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Pharmacological treatment of idiopathic pulmonary fibrosis - preclinical and clinical studies of pirfenidone, nintedanib, and N-acetylcysteine.

Myllärniemi M, Kaarteenaho R - Eur Clin Respir J (2015)

Bottom Line: Pirfenidone was discovered in 1976 but only recently received approval in most countries, and even now its exact mechanism of action is unknown.On the contrary, nintedanib (BIBF1120) was identified in large drug screening tests as a very specific inhibitor of certain tyrosine kinases, but no published data on preclinical tests existed until 2014.A better understanding of the molecular mechanisms of IPF as well as relevant preclinical tests including animal models and in vitro experiments on human lung cells are needed to promote the development of therapeutic drugs.

View Article: PubMed Central - PubMed

Affiliation: Department of Pulmonary Medicine, Helsinki University Central Hospital, Heart and Lung Center and the University of Helsinki, Helsinki, Finland.

ABSTRACT
Three recent clinical trials on the pharmacologic treatment of idiopathic pulmonary fibrosis (IPF) mark a new chapter in the management of patients suffering from this very severe fibrotic lung disease. This review article summarizes the published investigations on the preclinical studies of three novel IPF drugs, namely pirfenidone, nintedanib, and N-acetylcysteine (NAC). In addition, the study protocols, differences, and the main findings in the recent clinical trials of these pharmacological treatments are reviewed. The strategy for drug development and the timeline from the discovery to the clinical use have been very different in these regimens. Pirfenidone was discovered in 1976 but only recently received approval in most countries, and even now its exact mechanism of action is unknown. On the contrary, nintedanib (BIBF1120) was identified in large drug screening tests as a very specific inhibitor of certain tyrosine kinases, but no published data on preclinical tests existed until 2014. NAC, a mucolytic drug with an antioxidant mechanism of action was claimed to possess distinct antifibrotic properties in several experimental models but proved to be ineffective in a recent randomized placebo-controlled trial. At present, no curative treatment is available for IPF. A better understanding of the molecular mechanisms of IPF as well as relevant preclinical tests including animal models and in vitro experiments on human lung cells are needed to promote the development of therapeutic drugs.

No MeSH data available.


Related in: MedlinePlus

The timeline from discovery to clinical application of three IPF drugs. The pathway from preclinical discovery to clinical application varies from drug to drug. The development of NAC as an antifibrotic drug required nearly four decades but it did prove to be disappointing in the latest randomized clinical trial, whereas nintedanib had not been extensively tested in experimental animals even though it had been shown to accelerate the FVC decline in humans – only a few years after its initial discovery. The initiation of pirfenidone to clinical applications, on the other hand was delayed by several problems in trial design.
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Figure 0001: The timeline from discovery to clinical application of three IPF drugs. The pathway from preclinical discovery to clinical application varies from drug to drug. The development of NAC as an antifibrotic drug required nearly four decades but it did prove to be disappointing in the latest randomized clinical trial, whereas nintedanib had not been extensively tested in experimental animals even though it had been shown to accelerate the FVC decline in humans – only a few years after its initial discovery. The initiation of pirfenidone to clinical applications, on the other hand was delayed by several problems in trial design.

Mentions: Figure 1 lists the hallmark studies on the development of three pharmacological treatments for IPF, namely pirfenidone, nintedanib, and NAC. The time frame of each regimen shows a marked variation from the point of discovery to their entry into clinical use. The preclinical studies on nintedanib were not published before the drug was evaluated in a clinical IPF phase III trial, since the first preclinical study on pulmonary fibrosis was conducted in 2007 with BIBF1000, a sibling molecule of nintedanib, that is, BIBF1120 (9). Nintedanib, that is, BIBF1120 was discovered as a side product from large screening assays targeting the cyclin-dependent kinase (CDK4) kinase (10, 11). Nintedanib was systematically developed by a pharmaceutical company (Boehringer Ingelheim) as a potent angiogenesis inhibitor. In contrast, NAC was discovered in the 1960s and there was a vast amount of preclinical data demonstrating inhibitory effects involving several antifibrotic mechanisms both in vitro and in vivo, but there was still a lack of firm conclusive evidence to support its clinical use in the treatment of IPF.


Pharmacological treatment of idiopathic pulmonary fibrosis - preclinical and clinical studies of pirfenidone, nintedanib, and N-acetylcysteine.

Myllärniemi M, Kaarteenaho R - Eur Clin Respir J (2015)

The timeline from discovery to clinical application of three IPF drugs. The pathway from preclinical discovery to clinical application varies from drug to drug. The development of NAC as an antifibrotic drug required nearly four decades but it did prove to be disappointing in the latest randomized clinical trial, whereas nintedanib had not been extensively tested in experimental animals even though it had been shown to accelerate the FVC decline in humans – only a few years after its initial discovery. The initiation of pirfenidone to clinical applications, on the other hand was delayed by several problems in trial design.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4629756&req=5

Figure 0001: The timeline from discovery to clinical application of three IPF drugs. The pathway from preclinical discovery to clinical application varies from drug to drug. The development of NAC as an antifibrotic drug required nearly four decades but it did prove to be disappointing in the latest randomized clinical trial, whereas nintedanib had not been extensively tested in experimental animals even though it had been shown to accelerate the FVC decline in humans – only a few years after its initial discovery. The initiation of pirfenidone to clinical applications, on the other hand was delayed by several problems in trial design.
Mentions: Figure 1 lists the hallmark studies on the development of three pharmacological treatments for IPF, namely pirfenidone, nintedanib, and NAC. The time frame of each regimen shows a marked variation from the point of discovery to their entry into clinical use. The preclinical studies on nintedanib were not published before the drug was evaluated in a clinical IPF phase III trial, since the first preclinical study on pulmonary fibrosis was conducted in 2007 with BIBF1000, a sibling molecule of nintedanib, that is, BIBF1120 (9). Nintedanib, that is, BIBF1120 was discovered as a side product from large screening assays targeting the cyclin-dependent kinase (CDK4) kinase (10, 11). Nintedanib was systematically developed by a pharmaceutical company (Boehringer Ingelheim) as a potent angiogenesis inhibitor. In contrast, NAC was discovered in the 1960s and there was a vast amount of preclinical data demonstrating inhibitory effects involving several antifibrotic mechanisms both in vitro and in vivo, but there was still a lack of firm conclusive evidence to support its clinical use in the treatment of IPF.

Bottom Line: Pirfenidone was discovered in 1976 but only recently received approval in most countries, and even now its exact mechanism of action is unknown.On the contrary, nintedanib (BIBF1120) was identified in large drug screening tests as a very specific inhibitor of certain tyrosine kinases, but no published data on preclinical tests existed until 2014.A better understanding of the molecular mechanisms of IPF as well as relevant preclinical tests including animal models and in vitro experiments on human lung cells are needed to promote the development of therapeutic drugs.

View Article: PubMed Central - PubMed

Affiliation: Department of Pulmonary Medicine, Helsinki University Central Hospital, Heart and Lung Center and the University of Helsinki, Helsinki, Finland.

ABSTRACT
Three recent clinical trials on the pharmacologic treatment of idiopathic pulmonary fibrosis (IPF) mark a new chapter in the management of patients suffering from this very severe fibrotic lung disease. This review article summarizes the published investigations on the preclinical studies of three novel IPF drugs, namely pirfenidone, nintedanib, and N-acetylcysteine (NAC). In addition, the study protocols, differences, and the main findings in the recent clinical trials of these pharmacological treatments are reviewed. The strategy for drug development and the timeline from the discovery to the clinical use have been very different in these regimens. Pirfenidone was discovered in 1976 but only recently received approval in most countries, and even now its exact mechanism of action is unknown. On the contrary, nintedanib (BIBF1120) was identified in large drug screening tests as a very specific inhibitor of certain tyrosine kinases, but no published data on preclinical tests existed until 2014. NAC, a mucolytic drug with an antioxidant mechanism of action was claimed to possess distinct antifibrotic properties in several experimental models but proved to be ineffective in a recent randomized placebo-controlled trial. At present, no curative treatment is available for IPF. A better understanding of the molecular mechanisms of IPF as well as relevant preclinical tests including animal models and in vitro experiments on human lung cells are needed to promote the development of therapeutic drugs.

No MeSH data available.


Related in: MedlinePlus