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Nilotinib (Tasigna™) in the treatment of early diffuse systemic sclerosis: an open-label, pilot clinical trial
Jessica K Gordon1, Viktor Martyanov2, Cynthia Magro3
1Department of Rheumatology, Hospital for Special Surgery, 535 East 70th St, New York, NY, 10021, USA. gordonj@hss.edu.
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.
Insights
Nilotinib showed potential in treating systemic sclerosis (SSc) by improving skin scores and reducing fibrosis-related gene expression. Further research is needed to confirm these findings in SSc patients.
Area of Science:
- Rheumatology
- Dermatology
- Pharmacology
Background:
- Systemic Sclerosis (SSc) involves fibrosis, a process targeted by tyrosine kinase inhibitors (TKIs).
- Nilotinib (Tasigna™), a TKI, was investigated for its potential in treating diffuse cutaneous SSc (dcSSc).
Purpose of the Study:
- To assess the safety and efficacy of nilotinib in patients with early dcSSc.
- To evaluate molecular changes, including gene expression, associated with nilotinib treatment.
Main Methods:
- An open-label pilot trial involving ten adult patients with early dcSSc.
- Primary endpoints included safety and changes in modified Rodnan Skin Score (MRSS) at 6 months.
- Skin biopsies were analyzed using histopathology, immunohistochemistry, and DNA microarray.
Main Results:
- Seven patients completed 12 months of treatment; most adverse events were mild.
- Significant improvements in MRSS were observed at 6 and 12 months (p=0.02 and p=0.01).
- Patients with greater MRSS improvement showed higher baseline TGFBR and PDGFRB gene expression, which decreased post-treatment.
Conclusions:
- Nilotinib was generally well-tolerated, with QTc prolongation being the main limiting factor.
- The study observed significant MRSS improvement in early dcSSc patients, warranting further investigation.
- Higher baseline TGFBR and PDGFRB signaling gene expression correlated with better treatment response.
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