Nilotinib (Tasigna™) in the treatment of early diffuse systemic sclerosis: an open-label, pilot clinical trial

Jessica K Gordon, Viktor Martyanov, Cynthia Magro, Horatio F Wildman, Tammara A Wood, Wei-Ti Huang, Mary K Crow, Michael L Whitfield, Robert F Spiera, Jessica K Gordon, Viktor Martyanov, Cynthia Magro, Horatio F Wildman, Tammara A Wood, Wei-Ti Huang, Mary K Crow, Michael L Whitfield, Robert F Spiera

Abstract

Introduction: Tyrosine kinase inhibitors (TKI) are medications of interest in the treatment of Systemic Sclerosis (SSc) because of their ability to inhibit pathways involved in fibrosis. In this open-label pilot trial, our objectives were to assess the safety, efficacy, and molecular change associated with treatment of patients with diffuse cutaneous (dc)SSc with the TKI nilotinib (Tasigna™).

Methods: Ten adult patients with early dcSSc were treated with nilotinib. Primary endpoints were safety and change in modified Rodnan Skin Score (MRSS) after 6 months. Lesional skin biopsies at baseline, 6 and 12 months of treatment were assessed by histopathology, immunohistochemistry, and DNA microarray.

Results: Patients had early and active dcSSc with median disease duration of 0.7 years (range 0.5, 1.7) and increasing MRSS in the month prior to baseline (mean +2.9, p=0.02). Seven out of ten patients completed 6 and 12 months of treatment. Seventy-one adverse events (AEs) including 2 serious AEs were observed, and 92 % of AEs were grade 1-2. Two patients discontinued the medication due to mild QTc prolongation. MRSS improved by a mean of 4.2 points (16 %) at 6 months and by 6.3 points (23 %) at 12 months in the 7 completers, p=0.02 and 0.01, respectively. Patients with a decrease in MRSS >20 % from baseline at 12 months (classified as improvers) had significantly higher expression of transforming growth factor beta receptor (TGFBR) and platelet-derived growth factor receptor beta (PDGFRB) signaling genes at baseline than non-improvers, and the expression of these genes significantly decreased in improvers post-treatment.

Conclusion: Nilotinib was well tolerated by the majority of patients in this study, with tolerability limited primarily by mild QTc-prolongation. Significant MRSS improvement was observed in these early, active patients, but is not conclusive of treatment effect given the open-label study-design and small number of patients in this pilot study. Improvers had higher levels of expression of genes associated with TGFBR and PDGFRB signaling at baseline, and a significant decrease in the expression of these genes occurred only in patients with higher MRSS improvement. The findings of this pilot study warrant more conclusive evaluation.

Trial registration: Clinicaltrials.gov NCT01166139 , July 1, 2010.

Figures

Fig. 1
Fig. 1
Photomicrographs of forearm skin biopsy from one patient as studied by H&E at 0 (a) and 12 (b) months and by alpha smooth muscle actin (α-SMA) at 0 (c) and 12 (d) months of treatment. This specimen demonstrates morphological improvement as evidenced by decreased thickness of collagen bundles and increased interstitial space between the collagen bundles. Decreased intensity α-SMA is seen in this specimen as well. However, when looking at all of the specimens overall, significant morphological change was not observed
Fig. 2
Fig. 2
Intrinsic subset assignment. a Nilotinib sample tree: green normal-like, red fibroproliferative, purple inflammatory intrinsic subset samples, based on the expression patterns of intrinsic genes. Square brackets indicate samples from the same patient. b Heat map of intrinsic genes. The intrinsic subset row refers to subset assignments based on Spearman correlation statistics
Fig. 3
Fig. 3
Baseline differential gene expression and pathway enrichment analysis. a Baseline sample tree: blue improvers, orange non-improvers. b Sample genes differentially expressed at baseline between improvers and non-improvers. c Pathways differentially expressed at baseline between improvers and non-improvers
Fig. 4
Fig. 4
Improver differential gene expression and pathway enrichment analysis. a Improver array tree: blue baseline samples, black post-treatment samples. b Sample genes differentially expressed in improvers between baseline and post-treatment biopsies. c Improver gene signature trends across improver and non-improver samples. Graphs represent Tukey box and whiskers plots. d Pathways differentially expressed in improvers between baseline and post-treatment biopsies
Fig. 5
Fig. 5
Transforming growth factor beta receptor (TGFBR) and platelet-derived growth factor receptor beta (PDGFRB) signaling trends across nilotinib patients. a Expression trends for TGFBR signaling pathway across completers, improvers and non-improvers. b Expression trends for PDGFRB signaling pathway across completers, improvers and non-improvers. Scatter plots show mean with standard deviation

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