Zibotentan in systemic sclerosis-associated chronic kidney disease: a phase II randomised placebo-controlled trial

Stern, Edward P; Host, Lauren V; Wanjiku, Ivy; Escott, Jane; Gilmour, Peter S; Ochiel, Rachel; Unwin, Robert; Burns, Aine; Ong, Voon H; Cadiou, Helen; O'Keeffe, Aidan G; Denton, Christopher P

Abstract

Background We report results from a phase II randomised placebo-controlled trial assessing zibotentan, a highly selective endothelin receptor antagonist (ERA), in chronic kidney disease (CKD) secondary to systemic sclerosis (SSc).

Methods This trial included three sub-studies. ZEBRA 1: a randomised placebo-controlled, double-blind, trial of zibotentan in SSc patients with CKD2 or CKD3 (and glomerular filtration rate - GFR >45 ml/min) over 26 weeks. ZEBRA 2A: a 26-week placebo-controlled, single blind trial of zibotentan in scleroderma renal crisis patients not requiring dialysis. ZEBRA 2B: an open label pharmacokinetic study of zibotentan in patients on haemodialysis.

Results Sixteen patients were screened for ZEBRA 1. Of these, 6 patients were randomised to zibotentan and 7 to placebo. In ZEBRA 1 there were 47 non-serious adverse events (AE) during the trial. Twentyseven occurred in the placebo group and 20 in the zibotentan group. One serious adverse event (SAE) occurred during ZEBRA1, in the placebo arm. Descriptive statistics did not suggest an effect of study drug on serum sVCAM1. Estimated GFR numerically declined in patients treated with placebo at 26 weeks and 52 weeks. In contrast, average eGFR increased in zibotentan treated cases. The 4 patients in ZEBRA 2A experienced 8 non-serious AEs, distributed equally between placebo and zibotentan. There was one SAE each in placebo and zibotentan groups, both unrelated to study medication. ZEBRA 2B recruited 8 patients, 6 completed first dosing and 2 completed a second dosing visit. Pharmacokinetic analysis confirmed zibotentan levels within the therapeutic range. Three patients experienced 3 non-serious AEs. One SAE occurred and was unrelated to study drug.

Conclusions Zibotentan was generally well tolerated. ZEBRA 1 did not show any effect of zibotentan on serum sVCAM-1 but was associated with numerical improvement in eGFR at 26 weeks that was more marked at 52 weeks. ZEBRA 2B suggested a feasible dose regimen for haemodialysis patients.

Citation

Stern, E. P., Host, L. V., Wanjiku, I., Escott, J., Gilmour, P. S., Ochiel, R., Unwin, R., Burns, A., Ong, V. H., Cadiou, H., O'Keeffe, A. G., & Denton, C. P. (2022). Zibotentan in systemic sclerosis-associated chronic kidney disease: a phase II randomised placebo-controlled trial. Arthritis Research and Therapy, 24(1), Article 130. https://doi.org/10.1186/s13075-022-02818-6

• Journal Article Type: Article
• Acceptance Date: May 21, 2022
• Online Publication Date: Jun 1, 2022
• Publication Date: Jun 1, 2022
• Deposit Date: May 24, 2022
• Publicly Available Date: May 24, 2022
• Journal: Arthritis Research and Therapy
• Print ISSN: 1478-6354
• Electronic ISSN: 1478-6362
• Publisher: BioMed Central
• Peer Reviewed: Peer Reviewed
• Volume: 24
• Issue: 1
• Article Number: 130
• DOI: https://doi.org/10.1186/s13075-022-02818-6
• Public URL: https://nottingham-repository.worktribe.com/output/8220779
• Publisher URL: https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-022-02818-6