An investigational drug known as SAR100842, which inhibits lysophosphatidic acid (LPA), was safe, moderately effective, and well tolerated in patients with early diffuse cutaneous systemic sclerosis (SSc), according to an international team reporting their findings in Arthritis & Rheumatology.
While the pathogenesis of SSc remains uncertain, LPA is suspected of playing a role and may contribute to tissue fibrosis. Considering the unmet therapeutic needs of the population, investigators were interested in examining this LPA1 selective antagonist, to determine whether SAR100842 might fill this treatment gap. The trial was the first to evaluate oral administration in patients with early diffuse cutaneous SSc.
A double-blind randomized placebo-controlled phase 2a study (ClinicalTrials.gov identifier: NCT01651143) lasted 8 weeks and was followed by a 16-week open label extension. Participants with disease duration <36 months and a modified Rodnan skin score (mRSS) of ≥15 at baseline were randomly assigned to receive SAR100842 300 mg (n=15; mean age, 48.8 years, 60% women; mean disease duration, 20.4 months) or placebo (n=17; mean age, 50.6 years, 71% women; mean disease duration, 19.6 months) twice daily for 8 weeks. From 8 to 24 weeks, all 30 remaining patients received SAR100842 300 mg twice daily. The primary outcome was safety during the first 8 weeks, while secondary outcomes included LPA target engagement, biomarker assessment, and clinical efficacy.
During the initial 8 weeks, SAR100842 demonstrated an acceptable safety profile, and the most common adverse events included headache, nausea, diarrhea, and falls. In the treatment group, 80% of patients reported ≥1 treatment-emergent adverse event vs 71% in the placebo group. Most adverse events were mild or moderate. The safety profile remained acceptable through the rest of the trial, and there were no safety signals detected regarding vital signs, electrocardiogram, orthostatic hypotension, or laboratory parameters across 24 weeks.
After 8 weeks, upon gene signature analysis the forearm skin of patients receiving SAR100842 showed a larger decrease in LPA-linked genes vs the skin of patients receiving placebo, which indicated LPA1 target engagement. There was no significant difference in biomarker expression between the two patient groups.
Although it did not reach statistical significance, compared with the placebo group, the treatment arm experienced a numerically greater reduction in mRSS at 8 weeks (mean change, −3.57 vs −2.76; difference, −1.2; 95% CI, −4.37 to 2.02; P =.46). At 24 weeks, both groups had clinically relevant decreases in mRSS from baseline, with an improvement of ≥5 points in 78.6% and 69.2% of patients in the SAR100842/SAR100842 and placebo/SAR100842 groups, respectively.
Study limitations included a small sample size, short study duration, and lack of data regarding organ involvement.
The experimental drug SAR100842 was well tolerated, with an acceptable safety profile and clinically important effects on skin fibrosis. However, further studies of longer duration are needed. The investigators concluded, “Altogether these results suggest the potential clinical benefit of SAR100842 in [diffuse cutaneous] SSc patients for whom unmet needs remain and deserve its evaluation in confirmatory trials.”
Disclosures: The study was funded by Sanofi.
Allanore Y, Distler O, Jagerschmidt A, et al. Double-blind, randomized, 8-week placebo-controlled followed by a 16-week open label extension study, with the LPA1 receptor antagonist SAR100842 for patients with diffuse cutaneous systemic sclerosis [published online May 6, 2018]. Arthritis Rheumatol. doi:10.1002/art.40547