Anifrolumab

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Raj Tummala - One of the best experts on this subject based on the ideXlab platform.

  • Long‐term safety and efficacy of Anifrolumab in adults with systemic lupus erythematosus: results of a phase 2 open‐label extension study
    Arthritis & rheumatology (Hoboken N.J.), 2020
    Co-Authors: W. Winn Chatham, Philip Brohawn, Richard Furie, Erik Schwetje, Gabriel Abreu, Amit Saxena, Raj Tummala
    Abstract:

    OBJECTIVE To investigate long-term safety and tolerability of Anifrolumab, a human monoclonal antibody to the type I interferon (IFN) receptor subunit 1, in patients with moderate to severe systemic lupus erythematosus (SLE). METHODS This 3-year, multinational, open-label extension (OLE) enrolled adult patients who completed treatment (48 weeks Anifrolumab or placebo; 12-week follow-up) in the MUSE phase 2b randomized controlled trial (RCT). Patients initially received intravenous Anifrolumab 1000 mg every 4 weeks, reduced to 300 mg every 4 weeks based on the benefit/risk profile established in MUSE. Adverse events (AEs) were assessed monthly. Exploratory endpoints included SLE Disease Activity Index 2000 (SLEDAI-2K), SLICC Damage Index (SDI), pharmacodynamics, and health-related quality of life (HRQoL). RESULTS Of 246 patients who completed the RCT, 218 (88.6%) enrolled in the OLE; 139/218 (63.8%) completed 3 years of treatment. Approximately 69.7% of patients reported ≥1 AE during the first year of OLE treatment. Frequency and patterns of serious AEs and AEs of special interest over 3 years were consistent with those reported for 1 year of treatment in the RCT. Few patients (6.9%) discontinued treatment because of AEs. No new safety signals were identified. Improvement in SLEDAI-2K was sustained over 3 years. SDI and Short Form 36 Health Survey scores remained stable. Neutralization of type I IFN gene signatures was maintained in the IFN-high population, and C3, C4, and anti-dsDNA showed numeric trends toward sustained improvement. CONCLUSION Long-term Anifrolumab treatment demonstrated an acceptable safety profile with sustained improvement in disease activity, HRQoL, and serologies.

  • long term safety and efficacy of Anifrolumab in adults with systemic lupus erythematosus results of a phase 2 open label extension study
    Arthritis & Rheumatism, 2020
    Co-Authors: W. Winn Chatham, Philip Brohawn, Richard Furie, Erik Schwetje, Gabriel Abreu, Amit Saxena, Raj Tummala
    Abstract:

    OBJECTIVE To investigate long-term safety and tolerability of Anifrolumab, a human monoclonal antibody to the type I interferon (IFN) receptor subunit 1, in patients with moderate to severe systemic lupus erythematosus (SLE). METHODS This 3-year, multinational, open-label extension (OLE) enrolled adult patients who completed treatment (48 weeks Anifrolumab or placebo; 12-week follow-up) in the MUSE phase 2b randomized controlled trial (RCT). Patients initially received intravenous Anifrolumab 1000 mg every 4 weeks, reduced to 300 mg every 4 weeks based on the benefit/risk profile established in MUSE. Adverse events (AEs) were assessed monthly. Exploratory endpoints included SLE Disease Activity Index 2000 (SLEDAI-2K), SLICC Damage Index (SDI), pharmacodynamics, and health-related quality of life (HRQoL). RESULTS Of 246 patients who completed the RCT, 218 (88.6%) enrolled in the OLE; 139/218 (63.8%) completed 3 years of treatment. Approximately 69.7% of patients reported ≥1 AE during the first year of OLE treatment. Frequency and patterns of serious AEs and AEs of special interest over 3 years were consistent with those reported for 1 year of treatment in the RCT. Few patients (6.9%) discontinued treatment because of AEs. No new safety signals were identified. Improvement in SLEDAI-2K was sustained over 3 years. SDI and Short Form 36 Health Survey scores remained stable. Neutralization of type I IFN gene signatures was maintained in the IFN-high population, and C3, C4, and anti-dsDNA showed numeric trends toward sustained improvement. CONCLUSION Long-term Anifrolumab treatment demonstrated an acceptable safety profile with sustained improvement in disease activity, HRQoL, and serologies.

  • Anifrolumab, a monoclonal antibody to the type I interferon receptor subunit 1, for the treatment of systemic lupus erythematosus: an overview from clinical trials
    Modern rheumatology, 2020
    Co-Authors: Yoshiya Tanaka, Raj Tummala
    Abstract:

    Chronic activation of the type I interferon (IFN) pathway plays a critical role in systemic lupus erythematosus (SLE) pathogenesis. Anifrolumab is a human monoclonal antibody to the type I IFN rece...

  • OP0003 EARLY AND SUSTAINED RESPONSES WITH Anifrolumab TREATMENT IN PATIENTS WITH ACTIVE SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IN 2 PHASE 3 TRIALS
    Annals of the Rheumatic Diseases, 2020
    Co-Authors: Eric F. Morand, Kenneth Kalunian, Richard Furie, Ian N Bruce, Gabriel Abreu, Rubana N Kalyani, Lilia Pineda, Raj Tummala
    Abstract:

    Measuring genome size across different species can yield important insights into evolution of the genome and allow for more informed decisions when designing next-generation genomic sequencing projects. New techniques for estimating genome size using shallow genomic sequence data have emerged which have the potential to augment our knowledge of genome sizes, yet these methods have only been used in a limited number of empirical studies. In this project, we compare estimation methods using next-generation sequencing (k-mer methods and average read depth of single-copy genes) to measurements from flow cytometry, a standard method for genome size measures, using ground beetles (Carabidae) and other members of the beetle suborder Adephaga as our test system. We also present a new protocol for using read-depth of single-copy genes to estimate genome size. Additionally, we report flow cytometry measurements for five previously unmeasured carabid species, as well as 21 new draft genomes and six new draft transcriptomes across eight species of adephagan beetles. No single sequence-based method performed well on all species, and all tended to underestimate the genome sizes, although only slightly in most samples. For one species, Bembidion sp. nr. transversale, most sequence-based methods yielded estimates half the size suggested by flow cytometry.

  • O25 Efficacy of Anifrolumab in active systemic lupus erythematosus (SLE): patient subgroup analysis of BICLA response in 2 phase 3 trials
    Annals of the Rheumatic Diseases, 2020
    Co-Authors: Eric F. Morand, Richard Furie, Gabriel Abreu, Yoshiya Tanaka, Rubana N Kalyani, Lilia Pineda, Raj Tummala
    Abstract:

    Background: Treatment of patients with systemic lupus erythematosus (SLE) with the type I interferon (IFN) receptor inhibitor Anifrolumab resulted in higher British Isles Lupus Assessment Group (BILAG)–based Composite Lupus Assessment (BICLA) response rates vs placebo at Week 52 in the phase 3 randomized trials, TULIP-2 (primary endpoint; 16.3% difference)1 and TULIP-1 (secondary endpoint; 16.4% difference).2 BICLA is a validated composite global disease measure that registers both partial and complete improvement within organ systems. Objectives: TULIP-2 and TULIP-1 data were analyzed to evaluate BICLA responses to Anifrolumab vs placebo at Week 52 in protocol-defined subgroups of patients with active SLE. Methods: TULIP-2 and TULIP-1 were randomized, double-blind, placebo-controlled trials that evaluated efficacy and safety of intravenous Anifrolumab vs placebo administered every 4 weeks, with the primary endpoints assessed at Week 52, in patients with moderate to severe SLE despite standard-of-care treatment.1,2 BICLA responses are defined by all of the following: reduction of baseline BILAG-2004 A and B domain scores to B/C/D and C/D, respectively, and no worsening in any organ system; no worsening of the SLE Disease Activity Index 2000 (SLEDAI-2K) score; no worsening of ≥0.3 points in the Physician’s Global Assessment (range 0–3); no trial treatment discontinuation; and no use of medications restricted by the protocol.3 BICLA responses were compared between Anifrolumab 300 mg and placebo groups, and robustness of BICLA responses was assessed across protocol-defined subgroups. TULIP-1 data were analyzed incorporating the amended restricted medication rules, as described.2 Results: In TULIP-2 and TULIP-1, 180 patients in each trial received Anifrolumab 300 mg (182 and 184 patients received placebo, respectively). Baseline demographics, disease characteristics, and standard-of-care medications were balanced between Anifrolumab and placebo groups within both TULIP trials. Patients in TULIP-2 and TULIP-1 had comparable BICLA responses (Figure). Across multiple subgroups, higher percentages of patients achieved BICLA responses at Week 52 in the Anifrolumab vs placebo arms (Figure). There was concordance of BICLA responses favoring Anifrolumab across the protocol-defined subgroups of baseline disease severity (SLEDAI-2K Conclusion: The uniformity of robust BICLA response rates across prespecified subgroups in both phase 3 trials shows consistent clinical benefit of Anifrolumab irrespective of patient baseline characteristics. However, given the small patient numbers in some subgroups, these results should be interpreted with caution. References: [1]Morand EF, et al. N Engl J Med. 2020;382:211–221. [2]Furie RA, et al. Lancet Rheumatol. 2019;1:e208–e219. [3]Wallace DJ, et al. Ann Rheum Dis. 2014;73:183–190. Disclosure of Interests: Eric F. Morand Grant/research support from: AstraZeneca, Consultant of: AstraZeneca, Speakers bureau: AstraZeneca, Richard Furie Grant/research support from: AstraZeneca, Biogen, Consultant of: AstraZeneca, Biogen, Yoshiya Tanaka Grant/research support from: Asahi-kasei, Astellas, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Pfizer, and Ono, Consultant of: Abbvie, Astellas, Bristol-Myers Squibb, Eli Lilly, Pfizer, Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Sanofi, UCB, and Teijin, Rubana Kalyani Employee of: AstraZeneca, Gabriel Abreu Employee of: AstraZeneca, Lilia Pineda Employee of: AstraZeneca, Raj Tummala Employee of: AstraZeneca

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

  • long term safety and efficacy of Anifrolumab in adults with systemic lupus erythematosus results of a phase 2 open label extension study
    Arthritis & Rheumatism, 2020
    Co-Authors: W. Winn Chatham, Philip Brohawn, Richard Furie, Erik Schwetje, Gabriel Abreu, Amit Saxena, Raj Tummala
    Abstract:

    OBJECTIVE To investigate long-term safety and tolerability of Anifrolumab, a human monoclonal antibody to the type I interferon (IFN) receptor subunit 1, in patients with moderate to severe systemic lupus erythematosus (SLE). METHODS This 3-year, multinational, open-label extension (OLE) enrolled adult patients who completed treatment (48 weeks Anifrolumab or placebo; 12-week follow-up) in the MUSE phase 2b randomized controlled trial (RCT). Patients initially received intravenous Anifrolumab 1000 mg every 4 weeks, reduced to 300 mg every 4 weeks based on the benefit/risk profile established in MUSE. Adverse events (AEs) were assessed monthly. Exploratory endpoints included SLE Disease Activity Index 2000 (SLEDAI-2K), SLICC Damage Index (SDI), pharmacodynamics, and health-related quality of life (HRQoL). RESULTS Of 246 patients who completed the RCT, 218 (88.6%) enrolled in the OLE; 139/218 (63.8%) completed 3 years of treatment. Approximately 69.7% of patients reported ≥1 AE during the first year of OLE treatment. Frequency and patterns of serious AEs and AEs of special interest over 3 years were consistent with those reported for 1 year of treatment in the RCT. Few patients (6.9%) discontinued treatment because of AEs. No new safety signals were identified. Improvement in SLEDAI-2K was sustained over 3 years. SDI and Short Form 36 Health Survey scores remained stable. Neutralization of type I IFN gene signatures was maintained in the IFN-high population, and C3, C4, and anti-dsDNA showed numeric trends toward sustained improvement. CONCLUSION Long-term Anifrolumab treatment demonstrated an acceptable safety profile with sustained improvement in disease activity, HRQoL, and serologies.

  • Long‐term safety and efficacy of Anifrolumab in adults with systemic lupus erythematosus: results of a phase 2 open‐label extension study
    Arthritis & rheumatology (Hoboken N.J.), 2020
    Co-Authors: W. Winn Chatham, Philip Brohawn, Richard Furie, Erik Schwetje, Gabriel Abreu, Amit Saxena, Raj Tummala
    Abstract:

    OBJECTIVE To investigate long-term safety and tolerability of Anifrolumab, a human monoclonal antibody to the type I interferon (IFN) receptor subunit 1, in patients with moderate to severe systemic lupus erythematosus (SLE). METHODS This 3-year, multinational, open-label extension (OLE) enrolled adult patients who completed treatment (48 weeks Anifrolumab or placebo; 12-week follow-up) in the MUSE phase 2b randomized controlled trial (RCT). Patients initially received intravenous Anifrolumab 1000 mg every 4 weeks, reduced to 300 mg every 4 weeks based on the benefit/risk profile established in MUSE. Adverse events (AEs) were assessed monthly. Exploratory endpoints included SLE Disease Activity Index 2000 (SLEDAI-2K), SLICC Damage Index (SDI), pharmacodynamics, and health-related quality of life (HRQoL). RESULTS Of 246 patients who completed the RCT, 218 (88.6%) enrolled in the OLE; 139/218 (63.8%) completed 3 years of treatment. Approximately 69.7% of patients reported ≥1 AE during the first year of OLE treatment. Frequency and patterns of serious AEs and AEs of special interest over 3 years were consistent with those reported for 1 year of treatment in the RCT. Few patients (6.9%) discontinued treatment because of AEs. No new safety signals were identified. Improvement in SLEDAI-2K was sustained over 3 years. SDI and Short Form 36 Health Survey scores remained stable. Neutralization of type I IFN gene signatures was maintained in the IFN-high population, and C3, C4, and anti-dsDNA showed numeric trends toward sustained improvement. CONCLUSION Long-term Anifrolumab treatment demonstrated an acceptable safety profile with sustained improvement in disease activity, HRQoL, and serologies.

  • OP0003 EARLY AND SUSTAINED RESPONSES WITH Anifrolumab TREATMENT IN PATIENTS WITH ACTIVE SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IN 2 PHASE 3 TRIALS
    Annals of the Rheumatic Diseases, 2020
    Co-Authors: Eric F. Morand, Kenneth Kalunian, Richard Furie, Ian N Bruce, Gabriel Abreu, Rubana N Kalyani, Lilia Pineda, Raj Tummala
    Abstract:

    Measuring genome size across different species can yield important insights into evolution of the genome and allow for more informed decisions when designing next-generation genomic sequencing projects. New techniques for estimating genome size using shallow genomic sequence data have emerged which have the potential to augment our knowledge of genome sizes, yet these methods have only been used in a limited number of empirical studies. In this project, we compare estimation methods using next-generation sequencing (k-mer methods and average read depth of single-copy genes) to measurements from flow cytometry, a standard method for genome size measures, using ground beetles (Carabidae) and other members of the beetle suborder Adephaga as our test system. We also present a new protocol for using read-depth of single-copy genes to estimate genome size. Additionally, we report flow cytometry measurements for five previously unmeasured carabid species, as well as 21 new draft genomes and six new draft transcriptomes across eight species of adephagan beetles. No single sequence-based method performed well on all species, and all tended to underestimate the genome sizes, although only slightly in most samples. For one species, Bembidion sp. nr. transversale, most sequence-based methods yielded estimates half the size suggested by flow cytometry.

  • Anifrolumab in systemic lupus erythematosus: current knowledge and future considerations.
    Immunotherapy, 2020
    Co-Authors: Erik Anderson, Richard Furie
    Abstract:

    Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is potentially life-threatening and can affect any organ. The complex pathogenesis and heterogeneity of the disease, among other factors, present significant challenges in developing new therapies. Knowledge gained over many years has implicated type I interferon (IFN) in the pathogenesis of SLE and anti-IFN therapies hold promise as a much-needed future treatment for SLE. Anifrolumab, a human monoclonal antibody against the type I IFN receptor, has recently been evaluated in two Phase III clinical trials for the treatment of moderate-to-severe SLE. Here, we review the clinical efficacy and safety of Anifrolumab and discuss the potential challenges in determining the optimal SLE patient subgroup for treatment.

  • P186 Early and sustained responses with Anifrolumab in patients with systemic lupus erythematosus (SLE) in 2 phase 3 trials
    Poster presentations, 2020
    Co-Authors: Eric F. Morand, Kenneth Kalunian, Richard Furie, Ian N Bruce, Gabriel Abreu, Rubana N Kalyani, Lilia Pineda, Raj Tummala
    Abstract:

    Background In the phase 3 TULIP-2 and TULIP-1 trials in SLE, Anifrolumab treatment increased the percentages of patients with BICLA responses vs placebo at Week 52 (Morand et al, 2020; Furie et al, 2019). To better understand the time course of BICLA responses to Anifrolumab, we examined responses over time in TULIP-2 and TULIP-1, including sustained responses. Methods The TULIP-2 and TULIP-1 randomized, double-blind, placebo-controlled trials evaluated Anifrolumab (300 mg Q4W) over 52 weeks in patients with moderately to severely active SLE receiving standard-of-care treatment. Time to onset of BICLA response sustained from attainment through Week 52 was assessed. Results At the first 3 assessments (Weeks 4, 8, and 12) in TULIP-2, numerically greater percentages of Anifrolumab-treated patients (26.8%, 35.3%, and 42.9%, respectively; N=180) had a BICLA response compared with placebo (21.3%, 21.6%, and 31.8%; N=182). A similar trend was observed in TULIP-1 with Anifrolumab (23.3%, 34.2%, and 36.5%; N=180) vs placebo (18.3%, 23.2%, and 27.5%; N=184). Time to onset of BICLA response in patients who achieved sustained BICLA response from onset through Week 52 in TULIP-2 (Anifrolumab, n=86 [47.8%]; placebo, n=57 [31.3%]) and in TULIP-1 (Anifrolumab, n=85 [47.2%]; placebo, n=55 [29.9%]) favored Anifrolumab (HR=1.55, 95% CI 1.11–2.18 and HR=1.93, 95% CI 1.38–2.73, respectively; figure 1). Conclusions Anifrolumab resulted in numerically favorable differences in BICLA responses maintained through Week 52, and in time to onset thereof, across TULIP studies. These data support the sustainability of clinical benefit with Anifrolumab treatment in patients with active SLE.

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

  • Anifrolumab effects on rash and arthritis: impact of the type I interferon gene signature in the phase IIb MUSE study in patients with systemic lupus erythematosus.
    Lupus science & medicine, 2018
    Co-Authors: Joan T Merrill, Jorn Drappa, Liangwei Wang, Victoria P Werth, Munther Khamashta, Richard Furie, G. Illei, Raj Tummala
    Abstract:

    Objective This post hoc analysis compared Anifrolumab 300 mg every 4 weeks with placebo on rash and arthritis measures with different stringency in patients with moderate to severe SLE (phase IIb; MUSE; NCT01438489). Subgroups were analysed by type I interferon gene signature (IFNGS test–high or test–low). Methods Rash was measured with the SLE Disease Activity Index 2000 (SLEDAI-2K), British Isles Lupus Assessment Group (BILAG) Index and modified Cutaneous Lupus Erythematosus Disease Area and Severity Index (mCLASI). Arthritis was evaluated using SLEDAI-2K, BILAG and swollen and tender joint counts. Outcomes were measured at week 52. Results More Anifrolumab-treated patients demonstrated resolution of rash by SLEDAI-2K versus placebo: 39/88 (44.3%) versus 13/88 (14.8%), OR (90% CI) 4.56 (2.48 to 8.39), p Conclusions Anifrolumab treatment was associated with improvements versus placebo in specific SLE features of arthritis and rash using measures of different stringency. Although driven by robust data in the prevalent IFNGS test–high population, further evaluation in IFNGS test–low patients is warranted.

  • Type I interferon receptor blockade with Anifrolumab corrects innate and adaptive immune perturbations of SLE.
    Lupus science & medicine, 2018
    Co-Authors: Kerry A. Casey, Xiang Guo, L. Wang, Michael A Smith, Shiliang Wang, Dominic Sinibaldi, Miguel A. Sanjuan, G. Illei, Wendy I. White
    Abstract:

    Objective Anifrolumab is a fully human immunoglobulin G1 κ monoclonal antibody specific for subunit 1 of the type I interferon (IFN) α receptor. In a phase IIb study of adults with moderate to severe SLE, Anifrolumab treatment demonstrated substantial reductions in multiple clinical endpoints. Here, we evaluated serum proteins and immune cells associated with SLE pathogenesis, type I interferon gene signature (IFNGS) test status and disease activity, and how Anifrolumab affected these components. Methods Whole blood samples were collected from patients enrolled in MUSE (NCT01438489) for serum protein and cellular assessments at baseline and subsequent time points. Data were parsed by IFNGS test status (high/low) and disease activity. Protein expression and immune cell subsets were measured using multiplex immunoassay and flow cytometry, respectively. Blood samples from healthy donors were analysed for comparison. Results Baseline protein expression differed between patients with SLE and healthy donors, IFNGS test-high and -low patients, and patients with moderate and severe disease. Anifrolumab treatment lowered concentrations of IFN-induced chemokines associated with B, T and other immune cell migration in addition to proteins associated with endothelial activation that were dysregulated at baseline. IFNGS test-high patients and those with high disease activity were characterised by low baseline numbers of lymphocytes, circulating memory T-cell subsets and neutrophils. Anifrolumab treatment reversed lymphopenia and neutropenia in the total population, and normalised multiple T-cell subset counts in IFNGS test-high patients compared with placebo. Conclusions Anifrolumab treatment reversed IFN-associated changes at the protein and cellular level, indicating multiple modes of activity. Trial registration number NCT01438489.

  • Response to: 'Comment on: 'Lupus Low Disease Activity State(LLDAS) attainment discriminates responders in a systemic lupus erythematosus trial: post-hocanalysis of the Phase IIb MUSE trial of Anifrolumab' by Eric Morand et al' by Isenberg.
    Annals of the rheumatic diseases, 2018
    Co-Authors: Eric F. Morand, Anna Berglind, G. Illei, Teodora Trasieva, Raj Tummala
    Abstract:

    The authors thank Professor Isenberg1 for pointing out a drafting error on the manuscript reporting the use of the Lupus Low Disease Activity State (LLDAS) …

  • OP0174 Alteration of mediators of vascular inflammation by Anifrolumab in the phase iib muse study in sle
    THURSDAY 14 JUNE 2018, 2018
    Co-Authors: Wendy I. White, L. Wang, Kerry A. Casey, Michael A Smith, G. Illei, Nickie L. Seto, Martin P. Playford, Philip M. Carlucci, Nehal N. Mehta
    Abstract:

    Background Cardiovascular disease remains one of the leading causes of death for patients with systemic lupus erythematosus (SLE), and the disease is widely known to feature premature atherosclerosis promoted by immune dysregulation. Neutrophil extracellular traps (NETs) can induce endothelial dysfunction and promote inflammatory events. Furthermore, sources of reactive oxygen species released during NET formation promote oxidised HDL, leading to deficient cholesterol efflux capacity (CEC). Type I interferons (IFNs) stimulate NET formation and inhibit vascular repair. Anifrolumab is a fully human, IgG1 κ monoclonal antibody that binds to IFNAR1 and blocks signalling of all type I IFNs. Thus, Anifrolumab may decrease mechanisms of vascular damage in SLE. Objectives We evaluated the ability of Anifrolumab to reduce in-vivo NET formation and improve CEC relative to standard of care (SOC) in the MUSE study.1 Methods Baseline IFN gene signature (IFNGS) test status (high or low) of MUSE patients was determined as described.1 Plasma samples from fasting patients (n=190) were obtained at days 1 and 365 of the MUSE study. Plasma MPO-, HNE- and CitH3-DNA NET complexes were quantified by ELISAs in the MUSE and healthy donor (HD) samples (n=20) as described.2 Wilcoxon rank-sum test was used to assess differences between groups. Post-treatment samples from the placebo (n=52) and 300 mg Anifrolumab (n=73) groups were compared with baseline samples. Significance of change from baseline was determined using Wilcoxon signed-rank test. CEC was tested as described.3 Reproducibility of the CEC assay was assessed using percent coefficient of variation (CV) from the analysis of variance (ANOVA). SLE patients with defective baseline CEC were identified as those with CEC Results All three neutrophil NET complexes (NNCs) were elevated in SLE patients (p Conclusions Circulating NNCs were significantly elevated in patients with moderate to severe SLE as compared with HDs. Anifrolumab decreased circulating NNCs. Although changes in steroid dosages during MUSE did not affect CEC, Anifrolumab significantly improved CEC over SOC. This work supports continued assessment of Anifrolumab effects on vascular inflammation and endothelial damage in SLE. References [1] Furie R, et al. Arthritis Rheumatol2017;69:376–86. [2] Demoruelle MK, et al. Arthritis Rheumatol2017;69:1165–75. [3] Salahuddin T, et al. Eur Heart J2015;36:2662–5. Disclosure of Interest W. White Shareholder of: AstraZeneca, Employee of: MedImmune, N. Seto: None declared, M. Playford: None declared, K. Casey Shareholder of: AstraZeneca, Employee of: MedImmune, M. Smith Shareholder of: AstraZeneca, Employee of: MedImmune, P. Carlucci: None declared, B. Yu Shareholder of: AstraZeneca, Employee of: MedImmune, L. Wang Shareholder of: AstraZeneca, Employee of: MedImmune, G. Illei Shareholder of: AstraZeneca, Consultant for: MedImmune, N. Mehta Grant/research support from: Abbvie, Novartis, Janssen, Celgene, Employee of: NHLBI, M. Kaplan Grant/research support from: MedImmune

  • 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...

Eric F. Morand - One of the best experts on this subject based on the ideXlab platform.

  • OP0003 EARLY AND SUSTAINED RESPONSES WITH Anifrolumab TREATMENT IN PATIENTS WITH ACTIVE SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IN 2 PHASE 3 TRIALS
    Annals of the Rheumatic Diseases, 2020
    Co-Authors: Eric F. Morand, Kenneth Kalunian, Richard Furie, Ian N Bruce, Gabriel Abreu, Rubana N Kalyani, Lilia Pineda, Raj Tummala
    Abstract:

    Measuring genome size across different species can yield important insights into evolution of the genome and allow for more informed decisions when designing next-generation genomic sequencing projects. New techniques for estimating genome size using shallow genomic sequence data have emerged which have the potential to augment our knowledge of genome sizes, yet these methods have only been used in a limited number of empirical studies. In this project, we compare estimation methods using next-generation sequencing (k-mer methods and average read depth of single-copy genes) to measurements from flow cytometry, a standard method for genome size measures, using ground beetles (Carabidae) and other members of the beetle suborder Adephaga as our test system. We also present a new protocol for using read-depth of single-copy genes to estimate genome size. Additionally, we report flow cytometry measurements for five previously unmeasured carabid species, as well as 21 new draft genomes and six new draft transcriptomes across eight species of adephagan beetles. No single sequence-based method performed well on all species, and all tended to underestimate the genome sizes, although only slightly in most samples. For one species, Bembidion sp. nr. transversale, most sequence-based methods yielded estimates half the size suggested by flow cytometry.

  • O25 Efficacy of Anifrolumab in active systemic lupus erythematosus (SLE): patient subgroup analysis of BICLA response in 2 phase 3 trials
    Oral presentations, 2020
    Co-Authors: Eric F. Morand, Richard Furie, Gabriel Abreu, Yoshiya Tanaka, Rubana N Kalyani, Lilia Pineda, Raj Tummala
    Abstract:

    Background Treatment of patients with SLE with Anifrolumab resulted in higher BICLA response rates vs placebo at Week 52 in the phase 3 trials, TULIP-2 (16.3% difference; Morand et al, 2020) and TULIP-1 (16.4% difference; Furie et al, 2019). We evaluated BICLA responses to Anifrolumab vs placebo at Week 52 in protocol-defined subgroups of patients with active SLE enrolled in the TULIP trials. Methods TULIP-2 and TULIP-1 were randomized, double-blind, placebo-controlled trials that evaluated efficacy and safety of intravenous Anifrolumab vs placebo administered every 4 weeks, with the primary endpoints assessed at Week 52, in patients with moderate to severe SLE despite standard-of-care treatment.1,2 BICLA responses were compared between Anifrolumab 300 mg and placebo groups, and robustness of BICLA responses was assessed across protocol-defined subgroups. Results TULIP-2 (Anifrolumab, n=180; placebo, n=182) and TULIP-1 (Anifrolumab, n=180; placebo, n=184) had comparable BICLA responses (figure 1). Across multiple subgroups, higher percentages of patients achieved BICLA responses at Week 52 in the Anifrolumab vs placebo arms. There was concordance of BICLA responses favoring Anifrolumab across the protocol-defined subgroups of baseline disease severity (SLEDAI-2K Conclusions The uniformity of robust BICLA response rates across prespecified subgroups in both phase 3 trials shows consistent clinical benefit of Anifrolumab irrespective of patient baseline characteristics.

  • P186 Early and sustained responses with Anifrolumab in patients with systemic lupus erythematosus (SLE) in 2 phase 3 trials
    Poster presentations, 2020
    Co-Authors: Eric F. Morand, Kenneth Kalunian, Richard Furie, Ian N Bruce, Gabriel Abreu, Rubana N Kalyani, Lilia Pineda, Raj Tummala
    Abstract:

    Background In the phase 3 TULIP-2 and TULIP-1 trials in SLE, Anifrolumab treatment increased the percentages of patients with BICLA responses vs placebo at Week 52 (Morand et al, 2020; Furie et al, 2019). To better understand the time course of BICLA responses to Anifrolumab, we examined responses over time in TULIP-2 and TULIP-1, including sustained responses. Methods The TULIP-2 and TULIP-1 randomized, double-blind, placebo-controlled trials evaluated Anifrolumab (300 mg Q4W) over 52 weeks in patients with moderately to severely active SLE receiving standard-of-care treatment. Time to onset of BICLA response sustained from attainment through Week 52 was assessed. Results At the first 3 assessments (Weeks 4, 8, and 12) in TULIP-2, numerically greater percentages of Anifrolumab-treated patients (26.8%, 35.3%, and 42.9%, respectively; N=180) had a BICLA response compared with placebo (21.3%, 21.6%, and 31.8%; N=182). A similar trend was observed in TULIP-1 with Anifrolumab (23.3%, 34.2%, and 36.5%; N=180) vs placebo (18.3%, 23.2%, and 27.5%; N=184). Time to onset of BICLA response in patients who achieved sustained BICLA response from onset through Week 52 in TULIP-2 (Anifrolumab, n=86 [47.8%]; placebo, n=57 [31.3%]) and in TULIP-1 (Anifrolumab, n=85 [47.2%]; placebo, n=55 [29.9%]) favored Anifrolumab (HR=1.55, 95% CI 1.11–2.18 and HR=1.93, 95% CI 1.38–2.73, respectively; figure 1). Conclusions Anifrolumab resulted in numerically favorable differences in BICLA responses maintained through Week 52, and in time to onset thereof, across TULIP studies. These data support the sustainability of clinical benefit with Anifrolumab treatment in patients with active SLE.

  • O24 Flare assessments in patients with active systemic lupus erythematosus (SLE) treated with Anifrolumab in 2 phase 3 trials
    Oral presentations, 2020
    Co-Authors: Richard Furie, Gabriel Abreu, Eric F. Morand, Rubana N Kalyani, Lilia Pineda, Anca Askanase, E.m. Vital, Raj Tummala
    Abstract:

    Background Anifrolumab treatment improved BICLA response rates in patients with SLE in the phase 3 TULIP-2 and TULIP-1 trials (Morand et al, 2020; Furie et al, 2019). In addition, annualized flare rates were lower with Anifrolumab vs placebo. TULIP-2 and TULIP-1 data were analyzed to assess effects of Anifrolumab on the number of flares and time to first flare during 52 weeks of treatment. Methods The randomized, double-blind, placebo-controlled TULIP-2 and TULIP-1 trials evaluated efficacy and safety of intravenous Anifrolumab (300 mg Q4W) over 52 weeks in patients with moderate to severe SLE despite standard-of-care treatment. Flares were defined as ≥1 new BILAG-2004 A or ≥2 new (worsening) BILAG-2004 B domain scores compared with the prior month’s visit. Number of flares, time to first flare, and annualized flare rate were assessed. Results In TULIP-2 (Anifrolumab, n=180; placebo, n=182) and TULIP-1 (Anifrolumab, n=180; placebo, n=184), fewer Anifrolumab-treated patients experienced ≥1 flare (TULIP-2: 31.1%, n=56; TULIP-1: 36.1%, n=65) vs placebo-treated patients (TULIP-2: 42.3%, n=77; TULIP-1: 43.5%, n=80). Results favoring Anifrolumab were observed in time to first flare (TULIP-2: hazard ratio [HR]=0.65, 95% confidence interval [CI] 0.46–0.91; TULIP-1: HR=0.76, 95% CI 0.55–1.06; figure 1) and annualized flare rates (TULIP-2: adjusted rate ratio=0.67, 95% CI 0.48–0.94; TULIP-1: rate ratio=0.83, 95% CI 0.60–1.14). Conclusions Across 2 phase 3 trials, we observed reduced total number of flares and annualized flare rates, as well as prolongation of time to first flare with Anifrolumab treatment vs placebo. These results support the potential of Anifrolumab to reduce disease activity and reduce flares, benefiting patients with SLE.

  • O25 Efficacy of Anifrolumab in active systemic lupus erythematosus (SLE): patient subgroup analysis of BICLA response in 2 phase 3 trials
    Annals of the Rheumatic Diseases, 2020
    Co-Authors: Eric F. Morand, Richard Furie, Gabriel Abreu, Yoshiya Tanaka, Rubana N Kalyani, Lilia Pineda, Raj Tummala
    Abstract:

    Background: Treatment of patients with systemic lupus erythematosus (SLE) with the type I interferon (IFN) receptor inhibitor Anifrolumab resulted in higher British Isles Lupus Assessment Group (BILAG)–based Composite Lupus Assessment (BICLA) response rates vs placebo at Week 52 in the phase 3 randomized trials, TULIP-2 (primary endpoint; 16.3% difference)1 and TULIP-1 (secondary endpoint; 16.4% difference).2 BICLA is a validated composite global disease measure that registers both partial and complete improvement within organ systems. Objectives: TULIP-2 and TULIP-1 data were analyzed to evaluate BICLA responses to Anifrolumab vs placebo at Week 52 in protocol-defined subgroups of patients with active SLE. Methods: TULIP-2 and TULIP-1 were randomized, double-blind, placebo-controlled trials that evaluated efficacy and safety of intravenous Anifrolumab vs placebo administered every 4 weeks, with the primary endpoints assessed at Week 52, in patients with moderate to severe SLE despite standard-of-care treatment.1,2 BICLA responses are defined by all of the following: reduction of baseline BILAG-2004 A and B domain scores to B/C/D and C/D, respectively, and no worsening in any organ system; no worsening of the SLE Disease Activity Index 2000 (SLEDAI-2K) score; no worsening of ≥0.3 points in the Physician’s Global Assessment (range 0–3); no trial treatment discontinuation; and no use of medications restricted by the protocol.3 BICLA responses were compared between Anifrolumab 300 mg and placebo groups, and robustness of BICLA responses was assessed across protocol-defined subgroups. TULIP-1 data were analyzed incorporating the amended restricted medication rules, as described.2 Results: In TULIP-2 and TULIP-1, 180 patients in each trial received Anifrolumab 300 mg (182 and 184 patients received placebo, respectively). Baseline demographics, disease characteristics, and standard-of-care medications were balanced between Anifrolumab and placebo groups within both TULIP trials. Patients in TULIP-2 and TULIP-1 had comparable BICLA responses (Figure). Across multiple subgroups, higher percentages of patients achieved BICLA responses at Week 52 in the Anifrolumab vs placebo arms (Figure). There was concordance of BICLA responses favoring Anifrolumab across the protocol-defined subgroups of baseline disease severity (SLEDAI-2K Conclusion: The uniformity of robust BICLA response rates across prespecified subgroups in both phase 3 trials shows consistent clinical benefit of Anifrolumab irrespective of patient baseline characteristics. However, given the small patient numbers in some subgroups, these results should be interpreted with caution. References: [1]Morand EF, et al. N Engl J Med. 2020;382:211–221. [2]Furie RA, et al. Lancet Rheumatol. 2019;1:e208–e219. [3]Wallace DJ, et al. Ann Rheum Dis. 2014;73:183–190. Disclosure of Interests: Eric F. Morand Grant/research support from: AstraZeneca, Consultant of: AstraZeneca, Speakers bureau: AstraZeneca, Richard Furie Grant/research support from: AstraZeneca, Biogen, Consultant of: AstraZeneca, Biogen, Yoshiya Tanaka Grant/research support from: Asahi-kasei, Astellas, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Pfizer, and Ono, Consultant of: Abbvie, Astellas, Bristol-Myers Squibb, Eli Lilly, Pfizer, Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Sanofi, UCB, and Teijin, Rubana Kalyani Employee of: AstraZeneca, Gabriel Abreu Employee of: AstraZeneca, Lilia Pineda Employee of: AstraZeneca, Raj Tummala Employee of: AstraZeneca

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  • trial of Anifrolumab in active systemic lupus erythematosus
    The New England Journal of Medicine, 2020
    Co-Authors: Eric F. Morand, Philip Brohawn, Richard Furie, Ian N Bruce, Yoshiya Tanaka, Lilia Pineda, Anca Askanase, C Richez, Sangcheol Bae, Anna Berglind
    Abstract:

    Abstract Background Anifrolumab, a human monoclonal antibody to type I interferon receptor subunit 1 investigated for the treatment of systemic lupus erythematosus (SLE), did not have a significant...

  • Response to: 'Comment on: 'Lupus Low Disease Activity State(LLDAS) attainment discriminates responders in a systemic lupus erythematosus trial: post-hocanalysis of the Phase IIb MUSE trial of Anifrolumab' by Eric Morand et al' by Isenberg.
    Annals of the rheumatic diseases, 2018
    Co-Authors: Eric F. Morand, Anna Berglind, G. Illei, Teodora Trasieva, Raj Tummala
    Abstract:

    The authors thank Professor Isenberg1 for pointing out a drafting error on the manuscript reporting the use of the Lupus Low Disease Activity State (LLDAS) …

  • Safety, tolerability and pharmacokinetics of subcutaneous and intravenous Anifrolumab in healthy volunteers.
    Lupus science & medicine, 2018
    Co-Authors: Raj Tummala, Tomas Rouse, Anna Berglind, Linda Santiago
    Abstract:

    Objectives To compare the pharmacokinetics (PK), safety and tolerability of subcutaneous (SC) and intravenous Anifrolumab, an anti–type I interferon receptor monoclonal antibody in development for SLE, in healthy volunteers. Methods In this Phase I randomised, placebo-controlled study, 30 adults were assigned to three treatment cohorts (Anifrolumab 300 mg SC (n=6), Anifrolumab 300 mg intravenous (n=6), Anifrolumab 600 mg SC (n=6)) and placebo (n=4/cohort). Serial blood samples were collected up to Day 84 to measure Anifrolumab concentrations and antidrug antibodies (ADAs). PK parameters were estimated by noncompartmental analysis. Results Maximum serum concentrations in SC cohorts occurred after 4–7 days. Anifrolumab serum concentrations were below the limit of detection in all individuals by Day 84. Exposure to SC Anifrolumab increased dose proportionally from 300 mg to 600 mg based on area under the serum concentration-time curve. Anifrolumab 300 mg SC exposure reached 87% of the intravenous exposure. Anifrolumab 300 mg SC and placebo administration elicited minimal injection-site reactions. Transient injection-site induration occurred in five of six individuals after Anifrolumab 600 mg SC and two of four individuals after placebo. Transient, mild to moderate injection-site induration and pruritus occurred simultaneously in two of six individuals after Anifrolumab 600 mg SC. Adverse events were reported by 50% (n=9) of Anifrolumab-treated individuals and 33% (n=4) of placebo-treated individuals. ADAs were detected in only one individual in the Anifrolumab 300-mg intravenous group at the Day 84 assessment. Conclusion Anifrolumab 300-mg SC exposure was 87% of intravenous administration, with single SC Anifrolumab administrations well tolerated in healthy volunteers.

  • Lupus Low Disease Activity State (LLDAS) attainment discriminates responders in a systemic lupus erythematosus trial: post-hoc analysis of the Phase IIb MUSE trial of Anifrolumab
    Annals of the rheumatic diseases, 2018
    Co-Authors: Eric F. Morand, Anna Berglind, G. Illei, Teodora Trasieva, Raj Tummala
    Abstract:

    Objectives In a post-hoc analysis, we aimed to validate the Lupus Low Disease Activity State (LLDAS) definition as an endpoint in an systemic lupus erythematosus (SLE) Phase IIb randomised controlled trial (RCT) (MUSE [NCT01438489]) and then utilize LLDAS to discriminate between Anifrolumab and placebo. Methods Patients received intravenous placebo (n=102) or Anifrolumab (300 mg, n=99; 1,000 mg, n=104) Q4W plus standard of care for 48 weeks. LLDAS attainment (SLE Disease Activity Index 2000 ≤4 without major organ activity, no new disease activity, Physician’s Global Assessment ≤1, prednisolone ≤7.5 mg/d and standard immunosuppressant dosage tolerance) was assessed. Associations with endpoints and LLDAS attainment differences between treatments were explored. Results LLDAS attainment at Week 52 was associated with SLE Responder Index 4 (SRI[4]) and British Isles Lupus Assessment Group–based Composite Lupus Assessment (BICLA) (74/85[87%] and 62/84[74%] were also SRI[4] and BICLA responders, respectively; both nominal p Anifrolumab-treated patients achieved earlier LLDAS, and more spent at least half their observed time in LLDAS (OR vs. placebo; 300 mg: 3.04, 95% CI 1.34 to 6.92, nominal p=0.008; 1,000 mg: 2.17, 95% CI 0.93 to 5.03, nominal p=0.072) vs placebo-treated patients. At Week 52, 17/102 (17%), 39/99 (39%) and 29/104 (28%) of patients on placebo, Anifrolumab 300 and 1,000 mg, respectively, attained LLDAS (OR vs. placebo; 300 mg: 3.41, 95% CI 1.73 to 6.76, p Conclusions LLDAS attainment represents a clinically meaningful SLE outcome measure, and Anifrolumab is associated with more patients who met LLDAS criteria versus placebo. These data support LLDAS as an SLE RCT endpoint. Trial registration number NCT1438489; Post-results.

  • SAT0254 Safety, tolerability, and pharmacokinetics of subcutaneous and intravenous Anifrolumab in healthy volunteers
    Poster Presentations, 2017
    Co-Authors: Raj Tummala, Tomas Rouse, Anna Berglind, Linda Santiago
    Abstract:

    Background Anifrolumab is a fully human anti–interferon-α receptor monoclonal antibody in Phase III development for systemic lupus erythematosus (SLE). In Phase IIb trials, intravenous (IV) Anifrolumab (300 mg every 4 weeks) significantly decreased SLE disease activity with safety and tolerability comparable to placebo.1 Objectives The primary objective of this Phase I, double-blind, randomized, controlled study (NCT02601625) was to characterize the pharmacokinetics (PK), safety, and tolerability of Anifrolumab administered subcutaneously (SC) and intravenously to healthy volunteers. Methods Thirty male and female adults were assigned to three sequential treatment cohorts of equal size (Anifrolumab 300 mg SC injection; Anifrolumab 300 mg IV; Anifrolumab 600 mg SC by infusion). Individuals were randomized within each cohort to receive a single dose of either Anifrolumab (n=6/cohort) or placebo (PBO) (n=4/cohort). Serial blood samples were collected up to Day 85. Serum Anifrolumab concentrations were analyzed with a validated assay. PK parameters were estimated by noncompartmental analysis. Immunogenicity of Anifrolumab was assessed by measuring serum anti-drug antibodies (ADAs). Results Anifrolumab serum concentration-time profiles and primary PK parameters in healthy volunteers are presented in the figure and table, respectively. Anifrolumab serum concentrations were below the limit of detection in all individuals by 85 days post dose. Maximum serum concentrations in the SC cohorts occurred after 4 to 7 days. Exposure to SC Anifrolumab increased approximately dose proportionally from 300 mg to 600 mg based on AUC. At the 300-mg dose, Anifrolumab exposure after SC administration reached approximately 86% of the IV administration exposure. SC administration of Anifrolumab 300 mg and PBO elicited minimal injection-site reactions. Transient injection-site induration occurred in five of six individuals in the Anifrolumab 600-mg group and two of four in the PBO group. Transient, mild to moderate injection-site induration and pruritus occurred simultaneously in two of six individuals in the Anifrolumab 600-mg group, but not those in the PBO group. Adverse events were reported by 50% (n=9) of Anifrolumab-treated and 33% (n=4) of PBO-treated individuals. No serious adverse events were observed. ADAs were detected in only one individual in the Anifrolumab 300-mg IV group at the Day-85 assessment. Conclusions Exposure of Anifrolumab 300 mg SC was approximately 86% of IV administration, with single SC administrations of Anifrolumab being generally well-tolerated in healthy volunteers. References Furie R, et al. Arthritis Rheumatol. 2017;69:376–86. Disclosure of Interest R. Tummala Employee of: AstraZeneca, T. Rouse Employee of: AstraZeneca, A. Berglind Shareholder of: AstraZeneca, BMS, Employee of: AstraZeneca, L. Santiago Shareholder of: AstraZeneca, Employee of: MedImmune