Filgotinib Demonstrates Efficacy in Rheumatoid Arthritis Independent of Smoking Status: Post Hoc Analysis of Phase 3 Trials and Claims-Based Analysis

Objectives: To assess cigarette smoking’s effects on efficacy of the preferential Janus kinase (JAK) 1 inhibitor filgotinib and drug persistence in patients with rheumatoid arthritis (RA). Methods: Efficacy in non-smokers, former smokers, and current smokers from phase 3 filgotinib trials was analyzed, including patients with inadequate response (IR) to methotrexate (MTX) or biologic disease-modifying antirheumatic drugs (bDMARDs) or who were MTX-naïve. Proportions achieving Disease Activity Score in 28 joints with C-reactive protein (DAS28[CRP]) ≤ 3.2 were compared using logistic regression. Retrospective claims-based switching data were reviewed. Results: Week 12 (W12) DAS28(CRP) ≤ 3.2 was achieved by 50, 61, and 62% of MTX-IR non-smokers, former smokers, and current smokers taking filgotinib 200 mg (FIL200) + MTX vs. 23, 16, and 32% taking placebo + MTX (p < 0.001, < 0.001, and 0.001) and 50, 34, and 33% taking adalimumab + MTX (p = 0.97, 0.013, and 0.006 vs. FIL200 + MTX). W12 DAS28(CRP) ≤ 3.2 was achieved by 46, 48, and 32% of bDMARD-IR non-smokers, former smokers, and current smokers taking FIL200 + conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) vs. 16, 23, and 5% taking placebo + csDMARD (p < 0.001, 0.077, and 0.051); 57, 58, and 59% of respective MTX-naïve smoking groups achieved W12 DAS28(CRP) ≤ 3.2 with FIL200 + MTX vs. 28, 37, and 18% with MTX (p < 0.001, 0.026, and < 0.001). Claims data showed former/current smokers were likelier than non-smokers to switch from adalimumab to other biologics or JAK inhibitors. Conclusions: Greater proportions of MTX-IR current/former smokers responded to FIL200 + MTX vs. adalimumab + MTX. In non-smoking MTX-IR, bDMARD-IR, and MTX-naïve patients with RA, FIL200 + MTX demonstrated increased response vs. controls. Current/former smokers were likelier to discontinue adalimumab vs. non-smokers in real-world clinical settings. Trial Registration: NCT02889796, NCT02873936, NCT02886728

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BCR Responsiveness is associated with Time to First Treatment (TTFT) in B-Cell Chronic Lymphocytic Leukemia (B-CLL): results from a Single Cell Network Profiling (SCNP) verification study

Background: B-cell chronic lymphocytic leukemia (B-CLL) follows a highly variable clinical course, with some patients having indolent disease and not requiring treatment, whereas others experience rapid disease progression, treatment resistance, and death within 2 to 3 years. Widely accepted staging systems, biological parameters, and prognostic indices help stratify patients into risk groups, yet there remains substantial intragroup heterogeneity. Single cell network profiling (SCNP) is a multiparametric flow cytometry-based assay that simultaneously measures, quantitatively at the single cell level, both extracellular surface marker levels and changes in intracellular signaling proteins in response to extracellular modulators (Kornblau et al. Clin Cancer Res 2010). Previously, we reported the use of this assay to functionally characterize BCR signaling in 21 cryopreserved samples from Binet Stage A B-CLL patients. In that study, a panel of signaling nodes (a node is defined as the combination of extracellular modulator and corresponding intracellular readout and is abbreviated nodereadout) was examined and increased anti-IgM-induced phospho (p)-Erk signaling (anti-IgMp-Erk) was associated with shorter time from diagnosis to first treatment (TTFT) (Scupoli et al. EHA 2010). Objectives: The present study was undertaken to independently verify the association between BCR responsiveness and shorter TTFT, to assess repeatability of SCNP measurements in B-CLL cells, and to explore additional signaling nodes relevant to B-CLL biology. Methods: SCNP was performed as previously described on cryopreserved peripheral blood mononuclear cells (PBMC) collected between 2004 and 2009 from 32 patients with untreated Binet Stage A B-CLL at various points during their clinical follow up; at the time of the analysis, 9 (28%) progressed to active disease, requiring treatment. Median follow-up was 47 months (range 4 to 179 months). SCNP analysis of 21 signaling nodes investigating B cell receptor, survival and NFkB signaling in B-CLL cells was performed in replicate, on separate plates run on the same day. Repeatability was assessed by regressing paired induced signaling measurements from experimental replicates. Associations between SCNP measurements and TTFT were determined using Cox Proportional Hazards regression. Results: Excellent repeatability was observed for SCNP signaling measurements in B-CLL cells (e.g., anti-IgMp-Erk: R2=0.97, slope=1.01). Consistent with the previous study, an association between BCR responsiveness, measured by anti-IgMp-Erk, and shorter TTFT was also observed in this study, although the pre-specified significance criteria were not met (likelihood ratio (LR) Chi square (2) test p=0.07). A post hoc analysis excluding two samples with low viability (low % aqua negative cells) was also performed (Figure 1a) showing a statistically significant association between anti-IgMp-Erk signaling and TTFT (p=0.03, Figure 1b). Among the new nodes investigated in this study, an additional significant association between increased anti-IgDp-NFkB and shorter TTFT was identified (p=0.02). Conclusions: This study confirms, in an independent data set, the association between increased anti-IgMp-Erk signaling and shorter TTFT in B-CLL that was observed previously in a separate study. In addition, a newly identified association between anti-IgDp-NFkB and TTFT was observed, thus supporting the role of BCR signaling in the pathogenesis of the disease and the utility of SCNP assay in elucidating these signaling deregulations with the potential for the development of prognostic and predictive tests

Association between B-cell receptor responsiveness and disease progression in B-cell chronic lymphocytic leukemia: results from single cell network profiling studies

Background. While many prognostic markers in B-cell chronic lymphocytic leukemia provide insight into the biology of the disease, few have been demonstrated to be useful in the daily patient management. B-cell receptor signaling is a driving event in B-cell chronic lymphocytic leukemia progression and markers of B-cell receptor responsiveness have been shown to be of prognostic value. Single cell network profiling, a multiparametric flow cytometry-based assay, allows functional signaling analysis at the level of the single cell. Design and Methods. B-cell receptor signaling proteins (i.e. p-SYK, p-NF-\u3baB p65, p-ERK, p-p38, p-JNK) were functionally characterized by single cell network profiling in samples from patients with B-cell chronic lymphocytic leukemia in an exploratory study (n=27) after stimulation with anti-IgM. Significant association of single cell network profiling data with clinical outcome (i.e. time to first treatment) as assessed by Cox regression models were then confirmed in patient samples in other two sequential independent studies, i.e. test study 1 (n=30), and test study 2 (n=37). Results. In the exploratory study, higher responsiveness of the B-cell receptor signaling proteins to anti-IgM was associated with poor clinical outcomes. Patient clustering based on signaling response was at least as powerful in discriminating different disease courses as traditional prognostic markers. In an unselected subgroup of Binet Stage A patients (n=21), increased anti-IgM-modulated p-ERK signaling was shown to be a significant, independent predictor of shorter time to first treatment. This result was independently confirmed in 2 test cohorts from distinct patient populations. Conclusions. These findings support the utility of the single cell network profiling assay in elucidating signaling perturbations with the potential for the development of a clinically useful prognostic test in patients with early stage B-cell chronic lymphocytic leukemia. These data support the clinical relevance of B-cell receptor signaling in B-cell chronic lymphocytic leukemia, and suggest a key role of ERK activation in the physiopathology of this leukemia