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11-11-2020 | Rheumatology | News | Article

ACR 2020

​​​​​​​Ziritaxestat warrants further investigation in early diffuse cutaneous systemic sclerosis

Author: Laura Cowen

medwireNews: The autotaxin inhibitor ziritaxestat may improve skin fibrosis in patients with early diffuse cutaneous systemic sclerosis (dcSSc), show data from the phase 2a NOVESA study presented at the ACR Convergence 2020 virtual meeting.

Dinesh Khanna, from the University of Michigan in Ann Arbor, USA, explained that ziritaxestat is a small-molecule, selective autotaxin inhibitor that may modulate the production of lysophosphatidic acid (LPA), a pro-fibrotic and pro-inflammatory lysophospholipid.

For the study, 33 patients (mean age 49.3 years, 70% women) with early dcSSc (≤5 years duration) were randomly assigned to receive oral ziritaxestat 600 mg once daily (n=21) or matching placebo (n=12) for 24 weeks.

At baseline, the mean modified Rodnan skin score (mRSS) was 27.0 units in the ziritaxestat group and 22.5 units in the placebo group, with 95.2% and 83.3% of patients in the respective groups on stable background immunosuppressants.

By week 24, individuals receiving ziritaxestat had a least-squares mean reduction in mRSS of 8.3 units compared with a reduction of 5.7 units in the placebo group, resulting in a significant between-group difference.

Khanna noted that the divergence in scores between the two groups started at around week 16.

The researchers also assessed the ACR Combined Response Index for Systemic Sclerosis (CRISS) and found that at week 24 the median scores were 0.97 points with ziritaxestat and 0.83 points with placebo. However, one patient in the placebo group had an “implausible” improvement in forced vital capacity (FVC; 1381 mL ) at week 24, and when this patient was excluded the median ACR CRISS score was 0.69 points.

Khanna reported that 64.7% of patients receiving ziritaxestat showed likelihood of clinical improvement according to the ACR CRISS (score ≥0.6 points on a scale of 0.0–1.0) compared with 62.5% of patients receiving placebo and 57.1% of placebo-treated patients with the FVC outlier excluded.

Biochemical analyses of circulating LPA levels suggested that target inhibition was occurring among patients who received ziritaxestat, with a reduction of approximately 80% observed following the doses given at weeks 4 and 16.

There were no safety concerns highlighted during the study. Just over half (57.1%) of patients in the ziritaxestat group experienced a treatment-related adverse event, as did half of those in the placebo group, all of which were mild or moderate in severity.

There were two severe adverse events in the ziritaxestat group (pharyngitis in one patient and two cases of device-related infection in one patient) that were not thought to be related to the study drug.

Khanna concluded that the results of the NOVESA study “support a possible role for the autotaxin pathway in the pathogenesis of SSc skin disease and warrant further clinical research.”

He added that 31 of the 33 patients enrolled in the study have continued into an open label long-term extension of the NOVESA study and will be receiving ziritaxestat daily for the next 48 months.

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2020 Springer Healthcare Ltd, part of the Springer Nature Group

ACR Convergence virtual meeting; 5–9 November 2020

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