Khanna, Dinesh;
Denton, Christopher P;
Furst, Daniel E;
Mayes, Maureen D;
Matucci-Cerinic, Marco;
Smith, Vanessa;
de Vries, Dick;
... Ahmed, Sohail; + view all
(2023)
A 24-Week, Phase IIa, Randomized, Double-blind, Placebo-controlled Study of Ziritaxestat in Early Diffuse Cutaneous Systemic Sclerosis (NOVESA).
Arthritis & Rheumatology
, 75
(8)
pp. 1434-1444.
10.1002/art.42477.
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Abstract
OBJECTIVE: NOVESA explored 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, 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 endpoint was change from baseline in modified Rodnan skin score (mRSS) at Week 24. Secondary endpoints assessed safety and tolerability; other endpoints 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 versus placebo group (-8.9 vs. -6.0 units; 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; 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 reductions 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 available in the Supplement.
| Type: | Article |
|---|---|
| Title: | A 24-Week, Phase IIa, Randomized, Double-blind, Placebo-controlled Study of Ziritaxestat in Early Diffuse Cutaneous Systemic Sclerosis (NOVESA) |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/art.42477 |
| Publisher version: | https://doi.org/10.1002/art.42477 |
| Language: | English |
| Additional information: | Copyright © 2023 Galapagos NV and The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10165486 |
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