دورية أكاديمية
أعرض في EDS

A 24-Week, Phase IIa, Randomized, Double-Blind, Placebo-Controlled Study of Ziritaxestat in Early Diffuse Cutaneous Systemic Sclerosis.

التفاصيل البيبلوغرافية
العنوان: A 24-Week, Phase IIa, Randomized, Double-Blind, Placebo-Controlled Study of Ziritaxestat in Early Diffuse Cutaneous Systemic Sclerosis.
المؤلفون: Khanna D; University of Michigan Scleroderma Program, Ann Arbor, Michigan., Denton CP; Royal Free Hospital, University College London, London, UK., Furst DE; David Geffen School of Medicine at UCLA, Los Angeles, California, University of Washington, Seattle, Washington, and University of Florence, Florence, Italy., Mayes MD; University of Texas Health Science Center at Houston., Matucci-Cerinic M; Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, Milan, Italy, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy, and Division of Rheumatology, AOUC, Florence, Italy., Smith V; Department of Internal Medicine, Ghent University, Ghent, Belgium, and Department of Rheumatology, Ghent University Hospital, Ghent, Belgium, and Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center (IRC), Ghent, Belgium., de Vries D; Galapagos BV, Leiden, Netherlands., Ford P; Galapagos NV, Mechelen, Belgium., Bauer Y; Galapagos GmbH, Basel, Switzerland., Randall MJ; Galapagos GmbH, Basel, Switzerland., Ebrahimpoor M; Galapagos BV, Leiden, Netherlands., Kupcsik L; Galapagos NV, Mechelen, Belgium., Stiers PJ; Galapagos NV, Mechelen, Belgium., Deberdt L; Galapagos NV, Mechelen, Belgium., Prasad N; Galapagos NV, Mechelen, Belgium., Lim S; Gilead Sciences, Inc., Foster City, California., Pujuguet P; Galapagos SASU, Romainville, France., Ahmed S; Galapagos GmbH, Basel, Switzerland.
المصدر: Arthritis & rheumatology (Hoboken, N.J.) [Arthritis Rheumatol] 2023 Aug; Vol. 75 (8), pp. 1434-1444. Date of Electronic Publication: 2023 May 15.
نوع المنشور: Randomized Controlled Trial; Multicenter Study; Clinical Trial, Phase II; Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Wiley Country of Publication: United States NLM ID: 101623795 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2326-5205 (Electronic) Linking ISSN: 23265191 NLM ISO Abbreviation: Arthritis Rheumatol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Malden, MA : Wiley, [2014]-
مواضيع طبية MeSH: Scleroderma, Diffuse*/pathology, Adult ; Humans ; Treatment Outcome ; Skin/pathology ; Biopsy ; Double-Blind Method ; Fibrosis
مستخلص: Objective: We undertook this study to explore the efficacy, safety, and tolerability of ziritaxestat, a selective autotaxin inhibitor, in patients with early diffuse cutaneous systemic sclerosis (dcSSc).
Methods: NOVESA was a 24-week, multicenter, phase IIa, double-blind, placebo-controlled study. Adults with dcSSc were randomized to oral ziritaxestat 600 mg once daily or matching placebo. The primary efficacy end point was change from baseline in modified Rodnan skin score (MRSS) at week 24. Secondary end points assessed safety and tolerability; other end points included assessment of skin and blood biomarkers. Patients in NOVESA could enter a 104-week open-label extension (OLE).
Results: Patients were randomized to ziritaxestat (n = 21) or placebo (n = 12). Reduction in MRSS was significantly greater in the ziritaxestat group versus the placebo group (-8.9 versus -6.0 units, respectively; P = 0.0411). Placebo patients switching to ziritaxestat in the OLE showed similar reductions in MRSS to those observed for ziritaxestat patients in the parent study. Ziritaxestat was well tolerated; the most frequent treatment-related treatment-emergent adverse events were headache and diarrhea. Circulating lysophosphatidic acid (LPA) C18:2 was significantly reduced, demonstrating ziritaxestat target engagement, and levels of fibrosis biomarkers were reduced in the blood. No differentially expressed genes were identified in skin biopsies. Significant changes in 109 genes were identified in blood samples.
Conclusion: Ziritaxestat resulted in significantly greater reduction in MRSS at week 24 than placebo; no new safety signals emerged. Biomarker analysis suggests ziritaxestat may reduce fibrosis. Modulation of the autotaxin/LPA pathway could improve skin involvement in patients with dcSSc. A plain language summary is provided in the Supplementary Material, available on the Arthritis & Rheumatology website at https://onlinelibrary.wiley.com/doi/10.1002/art.42477.
(© 2023 Galapagos NV and The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)
التعليقات: Comment in: Arthritis Rheumatol. 2023 Aug;75(8):1328-1330. (PMID: 37011044)
References: Denton CP, Khanna D. Systemic sclerosis [review]. Lancet 2017;390:1685-99.
Fuschiotti P. Current perspectives on the immunopathogenesis of systemic sclerosis [review]. Immunotargets Ther 2016;5:21-35.
Brown M, O'Reilly S. The immunopathogenesis of fibrosis in systemic sclerosis [review]. Clin Exp Immunol 2019;195:310-21.
Hinchcliff M, O'Reilly S. Current and potential new targets in systemic sclerosis therapy: a new hope [review]. Curr Rheumatol Rep 2020;22:42.
Barsotti S, Orlandi M, Codullo V, et al. One year in review 2019: systemic sclerosis [review]. Clin Exp Rheumatol 2019;37 Suppl 119:3-14.
Khanna D, Lescoat A, Roofeh D, et al. Systemic sclerosis-associated interstitial lung disease: how to incorporate two Food and Drug Administration-approved therapies in clinical practice [review]. Arthritis Rheumatol 2022;74:13-27.
Denton CP. Systemic sclerosis: from pathogenesis to targeted therapy [review]. Clin Exp Rheumatol 2015;33:S3-7.
Kraljić K, Jelić D, Žiher D, et al. Benzoxaboroles-novel autotaxin inhibitors. Molecules 2019;24:3419.
Yuelling LM, Fuss B. Autotaxin (ATX): a multi-functional and multi-modular protein possessing enzymatic lysoPLD activity and matricellular properties [review]. Biochim Biophys Acta 2008;1781:525-30.
Allanore Y, Distler O, Jagerschmidt A, et al. Lysophosphatidic acid receptor 1 antagonist SAR100842 for patients with diffuse cutaneous systemic sclerosis: a double-blind, randomized, eight-week placebo-controlled study followed by a sixteen-week open-label extension study. Arthritis Rheumatol 2018;70:1634-43.
Xu Y. Targeting lysophosphatidic acid in cancer: the issues in moving from bench to bedside [review]. Cancers (Basel) 2019;11:1523.
Castelino FV, Bain G, Pace VA, et al. An autotaxin/lysophosphatidic acid/interleukin-6 amplification loop drives scleroderma fibrosis. Arthritis Rheumatol 2016;68:2964-74.
Pattanaik D, Postlethwaite AE. A role for lysophosphatidic acid and sphingosine 1-phosphate in the pathogenesis of systemic sclerosis [review]. Discov Med 2010;10:161-7.
Taneja A, Desrivot J, Diderichsen PM, et al. Population pharmacokinetic and pharmacodynamic analysis of GLPG1690, an autotaxin inhibitor, in healthy volunteers and patients with idiopathic pulmonary fibrosis. Clin Pharmacokinet 2019;58:1175-91.
Scherer M, Schmitz G, Liebisch G. High-throughput analysis of sphingosine 1-phosphate, sphinganine 1-phosphate, and lysophosphatidic acid in plasma samples by liquid chromatography-tandem mass spectrometry. Clin Chem 2009;55:1218-22.
Higuchi T, Takagi K, Tochimoto A, et al. Antifibrotic effects of 2-carba cyclic phosphatidic acid (2ccPA) in systemic sclerosis: contribution to the novel treatment. Arthritis Res Ther 2019;21:103.
Coornaert B, Duys I, Van Der Schueren J, et al. Autotaxin inhibitor GLPG1690 affects TGFβ-induced production of the pro-fibrotic mediators CTGF, IL-6 and ET-1 in fibroblasts [abstract]. Am J Respir Crit Care Med 2017;195:A2404.
Desroy N, Housseman C, Bock X, et al. Discovery of 2-[[2-ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methyli midazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a first-in-class autotaxin inhibitor undergoing clinical evaluation for the treatment of idiopathic pulmonary fibrosis. J Med Chem 2017;60:3580-90.
Van der Aar E, Desrivot J, Dupont S, et al. Safety, pharmacokinetics, and pharmacodynamics of the autotaxin inhibitor GLPG1690 in healthy subjects: phase 1 randomized trials. J Clin Pharmacol 2019;59:1366-78.
Maher TM, Kreuter M, Lederer DJ, et al. Rationale, design and objectives of two phase III, randomised, placebo-controlled studies of GLPG1690, a novel autotaxin inhibitor, in idiopathic pulmonary fibrosis (ISABELA 1 and 2). BMJ Open Respir Res 2019;6:e000422.
Maher TM, van der Aar EM, Van de Steen O, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1690, a novel autotaxin inhibitor, to treat idiopathic pulmonary fibrosis (FLORA): a phase 2a randomised placebo-controlled trial. Lancet Respir Med 2018;6:627-35.
Van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2013;65:2737-47.
LeRoy EC, Medsger TA, Jr. Criteria for the classification of early systemic sclerosis. J Rheumatol 2001;28:1573-6.
Lafyatis R, Kissin E, York M, et al. B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum 2009;60:578-83.
Kissin EY, Schiller AM, Gelbard RB, et al. Durometry for the assessment of skin disease in systemic sclerosis. Arthritis Rheum 2006;55:603-9.
Hänzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics 2013;14:7.
Merkel PA, Silliman NP, Clements PJ, et al. Patterns and predictors of change in outcome measures in clinical trials in scleroderma: an individual patient meta-analysis of 629 subjects with diffuse cutaneous systemic sclerosis. Arthritis Rheum 2012;64:3420-9.
Khanna D, Furst DE, Hays RD, et al. Minimally important difference in diffuse systemic sclerosis: results from the D-penicillamine study. Ann Rheum Dis 2006;65:1325-9.
Khanna D, Clements PJ, Volkmann ER, et al. Minimal clinically important differences for the modified Rodnan skin score: results from the scleroderma lung studies (SLS-I and SLS-II). Arthritis Res Ther 2019;21:23.
Gordon JK, Martyanov V, Franks JM, et al. Belimumab for the treatment of early diffuse systemic sclerosis: results of a randomized, double-blind, placebo-controlled, pilot trial. Arthritis Rheumatol 2018;70:308-16.
Khanna D, Allanore Y, Denton CP, et al. Riociguat in patients with early diffuse cutaneous systemic sclerosis (RISE-SSc): randomised, double-blind, placebo-controlled multicentre trial. Ann Rheum Dis 2020;79:618-25.
Spiera R, Hummers L, Chung L, et al. Safety and efficacy of lenabasum in a phase II, randomized, placebo-controlled trial in adults with systemic sclerosis. Arthritis Rheumatol 2020;72:1350-60.
Khanna D, Spino C, Johnson S, et al. Abatacept in early diffuse cutaneous systemic sclerosis: results of a phase II investigator-initiated, multicenter, double-blind, randomized, placebo-controlled trial. Arthritis Rheumatol 2020;72:125-36.
Chakravarty EF, Martyanov V, Fiorentino D, et al. Gene expression changes reflect clinical response in a placebo-controlled randomized trial of abatacept in patients with diffuse cutaneous systemic sclerosis. Arthritis Res Ther 2015;17:159.
Allanore Y, Wung P, Soubrane C, et al. A randomised, double-blind, placebo-controlled, 24-week, phase II, proof-of-concept study of romilkimab (SAR156597) in early diffuse cutaneous systemic sclerosis. Ann Rheum Dis 2020;79:1600-7.
Spiera R, Kuwana M, Khanna D, et al. Phase 3 TRIAL of lenabasum, a CB2 agonist, for the treatment of diffuse cutaneous systemic sclerosis (dcSSc) [abstract]. Ann Rheum Dis 2021;80:102-3.
Rice LM, Ziemek J, Stratton EA, et al. A longitudinal biomarker for the extent of skin disease in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheumatol 2015;67:3004-15.
Rice LM, Padilla CM, McLaughlin SR, et al. Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients. J Clin Invest 2015;125:2795-807.
Khanna D, Denton CP, Jahreis A, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial [published correction appears in Lancet 2018;391:1356]. Lancet 2016;387:2630-40.
Salgado-Polo F, Perrakis A. The structural binding mode of the four autotaxin inhibitor types that differentially affect catalytic and non-catalytic functions [review]. Cancers (Basel) 2019;11:1577.
Jethwa SA, Leah EJ, Zhang Q, et al. Exosomes bind to autotaxin and act as a physiological delivery mechanism to stimulate LPA receptor signalling in cells. J Cell Sci 2016;129:3948-57.
Matas-Rico E, Frijlink E, van der Haar Àvila I, et al. Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells. Cell Rep 2021;37:110013.
Zulfikar S, Mulholland S, Adamali H, et al. Inhibitors of the autotaxin-lysophosphatidic acid axis and their potential in the treatment of interstitial lung disease: current perspectives [review]. Clin Pharmacol 2020;12:97-108.
Huang LS, Fu P, Patel P, et al. Lysophosphatidic acid receptor-2 deficiency confers protection against bleomycin-induced lung injury and fibrosis in mice. Am J Respir Cell Mol Biol 2013;49:912-22.
Denton CP, Ong VH, Xu S, et al. Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the faSScinate clinical trial in systemic sclerosis. Ann Rheum Dis 2018;77:1362-71.
Clark KEN, Campochiaro C, Csomor E, et al. Molecular basis for clinical diversity between autoantibody subsets in diffuse cutaneous systemic sclerosis. Ann Rheum Dis 2021;80:1584-93.
تواريخ الأحداث: Date Created: 20230214 Date Completed: 20230731 Latest Revision: 20230801
رمز التحديث: 20231215
DOI: 10.1002/art.42477
PMID: 36787101
قاعدة البيانات: MEDLINE
الوصف
تدمد:2326-5205
DOI:10.1002/art.42477