In addition to directly targeting TGF-β, a number of other important pathways can lead to the activation of fibroblasts and to the production of TGF-β. Based on the preclinical work of LPA and its receptor, LPA1, in dermal fibrosis, a Phase 2 trial of an LPA1 antagonist, SAR100842, was recently completed and showed an excellent safety profile and promising clinical efficacy.18 A Phase 3 trial of the LPA1 antagonist in scleroderma is currently being planned.
Given the role of endothelin-1 in fibrosis and the use of endothelin-1 receptor antagonists (ERAs) in the treatment of SSc-associated PH, there has been promise that these medications might additionally provide benefit in skin fibrosis. However, a recent cohort study of patients from the EUSTAR database compared patients treated with an ERA vs. those who had not, and failed to show a difference in the change in mRSS between the two groups over the study period.19 In addition, the Bosentan in Interstitial Lung Disease in Systemic Sclerosis-2 (BUILD‑2) study, which randomized patients with SSc‑ILD to bosentan or placebo, found no difference in the six-minute walk test or in pulmonary function tests at 12 months, further suggesting that this group of medications may not be useful for the fibrotic manifestations of SSc.20
Tocilizumab, a monoclonal antibody against the IL-6 receptor, is currently approved for use in rheumatoid arthritis and is under evaluation for several rheumatic diseases. A recent Phase 2 trial of tocilizumab in SSc was completed.21 Although the primary endpoint of a reduction in mRSS was not met at Week 24, there was a trend toward improvement in skin scores in the tocilizumab group compared to the placebo group at Week 48. Interestingly, there was also a trend toward a slower FVC decline, although the study was not initially designed to look at this endpoint. Based on these results, a Phase 3 trial is currently being planned.
A number of other new therapeutics are currently under evaluation for SSc fibrosis. Pirfenidone and nintedanib, two anti-fibrotic medications approved for the treatment of idiopathic pulmonary fibrosis (IPF), are currently being studied in SSc-ILD. A Phase 2 trial of pirfenidone in SSc-ILD (LOTUSS) was completed and showed acceptable tolerability, even with over 60% of patients concurrently taking MMF.22 A Phase 3 trial of nintedanib in SSc-ILD is currently ongoing and recruiting patients (ClinicalTrials.gov identifier: NCT02597933).
Abatacept, a CTLA4-IgG fusion protein approved for use in rheumatoid arthritis, is currently being studied in patients with early dcSSc (ASSET; ClinicalTrials.gov identifier: NCT02161406).
