Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with primary Sjögren's syndrome: a randomised, double-blind, placebo-controlled, phase 2b dose-finding trial

Bowman, Simon; Fox, Robert I.; Dörner, Thomas; Mariette, Xavier; Papas, Athena; Grader‐Beck, Thomas; Fisher, Benjamin A; Barcelos, Filipe; Vita, Salvatore De; Schulze‐Koops, Hendrik; Moots, Robert J.; Junge, G.; Woznicki, J.; Sopala, Monika; Luo, Wen‐Lin; Hueber, Wolfgang

doi:10.1016/s0140-6736(21)02251-0

Cited by 116 publications

(55 citation statements)

References 22 publications

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“…Also, the lack of efficacy may be explained by the absence of assessment of important features in ESSDAI, such as patients’ symptoms and glandular function 11. Recent RCTs showed that improvement in ESSDAI does not necessarily translate to improvement in PROs 4–7 12. Thus, used as a unique primary endpoint, ESSDAI does not capture all important disease features.…”

Section: Introductionmentioning

confidence: 99%

Development and preliminary validation of the Sjögren’s Tool for Assessing Response (STAR): a consensual composite score for assessing treatment effect in primary Sjögren’s syndrome

et al. 2022

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ObjectiveTo develop a composite responder index in primary Sjögren’s syndrome (pSS): the Sjögren’s Tool for Assessing Response (STAR).MethodsTo develop STAR, the NECESSITY (New clinical endpoints in primary Sjögren’s syndrome: an interventional trial based on stratifying patients) consortium used data-driven methods based on nine randomised controlled trials (RCTs) and consensus techniques involving 78 experts and 20 patients. Based on reanalysis of rituximab trials and the literature, the Delphi panel identified a core set of domains with their respective outcome measures. STAR options combining these domains were proposed to the panel for selection and improvement. For each STAR option, sensitivity to change was estimated by the C-index in nine RCTs. Delphi rounds were run for selecting STAR. For the options remaining before the final vote, a meta-analysis of the RCTs was performed.ResultsThe Delphi panel identified five core domains (systemic activity, patient symptoms, lachrymal gland function, salivary gland function and biological parameters), and 227 STAR options combining these domains were selected to be tested for sensitivity to change. After two Delphi rounds, a meta-analysis of the 20 remaining options was performed. The candidate STAR was then selected by a final vote based on metrological properties and clinical relevance.ConclusionThe candidate STAR is a composite responder index that includes all main disease features in a single tool and is designed for use as a primary endpoint in pSS RCTs. The rigorous and consensual development process ensures its face and content validity. The candidate STAR showed good sensitivity to change and will be prospectively validated by the NECESSITY consortium in a dedicated RCT.

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Section: Introductionmentioning

confidence: 99%

Development and preliminary validation of the Sjögren’s Tool for Assessing Response (STAR): a consensual composite score for assessing treatment effect in primary Sjögren’s syndrome

et al. 2022

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“…An open-label clinical trial with belimumab (anti-BAFF) in pSS showed positive effects on ESSDAI in 60% of the patients [47]. In a smaller clinical trial, a single dose of ianalumab (anti-BAFFR) in pSS patients also showed positive effects on ESSDAI [48], and a larger and more recent phase IIb clinical trial with ianalumab again reported a dose-dependent amelioration of disease, as measured by decreases in ESSDAI score [49]. In addition to the BAFF-BAFFR axis, BTK has also been considered as a potential target for pSS treatment.…”

Section: Discussionmentioning

confidence: 97%

Decreased BAFF Receptor Expression and Unaltered B Cell Receptor Signaling in Circulating B Cells from Primary Sjögren’s Syndrome Patients at Diagnosis

Neys

Verstappen

Bootsma

et al. 2022

IJMS

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Animal models of autoimmunity and human genetic association studies indicate that the dysregulation of B-cell receptor (BCR) signaling is an important driver of autoimmunity. We previously showed that in circulating B cells from primary Sjögren’s syndrome (pSS) patients with high systemic disease activity, protein expression of the BCR signaling molecule Bruton’s tyrosine kinase (BTK) was increased and correlated with T-cell infiltration in the target organ. We hypothesized that these alterations could be driven by increased B-cell activating factor (BAFF) levels in pSS. Here, we investigated whether altered BCR signaling was already present at diagnosis and distinguished pSS from non-SS sicca patients. Using (phospho-)flow cytometry, we quantified the phosphorylation of BCR signaling molecules, and investigated BTK and BAFF receptor (BAFFR) expression in circulating B cell subsets in an inception cohort of non-SS sicca and pSS patients, as well as healthy controls (HCs). We found that both BTK protein levels and BCR signaling activity were comparable among groups. Interestingly, BAFFR expression was significantly downregulated in pSS, but not in non-SS sicca patients, compared with HCs, and correlated with pSS-associated alterations in B cell subsets. These data indicate reduced BAFFR expression as a possible sign of early B cell involvement and a diagnostic marker for pSS.

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“…; however, belimumab does not always have universal therapeutic benefits in all patients with SLE ( 93 ). Ianalumab, a mAb against BAFF-R, has shown promising results in a phase II trial in patients with primary Sjögren syndrome (pSS) ( 29 ). As a B cell depletion therapy, ianalumab has 2 modes of action: B-cell lysis by enhanced ADCC and blockade of BAFF signaling.…”

Section: Cell-targeted Therapymentioning

confidence: 99%

Targeted Immunotherapy for Autoimmune Disease

Jung

Kim

2022

Immune Netw

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In the past few decades, biological drugs and small molecule inhibitors targeting inflammatory cytokines, immune cells, and intracellular kinases have become the standard-of-care to treat autoimmune diseases. Inhibition of TNF, IL-6, IL-17, and IL-23 has revolutionized the treatment of autoimmune diseases, such as rheumatoid arthritis, ankylosing spondylitis, and psoriasis. B cell depletion therapy using anti-CD20 mAbs has shown promising results in patients with neuroinflammatory diseases, and inhibition of B cell survival factors is approved for treatment of systemic lupus erythematosus. Targeting co-stimulatory molecules expressed on Ag-presenting cells and T cells is also expected to have therapeutic potential in autoimmune diseases by modulating T cell function. Recently, small molecule kinase inhibitors targeting the JAK family, which is responsible for signal transduction from multiple receptors, have garnered great interest in the field of autoimmune and hematologic diseases. However, there are still unmet medical needs in terms of therapeutic efficacy and safety profiles. Emerging therapies aim to induce immune tolerance without compromising immune function, using advanced molecular engineering techniques.

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Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with primary Sjögren's syndrome: a randomised, double-blind, placebo-controlled, phase 2b dose-finding trial

Cited by 116 publications

References 22 publications

Development and preliminary validation of the Sjögren’s Tool for Assessing Response (STAR): a consensual composite score for assessing treatment effect in primary Sjögren’s syndrome

Development and preliminary validation of the Sjögren’s Tool for Assessing Response (STAR): a consensual composite score for assessing treatment effect in primary Sjögren’s syndrome

Decreased BAFF Receptor Expression and Unaltered B Cell Receptor Signaling in Circulating B Cells from Primary Sjögren’s Syndrome Patients at Diagnosis

Targeted Immunotherapy for Autoimmune Disease

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