Study Reveals Promising Data on Nilotinib as a Therapy for Diffuse Systemic Sclerosis

A new study recently published in the journal Arthritis Research & Therapy provides encouraging data on a pilot study evaluating nilotinib (Tasigna™) as a therapy for diffuse systemic sclerosis. The study is entitled “Nilotinib (Tasigna™) in the treatment of early diffuse systemic sclerosis: an open-label, pilot clinical trial” and was developed by researchers at the Hospital for Special Surgery, the Geisel School of Medicine at Dartmouth and Weill Cornell Medical Center.

Systemic sclerosis is a rare, chronic autoimmune disease in which the body’s own immune system attacks healthy tissues, resulting in a hardening and tightening of the skin and connective tissues due to excessive collagen deposition. The disease usually affects the skin, but it can also affect internal organs such as the lungs, heart, blood vessels, kidneys and the digestive tract. Systemic sclerosis can be classified into limited or diffuse based on the extent of skin tightening. In the limited disease, skin tightening is confined to the fingers, hands and forearms; it can also occur on the feet and legs. In the diffuse disease, the skin of the proximal extremities and trunk is also involved. Patients with diffuse systemic sclerosis are at greater risk of organ dysfunction.

Tyrosine kinase inhibitors (TKI) are a promising therapy for systemic sclerosis due to their ability to inhibit pathways related to fibrosis (tissue thickening and scarring).

In the study, researchers conducted an open-label pilot Phase 2 clinical trial (NCT01166139) to assess the safety and efficacy of the TKI nilotinib as a therapy for patients with diffuse systemic sclerosis. Nilotinib is a second generation TKI that is able to interfere with both transforming growth factor beta receptor (TGFBR) and platelet-derived growth factor receptor beta (PDGFRB) signaling. Deregulation of these two pathways has been associated with pathological fibrosis in systemic sclerosis patients.

In total, 10 adult patients with early diffuse cutaneous systemic sclerosis received nilotinib 400 mg twice a day for a period of 6 months. The primary endpoint of the trial was the safety and change in the modified Rodnan Skin Score (MRSS). The team also analyzed lesional skin biopsies from the patients at baseline, and after 6 and 12 months of treatment.

Of the 10 patients in the cohort, seven completed 6 and 12 months of treatment. In terms of safety, researchers reported 71 adverse events, in their majority mild or moderate (92%), including two serious events. Two of the patients discontinued treatment because of a mild QTc prolongation, a condition that can predispose the heart for the development of ventricular tachyarrhythmias (abnormal heart rhythm). The MRSS was found to improve by around 16% after 6 months of therapy and 23% after 12 months. Interestingly, patients who had a MRSS decrease higher than 20% at 12 months were found to have a higher expression of genes associated with the TGFBR and PDGFRB at baseline, genes which significantly decreased after 12 months of treatment.

The research team concluded that nilotinib was generally well-tolerated by systemic sclerosis patients, with tolerability being primarily limited by mild cardiovascular side effects. In terms of efficacy, the team mentions that controlled trials with a larger number of patients should be conducted in order to draw definitive conclusions, although the pilot study showed a significant improvement in MRSS with nilotinib therapy.