclusions Sifalimumab is a promising treatment for adults with SLE. Improvement was consistent across various clinical end points, including global and organ-specific measures of disease activity. Trial registration number NCT01283139; Results. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01283139&atom=%2Fannrheumdis%2F75%2F11%2F1909.atom

  • AB0189 Geographic Differences in Demographics, Clinical Characteristics, and Standard of Care in Multinational Studies of Patients with Moderate to Severe Sle
    Annals of the Rheumatic Diseases, 2015
    Co-Authors: Richard Furie, Jorn Drappa, Munther Khamashta, L. Wang, Warren Greth, G. Illei
    Abstract:

    Background Most randomized controlled clinical trials (RCTs) in systemic lupus erythematosus (SLE) include stratification factors to assure a balanced allocation of subgroups that might respond differently to therapeutic interventions. Strata could include baseline disease activity, baseline corticosteroid dosage, or race. Despite such stratification, geographic differences appear to impact responses in some studies. Sifalimumab and anifrolumab are fully human, IgG1 κ monoclonal antibodies in Phase IIb clinical development for SLE. Sifalimumab binds to and neutralizes the majority of IFN-α subtypes (Phase II study completed 1 ). Anifrolumab binds to and neutralizes the type I IFN receptor and thus prevents signaling by any of the type I IFNs (Phase II study ongoing). Objectives To assess geographic differences as potential confounders of efficacy analysis, we compared demographic data, baseline clinical characteristics, and standard of care (SOC) across geographic regions of 2 worldwide Sifalimumab and anifrolumab Phase IIb SLE RCTs. Methods This post-hoc analysis compared combined baseline data from the 2 RCTs between pre-specified geographic regions with an expected high placebo plus SOC response (Region 1 [R1]: Central America, South America, Eastern Europe, Asia) and low placebo plus SOC response (Region 2 [R2]: North America, Western Europe, South Africa). Eligibility criteria, similar for the 2 studies, resulted in enrollment of patients with moderate to severe SLE. Patients with active lupus nephritis or severe neuropsychiatric SLE were excluded. Results Of the 736 randomized patients, 507 (68.9%) were from R1, and 229 (31.1%) were from R2. There were no clinically meaningful differences between regions in mean scores of global measures of disease activity (SLEDAI-2K: 11.3 vs 10.8; BILAG-2004 composite: 19.3 vs 19.2; physician global assessment: 1.79 vs 1.83). However, differences were seen in mean values of several demographic characteristics: patients from R1 were younger (38.0 vs 43.0 years), had a lower BMI (25.2 vs 28.1 kg.m 2 ), a shorter duration of SLE (81.8 vs 131.2 months), and a lower SLICC/ACR damage index score (0.5 vs 1.1). In addition, higher percentages of R1 patients had elevated double-stranded DNA antibodies (85.0% vs 67.3%) and hypocomplementemia (C3: 44.8% vs 33.6%; C4: 29.0% vs 18.3%). Antimalarial use during the study was similar, but more R1 patients were treated with azathioprine (28.2%.vs 12.2%) and corticosteroids (94.1% vs 65.1%) and at higher corticosteroid dosages (≥10 mg/day: 66.9% vs 36.7%). In contrast, fewer patients received mycophenolate in R1 (5.1% vs 21.0%). Conclusions SLE patients enrolled in RCTs from different geographic regions had notable differences in some demographic and baseline clinical characteristics as well as prescribed SOC medications. These differences may impact the analysis of the treatment response with SOC and/or investigational drug. Therefore, an imbalance in patients from regions with expected high or low SOC response should be considered in the feasibility and statistical considerations in SLE RCTs. References Khamashta M et al. Arthritis Rheumatol. 2014;66:S10 (Abstract L4) Acknowledgements Funded: MedImmune. Editorial Assistance: Mark Hughes, PhD, QXV Communications, UK Disclosure of Interest R. Furie Consultant for: Medimmune, M. Khamashta Grant/research support from: Bayer, Consultant for: INOVA diagnostics, Medimmune, GSK, UCB, L. Wang Employee of: MedImmune, J. Drappa Employee of: MedImmune, W. Greth Shareholder of: AstraZeneca, Employee of: MedImmune/AstraZeneca, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune

  • AB0183 The Effect of Geography on the Efficacy of Sifalimumab, an Anti-Interferon-Alpha Monoclonal Antibody, in Moderate to Severe Systemic Lupus Erythematosus
    Annals of the Rheumatic Diseases, 2015
    Co-Authors: Munther Khamashta, Jorn Drappa, L. Wang, G. Illei, Warren Greth
    Abstract:

    Background The efficacy and safety of Sifalimumab were assessed in a Phase IIb, randomized, double-blind, placebo-controlled study of adults with moderate to severe systemic lupus erythematosus (SLE). Sifalimumab is 1 of 2 compounds targeting the type I interferon pathway that is currently under assessment for evaluation in Phase III studies. Objectives To assess geographic differences as potential confounders of efficacy in a worldwide Sifalimumab Phase IIb study. Methods 431 patients were randomized and received monthly intravenous Sifalimumab (200 mg, 600 mg, or 1200 mg) or placebo. The primary efficacy endpoint was the percentage of patients achieving an SLE responder index [SRI] at Week 52. Overall results from this study were presented at the 2014 American College of Rheumatology (ACR) annual meeting. 1 Here we present results from a pre-specified randomization stratification factor based on geographic region: Region 1: high expected response to standard of care (SOC) - Central America, South America, Eastern Europe, Asia; Region 2: low expected SOC response - North America, Western Europe, South Africa. Results Of the 431 patients, 296 (68.7%) were from Region 1 and 135 (31.3%) from Region 2. Compared with placebo, more patients who received Sifalimumab met the primary endpoint (placebo, 45.4%; 200 mg, 58.3%; 600 mg, 56.5%; 1200 mg, 59.8%) with greater response rates observed in Region 1 than in Region 2. There was a larger distinction (Δ) between Sifalimumab plus SOC and placebo plus SOC responses in Region 2 compared with Region 1. (Figure). This distinction was not attributable to differences in baseline SLE Disease Activity Index 2000 (SLEDAI-2K), physician global assessment, or British Isles Lupus Assessment Group (BILAG)-2004 scores which were similar for patients in both regions. Differences in several demographic and clinical characteristics were seen between patients in Region 1 vs Region 2: mean weight (64.7 kg vs 72.8 kg), mean age (38.0 years vs 42.5 years), median time from diagnosis to randomization (80.1 months vs 138.4 months), mean Systemic Lupus International Collaborating Clinics (SLICC)/ACR Damage Index (0.5 vs 1.1), and SOC (use of antimalarials [70.9% vs 78.5%], azathioprine [30.4% vs 15.6%], methotrexate [11.8% vs 21.5%], mycophenolate [3.7% vs 22.2%], and corticosteroids [92.9% vs 68.9%], as well as average corticosteroid dosage [11.7 mg/day vs 9.3 mg/day]). Conclusions Response to treatment with Sifalimumab in adult patients with moderate to severe SLE showed a greater distinction in the SRI endpoint in patients who received Sifalimumab vs placebo in Region 2 compared with Region 1. This may, in part, be reflective of regional populations with different baseline characteristics or differences in SOC. References Khamashta M et al. Arthritis Rheumatol. 2014;66:S10 (Abstract L4) Acknowledgements Funded: MedImmune. Editorial Assistance: Mark Hughes, PhD, QXV Communications, UK Disclosure of Interest M. Khamashta Grant/research support from: Bayer, Consultant for: INOVA diagnostics, Medimmune, GSK, UCB, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune, J. Drappa Employee of: MedImmune, L. Wang Employee of: MedImmune, W. Greth Shareholder of: AstraZeneca, Employee of: MedImmune/AstraZeneca

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

  • I9 Clinical trials with IFN blockers
    Invited talks, 2020
    Co-Authors: Richard Furie
    Abstract:

    Background Type I interferon (IFN) pathway activation has long been demonstrated in patients with systemic lupus erythematosus (SLE). The target of drug development in SLE, approaches to inhibit type I IFN have been quite eclectic. The initial strategy, which utilized a monoclonal antibody to interferon-alpha, was not successful as the phase 2 study in SLE with rontalizumab failed to achieve the primary end point of the study. Shortly thereafter, the results of a phase 2 SLE study with Sifalimumab, a second monoclonal antibody to interferon-alpha, were released. While benefit was achieved, the pharmacodynamic and clinical effects were not as robust as those attained in a phase 2 SLE study with anifrolumab, an antibody to the type I IFN receptor that inhibits all type I IFNs. The phase 3 anifrolumab program was comprised of two studies, known as TULIP 1 and TULIP 2. TULIP 1 evaluated two doses (150 and 300 mg) administered intravenously every 4 weeks through week 48 with the primary end point, SLE Responder Index response rate, at week 52. Although this study failed to achieve the primary end point, it was recognized after unblinding that 8% of study subjects were misclassified as non-responders because of NSAID use. While post-hoc revisions to the restricted medication rules did not change the primary outcome of TULIP 1, these modifications did result in several successful secondary outcomes, including the British Isles Lupus Assessment Group–based Composite Lupus Assessment response rates (BICLA: placebo [29.6%] vs anifrolumab 300 mg [46.1%]). An additional outcome of the post-hoc evaluation of TULIP 1 was the modification to the TULIP 2 primary end point. TULIP 2’s initial design was identical to TULIP 1 with the exception that just one dose of anifrolumab (300 mg) was compared to placebo. However, before unblinding, the end point was switched from SRI at week 52 to BICLA response rate at week 52. TULIP 2 not only achieved the primary outcome (BICLA: placebo [31.5%] vs anifrolumab 300 mg [47.8%]), but multiple secondary end points were also attained, chief of which were the ability to taper corticosteroids as well as improvement of cutaneous disease activity. Safety signals of note included a higher rate of herpes zoster reactivation (placebo: 1.1% vs anifrolumab: 7.2%). While not as advanced in development, there are several other programs that are targeting the IFN pathway. RSLV-132 is an RNase-Fc fusion protein that enzymatically degrades circulating RNA, thus inhibiting its ability to bind to toll-like receptors (TLR) and activate plasmacytoid dendritic cells. Direct inhibition of TLRs is yet another strategy being employed to target the innate immune system. Immunization with an IFN-alpha-KLH conjugate allows the host to produce his or her own antibodies to IFN-alpha. Plasmacytoid dendritic cells (pDC) are the major producers of type I IFN, and thus they represent a principal target for SLE drug development. BIIB059 is a monoclonal antibody that binds BDCA2, a protein uniquely expressed on pDCs. When BDCA2 is ligated with BIIB059, the protein is internalized, and production of cytokines, chemokines, and interferons is inhibited. In late 2019, it was announced that two phase 2 studies that evaluated cutaneous lupus as well as SLE achieved their respective end points. Baricitinib, an inhibitor of JAK1 and JAK2, achieved success in a phase 2 SLE study and is currently in phase 3. Let’s not forget hydroxychloroquine, which suppresses TLR activation through its inhibition of endosomal acidification. The future is bright for patients with SLE as research is providing greater insights into SLE pathogenesis that are being translated to drug discovery.

  • Systemic Lupus Erythematosus (SLE) Responder Index response is associated with global benefit for patients with SLE.
    Lupus, 2018
    Co-Authors: Richard Furie, L. Wang, G. Illei, Jorn Drappa
    Abstract:

    A post-hoc analysis of pooled data from two Phase IIb trials (Sifalimumab; NCT01283139, anifrolumab; NCT01438489) assessed the clinical significance of a Systemic Lupus Erythematosus (SLE) Responder Index (SRI(4)) response (Week 52) for 736 patients with moderate to severe SLE disease activity (study entry). SRI(4) responders achieved significantly greater improvements in clinical outcome measures (including percentages of patients with a ≥ 7-point reduction in SLE Disease Activity Index (SLEDAI)–2000 (2K), British Isles Lupus Assessment Group “A” or “2B” flare rate, and oral corticosteroid reduction to ≤7.5 mg/day; change from baseline in Physician’s Global Assessment; and numbers of SLEDAI–2K organ domains with improvement), as well as in patient-reported outcomes (Patient’s Global Assessment, Functional Assessment of Chronic Illness Therapy−Fatigue; Short-Form 36 Health Survey Physical Component Summary, Mental Component Summary, Vitality domain scores) vs. nonresponders. Of patients with abnormal sero...

  • OP0044 Systemic Lupus Erythematosus (SLE) Responder Index [SRI(4)] Response Is Associated with Global Benefit in Patients with Moderate To Severe SLE
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Richard Furie, Jorn Drappa, L. Wang, G. Illei
    Abstract:

    Background The SRI(4) is a composite endpoint used in SLE clinical trials. A post-hoc analysis of two Phase III studies of belimumab1 showed that the achievement of an SRI(4) response at 52 weeks is associated with clinically meaningful benefits, irrespective of the treatment assignments. Confirmation of these findings in independent cohorts will enhance the wider acceptance of SRI(4) as a measure of clinically meaningful improvement. Objectives We assessed the global clinical benefit represented by the achievement of an SRI(4) response in patients with moderate to severe SLE. Methods Changes from baseline in clinical, laboratory, and patient reported outcome measures at Day 365 were compared between SRI(4) responders (n=396) and non-responders (n=340) in the combined dataset of two Phase II studies that evaluated Sifalimumab and anifrolumab in moderate to severe SLE. Results (detailed in Table): Baseline demographics were similar between the two studies. At Day 365, a greater percentage of responders than non-responders had a ≥7-point reduction in SLE Disease Activity Index 2000 (SLEDAI-2K) and achieved a reduction of oral corticosteroid dose to ≤7.5 mg/day. Responders also had a greater percentage change from baseline in clinical SLEDAI scores, greater improvements in the Physician9s Global Assessment (PGA) score and the number of organ domains with improvement on SLEDAI-2K. The rates of British Isles Lupus Assessment Group (BILAG) “A” or “2B” flares were lower in SRI(4) responders compared with non-responders. Among patients with ≥8 swollen and ≥8 tender joints at baseline, a larger percentage of responders had a ≥50% improvement in swollen and tender joint counts. In patients with moderate to severe skin disease at baseline, defined as a Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity score ≥10, a greater percentage of responders had ≥50% improvement in CLASI. In patients with abnormal baseline serological parameters, responders had greater improvements in anti-double stranded DNA concentrations; however, the differences in complement C3 and C4 concentrations were not significant. Responders also had greater improvements in patient-reported outcomes: percentage change from baseline in Patient Global Assessment, and absolute change in Short Form 36 Health Survey (SF-36) [Physical Component Summary (PCS) score; Mental Component Summary (MCS) score; Vitality domain], and Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue scores. Conclusions SRI(4) response in patients with moderate to severe SLE was associated with broad improvements in clinical, laboratory, and patient reported outcome measures. These results confirm previous findings, indicating that SRI(4) response is associated with a global clinically important benefit. References Furie R, et al. Lupus Sci Med 2014;1:e000031 Acknowledgement Funded by MedImmune. Editorial assistance: K Alexander, QXV Comms, an Ashfield business, UK Disclosure of Interest R. Furie Consultant for: MedImmune, L. Wang Employee of: MedImmune, J. Drappa Shareholder of: AstraZeneca, Employee of: MedImmune, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune

  • Sifalimumab an anti interferon α monoclonal antibody in moderate to severe systemic lupus erythematosus a randomised double blind placebo controlled study
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Munther Khamashta, Jorn Drappa, Richard Furie, L. Wang, G. Illei, Joan T Merrill, Kenneth C Kalunian, Victoria P Werth, Warren Greth
    Abstract:

    Objectives The efficacy and safety of Sifalimumab were assessed in a phase IIb, randomised, double-blind, placebo-controlled study ([NCT01283139][1]) of adults with moderate to severe active systemic lupus erythematosus (SLE). Methods 431 patients were randomised and received monthly intravenous Sifalimumab (200 mg, 600 mg or 1200 mg) or placebo in addition to standard-of-care medications. Patients were stratified by disease activity, interferon gene-signature test (high vs low based on the expression of four genes) and geographical region. The primary efficacy end point was the percentage of patients achieving an SLE responder index response at week 52. Results Compared with placebo, a greater percentage of patients who received Sifalimumab (all dosages) met the primary end point (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg 59.8%). Other improvements were seen in Cutaneous Lupus Erythematosus Disease Area and Severity Index score (200 mg and 1200 mg monthly), Physician's Global Assessment (600 mg and 1200 mg monthly), British Isles Lupus Assessment Group-based Composite Lupus Assessment (1200 mg monthly), 4-point reductions in the SLE Disease Activity Index−2000 score and reductions in counts of swollen joints and tender joints. Serious adverse events occurred in 17.6% of patients on placebo and 18.3% of patients on Sifalimumab. Herpes zoster infections were more frequent with Sifalimumab treatment. Conclusions Sifalimumab is a promising treatment for adults with SLE. Improvement was consistent across various clinical end points, including global and organ-specific measures of disease activity. Trial registration number NCT01283139; Results. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01283139&atom=%2Fannrheumdis%2F75%2F11%2F1909.atom

  • AB0189 Geographic Differences in Demographics, Clinical Characteristics, and Standard of Care in Multinational Studies of Patients with Moderate to Severe Sle
    Annals of the Rheumatic Diseases, 2015
    Co-Authors: Richard Furie, Jorn Drappa, Munther Khamashta, L. Wang, Warren Greth, G. Illei
    Abstract:

    Background Most randomized controlled clinical trials (RCTs) in systemic lupus erythematosus (SLE) include stratification factors to assure a balanced allocation of subgroups that might respond differently to therapeutic interventions. Strata could include baseline disease activity, baseline corticosteroid dosage, or race. Despite such stratification, geographic differences appear to impact responses in some studies. Sifalimumab and anifrolumab are fully human, IgG1 κ monoclonal antibodies in Phase IIb clinical development for SLE. Sifalimumab binds to and neutralizes the majority of IFN-α subtypes (Phase II study completed 1 ). Anifrolumab binds to and neutralizes the type I IFN receptor and thus prevents signaling by any of the type I IFNs (Phase II study ongoing). Objectives To assess geographic differences as potential confounders of efficacy analysis, we compared demographic data, baseline clinical characteristics, and standard of care (SOC) across geographic regions of 2 worldwide Sifalimumab and anifrolumab Phase IIb SLE RCTs. Methods This post-hoc analysis compared combined baseline data from the 2 RCTs between pre-specified geographic regions with an expected high placebo plus SOC response (Region 1 [R1]: Central America, South America, Eastern Europe, Asia) and low placebo plus SOC response (Region 2 [R2]: North America, Western Europe, South Africa). Eligibility criteria, similar for the 2 studies, resulted in enrollment of patients with moderate to severe SLE. Patients with active lupus nephritis or severe neuropsychiatric SLE were excluded. Results Of the 736 randomized patients, 507 (68.9%) were from R1, and 229 (31.1%) were from R2. There were no clinically meaningful differences between regions in mean scores of global measures of disease activity (SLEDAI-2K: 11.3 vs 10.8; BILAG-2004 composite: 19.3 vs 19.2; physician global assessment: 1.79 vs 1.83). However, differences were seen in mean values of several demographic characteristics: patients from R1 were younger (38.0 vs 43.0 years), had a lower BMI (25.2 vs 28.1 kg.m 2 ), a shorter duration of SLE (81.8 vs 131.2 months), and a lower SLICC/ACR damage index score (0.5 vs 1.1). In addition, higher percentages of R1 patients had elevated double-stranded DNA antibodies (85.0% vs 67.3%) and hypocomplementemia (C3: 44.8% vs 33.6%; C4: 29.0% vs 18.3%). Antimalarial use during the study was similar, but more R1 patients were treated with azathioprine (28.2%.vs 12.2%) and corticosteroids (94.1% vs 65.1%) and at higher corticosteroid dosages (≥10 mg/day: 66.9% vs 36.7%). In contrast, fewer patients received mycophenolate in R1 (5.1% vs 21.0%). Conclusions SLE patients enrolled in RCTs from different geographic regions had notable differences in some demographic and baseline clinical characteristics as well as prescribed SOC medications. These differences may impact the analysis of the treatment response with SOC and/or investigational drug. Therefore, an imbalance in patients from regions with expected high or low SOC response should be considered in the feasibility and statistical considerations in SLE RCTs. References Khamashta M et al. Arthritis Rheumatol. 2014;66:S10 (Abstract L4) Acknowledgements Funded: MedImmune. Editorial Assistance: Mark Hughes, PhD, QXV Communications, UK Disclosure of Interest R. Furie Consultant for: Medimmune, M. Khamashta Grant/research support from: Bayer, Consultant for: INOVA diagnostics, Medimmune, GSK, UCB, L. Wang Employee of: MedImmune, J. Drappa Employee of: MedImmune, W. Greth Shareholder of: AstraZeneca, Employee of: MedImmune/AstraZeneca, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune