Abstract:GLPG1690 is a novel autotaxin inhibitor in development for the treatment of idiopathic pulmonary fibrosis (IPF). We report phase 1 studies investigating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GLPG1690 in healthy subjects. We performed a first‐in‐human randomized, double‐blind, placebo‐controlled trial of single (20, 60, 150, 300, 600, 1000, 1500 mg) and multiple (14 days: 150 mg twice daily; 600 and 1000 mg once daily) ascending oral doses of GLPG1690 (NCT02179502), and a… Show more
“…GLPG1690 showed superior results compared to pirfenidone and was similar to nintedanib, a tyrosine kinase inhibitor, in reducing the Ashcroft fibrotic score and collagen levels. 247 GLPG1690 was already tested in humans in order to test the safety, pharmacokinetics and pharmacodynamics of its doses, 248 and was well tolerated in a Phase 2a study (FLORA study) involving 23 patients with IPF. Treated patients had reduced plasma LPA C18:2 levels and showed improvement of disease control, such as stabilized FVC after 12 weeks of treatment.…”
Section: Lpa Signaling As a Therapeutic Targetmentioning
Lysophosphatidic acid (LPA) is an abundant bioactive phospholipid, with multiple functions both in development and in pathological conditions. Here, we review the literature about the differential signaling of LPA through its specific receptors, which makes this lipid a versatile signaling molecule. This differential signaling is important for understanding how this molecule can have such diverse effects during central nervous system development and angiogenesis; and also, how it can act as a powerful mediator of pathological conditions, such as neuropathic pain, neurodegenerative diseases, and cancer progression. Ultimately, we review the preclinical and clinical uses of Autotaxin, LPA, and its receptors as therapeutic targets, approaching the most recent data of promising molecules modulating both LPA production and signaling. This review aims to summarize the most update knowledge about the mechanisms of LPA production and signaling in order to understand its biological functions in the central nervous system both in health and disease.
“…GLPG1690 showed superior results compared to pirfenidone and was similar to nintedanib, a tyrosine kinase inhibitor, in reducing the Ashcroft fibrotic score and collagen levels. 247 GLPG1690 was already tested in humans in order to test the safety, pharmacokinetics and pharmacodynamics of its doses, 248 and was well tolerated in a Phase 2a study (FLORA study) involving 23 patients with IPF. Treated patients had reduced plasma LPA C18:2 levels and showed improvement of disease control, such as stabilized FVC after 12 weeks of treatment.…”
Section: Lpa Signaling As a Therapeutic Targetmentioning
Lysophosphatidic acid (LPA) is an abundant bioactive phospholipid, with multiple functions both in development and in pathological conditions. Here, we review the literature about the differential signaling of LPA through its specific receptors, which makes this lipid a versatile signaling molecule. This differential signaling is important for understanding how this molecule can have such diverse effects during central nervous system development and angiogenesis; and also, how it can act as a powerful mediator of pathological conditions, such as neuropathic pain, neurodegenerative diseases, and cancer progression. Ultimately, we review the preclinical and clinical uses of Autotaxin, LPA, and its receptors as therapeutic targets, approaching the most recent data of promising molecules modulating both LPA production and signaling. This review aims to summarize the most update knowledge about the mechanisms of LPA production and signaling in order to understand its biological functions in the central nervous system both in health and disease.
“…Moreover, potent (IC50 2 nM), long term (3 weeks) pharmacological inhibition of ATX with PF-8380 (120 mg/Kg - 4 times the effective concentration; PO; bid) had no effects in survival or gross pathology of major organs ( 135 ), suggesting that ATX pharmaceutical targeting is safe and well tolerated in mice. 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 ).…”
Section: Pharmacologic Targeting Of Atx As An Additional Therapeutic Option In Covid-19mentioning
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.
“…The pharmacokinetics (PK) of ziritaxestat have been reported separately. 18 Ziritaxestat is rapidly absorbed and eliminated, with exposure to parent increasing in a dose‐proportional manner. In vitro human recombinant cytochrome P450 (CYP) studies indicated that ziritaxestat was primarily metabolized by CYP3A4 with minor contributions (maximum of 2.1%) to metabolism from other phase 1 enzymes.…”
Ziritaxestat is a novel inhibitor of autotaxin, an enzyme responsible for the production of lysophosphatidic acid, the downstream signaling of which mediates responses to tissue injury and has been implicated in the pathogenesis of fibrotic conditions such as idiopathic pulmonary fibrosis and systemic sclerosis. This study (Clinical Trial Registration: NCT03787186) was designed to assess the absorption, distribution, metabolism, and excretion of orally administered 600‐mg ziritaxestat labeled with a carbon‐14 tracer (14C‐ziritaxestat). To understand the absolute bioavailability of ziritaxestat, an intravenous 100‐μg microdose, labeled with a microtracer amount of 14C radiation, was administered in a separate part of the study, following an unlabeled 600‐mg therapeutic oral dose of ziritaxestat. Six healthy male subjects completed each study part. The majority of the labeled oral dose was recovered in feces (77%), with a total mass balance of 84%. The absolute bioavailability of ziritaxestat was 54%. Ziritaxestat was the main (76%) circulating drug‐related product. There were 7 treatment‐emergent adverse events, all of which were considered mild and not considered to be related to the study drug.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.