{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T17:02:13Z","timestamp":1781888533831,"version":"3.54.5"},"reference-count":46,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T00:00:00Z","timestamp":1684108800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100019832","name":"Galapagos NV","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100019832","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>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).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>NOVESA was a 24\u2010week, multicenter, phase IIa, double\u2010blind, placebo\u2010controlled 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\u2010week open\u2010label extension (OLE).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Patients were randomized to ziritaxestat (n\u00a0=\u00a021) or placebo (n\u00a0=\u00a012). Reduction in MRSS was significantly greater in the ziritaxestat group versus the placebo group (\u20138.9 versus \u20136.0 units, respectively; <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0411). 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\u2010related treatment\u2010emergent 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>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 <jats:italic>Arthritis &amp; Rheumatology<\/jats:italic> website at <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/art.42477\">https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/art.42477<\/jats:ext-link>.<\/jats:p><jats:p><jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art42477-toc-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42477","type":"journal-article","created":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T10:27:39Z","timestamp":1676370459000},"page":"1434-1444","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["A <scp>24\u2010Week<\/scp>, Phase <scp>IIa<\/scp>, Randomized, <scp>Double\u2010Blind<\/scp>, <scp>Placebo\u2010Controlled<\/scp> Study of Ziritaxestat in Early Diffuse Cutaneous Systemic Sclerosis"],"prefix":"10.1002","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1412-4453","authenticated-orcid":false,"given":"Dinesh","family":"Khanna","sequence":"first","affiliation":[{"name":"University of Michigan Scleroderma Program  Ann Arbor Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3975-8938","authenticated-orcid":false,"given":"Christopher P.","family":"Denton","sequence":"additional","affiliation":[{"name":"Royal Free Hospital, University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7857-2373","authenticated-orcid":false,"given":"Daniel E.","family":"Furst","sequence":"additional","affiliation":[{"name":"David Geffen School of Medicine at UCLA, Los Angeles, California, University of Washington, Seattle, Washington, and University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5070-2535","authenticated-orcid":false,"given":"Maureen D.","family":"Mayes","sequence":"additional","affiliation":[{"name":"University of Texas Health Science Center at Houston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Matucci\u2010Cerinic","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Smith","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dick","family":"de Vries","sequence":"additional","affiliation":[{"name":"Galapagos BV  Leiden Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Ford","sequence":"additional","affiliation":[{"name":"Galapagos NV  Mechelen Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmina","family":"Bauer","sequence":"additional","affiliation":[{"name":"Galapagos GmbH  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Randall","sequence":"additional","affiliation":[{"name":"Galapagos GmbH  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitra","family":"Ebrahimpoor","sequence":"additional","affiliation":[{"name":"Galapagos BV  Leiden Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laszlo","family":"Kupcsik","sequence":"additional","affiliation":[{"name":"Galapagos NV  Mechelen Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter\u2010Jan","family":"Stiers","sequence":"additional","affiliation":[{"name":"Galapagos NV  Mechelen Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liesbeth","family":"Deberdt","sequence":"additional","affiliation":[{"name":"Galapagos NV  Mechelen Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niyati","family":"Prasad","sequence":"additional","affiliation":[{"name":"Galapagos NV  Mechelen Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharlene","family":"Lim","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.  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