Imatinib mesylate has been shown in preclinical studies, mouse models, and case reports to decrease fibrosis in Systemic Sclerosis (SSc). We present here the interim results of an investigator initiated phase IIa, single center, single arm, open label clinical trial examining safety and efficacy of imatinib to treat patients with diffuse cutaneous (dc)SSc (NCT00555581.)
Patients with severe dcSSc are treated with imatinib 400 mg orally per day. Patients are evaluated monthly for 12 months during treatment and are seen in follow-up 3 months after discontinuing imatinib. The primary endpoint is safety as assessed by number of serious adverse events (SAEs) and adverse events (AEs.) Secondary endpoints are change in the Modified Rodnan Skin Score (MRSS), forced vital capacity (FVC), and diffusion capacity (DLCO.) Additional endpoints include the HAQ-DI, SF-36, echocardiogram, and skin histology.
We have completed enrollment with 30 patients. Four patients (13.3%) are African American, and 26 (86.7%) are Caucasian, 4 of whom are Hispanic. Twenty patients have disease duration of less than 4 years and 10 have more than 4 years. Six patients have dropped out of the study.
There have been 156 AEs at least possibly related to imatinib. There have been 24 SAEs including one death from community acquired pneumonia in a patient with preexisting severe pulmonary fibrosis. The most common AEs related to imatinib are fluid retention (80%), nausea (73%), fatigue (53%), and elevation of creatine kinase (37%). These AEs are frequently self-limited or resolve with dose-adjustment, but fatigue led to discontinuance of drug in two patients.
In the 16 patients who have completed 12 months of treatment, mean MRSS improved from 30.8 ± 9.7 to 23.5 ± 11.1, (p < 0.001.) Improvements of MRSS are not seen at 3 months (Δ = -0.4 ± 3.2 points, p=0.42, n = 26), but were apparent beginning at 6 months (Δ= -4.9 ± 5.0, p < 0.001, n = 21), 9 months (Δ=-6.5 ± 4.3, p < 0.001, n = 19), and 12 months (Δ = -7.3 ± 4.6, p < 0.001, n=16.) Indices of pulmonary function improved at 1 year. Mean FVC improved from 84 ± 22 to 90 ± 23, p = 0.039. Mean DLCO improved from 80 ± 21 to 88 ± 27, p = 0.037. Skin histology showed improvement at the 12 month time point and is presented separately.
Our interim analysis demonstrates safety and efficacy of imatinib in the treatment of dcSSc. Imatinib is well-tolerated by most patients. Improvements in MRSS, FVC, and DLCO were observed. Translational investigations are ongoing to delineate mechanisms of action and predictors of response. Placebo-controlled investigation is warranted to better define the role of imatinib in the treatment of SSc.
Disclosure: J. Gordon, None; J. Mersten, Rudolph Rupert Scleroderma Research Program, 2 ; S. Lyman, None; S. A. Kloiber, None; H. F. Wildman, None; M. K. Crow, Rudolph Rupert Scleroderma Research Program, 2 ; K. A. Kirou, None; R. F. Spiera, Novartis Pharmaceutical Corporation, 2, Rudolph Rupert Scleroderma Research Program, 2 .