The autotaxin inhibitor ziritaxestat proved to be efficacious and tolerable in the first randomised, double-blind, placebo-controlled phase 2 trial ever conducted in patients with diffuse cutaneous systemic sclerosis.

Vasculopathy, inflammation, and fibrosis form a specific triad of features found in systemic sclerosis (SSc), a disease with a high unmet need for novel treatments [1]. Although tremendous strides have been made in understanding the biology of fibrosis, still no targeted therapies have been approved in SSc. While the pathogenesis of SSc remains uncertain, lysophosphatidic acid (LPA) is a well-known pro-fibrotic and pro-inflammatory lysophospholipid that has been implicated in the pathogenesis of SSc. LPA is generated at sites of inflammation by autotaxin-mediated hydrolysis of lysophosphatidylcholine and other lysophospholipids. Ziritaxestat is an autotaxin inhibitor with a novel mechanism of action that could be promising for modulating the skin pathology of SSc and as such might be able to fill the current treatment gap. The current phase 2a randomised, double-blind, placebo-controlled trial was the first to evaluate oral administration of ziritaxestat in patients with early diffuse cutaneous SSc.

Adult patients with diffuse cutaneous SSc (n=33) were randomised 2:1 to receive oral ziritaxestat 600 mg once daily or matching placebo for 24 weeks. Immunosuppressive background therapies were allowed to continue unchanged if doses were stable for ≥3 months prior to ziritaxestat treatment. All patients had a modified Rodnan skin score (mRSS) >10 at screening. The primary endpoint was change from baseline mRSS at 24 weeks. Other endpoints were Health Assessment Questionnaire Disability Index (HAQ-DI) and Combined Response Index for Systemic Sclerosis (ACR CRISS) score. In addition, safety data were collected.

Baseline criteria were comparable between the groups. The majority of patients in the ziritaxestat (95.2%) and placebo (83.3%) groups were on background immunosuppressive therapy. At baseline, mean (SD) mRSS was 27.0 (8.8) and 22.5 (6.2). A statistically significant difference was observed between groups for mRSS from week 16 up to week 24: least square mean difference was -2.8 (95% CI -5.6 to -0.1) for ziritaxestat versus placebo (P=0.0411) at week 24. “This effect is significant because this improvement happened despite the background immunosuppressive therapy,” Prof. Dinesh Khanna (University of Michigan Scleroderma Program, USA) explained. “It is a nice outcome because with only 33 patients we achieved a significant result,” he said.

In addition, the ACR CRISS showed likelihood for improvement. Treatment with ziritaxestat did not influence lung function. Target inhibition was reflected by an average reduction in circulating lysophosphatidic acid of about 80%.

Adverse events (AEs) were mild or moderate; no treatment-emergent AE led to study drug discontinuation. Serious treatment-emergent AEs occurred in 2 patients in the ziritaxestat group and 1 patient in the placebo group, all of them were considered unrelated or unlikely related to the study drug.

“We believe that these results support a possible role for the autotaxin pathway in early dermal SSc,” Prof. Khanna concluded. Of course, further clinical research in a larger-scale clinical study is warranted.


  1. Khanna D, et al. A Phase 2a Randomized, Double-blind, Placebo-controlled Study of Ziritaxestat in Early Diffuse Cutaneous Systemic Sclerosis (NOVESA). L09, ACR Convergence 2020 Virtual Annual Meeting, 5-9 November 2020.