A 24‐Week , Phase IIa , Randomized, Double‐Blind , Placebo‐Controlled Study of Ziritaxestat in Early Diffuse Cutaneous Systemic Sclerosis
Arthritis & Rheumatology, vol. 75, pp. 1434–1444
Abstract
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.
Authors 17
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University of Michigan · Michigan Medicine
Affiliation as printed
University of Michigan Scleroderma Program Ann Arbor Michigan
Joint first author
University of Michigan Scleroderma Program, Ann Arbor, Michigan, USA
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The Royal Free Hospital · University College London
Affiliation as printed
Royal Free Hospital, University College London London UK
Joint first author
Royal Free Hospital, University College London, London, UK
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University of California, Los Angeles · University of Washington · University of Florence
Affiliation as printed
David Geffen School of Medicine at UCLA, Los Angeles, California, University of Washington, Seattle, Washington, and University of Florence Florence Italy
David Geffen School of Medicine at UCLA, Los Angeles, California, University of Washington, Seattle, Washington, and University of Florence Florence Italy
University of Florence, Florence, Italy
University of Washington, Seattle, Washington, USA
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The University of Texas Health Science Center at Houston
Affiliation as printed
University of Texas Health Science Center at Houston
University of Texas Health Science Center at Houston, Houston, Texas, USA
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Azienda Ospedaliero-Universitaria Careggi · IRCCS Ospedale San Raffaele · University of Florence
Affiliation as printed
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
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
Division of Rheumatology, AOUC, Florence, Italy
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
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Ghent University Hospital · Ghent University · VIB-UGent Center for Inflammation Research
Affiliation as printed
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
Department of Internal Medicine, Ghent University, Ghent, Belgium
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
Department of Rheumatology, Ghent University Hospital, Ghent, Belgium
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Affiliation as printed
Galapagos BV Leiden Netherlands
Galapagos BV, Leiden, Netherlands
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Affiliation as printed
Galapagos NV Mechelen Belgium
Affiliation at the time of study commencement
Galapagos NV, Mechelen, Belgium
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Affiliation as printed
Galapagos GmbH Basel Switzerland
Galapagos GmbH, Basel, Switzerland
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Affiliation as printed
Galapagos GmbH Basel Switzerland
Galapagos GmbH, Basel, Switzerland
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Affiliation as printed
Galapagos BV Leiden Netherlands
Affiliation at the time of study commencement
Galapagos BV, Leiden, Netherlands
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Affiliation as printed
Galapagos NV Mechelen Belgium
Galapagos NV, Mechelen, Belgium
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Affiliation as printed
Galapagos NV Mechelen Belgium
Galapagos NV, Mechelen, Belgium
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Affiliation as printed
Galapagos NV Mechelen Belgium
Galapagos NV, Mechelen, Belgium
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Affiliation as printed
Galapagos NV Mechelen Belgium
Affiliation at the time of study commencement
Galapagos NV, Mechelen, Belgium
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Affiliation as printed
Galapagos SASU Romainville France
Galapagos SASU, Romainville, France
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Sohail Ahmed corresponding
Affiliation as printed
Galapagos GmbH Basel Switzerland
Affiliation at the time of study commencement
Current affiliation: Kling Biotherapeutics, Amsterdam, Netherlands
Galapagos GmbH, Basel, Switzerland
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