Safety and survival data in patients with idiopathic pulmonary fibrosis treated with nintedanib: pooled data from six clinical trials

Lancaster, Lisa; Crestani, Bruno; Hernández, Paul; Inoue, Yoshikazu; Wachtlin, Daniel; Loaiza, Lazaro; Quaresma, Manuel; Stowasser, Susanne; Richeldi, Luca

doi:10.1136/bmjresp-2018-000397

Cited by 145 publications

(119 citation statements)

References 24 publications

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“…Nintedanib reduced the rate of decline in FVC both in patients who were and were not receiving mycophenolate at baseline, with a numerically greater treatment effect in patients who were not taking mycophenolate. The adverse event profile of nintedanib was similar to that previously observed in patients with IPF, being characterized mainly by gastrointestinal events, particularly diarrhea of mild or moderate severity [56]. The efficacy and safety of nintedanib in patients with progressive fibrosing ILDs have also been assessed in the INBUILD® trial.…”

Section: Nintedanibsupporting

confidence: 59%

Current and future perspectives on management of systemic sclerosis-associated interstitial lung disease

Distler

Volkmann

Hoffmann-Vold

et al. 2019

Expert Review of Clinical Immunology

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Section: Nintedanibsupporting

confidence: 59%

Current and future perspectives on management of systemic sclerosis-associated interstitial lung disease

Distler

Volkmann

Hoffmann-Vold

et al. 2019

Expert Review of Clinical Immunology

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“…Nintedanib had a similar adverse event profile in patients with mild or moderate impairment in gas exchange in the INPULSIS trials and in patients with more severe disease in the INSTAGE trial, albeit with a greater frequency of serious adverse events in patients with more severe disease, as might be expected in a sicker population. Previous analyses of safety data from clinical trials of nintedanib have shown a consistent safety and tolerability profile across trials and patient subgroups [13,14,23]. Real-world data from clinical practice suggest that the safety and tolerability profile of nintedanib is similar in patients with IPF who have severe disease as in patients with milder disease, but that patients with more severe disease have a higher rate of treatment discontinuation [16,18,24].…”

Section: Discussionmentioning

confidence: 93%

Efficacy and safety of nintedanib in patients with advanced idiopathic pulmonary fibrosis

et al. 2020

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Background: The two 52-week INPULSIS trials investigated nintedanib versus placebo in patients with IPF, FVC ≥50% predicted and DLco 30-79% predicted. The 24-week INSTAGE trial investigated nintedanib plus sildenafil versus nintedanib alone in patients with IPF and DLco ≤35% predicted. We used data from INPULSIS and INSTAGE to compare the effects of nintedanib in patients with IPF with less versus more severe impairment in gas exchange at baseline. Methods: Analyses were conducted in patients treated with nintedanib alone in the INPULSIS and INSTAGE trials and in patients treated with placebo in the INPULSIS trials. Outcomes included the rate of decline in FVC over 24 weeks, the proportions of patients who had a confirmed or suspected idiopathic acute exacerbation over 24 weeks, deaths over 24 weeks, and adverse events. Analyses were descriptive. Results: In total, 638 and 136 patients received nintedanib alone in the INPULSIS and INSTAGE trials, respectively, and 423 patients received placebo in the INPULSIS trials. Rates of FVC decline were − 52.3 and − 66.7 mL/24 weeks in patients treated with nintedanib alone in INPULSIS and INSTAGE, respectively, and − 102.8 mL/24 weeks in patients treated with placebo in INPULSIS. Confirmed or suspected idiopathic acute exacerbations were reported in 0.6 and 3.7% of patients treated with nintedanib alone in INPULSIS and INSTAGE, respectively, and 2.1% of patients treated with placebo in INPULSIS. Deaths occurred in 2.0, 11.0 and 1.9% of patients in these groups, respectively. Diarrhoea adverse events were reported in 52.5 and 48.5% of patients treated with nintedanib alone in INPULSIS and INSTAGE, respectively, and 16.1% of patients treated with placebo in INPULSIS.Conclusions: Based on data from the INSTAGE and INPULSIS trials, nintedanib had a similar effect on FVC decline over 24 weeks, and a similar safety and tolerability profile, in patients with IPF and more versus less severe impairment in gas exchange. These data support the use of nintedanib in patients with IPF who have advanced disease.Trial registration: INPULSIS (NCT01335464 and NCT01335477); INSTAGE (NCT02802345).

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“…Indeed, the current FDA approved anti-fibrotic medications slow the progression of disease but patient-reported symptoms were largely unchanged. Pooled data from the INPULSIS and TOMORROW trials involving nintedanib demonstrated a reduction in acute exacerbations [59] and secondary endpoint analysis with pirfenidone and nintedanib suggest an improvement in all-cause and IPF related mortality [60,61]. These additional benefits need to be confirmed with larger randomized clinical trials.…”

Section: Discussionmentioning

confidence: 99%

The Role of the Ovarian Cancer G -Coupled Receptor (OGR1) in Idiopathic Pulmonary Fibrosis

Nagel

Clough

Bell³

et al. 2019

Preprint

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Idiopathic pulmonary fibrosis (IPF) is a disease characterized by irreversible scarring of the lung that is associated with significant mortality and morbidity. The pathophysiology is incompletely understood but it is well-established that fibroblast to myofibroblast differentiation is a key feature of pulmonary fibrosis. Our lab has established that a reduction in extracellular pH is one of several important pathways responsible for the activation of latent TGF-β in the extracellular space. TGF-β activation further decreases extracellular pH and creates a feed-forward mechanism that stimulates myofibroblast differentiation and activation of additional TGF-β. Given the importance of TGF-β and extracellular acidification to the progression of pulmonary fibrosis, we sought to identify novel mechanisms that are involved in pH-dependent fibrotic signaling. The proton sensing G-Protein Coupled family of receptors are activated in acidic environments, but their role in fibrotic signaling has not been studied. Here we report that the Ovarian Cancer G-Protein Coupled Receptor1 (OGR1 or GPR68), a member of the family of proton sensing G-Protein Coupled Receptors, negatively regulates pro-fibrotic signaling.We demonstrate that OGR1 expression is significantly reduced in lung tissue from patients with IPF and TGF-β decreases OGR1 expression. In fibroblasts, a reduction in expression of OGR1 (OGR knockout lung fibroblasts) and knockdown (OGR siRNA), promotes in vitro myofibroblast differentiation. In contrast, OGR1 overexpression inhibits myofibroblast differentiation. Finally, we demonstrate that OGR1 negatively regulates TGF-β stimulation through inhibition of focal adhesion kinase (FAK) phosphorylation. Our results suggest that preserving OGR1 expression may represent a novel therapeutic strategy in pulmonary fibrosis.

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Safety and survival data in patients with idiopathic pulmonary fibrosis treated with nintedanib: pooled data from six clinical trials

Cited by 145 publications

References 24 publications

Current and future perspectives on management of systemic sclerosis-associated interstitial lung disease

Current and future perspectives on management of systemic sclerosis-associated interstitial lung disease

Efficacy and safety of nintedanib in patients with advanced idiopathic pulmonary fibrosis

The Role of the Ovarian Cancer G -Coupled Receptor (OGR1) in Idiopathic Pulmonary Fibrosis

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