Late Breaking Abstract - BBT-877, a Potent Autotaxin Inhibitor in Clinical Development to Treat Idiopathic Pulmonary Fibrosis

Lee, Gwanghee; Kang, Sang Uk; Ryou, Jeong-Hyun; Lim, Jong In; Lee, Jun Young

doi:10.1183/13993003.congress-2019.pa1293

Cited by 7 publications

(8 citation statements)

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“…In humans, GLPG1690 was reported to be well tolerated in a phase 1 randomized clinical trial (NCT02179502), safe and efficacious in a phase 2a randomized placebo-controlled clinical trial (NCT02738801), supporting ATX inhibition as a novel treatment for IPF ( 136 , 137 ). In addition, administration of BBT-877, another orally available small molecule inhibitor targeting ATX (IC50 ~6.7 nM), to healthy volunteers in a phase I clinical trial (NCT03830125), did not reveal severe adverse events ( 138 , 139 ). However, the GLPG1690 phase III clinical trial was recently discontinued on account of “low benefit to risk ratio“.…”

Section: Pharmacologic Targeting Of Atx As An Additional Therapeutic Option In Covid-19mentioning

confidence: 99%

Commonalities Between ARDS, Pulmonary Fibrosis and COVID-19: The Potential of Autotaxin as a Therapeutic Target

et al. 2021

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Severe COVID-19 is characterized by acute respiratory distress syndrome (ARDS)-like hyperinflammation and endothelial dysfunction, that can lead to respiratory and multi organ failure and death. Interstitial lung diseases (ILD) and pulmonary fibrosis confer an increased risk for severe disease, while a subset of COVID-19-related ARDS surviving patients will develop a fibroproliferative response that can persist post hospitalization. Autotaxin (ATX) is a secreted lysophospholipase D, largely responsible for the extracellular production of lysophosphatidic acid (LPA), a pleiotropic signaling lysophospholipid with multiple effects in pulmonary and immune cells. In this review, we discuss the similarities of COVID-19, ARDS and ILDs, and suggest ATX as a possible pathologic link and a potential common therapeutic target.

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Section: Pharmacologic Targeting Of Atx As An Additional Therapeutic Option In Covid-19mentioning

confidence: 99%

Commonalities Between ARDS, Pulmonary Fibrosis and COVID-19: The Potential of Autotaxin as a Therapeutic Target

et al. 2021

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“…A number of small molecular weight inhibitors have been developed to ameliorate IPF and reverse fibrosis in patients. ATX inhibitors GWJ-A-23 [291], PF-8380 [216], BBT-877 [302], and GLPG1690 [303] have been shown to confer protection against bleomycin-induced PF in mice. Among the various ATX inhibitors, the Galapagos compound GLPG1690 has advanced to Phase III clinical trials and awaiting outcome on safety and side effects.…”

Section: Atx/lpa Signaling Axis In Pulmonary Fibrosismentioning

confidence: 99%

Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways

Suryadevara

Ramchandran

Kamp

et al. 2020

IJMS

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Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown etiology characterized by distorted distal lung architecture, inflammation, and fibrosis. The molecular mechanisms involved in the pathophysiology of IPF are incompletely defined. Several lung cell types including alveolar epithelial cells, fibroblasts, monocyte-derived macrophages, and endothelial cells have been implicated in the development and progression of fibrosis. Regardless of the cell types involved, changes in gene expression, disrupted glycolysis, and mitochondrial oxidation, dysregulated protein folding, and altered phospholipid and sphingolipid metabolism result in activation of myofibroblast, deposition of extracellular matrix proteins, remodeling of lung architecture and fibrosis. Lipid mediators derived from phospholipids, sphingolipids, and polyunsaturated fatty acids play an important role in the pathogenesis of pulmonary fibrosis and have been described to exhibit pro- and anti-fibrotic effects in IPF and in preclinical animal models of lung fibrosis. This review describes the current understanding of the role and signaling pathways of prostanoids, lysophospholipids, and sphingolipids and their metabolizing enzymes in the development of lung fibrosis. Further, several of the lipid mediators and enzymes involved in their metabolism are therapeutic targets for drug development to treat IPF.

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“…127 BBT-877 is another ATX inhibitor that has been developed for IPF. 128 It underwent phase I trials, demonstrating safety and tolerability as well as an 80% reduction in plasma LPA levels. 128 In addition to IPF, the LPA axis has been targeted for treating liver and skin fibrosis.…”

Section: Therapeutic Strategies In Fibrosismentioning

confidence: 99%

“…128 It underwent phase I trials, demonstrating safety and tolerability as well as an 80% reduction in plasma LPA levels. 128 In addition to IPF, the LPA axis has been targeted for treating liver and skin fibrosis. BLD-0409 is an ATX inhibitor undergoing phase I clinical trials for use in non-alcoholic steatohepatitis and chronic liver fibrosis.…”

Section: Therapeutic Strategies In Fibrosismentioning

confidence: 99%

The lysophosphatidic acid axis in fibrosis: Implications for glaucoma

O'Regan

O’Brien

Eivers

2021

Wound Repair Regeneration

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Glaucoma is a common progressive optic neuropathy that results in visual field defects and can lead to irreversible blindness. The pathophysiology of glaucoma involves dysregulated extracellular matrix remodelling in both the trabecular meshwork in the anterior chamber and in the lamina cribrosa of the optic nerve head. Fibrosis in these regions leads to raised intraocular pressure and retinal ganglion cell degeneration, respectively.Lysophosphatidic acid (LPA) is a bioactive lipid mediator which acts via six G-protein coupled receptors on the cell surface to activate intracellular pathways that promote cell proliferation, transcription and survival. LPA signalling has been implicated in both normal wound healing and pathological fibrosis. LPA enhances fibroblast proliferation, migration and contraction, and induces expression of pro-fibrotic mediators such as connective tissue growth factor. The LPA axis plays a major role in diseases such as idiopathic pulmonary fibrosis, where it has been identified as an important pharmacological target. In glaucoma, LPA is present in high levels in the aqueous humour, and its signalling has been found to increase resistance to aqueous humour outflow through altered trabecular meshwork cellular contraction and extracellular matrix deposition. LPA signalling may, therefore, also represent an attractive target for treatment of glaucoma. In this review we wish to describe the role of LPA and its related proteins in tissue fibrosis and glaucoma.

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Late Breaking Abstract - BBT-877, a Potent Autotaxin Inhibitor in Clinical Development to Treat Idiopathic Pulmonary Fibrosis

Cited by 7 publications

References 0 publications

Commonalities Between ARDS, Pulmonary Fibrosis and COVID-19: The Potential of Autotaxin as a Therapeutic Target

Commonalities Between ARDS, Pulmonary Fibrosis and COVID-19: The Potential of Autotaxin as a Therapeutic Target

Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways

The lysophosphatidic acid axis in fibrosis: Implications for glaucoma

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