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      First Data on Efficacy and Safety of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis and Forced Vital Capacity of ≤50 % of Predicted Value

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          Abstract

          In the Phase III INPULSIS ® trials, 52 weeks’ treatment with nintedanib reduced decline in forced vital capacity (FVC) versus placebo in patients with idiopathic pulmonary fibrosis (IPF). Patients who completed the INPULSIS ® trials could receive nintedanib in an open-label extension trial (INPULSIS ®-ON). Patients with FVC <50 % predicted were excluded from INPULSIS ®, but could participate in INPULSIS ®-ON. In patients with baseline FVC ≤50 % and >50 % predicted at the start of INPULSIS ®-ON, the absolute mean change in FVC from baseline to week 48 of INPULSIS ®-ON was −62.3 and −87.9 mL, respectively (n = 24 and n = 558, respectively). No new safety signals were identified in INPULSIS ®-ON compared with INPULSIS ®. The decline in FVC in INPULSIS ®-ON in both subgroups by baseline FVC % predicted was similar to that in INPULSIS ®, suggesting that nintedanib may have a similar effect on disease progression in patients with advanced disease as in less advanced disease.

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          Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis.

          Luca Richeldi, Ulrich Costabel, Moises Selman … (2011)
          Idiopathic pulmonary fibrosis is a progressive lung disease with a high mortality rate. Because the signaling pathways activated by several tyrosine kinase receptors have been shown to be involved in lung fibrosis, it has been suggested that the inhibition of these receptors may slow the progression of idiopathic pulmonary fibrosis. In a 12-month, phase 2 trial, we assessed the efficacy and safety of four different oral doses of the tyrosine kinase inhibitor BIBF 1120 as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Secondary end points included acute exacerbations, quality of life (measured with the St. George's Respiratory Questionnaire [SGRQ]), and total lung capacity. A total of 432 patients underwent randomization to receive one of four doses of BIBF 1120 (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo. In the group receiving 150 mg of BIBF 1120 twice a day, FVC declined by 0.06 liters per year, as compared with 0.19 liters per year in the placebo group, a 68.4% reduction in the rate of loss with BIBF 1120 (P = 0.06 with the closed testing procedure for multiplicity correction; P = 0.01 with the hierarchical testing procedure). This dose also resulted in a lower incidence of acute exacerbations, as compared with placebo (2.4 vs. 15.7 per 100 patient-years, P = 0.02) and a small decrease in the SGRQ score (assessed on a scale of 0 to 100, with lower scores indicating better quality of life) as compared with an increase with placebo (-0.66 vs. 5.46, P = 0.007). Gastrointestinal symptoms (which led to more discontinuations in the group receiving 150 mg twice a day than in the placebo group) and increases in levels of liver aminotransferases were more frequent in the group receiving 150 mg of BIBF 1120 twice daily than in the placebo group. In patients with idiopathic pulmonary fibrosis, BIBF 1120 at a dose of 150 mg twice daily, as compared with placebo, was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT00514683 .).
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            BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy.

            Frank Hilberg, Gerald Roth, Martin Krššák … (2008)
            Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a novel treatment modality in oncology. Preclinical findings suggest that long-term clinical outcomes may improve with blockade of additional proangiogenic receptor tyrosine kinases: platelet-derived growth factor receptors (PDGFR) and fibroblast growth factor receptors (FGFR). BIBF 1120 is an indolinone derivative potently blocking VEGF receptor (VEGFR), PDGFR and FGFR kinase activity in enzymatic assays (IC(50), 20-100 nmol/L). BIBF 1120 inhibits mitogen-activated protein kinase and Akt signaling pathways in three cell types contributing to angiogenesis, endothelial cells, pericytes, and smooth muscle cells, resulting in inhibition of cell proliferation (EC(50), 10-80 nmol/L) and apoptosis. In all tumor models tested thus far, including human tumor xenografts growing in nude mice and a syngeneic rat tumor model, BIBF 1120 is highly active at well-tolerated doses (25-100 mg/kg daily p.o.), as measured by magnetic resonance imaging of tumor perfusion after 3 days, reducing vessel density and vessel integrity after 5 days, and inducing profound growth inhibition. A distinct pharmacodynamic feature of BIBF 1120 in cell culture is sustained pathway inhibition (up to 32 hours after 1-hour treatment), suggesting slow receptor off-kinetics. Although BIBF 1120 is rapidly metabolized in vivo by methylester cleavage, resulting in a short mean residence time, once daily oral dosing is fully efficacious in xenograft models. These distinctive pharmacokinetic and pharmacodynamic properties may help explain clinical observations with BIBF 1120, currently entering phase III clinical development.
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              Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis

              Lutz Wollin, Eva Wex, Alexander Pautsch … (2015)
              Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease characterised by fibrosis of the lung parenchyma and loss of lung function. Although the pathogenic pathways involved in IPF have not been fully elucidated, IPF is believed to be caused by repetitive alveolar epithelial cell injury and dysregulated repair, in which there is uncontrolled proliferation of lung fibroblasts and differentiation of fibroblasts into myofibroblasts, which excessively deposit extracellular matrix (ECM) proteins in the interstitial space. A number of profibrotic mediators including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) and transforming growth factor-β are believed to play important roles in the pathogenesis of IPF. Nintedanib is a potent small molecule inhibitor of the receptor tyrosine kinases PDGF receptor, FGF receptor and vascular endothelial growth factor receptor. Data from in vitro studies have shown that nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation, and the secretion of ECM. In addition, nintedanib has shown consistent anti-fibrotic and anti-inflammatory activity in animal models of lung fibrosis. These data provide a strong rationale for the clinical efficacy of nintedanib in patients with IPF, which has recently been demonstrated in phase III clinical trials.
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                Author and article information

                Contributors
                Wim A. Wuyts: +32 16 34 68 05 , wim.wuyts@uzleuven.be
                Journal
                Journal ID (nlm-ta): Lung
                Journal ID (iso-abbrev): Lung
                Title: Lung
                Publisher: Springer US (New York )
                ISSN (Print): 0341-2040
                ISSN (Electronic): 1432-1750
                Publication date (Electronic): 4 July 2016
                Publication date PMC-release: 4 July 2016
                Publication date (Print): 2016
                Volume: 194
                Issue: 5
                Pages: 739-743
                Affiliations
                [1 ]Unit for Interstitial Lung Diseases, Department of Respiratory Medicine, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
                [2 ]McMaster University, 50 Charlton Ave East, Hamilton, ON L8N 4A6 Canada
                [3 ]Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Str. 173, 55216 Ingelheim Am Rhein, Germany
                [4 ]Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425 USA
                [5 ]University of Washington, 1959 N.E. Pacific, Campus Box 356175, Seattle, WA 98195-6522 USA
                Article
                Publisher ID: 9912
                DOI: 10.1007/s00408-016-9912-1
                PMC ID: 5031742
                PubMed ID: 27377558
                SO-VID: 391c3eab-f735-4802-8876-03c132650d4c
                Copyright © © The Author(s) 2016
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Date received : 30 March 2016
                Date accepted : 14 June 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100008349, Boehringer Ingelheim;
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © Springer Science+Business Media New York 2016

                ScienceOpen disciplines: Respiratory medicine
                Keywords: interstitial lung diseases,clinical trial,disease progression,tyrosine kinase
                Data availability:
                ScienceOpen disciplines: Respiratory medicine
                Keywords: interstitial lung diseases, clinical trial, disease progression, tyrosine kinase

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