OBJECTIVE: Preclinical studies suggest a role for lysophosphatidic acid (LPA) in the pathogenesis of systemic sclerosis (SSc). We undertook this study to assess SAR100842, a potent selective oral antagonist of the LPA1 receptor, for safety, biomarkers, and clinical efficacy in patients with diffuse cutaneous SSc (dcSSc). METHODS: An 8-week double-blind, randomized, placebo-controlled study followed by a 16-week open-label extension with SAR100842 was performed in patients with early dcSSc 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 SAR100842; 30 patients participated in the open-label extension study. The most frequent adverse events reported for SAR100842 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 SAR100842 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 SAR100842 group at week 8, indicating LPA1 target engagement. CONCLUSION: SAR100842, a selective orally available LPA1 receptor antagonist, was well tolerated in patients with dcSSc. 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.
RCT Entities:
OBJECTIVE: Preclinical studies suggest a role for lysophosphatidic acid (LPA) in the pathogenesis of systemic sclerosis (SSc). We undertook this study to assess SAR100842, a potent selective oral antagonist of the LPA1 receptor, for safety, biomarkers, and clinical efficacy in patients with diffuse cutaneous SSc (dcSSc). METHODS: An 8-week double-blind, randomized, placebo-controlled study followed by a 16-week open-label extension with SAR100842 was performed in patients with early dcSSc 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 SAR100842; 30 patients participated in the open-label extension study. The most frequent adverse events reported for SAR100842 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 SAR100842 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 SAR100842 group at week 8, indicating LPA1 target engagement. CONCLUSION:SAR100842, a selective orally available LPA1 receptor antagonist, was well tolerated in patients with dcSSc. 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.
Authors: Anna Axelsson Raja; Hiroko Wakimoto; Daniel M DeLaughter; Daniel Reichart; Joshua Gorham; David A Conner; Mingyue Lun; Clemens K Probst; Norihiko Sakai; Rachel S Knipe; Sydney B Montesi; Barry Shea; Leonard P Adam; Leslie A Leinwand; William Wan; Esther Sue Choi; Eric L Lindberg; Giannino Patone; Michela Noseda; Norbert Hübner; Christine E Seidman; Andrew M Tager; J G Seidman; Carolyn Y Ho Journal: Proc Natl Acad Sci U S A Date: 2022-07-05 Impact factor: 12.779
Authors: Laetitia Ledein; Bertrand Léger; Clara Dees; Christian Beyer; Alfiya Distler; Serena Vettori; Rachid Boukaiba; Jean Pierre Bidouard; Matthias Schaefer; Josef Pernerstorfer; Hartmut Ruetten; Alexandre Jagerschmidt; Philip Janiak; Jörg H W Distler; Oliver Distler; Stéphane Illiano Journal: Br J Pharmacol Date: 2020-08-05 Impact factor: 8.739