Background/Purpose: Tyrosine kinase inhibitors (TKI) which selectively antagonize c-abl and PDGFR have been shown in preclinical models to decrease fibrosis.  TKIs are therapies of interest for Systemic Sclerosis (SSc) with potential efficacy observed in several, but not all, open label studies of imatinib.  Side effects relating to fluid retention were common and led to intolerance in some patients.  Nilotinib is a second-generation TKI with increased potency and a different side effect profile compared to imatinib, specifically with less associated fluid retention.

Methods: In this single group, open label, pilot trial, we recruited 10 adult patients with diffuse cutaneous (dc) SSc of less than 3 yrs duration since the initial SSc symptom apart from the Raynaud’s Phenomenon.  Patients were treated with nilotinib 400 mg po twice daily. Patients were excluded if they had a QTc>450 msec.  Concurrent immunosuppressive treatment was not allowed.  The primary endpoint was safety as assessed by the number of adverse effects (AEs) and serious (S)AEs, and the primary efficacy endpoint was change in the Modified Rodnan Skin Score (MRSS) after 6 mo.  Secondary endpoints include forced vital capacity (FVC), diffusion lung capacity (DLCO) and other measures. After 6 mo patients are offered continued treatment for an additional 24 mo.  Skin biopsies are performed at baseline and after 6 and 12 mos.

Results: Nineteen patients were initially screened; 5 were excluded due to baseline QTc>450 msec.  At baseline the median age was 46 (IQR 33, 52), 80% were female, 50% were Caucasian, and disease duration was 0.7 yrs (0.5, 1.7). 30% were SCL70 and 50% were PolIII positive. 30% had ILD. 70% demonstrated an increase in the MRSS in the 1 mo btwn screen and baseline, and 40% had tendon friction rubs.  The baseline MRSS was 27.5 (IQR 22, 35).   

Seven patients completed 6 mo; 3 patients stopped early – 2 due to Grade 1-2 QTc prolongation and 1 due to progression of preexisting coronary artery disease.  42 AEs and 2 SAEs were observed during the treatment period; 83% were considered to be at least possibly related to nilotinib.  97% of AEs were grade 1 or 2.  No fluid retention was observed.  

In the 7 patients who completed 6 mo of treatment, the MRSS improved from a baseline of 27 (IQR 22, 30) to 22 (16, 28) at 6 mo, p=0.047.  The FVC was 81% predicted (73, 86) at baseline and 74% (69, 83) at 6 mo, p=0.25, and the DLCO was 73.5% (67, 81) at baseline and 68% (66, 84) at 6 mo, p=0.5.  The physician global assessment improved from 61.3 (56.7, 81.3) to 32 (42.3, 55.3), p<0.01.  There were no significant differences noted in the following: oral aperture, hand extension, finger to palm distance, ESR, SHAQ-DI, SF-36 mental or physical components, or the Medsger Severity Scale.

Conclusion: Nilotinib was tolerated by the majority of patients in this study.  The MRSS improved significantly with 6 mo of treatment in this very early and active group of patients. The FVC and DLCO remained stable as did the additional outcome measures. Tolerability was limited primarily by mildly prolonged QTc, which is a known side effect of nilotinib and an exclusion criterion for continuation in this study.  Baseline QTc prolongation also limited patient eligibility.  Further study of nilotinib is warranted in a randomized controlled manner.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/nilotinib-tasigna-in-the-treatment-of-early-diffuse-systemic-sclerosis-a-single-group-open-label-pilot-clinical-trial/