Background/Purpose:

Tyrosine kinase inhibitors (TKI) are under investigation for the treatment of diffuse cutaneous Systemic Sclerosis (dcSSc.)  Nilotinib is a second-generation TKI which selectively antagonizes c-abl and PDGFR and has a different side-effect profile from imatinib and other TKIs.  One year follow-up data from a single group, open label, pilot trial are presented here. 

Methods:

Ten adult patients (pts) with early progressive dcSSc of <3 yrs since the initial SSc symptom excluding Raynaud’s were recruited.  Pts were treated with nilotinib 400 mg PO twice daily. Pts were excluded if they had a QTc>450 ms.  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 of treatment.  Secondary endpoints include forced vital capacity (FVC), diffusion capacity (DLCO) and other measures. After 6 mo pts were offered continued treatment for 24 mo.  Forearm skin biopsies were performed at baseline and after 6 and 12 mo. 

Results:

Nineteen pts were screened; 5 were excluded due to QTc>450 ms, and 10 were enrolled.  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 RNAPol3+. 30% had ILD. 40% had tendon friction rubs.  70% had a worsening MRSS in the month prior to baseline, with a mean MRSS increase between screen and baseline of 2.9 (p=0.02) in the group.

Seven pts completed 12 mo of treatment and elected to continue on nilotinib.  Three pts discontinued nilotinib within the first 3 mo of treatment – 2 due to Grade 1-2 QTc prolongation and 1 due to progression of preexisting coronary artery disease.  During the 12 mo period of observation 71 AEs including 2 SAEs were observed; 75% were considered to be at least possibly related to nilotinib.  92% of AEs were grade 1 or 2.

The MRSS was significantly improved by a mean of 4.1 points or 15% at 6 months and by 6.7 or 25% at 12 months in the 7 completers.  The physician global assessment improved significantly as well. No significant difference was observed in the FVC, DLCO, or Scleroderma health assessment questionnaire. 

	Baseline	6 months	12 months	p-value 6 mo	p-value 12 mo
MRSS	26.9 ± 5.4	22.7 ± 8.0	20.1 ± 7.3	0.02	0.01
FVC (%pred)	77.4 ± 12.9	75.4 ± 12.5	71.7±11.7	0.17	0.054
DLCO (%pred)	72 ± 9.9	69.9 ±18.1	69.3±12.39	0.56	0.26
Physician Global Assessment	62.5 ± 10.8	40.2 ± 12.7	32.3 ± 15.3	<0.01	<0.01

Skin biopsies were assessed in a blinded fashion by a dermatopathologist. No significant difference in morphology or skin thickness was observed. 

Conclusion:

Nilotinib was tolerated by the majority of patients in this study.   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. QTc elevation can be seen in dcSSc independent of nilotinib therapy and limited patient eligibility. Although this single-group pilot study is not conclusive, significant improvement of MRSS was seen in an early and actively progressing group of patients.   Further study of TKI is warranted in a randomized controlled manner.

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« Back to 2013 ACR/ARHP Annual Meeting

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-one-year-results/