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


CONCLUSIONS
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.


BACKGROUND
Clinicaltrials.gov NCT01166139 , July 1, 2010.
Department of Rheumatology, Hospital for Special Surgery, 535 East 70th St, New York, NY, 10021, USA. gordonj@hss.edu.
Jessica K
JK
Gordon
Geisel School of Medicine at Dartmouth, Department of Genetics, Remsen 7400, Hanover, NH, 03755, USA. Viktor.Martyanov@dartmouth.edu.
Viktor
V
Martyanov
Weill Cornell Medical Center, Department of Dermatopathology, 525 East 68th St, New York, NY, 10065, USA. cym2003@med.cornell.edu.
Cynthia
C
Magro
Weill Cornell Medical Center, Department of Dermatology, 1305 York Ave, New York, NY, 10021, USA. hfw2001@med.cornell.edu.
Horatio F
HF
Wildman
Geisel School of Medicine at Dartmouth, Department of Genetics, Remsen 7400, Hanover, NH, 03755, USA. Tammara.A.Wood@dartmouth.edu.
Tammara A
TA
Wood
Department of Rheumatology, Hospital for Special Surgery, 535 East 70th St, New York, NY, 10021, USA. yorick838@gmail.com.
Wei-Ti
WT
Huang
Department of Rheumatology, Hospital for Special Surgery, 535 East 70th St, New York, NY, 10021, USA. crowm@hss.edu.
Mary K
MK
Crow
Geisel School of Medicine at Dartmouth, Department of Genetics, Remsen 7400, Hanover, NH, 03755, USA. Michael.L.Whitfield@dartmouth.edu.
Michael L
ML
Whitfield
Department of Rheumatology, Hospital for Special Surgery, 535 East 70th St, New York, NY, 10021, USA. spierar@hss.edu.
Robert F
RF
Spiera
D000293:Adolescent; D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D002318:Cardiovascular Diseases / Q000139:chemically induced; D005260:Female; D006261:Headache / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D020411:Oligonucleotide Array Sequence Analysis; D010865:Pilot Projects; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D045743:Scleroderma, Diffuse / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D059467:Transcriptome / Q000187:drug effects* / Q000235:genetics; D016896:Treatment Outcome; D055815:Young Adult
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D018125:Receptors, Transforming Growth Factor beta; D020797:Receptor, Platelet-Derived Growth Factor beta; C498826:nilotinib