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Lysophosphatidic Acid Receptor 1 Antagonist SAR100842 for Patients With Diffuse Cutaneous Systemic Sclerosis
Author(s) -
Allanore Yannick,
Distler Oliver,
Jagerschmidt Alexandre,
Illiano Stephane,
Ledein Laetitia,
Boitier Eric,
Agueusop Icent,
Denton Christopher P.,
Khanna Dinesh
Publication year - 2018
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.40547
Subject(s) - lysophosphatidic acid , placebo , medicine , nausea , clinical endpoint , gastroenterology , adverse effect , phases of clinical research , antagonist , diarrhea , confidence interval , clinical trial , receptor , pathology , alternative medicine
Objective Preclinical studies suggest a role for lysophosphatidic acid ( LPA ) in the pathogenesis of systemic sclerosis ( SS c). We undertook this study to assess SAR 100842, a potent selective oral antagonist of the LPA 1 receptor, for safety, biomarkers, and clinical efficacy in patients with diffuse cutaneous SS c (dc SS c). Methods An 8‐week double‐blind, randomized, placebo‐controlled study followed by a 16‐week open‐label extension with SAR 100842 was performed in patients with early dc SS c who had a baseline modified Rodnan skin thickness score ( MRSS ) of at least 15. The primary end point was safety during the double‐blind phase of the trial. Exploratory end points included the identification of an LPA ‐induced gene signature in patients’ skin. Results Seventeen of 32 patients were randomly assigned to receive placebo and 15 to receive SAR 100842; 30 patients participated in the open‐label extension study. The most frequent adverse events reported for SAR 100842 during the blinded phase were headache, diarrhea, nausea, and falling, and the safety profile was acceptable during the open‐label extension. At week 8, the reduction in MRSS was numerically greater in the SAR 100842 group than in the placebo group (mean ± SD change −3.57 ± 4.18 versus −2.76 ± 4.85; treatment effect −1.2 [95% confidence interval −4.37, 2.02]; P = 0.46). A greater reduction of LPA ‐related genes was observed in skin samples from the SAR 100842 group at week 8, indicating LPA 1 target engagement. Conclusion SAR 100842, a selective orally available LPA 1 receptor antagonist, was well tolerated in patients with dc SS c. The MRSS improved during the study although the difference was not significant, and additional gene signature analysis suggested target engagement. These results need to be confirmed in a larger controlled trial.