A phase 2, randomised, placebo-controlled clinical trial of blisibimod, an inhibitor of B cell activating factor, in patients with moderate-to-severe systemic lupus erythematosus, the PEARL-SC study

Furie, Richard; Léon, G.; Thomas, Mathew; Petri, Michelle; Chu, Alvina D.; Hislop, Colin; Martin, Renée S.; Scheinberg, Morton

doi:10.1136/annrheumdis-2013-205144

Cited by 137 publications

(100 citation statements)

References 22 publications

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“…BAFF-transgenic mouse studies demonstrated that overexpression of BAFF results in development of SLE-like autoimmune pathology including increased autoantibody production (46)(47)(48). Belimumab (Benlysta), a specific inhibitor of BAFF, shows significant efficacy in evidence-based clinical trials for SLE, further supporting the role of BAFF in SLE pathology (49)(50)(51)(52)(53)(54).…”

mentioning

confidence: 99%

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Nakayama¹,

Kosek²,

Capone³

et al. 2017

The Journal of Immunology

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BAFF is a B cell survival and maturation factor implicated in the pathogenesis of systemic lupus erythematosus (SLE). In this in vitro study, we describe that soluble BAFF in combination with IL-2 and IL-21 is a T cell contact-independent inducer of human B cell proliferation, plasmablast differentiation, and IgG secretion from circulating CD27+ memory and memory-like CD27−IgD− double-negative (DN) B cells, but not CD27−IgD+ naive B cells. In contrast, soluble CD40L in combination with IL-2 and IL-21 induces these activities in both memory and naive B cells. Blood from healthy donors and SLE patients have similar circulating levels of IL-2, whereas SLE patients exhibit elevated BAFF and DN B cells and reduced IL-21. B cell differentiation transcription factors in memory, DN, and naive B cells in SLE show elevated levels of Aiolos, whereas Ikaros levels are unchanged. Treatment with CC-220, a modulator of the cullin ring ligase 4-cereblon E3 ubiquitin ligase complex, reduces Aiolos and Ikaros protein levels and BAFF- and CD40L-induced proliferation, plasmablast differentiation, and IgG secretion. The observation that the soluble factors BAFF, IL-2, and IL-21 induce memory and DN B cell activation and differentiation has implications for extrafollicular plasmablast development within inflamed tissue. Inhibition of B cell plasmablast differentiation by reduction of Aiolos and Ikaros may have utility in the treatment of SLE, where elevated levels of BAFF and Aiolos may prime CD27+ memory and DN memory-like B cells to become Ab-producing plasmablasts in the presence of BAFF and proinflammatory cytokines.

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confidence: 99%

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Nakayama¹,

Kosek²,

Capone³

et al. 2017

The Journal of Immunology

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“…Results from phase-Ia and phase-Ib studies in SLE documented a favorable safety profile for blisibimod [66]. However, a phase-IIb study in SLE of blisibimod at multiple dosing regimens failed to meet its primary endpoint with any dosing regimen [67].…”

Section: ) Blisibimodmentioning

confidence: 99%

“…Of the eight late-stage clinical trials of BAFF antagonists in SLE reported to date in complete manuscript form, only four met their respective primary endpoints: each of the three phase-III trials of belimumab [57,58,64], and one of the two phase-III trials of tabalumab [69]. The phase-II belimumab trial, the phase-IIb blisibimod trial, the phase-II/III atacicept trial, and one of the two phase-III tabalumab trials all failed [67,70,72,73]. Even in the successful trials, the absolute percentage differences in clinical responses between BAFF-antagonist-treated and placebo-treated patients were only 10%∼14%.…”

Section: Can the Limited Clinical Efficacy Of Baff Antagonists Be Ovementioning

confidence: 99%

“…That is, the candidate subject must not only be sufficiently fit from a cardiopulmonary standpoint, but he/she must also not be on an immunosuppressive regimen that would increase the risk of infection to an "unacceptable" level. Accordingly, SLE patients with active nephritis or active CNS disease (who routinely require high-dose corticosteroid therapy plus mycophenolate or cyclophosphamide) have been excluded from the vast majority of the phase-II and phase-III trials of BAFF antagonists in SLE reported to date [57,58,67,69,70,72,73]. To address this deficiency, a phase-III trial of belimumab (along with standard-of-care therapy, including high-dose corticosteroids plus cyclophosphamide or mycophenolate) in SLE nephritis patients (NCT01639339) is currently recruiting subjects.…”

Section: Can the Limited Clinical Efficacy Of Baff Antagonists Be Ovementioning

confidence: 99%

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The Future of B-cell Activating Factor Antagonists in the Treatment of Systemic Lupus Erythematosus

Stohl

2017

J Rheum Dis

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s personal library were searched. BAFF-antagonist therapy in SLE has a checkered past, with four late-stage clinical trials meeting their primary endpoints and four failing to do so. Additional late-stage clinical trials are enrolling subjects to address some of the remaining unresolved questions, and novel approaches are proposed to improve results. The BAFF-centric pathway is a proven therapeutic target in SLE. As the only pathway in the past 50+ years to have yielded an United States Food and Drug Administration-approved drug for SLE, it occupies a unique place in the armamentarium of the practicing rheumatologist. The challenges facing clinicians and investigators are how to better tweak the BAFF-centric pathway and improve on the successes realized. (J Rheum Dis 2017;24:65-73)

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“…Blisibimod changed the constituency of the B-cell pool and single and multiple doses of blisibimod exhibited approximate dose-proportional pharmacokinetics across the dose range 1.0-6.0 mg/kg. The PEARL-SC study was a 24-week treatment, Phase IIb randomized trial of 547 SLE patients with moderate-to-severe disease (SELENA-SLEDAI) score equal to or greater than 6 at baseline) who received placebo or blisibimod at one of three dose levels in an evaluation of the efficacy and safety of blisibimod [144]. Although the SRI-5 response rates were not significantly improved in the pooled blisibimod groups compared with placebo, they were higher in the patients randomized to the highest dose of blisibimod (200 mg once-weekly) compared to the pooled placebo group at week 20.…”

Section: Blisibimodmentioning

confidence: 99%

The Roles of the TNF-Family Member B-Cell Activation Factor Belonging to the TNF-Family (BAFF) in Autoimmunity

Hirayama¹,

Nagai²

2017

Immunopathogenesis and Immune-Based Therapy for Selected Autoimmune Disorders

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The tumor necrosis factor superfamily (TNFSF) member and cytokine known as B-cell activation factor belonging to the TNF-family (BAFF) has been identified as one of the key factors in the selection and survival of B cells. Overexpression of BAFF in mice leads to autoimmunity, whereas BAFF-deficient mice lack mature B cells. Although under normal concentrations of BAFF, non-self-reactive B cells survived and autoreactive B cells were deleted, a higher concentration of BAFF contributed to the survival of autoreactive B cells and elevated autoantibody production. Lupus-prone mice have increased serum levels of BAFF during the onset and progression of disease. The serum BAFF levels are elevated in patients with autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome and ANCA-associated vasculitis, and showed positive correlations with autoantibodies.

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A phase 2, randomised, placebo-controlled clinical trial of blisibimod, an inhibitor of B cell activating factor, in patients with moderate-to-severe systemic lupus erythematosus, the PEARL-SC study

Abstract: NCT01162681.

Cited by 137 publications

References 22 publications

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

The Future of B-cell Activating Factor Antagonists in the Treatment of Systemic Lupus Erythematosus

The Roles of the TNF-Family Member B-Cell Activation Factor Belonging to the TNF-Family (BAFF) in Autoimmunity

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