Fibrocytes in Human Pulmonary Fibrosis: Double-Blind Placebo-Controlled Crossover Pilot Study of Sirolimus in Idiopathic Pulmonary Fibrosis

Abstract

SESSION TITLE: Diffuse Lung Disease I SESSION TYPE: Original Investigation Slide PRESENTED ON: Sunday, October 29, 2017 at 03:15 PM - 04:15 PM PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a progressive disease associated with poor prognosis. Fibrocytes are a novel population of bone marrow-derived circulating cells that traffic to the lungs and contribute to fibrosis in animal models of pulmonary fibrosis via the interaction of the chemokine CXCL12, made in the lung, and the chemokine receptor CXCR4, expressed on fibrocytes. In human interstitial lung disease, the concentration of CXCR4+ circulating fibrocytes correlates with survival. The expression of fibrocyte CXCR4 is dependent on the mTOR pathway, and is reduced by in vitro treatment with the mTOR inhibitor, sirolimus. In animal models of lung fibrosis, sirolimus therapy reduces both the trafficking of fibrocytes to the lungs and the extent of lung fibrosis. The effect of sirolimus in human IPF has not been examined. We hypothesized that therapy with the mTOR inhibitor sirolimus reduces the number of circulating fibrocytes in patients with idiopathic pulmonary fibrosis and is associated with an acceptable side-effect profile. METHODS: We performed a short-term randomized double-blinded placebo-controlled crossover study of 30 subjects diagnosed with IPF by consensus definition. Subjects were randomized to placebo or sirolimus for a 1-3 week run-in period with dose adjustment to achieve therapeutic drug levels, followed by 4 weeks of dose maintenance, and then a 4 week washout period. Subjects were then crossed over to the alternate treatment (placebo or sirolimus) for same length run-in, maintenance and washout periods. The concentration of circulating fibrocytes plasma chemokine ligands, pulmonary function tests, and adverse events were measured at specific time points. Adverse events were classified as serious per the NCI CTCAE criteria and were adjudicated as unrelated or possibly related to the study drug by an independent DSMB. RESULTS: We enrolled 30 subjects between 2011 and 2015; 2 withdrew prior to randomization. The remaining 28 had a median age of 69 (IQR 65-73), 22 were men and 8 were on concurrent therapy with pirfenidone or nintedanib. Sirolimus therapy resulted in a statistically significant reduction in the concentration of circulating fibrocytes (median change -62%, IQR -40% to -29%) whereas placebo did not (median change -32%; IQR -47% to +6%). A total of 49 adverse events occurred during treatment with sirolimus and 29 with placebo, of which 35 (2 serious: elevated liver enzymes and angioedema) were adjudicated as possibly related to therapy during sirolimus and 15 (1 serious: worsened dyspnoea) during placebo treatments. The incidence of total adverse events, serious adverse events, and total and serious adverse events that were potentially related to therapy did not differ significantly during therapy with drug and placebo. CONCLUSIONS: As compared with placebo, short-term treatment with sirolimus resulted in reduction of circulating fibrocyte concentrations in subjects with IPF and was associated with an acceptable safety profile. CLINICAL IMPLICATIONS: Given the benefit of sirolimus in animal models of pulmonary fibrosis and evidence of similar mechanism of action in human IPF in this study, future studies should assess the effect of long-term sirolimus treatment on the natural history of IPF. DISCLOSURE: The following authors have nothing to disclose: Dierdre Axell-House, Victor Yu, Zhimin Zhang, Marie Burdick, Robert Strieter, Borna Mehrad No Product/Research Disclosure Information