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A4353 - Fibrocytes in Pulmonary Fibrosis: Double-Blind Placebo-Controlled Crossover Pilot Study of Sirolimus in Idiopathic Pulmonary Fibrosis
Author Block: D. B. Axell-House1, V. Yu1, Z. Zhang1, M. D. Burdick1, R. M. Strieter2, B. Mehrad3; 1University of Virginia, Charlottesville, VA, United States, 2Novartis Institutes for Biomedical Research, Cambridge, MA, United States, 3Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, Gainesville, FL, United States.
Rationale: Fibrocytes are a population of bone marrow-derived circulating progenitor cells that have been implicated in the pathogenesis of fibrotic diseases. In animal models of pulmonary fibrosis, fibrocytes are recruited to the lungs via the chemokine CXCL12, made in the lung, and its receptor CXCR4, expressed on fibrocytes. In human idiopathic pulmonary fibrosis (IPF), the concentration of CXCR4+ circulating fibrocytes is elevated and correlates with survival. Fibrocyte CXCR4 expression is dependent on the mTOR pathway, and in animal models of lung fibrosis, sirolimus therapy reduced both the trafficking of fibrocytes to the lungs and attenuates lung fibrosis.
Hypothesis: 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: Subjects diagnosed with IPF by consensus criteria were randomized to placebo or sirolimus for a 1-3 week run-in period, followed by 4 weeks of dose maintenance, a 4 week washout period, followed by cross over to the alternate treatment (placebo or sirolimus) for run-in, maintenance and washout periods. The concentration of circulating fibrocytes were measured at specific time points. Adverse events were classified per the NCI CTCAE criteria and 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 sirolimus. The incidence of serious adverse events did not differ significantly during therapy with drug and placebo.
Conclusion: As compared with placebo, short-term treatment with sirolimus resulted in reduction of circulating fibrocyte concentrations in subjects with IPF, similar to animal models, and was associated with an acceptable safety profile. Future studies to assess the effect of long-term sirolimus treatment on the natural history of IPF are warranted.