The Experts below are selected from a list of 2172 Experts worldwide ranked by ideXlab platform
Lutz Wollin - One of the best experts on this subject based on the ideXlab platform.
-
Nintedanib decreases muscle fibrosis and improves muscle function in a murine model of dystrophinopathy
Cell Death and Disease, 2018Co-Authors: Patricia Pinoljurado, Xavier Suarezcalvet, Esther Fernandezsimon, Eduard Gallardo, Natalia De La Oliva, Anna Martinezmuriana, Pedro Gomezgalvez, Luis M Escudero, Maria Perezpeiro, Lutz WollinAbstract:Duchenne muscle dystrophy (DMD) is a genetic disorder characterized by progressive skeletal muscle weakness. Dystrophin deficiency induces instability of the sarcolemma during muscle contraction that leads to muscle necrosis and replacement of muscle by fibro-adipose tissue. Several therapies have been developed to counteract the fibrotic process. We report the effects of Nintedanib, a tyrosine kinase inhibitor, in the mdx murine model of DMD. Nintedanib reduced proliferation and migration of human fibroblasts in vitro and decreased the expression of fibrotic genes such as COL1A1, COL3A1, FN1, TGFB1, and PDGFA. We treated seven mdx mice with 60 mg/kg/day Nintedanib for 1 month. Electrophysiological studies showed an increase in the amplitude of the motor action potentials and an improvement of the morphology of motor unit potentials in the animals treated. Histological studies demonstrated a significant reduction of the fibrotic areas present in the skeletal muscles. Analysis of mRNA expression from muscles of treated mice showed a reduction in Col1a1, Col3a1, Tgfb1, and Pdgfa. Western blot showed a reduction in the expression of collagen I in skeletal muscles. In conclusion, Nintedanib reduced the fibrotic process in a murine model of dystrophinopathy after 1 month of treatment, suggesting its potential use as a therapeutic drug in DMD patients.
-
Nintedanib reduces radiation induced microscopic lung fibrosis but this cannot be monitored by ct imaging a preclinical study with a high precision image guided irradiator
Radiotherapy and Oncology, 2017Co-Authors: Dirk De Ruysscher, Lutz Wollin, Patrick V Granton, Natasja G Lieuwes, Stefan J Van Hoof, Birgit Weynand, Annemarie C Dingemans, Frank Verhaegen, Ludwig DuboisAbstract:Abstract Background Nintedanib has anti-fibrotic and anti-inflammatory activity and is approved for the treatment of idiopathic pulmonary fibrosis. The aim of this study was to noninvasively assess the efficacy of Nintedanib in a mouse model of partial lung irradiation to prevent radiation-induced lung damage (RILD). Methods 266 C57BL/6 adult male mice were irradiated with a single radiation dose (0, 4, 8, 12, 16 or 20 Gy) using parallel-opposed fields targeting the upper right lung using a precision image-guided small animal irradiator sparing heart and spine based on micro-CT images. One week post irradiation, mice were randomized across Nintedanib daily oral gavage treatment (0, 30 or 60 mg/kg). CT density analysis of the lungs was performed on monthly acquired micro-CT images. After 39 weeks, lungs were processed to evaluate the fibrotic phenotype. Results Although the CT density increase correlated with the radiation dose, Nintedanib did not influence this relationship. Immunohistochemical analysis confirmed the ability of Nintedanib to reduce the microscopic fibrotic phenotype, in particular interstitial edema, interstitial and perivascular fibrosis and inflammation, and vasculitis. Conclusions Nintedanib reduces radiation-induced lung fibrosis after partial lung irradiation without adverse effects, however, noninvasive CT imaging measuring electron density cannot be applied for monitoring its effects.
-
Effects of Nintedanib on the microvascular architecture in a lung fibrosis model
Angiogenesis, 2017Co-Authors: Maximilian Ackermann, Lutz Wollin, Yong Ook Kim, Willi L. Wagner, Detlef Schuppan, Cristian D. Valenzuela, Steven J. Mentzer, Sebastian Kreuz, Detlef Stiller, Moritz A. KonerdingAbstract:Nintedanib, a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis, has anti-fibrotic, anti-inflammatory, and anti-angiogenic activity. We explored the impact of Nintedanib on microvascular architecture in a pulmonary fibrosis model. Lung fibrosis was induced in C57Bl/6 mice by intratracheal bleomycin (0.5 mg/kg). Nintedanib was started after the onset of lung pathology (50 mg/kg twice daily, orally). Micro-computed tomography was performed via volumetric assessment. Static lung compliance and forced vital capacity were determined by invasive measurements. Mice were subjected to bronchoalveolar lavage and histologic analyses, or perfused with a casting resin. Microvascular corrosion casts were imaged by scanning electron microscopy and synchrotron radiation tomographic microscopy, and quantified morphometrically. Bleomycin administration resulted in a significant increase in higher-density areas in the lungs detected by micro-computed tomography, which was significantly attenuated by Nintedanib. Nintedanib significantly reduced lung fibrosis and vascular proliferation, normalized the distorted microvascular architecture, and was associated with a trend toward improvement in lung function and inflammation. Nintedanib resulted in a prominent improvement in pulmonary microvascular architecture, which outperformed the effect of Nintedanib on lung function and inflammation. These findings uncover a potential new mode of action of Nintedanib that may contribute to its efficacy in idiopathic pulmonary fibrosis.
-
Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis
Annals of the Rheumatic Diseases, 2015Co-Authors: Jingang Huang, Oliver Distler, Christian Beyer, Katrin Palumbozerr, Yun Zhang, Andreas Ramming, Alfiya Distler, Kolja Gelse, Georg Schett, Lutz WollinAbstract:Background Nintedanib is a tyrosine kinase inhibitor that has recently been shown to slow disease progression in idiopathic pulmonary fibrosis in two replicate phase III clinical trials. The aim of this study was to analyse the antifibrotic effects of Nintedanib in preclinical models of systemic sclerosis (SSc) and to provide a scientific background for clinical trials in SSc. Methods The effects of Nintedanib on migration, proliferation, myofibroblast differentiation and release of extracellular matrix of dermal fibroblasts were analysed by microtitre tetrazolium and scratch assays, stress fibre staining, qPCR and SirCol assays. The antifibrotic effects of Nintedanib were evaluated in bleomycin-induced skin fibrosis, in a murine sclerodermatous chronic graft-versus-host disease model and in tight-skin-1 mice. Results Nintedanib dose-dependently reduced platelet-derived growth factor-induced and transforming growth factor-β-induced proliferation and migration as well as myofibroblast differentiation and collagen release of dermal fibroblasts from patients with and healthy individuals. Nintedanib also inhibited the endogenous activation of SSc fibroblasts. Nintedanib prevented bleomycin-induced skin fibrosis in a dose-dependent manner and was also effective in the treatment of established fibrosis. Moreover, treatment with Nintedanib ameliorated fibrosis in the chronic graft-versus-host disease model and in tight-skin-1 mice in well-tolerated doses. Conclusions We demonstrate that Nintedanib effectively inhibits the endogenous as well as cytokine-induced activation of SSc fibroblasts and exerts potent antifibrotic effects in different complementary mouse models of SSc. These data have direct translational implications for clinical trials with Nintedanib in SSc.
-
mode of action of Nintedanib in the treatment of idiopathic pulmonary fibrosis
European Respiratory Journal, 2015Co-Authors: Lutz Wollin, Susanne Stowasser, Alexander Pautsch, Gisela Schnapp, Katrin Hostettler, Martin KolbAbstract: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.
Susanne Stowasser - One of the best experts on this subject based on the ideXlab platform.
-
Nintedanib in patients with progressive fibrosing interstitial lung diseases subgroup analyses by interstitial lung disease diagnosis in the inbuild trial a randomised double blind placebo controlled parallel group trial
The Lancet Respiratory Medicine, 2020Co-Authors: Athol U Wells, Bruno Crestani, Luca Richeldi, Kevin K Brown, Kevin R Flaherty, Yoshikazu Inoue, Wim Wuyts, Anand Devaraj, Teng Moua, Susanne StowasserAbstract:Background The INBUILD trial investigated the efficacy and safety of Nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of Nintedanib in subgroups based on ILD diagnosis. Methods The INBUILD trial was a randomised, double-blind, placebo-controlled, parallel group trial done at 153 sites in 15 countries. Participants had an investigator-diagnosed fibrosing ILD other than IPF, with chest imaging features of fibrosis of more than 10% extent on high resolution CT (HRCT), forced vital capacity (FVC) of 45% or more predicted, and diffusing capacity of the lung for carbon monoxide (DLco) of at least 30% and less than 80% predicted. Participants fulfilled protocol-defined criteria for ILD progression in the 24 months before screening, despite management considered appropriate in clinical practice for the individual ILD. Participants were randomly assigned 1:1 by means of a pseudo-random number generator to receive Nintedanib 150 mg twice daily or placebo for at least 52 weeks. Participants, investigators, and other personnel involved in the trial and analysis were masked to treatment assignment until after database lock. In this subgroup analysis, we assessed the rate of decline in FVC (mL/year) over 52 weeks in patients who received at least one dose of Nintedanib or placebo in five prespecified subgroups based on the ILD diagnoses documented by the investigators: hypersensitivity pneumonitis, autoimmune ILDs, idiopathic non-specific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, and other ILDs. The trial has been completed and is registered with ClinicalTrials.gov, number NCT02999178. Findings Participants were recruited between Feb 23, 2017, and April 27, 2018. Of 663 participants who received at least one dose of Nintedanib or placebo, 173 (26%) had chronic hypersensitivity pneumonitis, 170 (26%) an autoimmune ILD, 125 (19%) idiopathic non-specific interstitial pneumonia, 114 (17%) unclassifiable idiopathic interstitial pneumonia, and 81 (12%) other ILDs. The effect of Nintedanib versus placebo on reducing the rate of FVC decline (mL/year) was consistent across the five subgroups by ILD diagnosis in the overall population (hypersensitivity pneumonitis 73·1 [95% CI -8·6 to 154·8]; autoimmune ILDs 104·0 [21·1 to 186·9]; idiopathic non-specific interstitial pneumonia 141·6 [46·0 to 237·2]; unclassifiable idiopathic interstitial pneumonia 68·3 [-31·4 to 168·1]; and other ILDs 197·1 [77·6 to 316·7]; p=0·41 for treatment by subgroup by time interaction). Adverse events reported in the subgroups were consistent with those reported in the overall population. Interpretation The INBUILD trial was not designed or powered to provide evidence for a benefit of Nintedanib in specific diagnostic subgroups. However, its results suggest that Nintedanib reduces the rate of ILD progression, as measured by FVC decline, in patients who have a chronic fibrosing ILD and progressive phenotype, irrespective of the underlying ILD diagnosis. Funding Boehringer Ingelheim.
-
does brain natriuretic peptide bnp at baseline influence the effects of Nintedanib plus sildenafil in patients with ipf
European Respiratory Journal, 2019Co-Authors: Jurgen Behr, Jin Woo Song, M Quaresma, Martin Kolb, Horst Olschewski, Fabrizio Luppi, Birgit Schinzel, Susanne Stowasser, Fernando J MartinezAbstract:Introduction: In the INSTAGE trial in patients with IPF and DLco ≤35% predicted, Nintedanib plus sildenafil was not associated with a significant benefit on SGRQ total score (primary endpoint) vs Nintedanib alone. However, Nintedanib plus sildenafil was associated with stabilisation in BNP, a marker of right ventricular strain, and reduced decline in FVC vs Nintedanib alone. Aim: To assess whether baseline BNP influenced the effects of Nintedanib plus sildenafil vs Nintedanib alone. Methods: In post-hoc analyses, patients with baseline BNP ≤ vs > median were compared on changes from baseline in BNP at week 24 and in SGRQ total score and FVC at weeks 12 and 24; time to absolute FVC ≥5% predicted or death; and time to relative FVC decline ≥10% predicted or death. Results: At baseline, median BNP was 52 ng/L; 140 patients had BNP ≤52 ng/L and 133 had BNP >52 ng/L. All endpoints showed numerical benefits of Nintedanib plus sildenafil vs Nintedanib alone in both subgroups. Compared with patients with baseline BNP below the median, the combination provided a significantly greater benefit on BNP levels and a numerical benefit on FVC in patients with higher baseline BNP. Conclusions: In patients with IPF and severely impaired gas exchange, the benefit of Nintedanib plus sildenafil vs Nintedanib alone on changes in BNP and FVC seemed more pronounced in patients with baseline BNP above the median.
-
Nintedanib plus sildenafil in patients with idiopathic pulmonary fibrosis
The New England Journal of Medicine, 2018Co-Authors: Martin Kolb, M Quaresma, Jurgen Behr, Birgit Schinzel, Susanne Stowasser, Luca Richeldi, Ganesh Raghu, Athol U Wells, Fernando J MartinezAbstract:Abstract Background Nintedanib is an approved treatment for idiopathic pulmonary fibrosis (IPF). A subgroup analysis of a previously published trial suggested that sildenafil may provide benefits regarding oxygenation, gas exchange as measured by the diffusion capacity of the lungs for carbon monoxide (DlCO), symptoms, and quality of life in patients with IPF and severely decreased DlCO. That idea was tested in this trial. Methods We randomly assigned, in a 1:1 ratio, patients with IPF and a DlCO of 35% or less of the predicted value to receive Nintedanib at a dose of 150 mg twice daily plus sildenafil at a dose of 20 mg three times daily (Nintedanib-plus-sildenafil group) or Nintedanib at a dose of 150 mg twice daily plus placebo three times daily (Nintedanib group) for 24 weeks. The primary end point was the change from baseline in the total score on the St. George’s Respiratory Questionnaire (SGRQ) at week 12 (the total score ranges from 0 to 100, with higher scores indicating worse health-related qual...
-
Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume
Thorax, 2017Co-Authors: Martin Kolb, Toby M Maher, Susanne Stowasser, Luca Richeldi, J Behr, W Tang, Christoph Hallmann, Roland M Du BoisAbstract:Rationale There is no consensus as to when treatment for idiopathic pulmonary fibrosis (IPF) should be initiated. Some physicians prefer not to treat patients with preserved lung volume. Objective To investigate whether patients with IPF and preserved lung volume receive the same benefit from Nintedanib as patients with more impaired lung volume. Methods Post hoc subgroup analyses of pooled data from the two replicate phase III INPULSIS trials by baseline FVC % predicted (≤90%, >90%). Results At baseline, 274 patients had FVC >90% predicted and 787 patients had FVC ≤90% predicted. In patients treated with placebo, the adjusted annual rate of decline in FVC was consistent between patients with FVC >90% predicted and FVC ≤90% predicted (−224.6 mL/year and −223.6 mL/year, respectively). There was no statistically significant difference between these subgroups in the effect of Nintedanib on annual rate of decline in FVC, change from baseline in St George's Respiratory Questionnaire total score or time to first acute exacerbation. In patients with baseline FVC >90% predicted and ≤90% predicted, respectively, the adjusted annual rate of decline in FVC with Nintedanib was −91.5 mL/year (difference vs placebo: 133.1 mL/year (95% CI 68.0 to 198.2)) and −121.5 mL/year (difference vs placebo: 102.1 mL/year (95% CI 61.9 to 142.3)). Adverse events associated with Nintedanib were similar in both subgroups. Conclusions Patients with IPF and preserved lung volume (FVC >90% predicted) have the same rate of FVC decline and receive the same benefit from Nintedanib as patients with more impaired lung volume. Trial registration number NCT01335464 and [NCT01335477][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01335477&atom=%2Fthoraxjnl%2Fearly%2F2016%2F09%2F26%2Fthoraxjnl-2016-208710.atom
-
no effect of baseline diffusing capacity of lung for carbon monoxide on benefit of Nintedanib
European Respiratory Journal, 2016Co-Authors: Toby M Maher, Wibke Stansen, Susanne Stowasser, Luca Richeldi, Kevin R Flaherty, Yoshikazu Inoue, Moises Selman, Athol U WellsAbstract:Background: The two replicate, 52-week, Phase III INPULSIS ® trials investigated the efficacy and safety of Nintedanib 150 mg twice daily (bid) in patients with idiopathic pulmonary fibrosis. Inclusion criteria included a diffusing capacity of the lung for carbon monoxide (DLco) of 30–79% predicted. In both trials, Nintedanib significantly reduced the annual rate of decline in forced vital capacity (FVC), the primary endpoint, versus placebo. Aim: To assess the potential impact of DLco % predicted on the treatment effect of Nintedanib. Methods: Post-hoc analyses of patients with baseline DLco >40% versus ≤40% predicted were conducted using pooled data from both INPULSIS ® trials. Results: A total of 709 patients (Nintedanib 428; placebo 281) had DLco >40% predicted and 351 patients (Nintedanib 210; placebo 141) had DLco ≤40% predicted. For patients with baseline DLco >40% predicted, mean age was 66.4 years, 80.8% were male and mean FVC was 83.3% predicted. For patients with baseline DLco ≤40% predicted, mean age was 67.4 years, 76.4% were male and mean FVC was 72.1% predicted. In patients with baseline DLco >40% predicted, the Nintedanib versus placebo difference in adjusted annual rate of decline in FVC was 103.1 mL/year (95% CI: 63.6, 142.6); in patients with baseline DLco ≤40% predicted, it was 124.3 mL/year (95% CI: (56.2, 192.4). There was no significant treatment-by-time-by-subgroup interaction (p=0.1468), indicating that the treatment effect of Nintedanib was not different between the subgroups. Conclusion: In a subgroup analysis of pooled data from the INPULSIS ® trials, Nintedanib slowed disease progression irrespective of the level of gas exchange impairment at baseline.
Sanjay Popat - One of the best experts on this subject based on the ideXlab platform.
-
Nintedanib in combination with pemetrexed and cisplatin for chemotherapy naive patients with advanced malignant pleural mesothelioma lume meso a double blind randomised placebo controlled phase 3 trial
The Lancet Respiratory Medicine, 2019Co-Authors: Giorgio V Scagliotti, Federica Grosso, Anna K Nowak, Sanjay Popat, Rabab Gaafar, Takashi Nakano, Jan P Van Meerbeeck, Nicholas J Vogelzang, Rasha AboelhassanAbstract:Summary Background Nintedanib targets VEGF receptors 1–3, PDGF receptors α and β, FGF receptors 1–3, and Src and Abl kinases, which are all implicated in malignant pleural mesothelioma pathogenesis. Here, we report the final results of the phase 3 part of the LUME-Meso trial, which aimed to investigate the efficacy and safety of pemetrexed plus cisplatin combined with Nintedanib or placebo in unresectable malignant pleural mesothelioma. Methods This double-blind, randomised, placebo-controlled phase 3 trial was done at 120 academic medical centres and community clinics in 27 countries across the world. Chemotherapy-naive adults (aged ≥18 years) with unresectable epithelioid malignant pleural mesothelioma and ECOG performance status 0–1 were randomly assigned 1:1 via an independently verified random number-generating system to receive up to six 21-day cycles of pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) on day 1, then Nintedanib (200 mg twice daily) or matched placebo on days 2–21. Patients without disease progression after six cycles received Nintedanib or placebo maintenance on days 1–21 of each cycle. The primary endpoint was progression-free survival (investigator-assessed according to mRECIST) in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of their assigned study drug. This study is registered with ClinicalTrials.gov , number NCT01907100 . Findings Between April 14, 2016, and Jan 5, 2018, 541 patients were screened and 458 were randomly assigned to either the Nintedanib group (n=229) or the placebo group (n=229). Median treatment duration was 5·3 months (IQR 2·8–7·3) in the Nintedanib group and 5·1 months (2·7–7·8) in the placebo group. After 250 events, progression-free survival was not different between the Nintedanib group (median 6·8 months [95% CI 6·1–7·0]) and the placebo group (7·0 months [6·7–7·2]; HR 1·01 [95% CI 0·79–1·30], p=0·91). The most frequently reported grade 3 or worse adverse event in both treatment groups was neutropenia (73 [32%] in the Nintedanib group vs 54 [24%] in the placebo group). Serious adverse events were reported in 99 (44%) patients in the Nintedanib group and 89 (39%) patients in the placebo group. The only serious adverse event occurring in at least 5% of patients in either group was pulmonary embolism (13 [6%] vs seven [3%]). Interpretation The primary progression-free survival endpoint of the phase 3 part of LUME-Meso was not met and phase 2 findings were not confirmed. No unexpected safety findings were reported. Funding Boehringer Ingelheim.
-
Nintedanib plus pemetrexed cisplatin in patients with malignant pleural mesothelioma phase ii results from the randomized placebo controlled lume meso trial
Journal of Clinical Oncology, 2017Co-Authors: Federica Grosso, Nicola Steele, Silvia Novello, Anna K Nowak, Sanjay Popat, L Greillier, Thomas John, Natasha B Leighl, Martin Reck, Paul TaylorAbstract:Purpose LUME-Meso is a phase II/III randomized, double-blind trial designed to assess efficacy and safety of Nintedanib plus chemotherapy as first-line treatment of malignant pleural mesothelioma (MPM). Phase II results are reported here. Patients and Methods Chemotherapy-naive patients with unresectable, nonsarcomatoid MPM (Eastern Cooperative Oncology Group performance status 0 to 1), stratified by histology (epithelioid or biphasic), were randomly assigned in a 1:1 ratio to up to six cycles of pemetrexed and cisplatin plus Nintedanib (200 mg twice daily) or placebo followed by Nintedanib plus placebo monotherapy until progression. The primary end point was progression-free survival (PFS). Results Eighty-seven patients were randomly assigned. The median number of pemetrexed and cisplatin cycles was six; the median treatment duration for Nintedanib was 7.8 months and 5.3 months for placebo. Primary PFS favored Nintedanib (hazard ratio [HR], 0.56; 95% CI, 0.34 to 0.91; P = .017), which was confirmed in updated PFS analyses (HR, 0.54; 95% CI, 0.33 to 0.87; P = .010). A trend toward improved overall survival also favored Nintedanib (HR, 0.77; 95% CI, 0.46 to 1.29; P = .319). Benefit was evident in epithelioid histology, with a median overall survival gain of 5.4 months (HR, 0.70; 95% CI, 0.40 to 1.21; P = .197; median [Nintedanib v placebo], 20.6 months v 15.2 months) and median PFS gain of 4.0 months (HR, 0.49; 95% CI, 0.30 to 0.82; P = .006; median [Nintedanib v placebo], 9.7 v 5.7 months). Neutropenia was the most frequent grade ≥ 3 adverse event (AE; Nintedanib 43.2% v placebo 12.2%); rates of febrile neutropenia were low (4.5% in Nintedanib group v 0% in placebo group). AEs leading to discontinuation were reported in 6.8% of those receiving Nintedanib versus 17.1% of those in the placebo group. Conclusion Addition of Nintedanib to pemetrexed plus cisplatin resulted in PFS improvement. AEs were manageable. The clinical benefit was evident in patients with epithelioid histology. The confirmatory phase III part of the study is ongoing.
-
Nintedanib plus docetaxel as second line therapy in patients with non small cell lung cancer of adenocarcinoma histology a network meta analysis vs new therapeutic options
Future Oncology, 2017Co-Authors: Sanjay Popat, Martin Reck, Anders Mellemgaard, Claudia Hastedt, Ingolf GriebschAbstract:Patients & methods: We provide an update to a network meta-analysis evaluating the relative efficacy of Nintedanib + docetaxel versus other second-line agents in adenocarcinoma histology non-small-cell lung cancer. Results: Overall similarity of Nintedanib + docetaxel versus ramucirumab + docetaxel, and versus nivolumab. Comparing Nintedanib + docetaxel with nivolumab, hazards ratio (HR) of overall survival and progression-free survival (PFS) pointed in opposite directions (overall survival: HR: 1.20 [95% credible interval: 0.92–1.58]; PFS: HR: 0.91 [0.68–1.21]). Exploratory subgroup analysis indicated superiority of nivolumab in high PD-L1 expression level subgroups; results were more favorable for Nintedanib in all subgroups with low (<1%, <5%, <10%) PD-L1 expression levels – in particular, with regard to PFS. Conclusion: Results demonstrated similar efficacy of Nintedanib + docetaxel compared with the new therapeutic options ramucirumab + docetaxel and nivolumab, with potential differences in subgroups...
Luca Richeldi - One of the best experts on this subject based on the ideXlab platform.
-
Nintedanib in patients with progressive fibrosing interstitial lung diseases subgroup analyses by interstitial lung disease diagnosis in the inbuild trial a randomised double blind placebo controlled parallel group trial
The Lancet Respiratory Medicine, 2020Co-Authors: Athol U Wells, Bruno Crestani, Luca Richeldi, Kevin K Brown, Kevin R Flaherty, Yoshikazu Inoue, Wim Wuyts, Anand Devaraj, Teng Moua, Susanne StowasserAbstract:Background The INBUILD trial investigated the efficacy and safety of Nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of Nintedanib in subgroups based on ILD diagnosis. Methods The INBUILD trial was a randomised, double-blind, placebo-controlled, parallel group trial done at 153 sites in 15 countries. Participants had an investigator-diagnosed fibrosing ILD other than IPF, with chest imaging features of fibrosis of more than 10% extent on high resolution CT (HRCT), forced vital capacity (FVC) of 45% or more predicted, and diffusing capacity of the lung for carbon monoxide (DLco) of at least 30% and less than 80% predicted. Participants fulfilled protocol-defined criteria for ILD progression in the 24 months before screening, despite management considered appropriate in clinical practice for the individual ILD. Participants were randomly assigned 1:1 by means of a pseudo-random number generator to receive Nintedanib 150 mg twice daily or placebo for at least 52 weeks. Participants, investigators, and other personnel involved in the trial and analysis were masked to treatment assignment until after database lock. In this subgroup analysis, we assessed the rate of decline in FVC (mL/year) over 52 weeks in patients who received at least one dose of Nintedanib or placebo in five prespecified subgroups based on the ILD diagnoses documented by the investigators: hypersensitivity pneumonitis, autoimmune ILDs, idiopathic non-specific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, and other ILDs. The trial has been completed and is registered with ClinicalTrials.gov, number NCT02999178. Findings Participants were recruited between Feb 23, 2017, and April 27, 2018. Of 663 participants who received at least one dose of Nintedanib or placebo, 173 (26%) had chronic hypersensitivity pneumonitis, 170 (26%) an autoimmune ILD, 125 (19%) idiopathic non-specific interstitial pneumonia, 114 (17%) unclassifiable idiopathic interstitial pneumonia, and 81 (12%) other ILDs. The effect of Nintedanib versus placebo on reducing the rate of FVC decline (mL/year) was consistent across the five subgroups by ILD diagnosis in the overall population (hypersensitivity pneumonitis 73·1 [95% CI -8·6 to 154·8]; autoimmune ILDs 104·0 [21·1 to 186·9]; idiopathic non-specific interstitial pneumonia 141·6 [46·0 to 237·2]; unclassifiable idiopathic interstitial pneumonia 68·3 [-31·4 to 168·1]; and other ILDs 197·1 [77·6 to 316·7]; p=0·41 for treatment by subgroup by time interaction). Adverse events reported in the subgroups were consistent with those reported in the overall population. Interpretation The INBUILD trial was not designed or powered to provide evidence for a benefit of Nintedanib in specific diagnostic subgroups. However, its results suggest that Nintedanib reduces the rate of ILD progression, as measured by FVC decline, in patients who have a chronic fibrosing ILD and progressive phenotype, irrespective of the underlying ILD diagnosis. Funding Boehringer Ingelheim.
-
Nintedanib plus sildenafil in patients with idiopathic pulmonary fibrosis
The New England Journal of Medicine, 2018Co-Authors: Martin Kolb, M Quaresma, Jurgen Behr, Birgit Schinzel, Susanne Stowasser, Luca Richeldi, Ganesh Raghu, Athol U Wells, Fernando J MartinezAbstract:Abstract Background Nintedanib is an approved treatment for idiopathic pulmonary fibrosis (IPF). A subgroup analysis of a previously published trial suggested that sildenafil may provide benefits regarding oxygenation, gas exchange as measured by the diffusion capacity of the lungs for carbon monoxide (DlCO), symptoms, and quality of life in patients with IPF and severely decreased DlCO. That idea was tested in this trial. Methods We randomly assigned, in a 1:1 ratio, patients with IPF and a DlCO of 35% or less of the predicted value to receive Nintedanib at a dose of 150 mg twice daily plus sildenafil at a dose of 20 mg three times daily (Nintedanib-plus-sildenafil group) or Nintedanib at a dose of 150 mg twice daily plus placebo three times daily (Nintedanib group) for 24 weeks. The primary end point was the change from baseline in the total score on the St. George’s Respiratory Questionnaire (SGRQ) at week 12 (the total score ranges from 0 to 100, with higher scores indicating worse health-related qual...
-
Nintedanib with add on pirfenidone in idiopathic pulmonary fibrosis results of the injourney trial
American Journal of Respiratory and Critical Care Medicine, 2017Co-Authors: Carlo Vancheri, Wibke Stansen, Michael Kreuter, Luca Richeldi, Christopher J Ryerson, Dominique Valeyre, Jan C Grutters, Sabrina Wiebe, Manuel QuaresmaAbstract:Rationale: Nintedanib and pirfenidone slow the progression of idiopathic pulmonary fibrosis (IPF), but the disease continues to progress. More data are needed on the safety and efficacy of combination therapy with Nintedanib and add-on pirfenidone.Objectives: To investigate safety, tolerability, and pharmacokinetic and exploratory efficacy endpoints in patients treated with Nintedanib and add-on pirfenidone versus Nintedanib alone.Methods: Patients with IPF and FVC greater than or equal to 50% predicted at screening who completed a 4- to 5-week run-in with Nintedanib 150 mg twice daily without dose reduction or treatment interruption were randomized to receive Nintedanib 150 mg twice daily with add-on pirfenidone (titrated to 801 mg three times daily) or Nintedanib 150 mg twice daily alone in an open-label manner for 12 weeks. The primary endpoint was the percentage of patients with on-treatment gastrointestinal adverse events from baseline to Week 12. Analyses were descriptive and exploratory.Measurement...
-
Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume
Thorax, 2017Co-Authors: Martin Kolb, Toby M Maher, Susanne Stowasser, Luca Richeldi, J Behr, W Tang, Christoph Hallmann, Roland M Du BoisAbstract:Rationale There is no consensus as to when treatment for idiopathic pulmonary fibrosis (IPF) should be initiated. Some physicians prefer not to treat patients with preserved lung volume. Objective To investigate whether patients with IPF and preserved lung volume receive the same benefit from Nintedanib as patients with more impaired lung volume. Methods Post hoc subgroup analyses of pooled data from the two replicate phase III INPULSIS trials by baseline FVC % predicted (≤90%, >90%). Results At baseline, 274 patients had FVC >90% predicted and 787 patients had FVC ≤90% predicted. In patients treated with placebo, the adjusted annual rate of decline in FVC was consistent between patients with FVC >90% predicted and FVC ≤90% predicted (−224.6 mL/year and −223.6 mL/year, respectively). There was no statistically significant difference between these subgroups in the effect of Nintedanib on annual rate of decline in FVC, change from baseline in St George's Respiratory Questionnaire total score or time to first acute exacerbation. In patients with baseline FVC >90% predicted and ≤90% predicted, respectively, the adjusted annual rate of decline in FVC with Nintedanib was −91.5 mL/year (difference vs placebo: 133.1 mL/year (95% CI 68.0 to 198.2)) and −121.5 mL/year (difference vs placebo: 102.1 mL/year (95% CI 61.9 to 142.3)). Adverse events associated with Nintedanib were similar in both subgroups. Conclusions Patients with IPF and preserved lung volume (FVC >90% predicted) have the same rate of FVC decline and receive the same benefit from Nintedanib as patients with more impaired lung volume. Trial registration number NCT01335464 and [NCT01335477][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01335477&atom=%2Fthoraxjnl%2Fearly%2F2016%2F09%2F26%2Fthoraxjnl-2016-208710.atom
-
no effect of baseline diffusing capacity of lung for carbon monoxide on benefit of Nintedanib
European Respiratory Journal, 2016Co-Authors: Toby M Maher, Wibke Stansen, Susanne Stowasser, Luca Richeldi, Kevin R Flaherty, Yoshikazu Inoue, Moises Selman, Athol U WellsAbstract:Background: The two replicate, 52-week, Phase III INPULSIS ® trials investigated the efficacy and safety of Nintedanib 150 mg twice daily (bid) in patients with idiopathic pulmonary fibrosis. Inclusion criteria included a diffusing capacity of the lung for carbon monoxide (DLco) of 30–79% predicted. In both trials, Nintedanib significantly reduced the annual rate of decline in forced vital capacity (FVC), the primary endpoint, versus placebo. Aim: To assess the potential impact of DLco % predicted on the treatment effect of Nintedanib. Methods: Post-hoc analyses of patients with baseline DLco >40% versus ≤40% predicted were conducted using pooled data from both INPULSIS ® trials. Results: A total of 709 patients (Nintedanib 428; placebo 281) had DLco >40% predicted and 351 patients (Nintedanib 210; placebo 141) had DLco ≤40% predicted. For patients with baseline DLco >40% predicted, mean age was 66.4 years, 80.8% were male and mean FVC was 83.3% predicted. For patients with baseline DLco ≤40% predicted, mean age was 67.4 years, 76.4% were male and mean FVC was 72.1% predicted. In patients with baseline DLco >40% predicted, the Nintedanib versus placebo difference in adjusted annual rate of decline in FVC was 103.1 mL/year (95% CI: 63.6, 142.6); in patients with baseline DLco ≤40% predicted, it was 124.3 mL/year (95% CI: (56.2, 192.4). There was no significant treatment-by-time-by-subgroup interaction (p=0.1468), indicating that the treatment effect of Nintedanib was not different between the subgroups. Conclusion: In a subgroup analysis of pooled data from the INPULSIS ® trials, Nintedanib slowed disease progression irrespective of the level of gas exchange impairment at baseline.
Jie Wu - One of the best experts on this subject based on the ideXlab platform.
-
structural basis of resistance of mutant ret protein tyrosine kinase to its inhibitors Nintedanib and vandetanib
Journal of Biological Chemistry, 2019Co-Authors: Simon Terzyan, Qingling Huang, Tao Shen, Frank Hilberg, Blaine H M Mooers, Peng Teng, Mi Zhou, Jie WuAbstract:: RET is a transmembrane growth factor receptor. Aberrantly activated RET is found in several types of human cancer and is a target for treating RET aberration-associated cancer. Multiple clinically relevant RET protein-tyrosine kinase inhibitors (TKIs) have been identified, but how TKIs bind to RET is unknown except for vandetanib. Nintedanib is a RET TKI that inhibits the vandetanib-resistant RET(G810A) mutant. Here, we determined the X-ray co-crystal structure of RET kinase domain-Nintedanib complex to 1.87 A resolution and a RET(G810A) kinase domain crystal structure to 1.99 A resolution. We also identified a vandetanib-resistant RET(L881V) mutation previously found in familial medullary thyroid carcinoma. Drug-sensitivity profiling of RET(L881V) revealed that it remains sensitive to Nintedanib. The RET-Nintedanib co-crystal structure disclosed that Leu-730 in RET engages in hydrophobic interactions with the piperazine, anilino, and phenyl groups of Nintedanib, providing a structural basis for explaining that the p.L730V mutation identified in nine independently isolated cell lines resistant to Nintedanib. Comparisons of RET-Nintedanib, RET(G810A), and RET-vandetanib crystal structures suggested that the solvent-front Ala-810 makes hydrophobic contacts with a methyl group and aniline in Nintedanib and blocks water access to two oxygen atoms of vandetanib, resulting in an energetic penalty for burying polar groups. Of note, even though the p.L881V mutation did not affect sensitivity to Nintedanib, RET(L881V) was resistant to Nintedanib analogs lacking a phenyl group. These results provide structural insights into resistance of RET mutants against the TKIs Nintedanib and vandetanib.
-
abstract 2117 different sensitivities of four protein tyrosine kinase inhibitors towards drug resistant ret mutations
Cancer Research, 2019Co-Authors: Tao Shen, Qingling Huang, Teng Peng, Frank Hilberg, Blaine H M Mooers, Jie WuAbstract:The RET protein tyrosine kinase (PTK) is a clinically validated target of therapy in non-small cell lung cancer (NSCLC) and thyroid cancer. Mutations in the targeted PTKs is a mechanism of drug resistance in cancer therapy with tyrosine kinase inhibitors (TKIs). Mutation-sensitive secondary drugs have been used successfully to overcome acquired drug-resistance to the first line TKIs. Cabozantinib, lenvatinib, vandetanib, and Nintedanib are FDA-approved multikinase TKIs with anti-RET activity. Using RET kinase-dependent BaF3/KIF5B-RET cells, we isolated thirteen mutations resistant to one of these TKIs. Cross-analysis of sensitivities of these four TKIs on these drug-resistant RET mutants and the RETM918T mutant, which is found in medullary thyroid carcinoma, revealed different TKI resistance-sensitivity profiles. In particular, the RETM918T mutant was resistant to cabozantinib, lenvatinib, and vandetanib but did not affect the potency of Nintedanib. RETL881V was isolated as a vandetanib-resistant mutation. The RETL881V mutation also induced resistance to cabozantinib and lenvatinib but did not affect the Nintedanib sensitivity. Examination of the RET-vandetanib co-crystal structure and the chemical structures of vandetanib and Nintedanib suggested that a phenyl group in Nintedanib, which corresponds to a methoxy group in vandetanib, may form hydrophobic interaction with the shorter side chain of Val881 and thus allows Nintedanib to inhibit RETL881V. To test this possibility, we synthesized two Nintedanib analogs (Compound 1 and Compound 2) without the phenyl group and tested their activities. The data showed that RETL881V was resistant to Compound 1 and Compound 2, supporting a role of the phenyl group of Nintedanib in mediating inhibition of RETL881V. Taken together, we have identified 13 RET mutations that display different resistance-sensitivity profiles against four anti-RET TKIs. Moreover, Nintedanib is effective in inhibiting RETM918T and RETL881V mutants that are resistant to the other three TKIs. Citation Format: Xuan Liu, Tao Shen, Qingling Huang, Teng Peng, Frank Hilberg, Jianfeng Cai, Blaine H. Mooers, Jie Wu. Different sensitivities of four protein tyrosine kinase inhibitors towards drug-resistant RET mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2117.