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Nintedanib: evidence for its therapeutic potential in idiopathic pulmonary fibrosis.

Inomata M, Nishioka Y, Azuma A - Core Evid (2015)

Bottom Line: The molecular mechanisms involved in the progression of IPF are not fully understood; however, the platelet-derived growth factor (PDGF)/PDGF receptor pathway is thought to play a critical role in fibrogenesis of the lungs.Other growth factors, including fibroblast growth factor and vascular endothelial growth factor, are also thought to contribute to the pathogenesis of pulmonary fibrosis.Nintedanib is an inhibitor of multiple tyrosine kinases, including receptors for PDGF, fibroblast growth factor, and vascular endothelial growth factor.

View Article: PubMed Central - PubMed

Affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Sendagi, Bunkyo-ku, Tokyo.

ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis. The molecular mechanisms involved in the progression of IPF are not fully understood; however, the platelet-derived growth factor (PDGF)/PDGF receptor pathway is thought to play a critical role in fibrogenesis of the lungs. Other growth factors, including fibroblast growth factor and vascular endothelial growth factor, are also thought to contribute to the pathogenesis of pulmonary fibrosis. Nintedanib is an inhibitor of multiple tyrosine kinases, including receptors for PDGF, fibroblast growth factor, and vascular endothelial growth factor. In the Phase II TOMORROW trial, treatment with 150 mg of nintedanib twice daily showed a trend to slow the decline in lung function and significantly decrease acute exacerbations in patients with IPF, while showing an acceptable safety profile. The Phase III INPULSIS trials demonstrated a significant decrease in the annual rate of decline in forced vital capacity in IPF patients treated with 150 mg nintedanib twice daily. In the INPULSIS-2 trial, the time to the first acute exacerbation significantly increased in IPF patients who were treated with 150 mg of nintedanib twice daily. Pirfenidone, another antifibrotic drug, was shown to limit the decline in pulmonary function in patients with IPF in the ASCEND trial. Combination therapy with nintedanib and pirfenidone is anticipated, although further evaluation of its long-term safety is needed. There is limited evidence for the safety of the combination therapy although a Phase II trial conducted in Japan demonstrated that combination therapy with nintedanib and pirfenidone was tolerable for 1 month. Available antifibrotic agents (ie, pirfenidone and N-acetylcysteine) have limited efficacy as single therapies for IPF; therefore, further study of combination therapy with antifibrotic agents is needed.

No MeSH data available.


Related in: MedlinePlus

Chemical structure of nintedanib.Notes: Indolinone lead compounds substituted at position 6 were selected by assessing inhibition of tumor angiogenesis and shown to inhibit VEGFR-2. Derivatives of the lead compound were further screened to enhance triple angiokinase (VEGFR-2, FGFR-1, and PDGFR-α) inhibitory activity. Two compounds, BIBF1000 and BIBF1120, were tested in assays of antitumor activity, and BIBF1120 was selected for clinical trials.Abbreviations: VEGFR, vascular endothelial growth factor receptor; FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor.
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f1-ce-10-089: Chemical structure of nintedanib.Notes: Indolinone lead compounds substituted at position 6 were selected by assessing inhibition of tumor angiogenesis and shown to inhibit VEGFR-2. Derivatives of the lead compound were further screened to enhance triple angiokinase (VEGFR-2, FGFR-1, and PDGFR-α) inhibitory activity. Two compounds, BIBF1000 and BIBF1120, were tested in assays of antitumor activity, and BIBF1120 was selected for clinical trials.Abbreviations: VEGFR, vascular endothelial growth factor receptor; FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor.

Mentions: The development of nintedanib began with the identification of a lead compound from a group of six-substituted indolinones via assessment of tumor angiogenesis inhibition, and this compound was shown to inhibit VEGFR-2.54 Derivatives of the lead compound were screened for triple angiokinase (eg, VEGFR-2, FGFR-1, and PDGFRα) inhibitory activity. Two compounds, BIBF1000 and BIBF1120, were developed, their antitumor activities were assessed, and BIBF1120 was selected for clinical trials (Figure 1).54 The kinase inhibition profile of BIBF1120 is provided in Table 2.4


Nintedanib: evidence for its therapeutic potential in idiopathic pulmonary fibrosis.

Inomata M, Nishioka Y, Azuma A - Core Evid (2015)

Chemical structure of nintedanib.Notes: Indolinone lead compounds substituted at position 6 were selected by assessing inhibition of tumor angiogenesis and shown to inhibit VEGFR-2. Derivatives of the lead compound were further screened to enhance triple angiokinase (VEGFR-2, FGFR-1, and PDGFR-α) inhibitory activity. Two compounds, BIBF1000 and BIBF1120, were tested in assays of antitumor activity, and BIBF1120 was selected for clinical trials.Abbreviations: VEGFR, vascular endothelial growth factor receptor; FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4555978&req=5

f1-ce-10-089: Chemical structure of nintedanib.Notes: Indolinone lead compounds substituted at position 6 were selected by assessing inhibition of tumor angiogenesis and shown to inhibit VEGFR-2. Derivatives of the lead compound were further screened to enhance triple angiokinase (VEGFR-2, FGFR-1, and PDGFR-α) inhibitory activity. Two compounds, BIBF1000 and BIBF1120, were tested in assays of antitumor activity, and BIBF1120 was selected for clinical trials.Abbreviations: VEGFR, vascular endothelial growth factor receptor; FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor.
Mentions: The development of nintedanib began with the identification of a lead compound from a group of six-substituted indolinones via assessment of tumor angiogenesis inhibition, and this compound was shown to inhibit VEGFR-2.54 Derivatives of the lead compound were screened for triple angiokinase (eg, VEGFR-2, FGFR-1, and PDGFRα) inhibitory activity. Two compounds, BIBF1000 and BIBF1120, were developed, their antitumor activities were assessed, and BIBF1120 was selected for clinical trials (Figure 1).54 The kinase inhibition profile of BIBF1120 is provided in Table 2.4

Bottom Line: The molecular mechanisms involved in the progression of IPF are not fully understood; however, the platelet-derived growth factor (PDGF)/PDGF receptor pathway is thought to play a critical role in fibrogenesis of the lungs.Other growth factors, including fibroblast growth factor and vascular endothelial growth factor, are also thought to contribute to the pathogenesis of pulmonary fibrosis.Nintedanib is an inhibitor of multiple tyrosine kinases, including receptors for PDGF, fibroblast growth factor, and vascular endothelial growth factor.

View Article: PubMed Central - PubMed

Affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Sendagi, Bunkyo-ku, Tokyo.

ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis. The molecular mechanisms involved in the progression of IPF are not fully understood; however, the platelet-derived growth factor (PDGF)/PDGF receptor pathway is thought to play a critical role in fibrogenesis of the lungs. Other growth factors, including fibroblast growth factor and vascular endothelial growth factor, are also thought to contribute to the pathogenesis of pulmonary fibrosis. Nintedanib is an inhibitor of multiple tyrosine kinases, including receptors for PDGF, fibroblast growth factor, and vascular endothelial growth factor. In the Phase II TOMORROW trial, treatment with 150 mg of nintedanib twice daily showed a trend to slow the decline in lung function and significantly decrease acute exacerbations in patients with IPF, while showing an acceptable safety profile. The Phase III INPULSIS trials demonstrated a significant decrease in the annual rate of decline in forced vital capacity in IPF patients treated with 150 mg nintedanib twice daily. In the INPULSIS-2 trial, the time to the first acute exacerbation significantly increased in IPF patients who were treated with 150 mg of nintedanib twice daily. Pirfenidone, another antifibrotic drug, was shown to limit the decline in pulmonary function in patients with IPF in the ASCEND trial. Combination therapy with nintedanib and pirfenidone is anticipated, although further evaluation of its long-term safety is needed. There is limited evidence for the safety of the combination therapy although a Phase II trial conducted in Japan demonstrated that combination therapy with nintedanib and pirfenidone was tolerable for 1 month. Available antifibrotic agents (ie, pirfenidone and N-acetylcysteine) have limited efficacy as single therapies for IPF; therefore, further study of combination therapy with antifibrotic agents is needed.

No MeSH data available.


Related in: MedlinePlus