Novel systemic sclerosis drugs: an overview of what might be to come

A plethora of therapies have been tested in SSc, and many eventually failed. Currently, multiple therapies are being tested that modify the immune and vascular system as pathogenetic nodes underlying the pathogenesis of SSc. Among these is abatacept, targeting T-cell activation. Although the completed clinical trial data is still embargoed at the time of writing, there was a significant difference between placebo and abatacept in terms of percentage improvement in skin scores.

Another new agent is belimumab, a B-cell inhibitor. Data show that it needs to be used very early on in the disease, but the results so far are encouraging. Lenabasum, an oral endocannabinoid-mimetic medicine designed to target chronic inflammation and fibrosis simultaneously, has been studied in a small study (n=25) vs placebo. Patients who had completed 52 weeks of lenabasum treatment in the extension trial showed an improvement by 56% on their ACR CRISS (American College of Rheumatology’s diffuse cutaneous systemic sclerosis) score. Skin thickness improved by 8.6 points (measured by modified Rodnan Skin Score [mRSS]). Safety and tolerability has been considered to be acceptable with no severe or serious AEs.[1] A Phase 3 trial (RESOLVE-1) using lenabasum, is currently underway in Europe.[2]

Pirfenidone, a small molecule inhibitor of several pathways, including transforming growth factor beta, fibroblast growth factor, and platelet-derived growth factor is approved for idiopathic pulmonary fibrosis (IPF) and may be another option for SSc; a systematic literature review of five randomised controlled trials showed it decreased all-cause mortality vs placebo. Furthermore, main AEs during pirfenidon seem to be gastrointestinal by nature. [3]

Encouraging data are also seen with nintedanib, approved for IPF, and therefore may also promising for SSc.[4] Nintedanib is a tyrosine kinase inhibitor which specifically aims at platelet-derived growth factor receptors, fibroblast growth factor receptors, and vascular endothelial growth factor receptors.[5] However, the available data on IPF require caution since they differ from SSc (e.g. more male patients) and warrants further study.

Tocilizumab, an IL-6 receptor inhibitor, has shown interesting results in a Phase 2 trial in SSc patients in comparison to placebo. Although tocilizumab was not associated with a significant reduction in skin thickening, the difference was greater in those receiving tocilizumab than those on placebo. Furthermore, some evidence of diminished forced vital capacity was observed.[6] Phase 3 data are needed to support these findings with regard to efficacy and safety of tocilizumab.

A very different approach is the use of adipose derived mesenchymal cells and mesenchymal products such as exosomes and microparticles that are studied in early clinical studies in SSc. Overall, this is an exciting and encouraging time for novel therapies to treat SSc, one of the most detrimental systemic rheumatic disease.[7]