A 24‐Week, Phase IIa, Randomized, Double‐Blind, Placebo‐Controlled Study of Ziritaxestat in Early Diffuse Cutaneous Systemic Sclerosis

Abstract

Objective We undertook this study to explore the efficacy, safety, and tolerability of ziritaxestat, a selective autotaxin inhibitor, in patients with early diffuse cutaneous systemic sclerosis (dcSSc). Methods NOVESA was a 24‐week, multicenter, phase IIa, double‐blind, placebo‐controlled study. Adults with dcSSc were randomized to oral ziritaxestat 600 mg once daily or matching placebo. The primary efficacy end point was change from baseline in modified Rodnan skin score (MRSS) at week 24. Secondary end points assessed safety and tolerability; other end points included assessment of skin and blood biomarkers. Patients in NOVESA could enter a 104‐week open‐label extension (OLE). Results Patients were randomized to ziritaxestat (n = 21) or placebo (n = 12). Reduction in MRSS was significantly greater in the ziritaxestat group versus the placebo group (–8.9 versus –6.0 units, respectively; P = 0.0411). Placebo patients switching to ziritaxestat in the OLE showed similar reductions in MRSS to those observed for ziritaxestat patients in the parent study. Ziritaxestat was well tolerated; the most frequent treatment‐related treatment‐emergent adverse events were headache and diarrhea. Circulating lysophosphatidic acid (LPA) C18:2 was significantly reduced, demonstrating ziritaxestat target engagement, and levels of fibrosis biomarkers were reduced in the blood. No differentially expressed genes were identified in skin biopsies. Significant changes in 109 genes were identified in blood samples. Conclusion Ziritaxestat resulted in significantly greater reduction in MRSS at week 24 than placebo; no new safety signals emerged. Biomarker analysis suggests ziritaxestat may reduce fibrosis. Modulation of the autotaxin/LPA pathway could improve skin involvement in patients with dcSSc. A plain language summary is provided in the Supplementary Material, available on the Arthritis & Rheumatology website at https://onlinelibrary.wiley.com/doi/10.1002/art.42477.

Pharmacokinetics and Metabolism of Ziritaxestat (GLPG1690) in Healthy Male Volunteers Following Intravenous and Oral Administration

“…12,16 Ziritaxestat is a novel ATX inhibitor 17 that was in development as a treatment for IPF and systemic sclerosis. 18 Phase 2 studies have been completed in patients with IPF 19 and systemic sclerosis 20 ; however, phase 3 trials of ziritaxestat in addition to standard-ofcare treatment in patients with IPF were halted because the benefit-risk profile of ziritaxestat was found to no longer support continuation of these trials. The pharmacokinetics (PK) of ziritaxestat have been reported separately.…”

Clinical Trials in Systemic Sclerosis: Crossroads and Opportunities

“…These data suggest that MMF may have some therapeutic effect, but certainly not as robust as anyone would like. When we examine ACR CRISS scores reported in the study by Khanna et al (13), which was a secondary end point, the ziritaxestat and placebo groups both showed high probability of improvement at 24 weeks (0.97 versus 0.83, respectively), again raising the concern for a ceiling effect possibly limiting the ability to discriminate treatments and highlighting the impact of background immune‐suppressing therapy. ACR CRISS was able to discriminate treatment groups in the lenabasum phase II study and tocilizumab and abatacept studies.…”

“…It is with this backdrop that we read with keen interest the results of the clinical trial of the autotaxin inhibitor, ziritaxestat, conducted by Khanna et al for the treatment of patients with early diffuse cutaneous SSc (13). This study allowed for background immune‐suppressing therapy, which was utilized in the vast majority of patients in both treatment groups of this study.…”

“…This study allowed for background immune‐suppressing therapy, which was utilized in the vast majority of patients in both treatment groups of this study. Patients treated with ziritaxestat had a statistically significant improvement in the MRSS at week 24 compared to the placebo group, although scrutiny of the overall trajectory of the skin disease in both groups was not convincingly different (see Figure 2A in Khanna et al [13]). Like many prior studies, this study examined a drug that modulates a pathway that is thought to be clinically relevant in SSc.…”

Role of autotaxin in systemic lupus erythematosus

“…The ATX-LPA axis may be a potential therapeutic target in IPF, and clinical trials of ziritaxestat, an ATX inhibitor, are being conducted ( 9 , 36 ). The ATX-LPA axis is also involved in skin fibrosis in systemic sclerosis ( 37 ), and a recent clinical trial of ziritaxestat for patients with early diffuse cutaneous systemic sclerosis indicated that inhibition of ATX may improve skin symptoms ( 38 ).…”