Background Preclinical genetic and pharmacological studies suggest a role for Lysophosphatidic acid (LPA) in the three key processes characterizing systemic sclerosis (SSc): fibrosis, microangiopathy and immunoinflammation.
Objectives We have assessed SAR100842, a potent orally available selective antagonist of the LPA1 receptor and explored safety, skin biomarkers of LPA pathway, and clinical efficacy in patients with early diffuse cutaneous SSc (dcSSc) in a phase 2a clinical trial.
Methods ACT12339, study NCT01651143 sponsored by SANOFI, was an 8-week double-blind, randomized, placebo-controlled study followed by a 16 week open label extension study with SAR100842. 32 patients with dcSSc <36 months since the onset of the first non-Raynaud's SSc manifestation and an mRSS ≥15 were included. Patients with severe organ involvement that was deemed unsafe were excluded. Background stable immunosuppressant therapy was allowed. The primary endpoint was safety. Secondary end-points included effect on potential biomarkers from skin biopsies and blood samples as well as change in mRSS and S-HAQ at week 8 and 24 in the modified intent to treat (ITT) population defined as any patient with a post investigational product evaluation in each part of the study.
Results 17 patients were randomized to the placebo group and 15 to the SAR100842 group. 30 patients participated in the extension study.
The most frequent adverse events reported under SAR100842 during the blinded period were headache, diarrhea and nausea.
No statistically significant difference between the 2 groups was observed in skin biopsy and blood biomarkers at week 8. However, a greater reduction of some skin LPA-induced marker mRNA levels (e.g. Wnt2, PAI1 and SFRP4) was observed in the SAR100842 group compared to placebo, consistent with successful target engagement. At week 8 an improvement in mRSS (median improvement= - 4.0 versus -1.0 units) and in HAQ-DI were observed in the SAR100842 group compared to placebo, respectively.
The safety profile was good during the extension part. The most frequent adverse events in this part were headache, arthralgia, fatigue and nausea. After 24 weeks of treatment with SAR100842 key skin fibrotic biomarkers (COMP and TSP1) were reduced from baseline. LPA-associated biomarker mRNA levels were improved after 16 weeks of treatment with SAR100842 in the group of patients who initially received placebo. In parallel, there was a clinically meaningful improvement of clinical parameters as indicated in the table below. 78.5% of patients achieved Minimal Clinically Important Difference estimate of mRSS.
Conclusions SAR100842 was well tolerated in patients with dcSSc and resulted in a reduction of skin thickness assessed by mRSS. The clinical efficacy was supported by biological evidence of the LPA target engagement. Altogether these data suggest that SAR100842 may be an effective treatment for dcSSc which needs to be confirmed in a larger controlled trial.
Disclosure of Interest Y. Allanore Grant/research support from: Actelion, Bayer, Biogen Idec, BMS, Genentech/ Roche, Inventive, Medac, Pfizer, Sanofi/Genzyme, Servier and UCB, Consultant for: Actelion, Bayer, Biogen Idec, BMS, Genentech/ Roche, Inventive, Medac, Pfizer, Sanofi/Genzyme, Servier and UCB, A. Jagerschmidt Employee of: Sanofi R&D, M. Jasson Employee of: Sanofi R&D, O. Distler Grant/research support from: 4D Science, Actelion, Active Biotec, Bayer-Schering, Biogen, Biovitrium, BMS, Boehringer Ingelheim Pharma, EpiPharm, Ergonex, GSK, Inventiva, Medac, Novartis, Pfizer, Pharmacyclics, Roche/Genentech, Sanofi/Genzyme, Serodapharm, Sinoxa and United BioSource Corporation., Consultant for: 4D Science, Actelion, Active Biotec, Bayer-Schering, Biogen, Biovitrium, BMS, Boehringer Ingelheim Pharma, EpiPharm, Ergonex, GSK, Inventiva, Medac, Novartis, Pfizer, Pharmacyclics, Roche/Genentech, Sanofi/Genzyme, Serodapharm, Sinoxa and United BioSource Corporation., C. Denton Grant/research support from: Actelion, CSL Behring, Novartis, Consultant for: Sanofi-Aventis, Actelion, GSK, Bayer, Inventiva, Takeda, D. Khanna Grant/research support from: Actelion, Bayer, Bristol-Myers Squibb, EMD Serono, Gilead, InterMune, NIH/NIAMS, NIH/NIAID, Pulmonary Hypertension Association, Consultant for: Actelion, Bayer, Bristol-Myers Squibb, EMD Serono, InterMune, Biogen Idec, Genentech/Roche, Cytori, Lycera, Sanofi/Genzyme, GlaxoSmith/Kline