Inhibitors of the Autotaxin-Lysophosphatidic Acid Axis and Their Potential in the Treatment of Interstitial Lung Disease: Current Perspectives

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Abstract

Idiopathic pulmonary fibrosis is a progressive fibrosing interstitial lung disease for which there is no known cure. Currently available therapeutic options have been shown at best to slow the progression of the disease and thus there remains an urgent unmet need to identify new therapies. In this article, we will discuss the mechanisms of action, pre-clinical and clinical trial data surrounding inhibitors of the autotaxin-lysophosphatidic acid axis, which show promise as emerging novel therapies for fibrotic lung disease.

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Most cited references 69

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Nintedanib in Progressive Fibrosing Interstitial Lung Diseases

Kevin R. Flaherty, Athol Wells, Vincent Cottin … (2019)

Preclinical data have suggested that nintedanib, an intracellular inhibitor of tyrosine kinases, inhibits processes involved in the progression of lung fibrosis. Although the efficacy of nintedanib has been shown in idiopathic pulmonary fibrosis, its efficacy across a broad range of fibrosing lung diseases is unknown.

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Systemic sclerosis.

Christopher P. Denton, Dinesh Khanna (2017)

Systemic sclerosis, also called scleroderma, is an immune-mediated rheumatic disease that is characterised by fibrosis of the skin and internal organs and vasculopathy. Although systemic sclerosis is uncommon, it has a high morbidity and mortality. Improved understanding of systemic sclerosis has allowed better management of the disease, including improved classification and more systematic assessment and follow-up. Additionally, treatments for specific complications have emerged and a growing evidence base supports the use of immune suppression for the treatment of skin and lung fibrosis. Some manifestations of the disease, such as scleroderma renal crisis, pulmonary arterial hypertension, digital ulceration, and gastro-oesophageal reflux, are now treatable. However, the burden of non-lethal complications associated with systemic sclerosis is substantial and is likely to become more of a challenge. Here, we review the clinical features of systemic sclerosis and describe the best practice approaches for its management. Furthermore, we identify future areas for development.

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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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Author and article information

Journal

Journal ID (nlm-ta): Clin Pharmacol

Journal ID (iso-abbrev): Clin Pharmacol

Journal ID (publisher-id): CPAA

Journal ID (pmc): cpaa

Title: Clinical Pharmacology : Advances and Applications

Publisher: Dove

ISSN (Electronic): 1179-1438

Publication date (Electronic): 13 July 2020

Publication date Collection: 2020

Volume: 12

Pages: 97-108

Affiliations

[1 ]Bristol Interstitial Lung Disease Service, North Bristol NHS Trust , Bristol, UK

Author notes

Correspondence: Shaney L Barratt Consultant Respiratory Physician and Honorary Associate Researcher, North Bristol NHS Trust, Southmead Hospital , Southmead, BristolBS10 5NB, UK Email Shaney.Barratt@nbt.nhs.uk

Author information

Huzaifa Adamali http://orcid.org/0000-0002-8230-175X

Shaney L Barratt http://orcid.org/0000-0003-3067-7349

Article

Publisher ID: 228362

DOI: 10.2147/CPAA.S228362

PMC ID: 7367740

PubMed ID: 32765123

SO-VID: fa6aae67-3de8-4384-88f0-c603f007f17f

License:

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

History

Date received : 11 March 2020

Date accepted : 17 June 2020

Page count

Figures: 1, Tables: 2, References: 85, Pages: 12

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Funded by: no funding

There is no funding to report.

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Inhibitors of the Autotaxin-Lysophosphatidic Acid Axis and Their Potential in the Treatment of Interstitial Lung Disease: Current Perspectives

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In vitro alveolar region models

Most cited references 69

Nintedanib in Progressive Fibrosing Interstitial Lung Diseases

Systemic sclerosis.

Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis.

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