Belumosudil in diffuse cutaneous systemic sclerosis: a randomized, double-blind, open-label extension, placebo-controlled, phase 2 study

Abstract

Objectives: To determine the efficacy, safety and pharmacodynamics of belumosudil in patients with diffuse cutaneous systemic sclerosis (dcSSc) treated with background immunosuppressive therapies.

Methods: Eligible patients were randomised 1:1:1 to receive belumosudil 200 mg once daily (QD) or twice daily (BID), or placebo for 28 weeks (double-blind period). After unblinding, the patients who received belumosudil continued the same dose, whereas the patients who received placebo were re-randomised for one of the belumosudil doses for 24 weeks (open-label extension).

Results: Thirty-five and 31 patients were treated in the double-blind and open-label periods, respectively. The study was terminated prematurely, and target enrolment was not met. The primary end point, of CRISS score ≥0.60 at week 24, did not exhibit an efficacy signal in the belumosudil vs placebo groups [odds ratio: 1.06 (0.19-5.82; P = 0.9472) for the QD, and 0.39 (0.07-2.35; P = 0.3078) for the BID group]. Belumosudil was well tolerated and exhibited similar safety profiles in both double-blind and open-label periods. Tissue-based RNA sequencing analysis revealed FOXP3 upregulation and STAT3, IL23A and TGF-β downregulation in patients with CRISS score ≥0.60, which supported the mechanism of action of belumosudil. In blood and tissue samples, trends of decreased fibrosis biomarker levels were seen in the belumosudil-treated group vs placebo.

Conclusion: Efficacy signal for belumosudil could not be detected. Signalling pathway modulation analysis supported the mechanism of action of belumosudil. A trend for decreased fibrosis-related biomarkers was observed in the belumosudil-treated group.

Trial registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT03919799.

Keywords: CRISS; belumosudil; biomarker; clinical trial; diffuse cutaneous systemic sclerosis.

Figure 1.

CONSORT diagram for patient disposition in the treated population. BID: twice daily; CONSORT: consolidated standards of reporting trials; N/n: number of patients; QD: once daily

Figure 2.

Signalling pathway modulation observed in tissue samples analysed using RNA sequencing. (A) Heatmap^a,b representing the summary analysis of gene expression changes across treatment arms. (B) Heatmap^a,c representing the summary of pathway changes across treatment arms. (C) Phenotype assessment in paired biopsies collected from placebo and belumosudil-treated groups (BID/QD), using RNA sequencing. ^aHeatmaps colour coding: Green = significant decrease at Week 24 versus the baseline; red = significant increase at Week 24 versus the baseline; black = NSC. ^bColumn = treatment arm (all participants or stratified by clinical response), row = individual gene. Cell log2 fold change representing the significance of enrichment at Week 24 relative to baseline. ^cColumn = treatment arm stratified by clinical response. Row = pathway (gene set) from Hallmarks gene set database. Cell = NES of a particular pathway representing the significance of enrichment at Week 24 versus the baseline. BASE: baseline; BID: twice daily; CRISS: Combined Response Index in Diffuse Cutaneous Systemic Sclerosis; FIB: fibroproliferative; GSEA: gene set enrichment analysis; IL: interleukin; KRAS: Kirsten rat sarcoma virus; MoA: mechanism of action; MTORC1: mammalian target of rapamycin complex 1; NES: normalised enrichment score; NFKB: nuclear factor kappa B; NOR: normal-like; NSC: no significant change; QD: once daily; TGF: transforming growth factor; TNFA: tumour necrosis factor alpha; WK: week

Figure 3.

Treatment-related impact on tissue fibrosis in patients treated with belumosudil vs placebo till week 52. The analysis was done using Masson’s trichome staining. Box centre and upper/lower lines indicate the median and upper/lower quartile, respectively. Vertical lines above and below the box indicate 1.5 times the interquartile range. EOT: end of treatment; ID: twice daily; N: number of patients; QD: once daily