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

Lee, G.; Kang, Sung-Hyun; Ryou, Jeong-Hyun; Lim, Jisun; Lee, D.-Y.; Kwon, Hee Uk; Ha, Grillo; Lee, Y.-H.

doi:10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a2577

Cited by 4 publications

(7 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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“…BBT-877 is an orally available small molecule inhibitor of ATX that mimics LPA receptor antagonism, leading to the suppression of fibrosis in lung tissue [ 24 , 29 ]. Our current data reveal that BBT-877 administration similarly attenuates kidney hyperfiltration and kidney dysfunction in diabetic states, as revealed by the reduced water intake, urination, and ACR compared to the STZ-vehicle group, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Toll-like receptor signaling, oxidative stress, and proinflammatory cytokines (such as IL-1β, TNF-α, and IL-6) can stimulate the transcription of TGF-β isoforms in fibrotic tissues [ 15 , 43 , 44 ]. Recently, Lee et al showed that BBT-877 attenuated fibrosis in a mouse model of bleomycin-induced pulmonary fibrosis [ 24 ]. Consistently, our data also showed that TGF-β expression was significantly increased with the expression levels of fibrotic factors, including fibronectin, CTGF, and COL1A1 in diabetic mice.…”

Section: Discussionmentioning

confidence: 99%

“…BBT-877 and PF-8380 are orally available small molecule inhibitors of ATX. Recently, Lee et al showed that BBT-877 treatment effectively decreased LPA production in in vitro and ex vivo systems [ 24 ]. In addition, several ATX inhibitors, including BBT-877, suppressed fibrosis in bleomycin-induced pulmonary fibrotic mice [ 25 ] and in liver fibrotic mice [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, several ATX inhibitors, including BBT-877, suppressed fibrosis in bleomycin-induced pulmonary fibrotic mice [ 25 ] and in liver fibrotic mice [ 26 ]. In particular, BBT-877 was less cytotoxic to various cell types, such as hepatocellular carcinoma cells and normal lung fibroblasts [ 24 ]. These exciting observations indicate that BBT-877 may have a potential therapeutic effect on DN by suppressing the ATX-LPA-LPAR signaling-mediated renal inflammation and fibrosis.…”

Section: Introductionmentioning

confidence: 99%

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Effect of BBT-877, a novel inhibitor of ATX, on a mouse model of type 1 diabetic nephropathy

Lee

Khin

Lee³

et al. 2022

Aging

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Diabetic nephropathy (DN) is one of the common microvascular complications of diabetes. Autotaxin (ATX) is an enzyme with lysophospholipase D activity, producing lysophosphatidic acid (LPA). LPA signaling has been implicated in renal fibrosis, thereby inducing renal dysfunction. BBT-877 is an orally administered small molecule inhibitor of ATX. However, its effect on DN has not been studied so far. In this study, we investigated the effect of BBT-877, a novel inhibitor of ATX, on the pathogenesis of DN in a mouse model of streptozotocin (STZ)-induced diabetes. BBT-877 treatment significantly reduced albuminuria, albumin-to-creatinine ratio (ACR), neutrophil gelatinase-associated lipocalin (NGAL), and glomerular volume compared to the STZ-vehicle group. Interestingly, BBT-877 treatment attenuated hyperglycemia and dyslipidemia in STZ-induced diabetes mice. In the liver, the expression levels of β-oxidation-related genes such as PPAR α and CPT1 were significantly decreased in STZ-induced diabetic mice. However, this effect was reversed by BBT-877 treatment. BBT-877 treatment also suppressed mRNA levels of pro-inflammatory cytokines IL-6, MCP-1, and TNF-α and protein levels of fibrotic factors (TGF-β, fibronectin, CTGF, and collagen type Ι alpha Ι (COL1A1)) in the kidneys of STZ-induced diabetic mice. In conclusion, our results indicate that BBT-877 is effective in preventing the pathogenesis of DN by reducing systemic blood glucose levels and inhibiting inflammation and fibrosis in the renal tissue of diabetes mice. These novel findings suggest that inhibition of ATX may be a potential therapeutic target for DN.

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Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis

Maher

Ford

Brown

et al. 2023

JAMA

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ImportanceThere is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF).ObjectiveTo assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF.Design, Setting, and ParticipantsThe 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2.InterventionsPatients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks.Main Outcomes and MeasuresThe primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George’s Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life).ResultsAt the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was –124.6 mL (95% CI, −178.0 to −71.2 mL) with 600 mg of ziritaxestat vs –147.3 mL (95% CI, −199.8 to −94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, −52.3 to 97.6 mL]), and –173.9 mL (95% CI, −225.7 to −122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, −26.7 mL [95% CI, −100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was –173.8 mL (95% CI, −209.2 to −138.4 mL) with 600 mg of ziritaxestat vs –176.6 mL (95% CI, −211.4 to −141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, −46.9 to 52.4 mL]) and –174.9 mL (95% CI, −209.5 to −140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, −47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo.Conclusions and RelevanceZiritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment.Trial RegistrationClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444

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

Cited by 4 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

Effect of BBT-877, a novel inhibitor of ATX, on a mouse model of type 1 diabetic nephropathy

Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis

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