Selective autotaxin inhibition shows promise in diffuse cutaneous systemic sclerosis

The selective autotaxin inhibitor ziritaxestat shows therapeutic potential in patients with early diffuse cutaneous systemic sclerosis (dcSSc), conferring greater reductions in modified Rodnan skin score (MRSS) compared with placebo and potentially reducing fibrosis, according to data from the phase IIa NOVESA study.

NOVESA was a multicentre, double-blind, placebo-controlled trial that included 33 adults (mean age 49.3 years, 70 percent women) with dcSSc (mean duration 1.9 years). They were randomly assigned to receive oral ziritaxestat 600 mg (n=21) or matching placebo (n=12) once daily for 24 weeks. Afterwards, patients could enter the 104-week open-label extension (OLE) phase.

The primary endpoint was the change from baseline in MRSS at week 24. Secondary endpoints were safety and tolerability. Skin and blood biomarkers were also examined.

Over 24 weeks, MRSS decreased at a significantly greater magnitude in the ziritaxestat group than in the placebo group (–8.9 vs –6.0 units; p=0.0411). Placebo-treated patients who switched to ziritaxestat in the OLE achieved reductions in MRSS similar to those seen for ziritaxestat-treated patients in the double-blind treatment phase.

Ziritaxestat was tolerated well, with headache and diarrhoea being the most frequent treatment-related adverse events.

Biomarker analysis showed a marked reduction in circulating lysophosphatidic acid (LPA) C18:2, which indicated that ziritaxestat successfully engaged its target. Moreover, the levels of fibrosis biomarkers in the blood dropped.

There were no differentially expressed genes identified in skin biopsies. Significant changes in 109 genes were noted in blood samples.