Testing New Drugs for Early Diffuse Systemic Sclerosis

A Single Group, Open Label, Pilot Clinical Trial of Nilotinib (Tasigna™)

For patients with the connective tissue disease known as systemic sclerosis (SSc) – or scleroderma – there are few reliable drug treatments. There has been emerging interest in the potential of a class of drugs called tyrosine kinase inhibitors (TKI) to ameliorate a major feature of the disease called fibrosis, which is the growth of excess connective tissue.

Attending Rheumatologist Robert F. Spiera, MD, and his team, including Assistant Attending Rheumatologist, Jessica K. Gordon, MD, have been leading the testing of TKIs to treat scleroderma, including the HSS clinical trials of a TKI called imantib, known commercially as Gleevec™.  Those clinical trials have suggested improvement for some patients with scleroderma, but not all. 

Since there are few current drug options for treating SSc, a potential therapy that could help even some patients is worth testing, both to determine if its results are safe and reliable and to refine which people may or may not be helped by the treatment.

TKI Side Effects Not Always Tolerated

TKIs are powerful drugs, originally developed to treat stomach and stromal tumors in intestinal cancers. They are known to have side effects, sometimes severe, notably related to fluid retention. Drugs affect people individually. Some patients in the TKI imantib clinical trials, for example, had modest side effects, while others could not tolerate the side effects and had to discontinue treatment.

A second generation of TKIs now exists that aims to be more efficacious with less side effects. One such drug is called nilotinib, known commercially as Tasigna™. Recently, nilotinib was tested at HSS to assess how the new generation TKI might affect patients.

Results of this early pilot study show that nilotinib was tolerated by the majority of patients in the study, and investigators observed improvements in skin thickening in a group of patients with early active scleroderma. Further testing in randomized placebo controlled trials will ultimately be necessary to determine whether the benefits seen were truly related to the medication tested.

Skin Test Scores Improved

In this pilot study, 10 adult patients who had been diagnosed with diffuse cutaneous (dc) SSc for less than 3 years were treated twice daily with a 400 mg oral dose of nilotinib. Because this was a test, the patients could not be having treatment with other immunosuppressive drugs so that any results could be attributed to nilotinib, or to spontaneous improvement in the disease.

Disease duration for the group ranged from 6 to 20 months and the average disease duration was 1.1 years at the start of the study. 80% were female, 50% were Caucasian. The patients’ median age was 46, ranging in age from 33 to 52.

7 of the 10 patients completed the test’s 6 months of treatment. Their scores on the standard test called Modified Rodnan Skin Score (MRSS) improved from a median baseline of 27 to 22 at the end of the test period. Pulmonary functions remained stable, as did the physician’s global assessment scores.

Side Effects Did Occur

Patients did experience side effects during the trial, though no fluid retention was seen. 42 adverse events (AE) and 2 serious adverse events (SAE) were observed during the treatment period. 83% of the events were considered to be at least possibly related to nilotinib. 3 of the 10 initially enrolled patients stopped treatment early because of side effects – 2 because of nilotinib intolerance and 1 because a pre-existing heart condition progressed.

There is a known side effect of nilotnib on the electrocardiogram (electrical study of the heart) called Qtc prolongation. Patients who had the condition were excluded from being in the clinical trial from the start, and if it developed, a patient was to be immediately discontinued from further participation. 

Additional Study Warranted

The results of this pilot study, including both improvement of skin scores and sufficient tolerability of nilotnib showed enough potential to recommend further patient tests of the drug in a randomized controlled manner. Because improved results were seen, patients who completed the trial are able to elect continued, closely monitored treatment on the drug at HSS.

The results of this initial pilot study were recently presented by Dr. Gordon at the 2012 Annual Meeting of the American College of Rheumatology in Washington, DC.


HSS Authors:
Jessica K. Gordon, MD
Morgana L. Davids
Kamini Doobay
Stephen L. Lyman, PhD
Mary K. Crow, MD
Robert F. Spiera, MD

Weill-Cornell Medical Center:
Cynthia Magro, MD
Horatio F. Wildman, MD

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