Biologic activity and safety of belimumab, a neutralizing anti-B-lymphocyte stimulator (BLyS) monoclonal antibody: a phase I trial in patients with systemic lupus erythematosus

Furie, Richard; Stohl, William; Ginzler, Ellen M.; Becker, Michael A.; Mishra, Nilamadhab; Chatham, W. Winn; Merrill, Joan T.; Weinstein, Arthur; McCune, W. Joseph; Zhong, John; Cai, Wendy; Freimuth, William W.; Group, Belimumb Study

doi:10.1186/ar2506

Cited by 236 publications

(160 citation statements)

References 47 publications

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“…A half-life for terminal phase ( t ½,β ) of 12–16 days supports dosing every 28 days in clinical program of belimumab. Although the study did not have the power to detect ethnic differences, this PK result seems to be similar to previous reports assessed non-Japanese population8,14.…”

Section: Discussionsupporting

confidence: 89%

“…In the first study of belimumab, SLE patients with stable disease were given various doses of belimumab to study the in vivo safety of the drug as well as its pharmacokinetics and pharmacodynamics8. The results of the study concluded that belimumab had a good safety profile in vivo , predictable linear pharmacokinetics over a dosage range from 1 to 20 mg/kg, small volume of distribution, slow clearance and a half-life ranging from 8 to 14 days.…”

Section: Introductionmentioning

confidence: 99%

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Safety, tolerability, pharmacokinetics and pharmacodynamics of belimumab in Japanese patients with mild-to-moderate systemic lupus erythematosus

Yamada

Akita

Nakagawa

et al. 2013

Journal of Drug Assessment

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ObjectivesBelimumab, an anti-B lymphocyte stimulator (BLyS) human monoclonal antibody, was approved in the United States, Canada and European Union for the treatment of the patients with systemic lupus erythematosus (SLE). However, belimumab had not been evaluated in Japanese patients. The objectives of this study were to evaluate the safety and tolerability of belimumab in Japanese patients with SLE, as well as to investigate the pharmacokinetics (PK) and biological activity of belimumab in this population.MethodsA total of 12 Japanese patients were enrolled in a randomized, single-blind, placebo-controlled, dose-ascending design study. A dosing regimen of a single intravenous infusion over 1 hour of belimumab (1 mg/kg and 10 mg/kg) was employed. Patients were followed for 84 days after dosing to assess adverse events, pharmacokinetics, biomarkers and SLE disease activity.Clinical trial registration numberClinicalTrials.gov identifier is NCT01381536.ResultsBelimumab (1 mg/kg and 10 mg/kg) demonstrated a favorable clinical safety and tolerability profile in Japanese patients with SLE. The incidence of adverse events was similar among the two belimumab groups and placebo group. The PK profile of single-dose belimumab was approximately dose proportional, and the long terminal elimination half-life (12.4–15.7 days), low clearance (3.55–4.65 mL/day/kg), and small volume of distribution (76.2–80.1 mL/kg) were consistent with a fully humanized antibody. Effects of belimumab on B cells suggested biological activity effects expected as an inhibitor of BLyS.LimitationThe small sample size and single dose design of this study prevent definitive conclusions regarding the safety, pharmacokinetics or pharmacodynamics of belimumab in a Japanese population being made.ConclusionsThe preliminary safety, PK profile, and observed biological activity of belimumab support further evaluation of its safety and efficacy in Japanese patient with SLE.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Safety, tolerability, pharmacokinetics and pharmacodynamics of belimumab in Japanese patients with mild-to-moderate systemic lupus erythematosus

Yamada

Akita

Nakagawa

et al. 2013

Journal of Drug Assessment

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“…36,37 Recent clinical trials with BAFF blockade have shown clinical benefit in SLE and RA. 38,39 Treatment of lupus-prone New Zealand black/white F1 mice with both BR3-Fc and TACI-Ig significantly decreased the proteinuria and glomerular damage in these mice. 40 These findings in conjunction with the evidence of in vitro test and joint BAFF elevations in patients with autoimmune disease offer further support to the contention that blockade of BAFF signaling may be of therapeutic benefit in a variety of autoimmune diseases, such as SLE and RA.…”

Section: Discussionmentioning

confidence: 99%

The effects of BAFF and BAFF-R-Fc fusion protein in immune thrombocytopenia

Zhu

Shi

Peng

et al. 2009

Blood

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IntroductionImmune thrombocytopenia (ITP) is an autoimmune disorder in which the patient's immune system is activated by platelet autoantigens resulting in immune-mediated platelet destruction and/or suppression of platelet production. 1 The autoantibodies produced by autoreactive B cells against self-antigens, specifically immunoglobulin G (IgG) antibodies against glycoprotein IIb (GPIIb)/IIIa and/or GPIb/IX, are considered to play a crucial role. 2 In addition, several abnormalities involving the cellular mechanisms of immune modulation, such as the T helper 1 (Th1) bias, 3,4 the decreased number or defective suppressive function of regulatory T cells, 5-7 and the platelet destruction by cytotoxic T cells (CTLs), [8][9][10] have been described. The cause for these abnormalities remains unknown. Moreover, the treatment regimens for ITP including glucorticosteroids, intravenous immunoglobulin G, anti-D, and splenectomy are not always effective, and only one-third of adult patients achieve long-term remission.B-cell activating factor (BAFF; also known as B-lymphocyte stimulator, tumor necrosis factor and apoptosis ligand-related leukocyte-expressed ligand 1, tumor necrosis factor homologue that activates apoptosis, nuclear factor B, and c-Jun NH 2 -terminal kinase, and tumor necrosis factor superfamily 13B) belonging to the family of tumor necrosis factor (TNF) ligands is critical for the maintenance of normal B-cell development, homeostasis, and autoreactivity 11,12 and T-cell costimulation. [13][14][15] In addition, BAFF also augments certain Th1-associated inflammatory responses. 16 BAFF binds to 3 receptors: B-cell maturation antigen (tumor necrosis factor receptor superfamily, member 17 [TNFRSF17]), transmembrane activator and calcium-modulating cyclophilin ligand (CAML) interactor (TACI; TNFRSF13B), and BAFF receptor (BR3/BAFF-R; TNFRSF13C). 17,18 BR3, identified as the crucial receptor for B-cell survival, is expressed on a wide range of B-cell subsets, including immature, transitional, mature, memory, and germinal center B cells, as well as on plasma cells. 19 Furthermore, BAFF binding to BR3 on T cells has been shown to costimulate T-cell proliferation both in vitro and in vivo. 15 Several lines of evidence suggested that BAFF may play an important role in autoimmunity. Autoantigen-binding B cells may have an increased dependence on the BAFF survival signal. 20 In addition, elevated BAFF plasma level was observed in many patients with autoimmune diseases such as rheumatoid arthritis (RA), 21 systemic lupus erythematosus (SLE), 22 Sjögren syndrome (SS), 23 and multiple sclerosis. 24 Inhibition of BAFF signaling is a potentially therapeutic option for treatment of B cell-mediated autoimmune conditions. Data from animal tests and clinical trials had proved that blockade of BAFF by blocking reagents (TACI-Ig, BAFF-R-Ig, BR3-Fc) was an effective therapeutic approach for some autoimmune diseases. [25][26][27] In our study, we focused on the effects of BAFF and BR3-Fc in ITP, and found recombinant human BAFF (r...

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“…There were no significant differences in the clearance, half-life and volume of distribution between the patients who received the drug either singly or as two infusions. 19 Belimumab resulted in reductions in CD20+ B lymphocytes and anti-dsDNA antibody, exhibiting promise for further trials. The results of this study demonstrated that treatment with belimumab was safe and well tolerated in patients with mild to moderate SLE.…”

Section: Preclinical and Phase 1 Trialsmentioning

confidence: 99%

“…18 The phase 1 dose-escalating trial of belimumab was undertaken in 70 patients of SLE with mild to moderate disease activity (Table 1). 19 The patients were randomized to receive either the drug in a dose of 1, 4, 10 or 20 mg/kg or placebo. The treatment was administered as a single infusion or as two infusions separated by 21 days.…”

Section: Preclinical and Phase 1 Trialsmentioning

confidence: 99%

Belimumab: targeted therapy for lupus

Chugh

Kalra

2012

Int J of Rheum Dis

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Systemic lupus erythematosus (SLE), a complex autoimmune disease with multisystem involvement, is characterised by recurring flares and remissions throughout the course of illness. The agents currently being used for management include corticosteroids, antimalarials and various immunosuppressants. Belimumab, a B lymphocyte stimulator (BLyS) inhibitor has been recently approved for the treatment of SLE. This review aims to discuss the role of belimumab in the treatment of SLE and the trials leading to its FDA approval. Belimumab demonstrated high degree of activity in patients with autoantibody-positive active SLE disease on a stable treatment regimen. There was a significantly greater response compared to placebo as assessed with the SLE Responder Index (SRI) in two randomized, double-blind, phase III trials (BLISS-52 and BLISS-76). The treatment was well tolerated. Additional studies are required to evaluate belimumab in special populations and assess its long-term safety. This therapy could change the focus of management from symptomatic treatment to targeting an important step in the disease pathogenesis. It could enable development of treatment which could halt long-term progression, minimize target organ damage and thus provide a better quality of life for these patients.

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Biologic activity and safety of belimumab, a neutralizing anti-B-lymphocyte stimulator (BLyS) monoclonal antibody: a phase I trial in patients with systemic lupus erythematosus

Cited by 236 publications

References 47 publications

Safety, tolerability, pharmacokinetics and pharmacodynamics of belimumab in Japanese patients with mild-to-moderate systemic lupus erythematosus

Safety, tolerability, pharmacokinetics and pharmacodynamics of belimumab in Japanese patients with mild-to-moderate systemic lupus erythematosus

The effects of BAFF and BAFF-R-Fc fusion protein in immune thrombocytopenia

Belimumab: targeted therapy for lupus

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