BMS-986278, an LPA<sub>1</sub> Receptor Antagonist for Idiopathic Pulmonary Fibrosis: Preclinical Assessments of Potential Hepatobiliary Toxicity

Gill, Michael; Lakshmi, Subbu; Cheng, Peter T.; Murphy, Brian J.; Chadwick, Kristina D.; Lehman‐McKeeman, Lois D.; Graziano, Michael J.

doi:10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a5882

Cited by 9 publications

(15 citation statements)

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“…Although the trial was terminated because of unexpected hepatobiliary effects associated with BMS-986020 treatment, 21 22 retrospective, non-clinical investigations show that these compound-specific effects associated with BMS-986020 are not expected with the second-generation BMS-986278 compound. 22 For example, in contrast to BMS-986020, BMS-986278 has not been shown to inhibit liver efflux transporters, particularly BSEP and MDR3, which function to maintain normal bile acid flow and are required for the formation of protective biliary phospholipids. 22 Additionally, no evidence of direct hepatobiliary toxicity has been seen through in vivo evaluations or phase 1 studies.…”

Section: Discussionmentioning

confidence: 99%

“… 22 For example, in contrast to BMS-986020, BMS-986278 has not been shown to inhibit liver efflux transporters, particularly BSEP and MDR3, which function to maintain normal bile acid flow and are required for the formation of protective biliary phospholipids. 22 Additionally, no evidence of direct hepatobiliary toxicity has been seen through in vivo evaluations or phase 1 studies. 22 23 Coupled with previous efficacy observed with LPA 1 antagonism in IPF and an anticipated improved hepatobiliary safety profile, BMS-986278 shows promise for the treatment of progressive forms of pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…21 Subsequent non-clinical investigations have indicated that the hepatobiliary toxicity was an unexpected effect specific to BMS-986020 and is unlikely to be associated with secondgeneration, structurally distinct LPA 1 antagonists. 22 BMS-986278 is a second-generation LPA 1 antagonist in development for the treatment of patients with IPF or PF-ILD. Results from in vitro studies show that, unlike BMS-986020, BMS-986278 does not inhibit liver efflux transporters, particularly bile salt export protein (BSEP) and multidrug resistance 3 (MDR3), and no evidence of direct hepatobiliary toxicity has been seen through in vivo evaluations or phase 1 studies.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Results from in vitro studies show that, unlike BMS-986020, BMS-986278 does not inhibit liver efflux transporters, particularly bile salt export protein (BSEP) and multidrug resistance 3 (MDR3), and no evidence of direct hepatobiliary toxicity has been seen through in vivo evaluations or phase 1 studies. 22 23 Given that LPA 1 antagonism was shown to be effective in patients with IPF, this phase 2 study will evaluate BMS-986278 in patients with IPF or PF-ILD.…”

Section: Introductionmentioning

confidence: 99%

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Phase 2 trial design of BMS-986278, a lysophosphatidic acid receptor 1 (LPA₁) antagonist, in patients with idiopathic pulmonary fibrosis (IPF) or progressive fibrotic interstitial lung disease (PF-ILD)

et al. 2021

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IntroductionIdiopathic pulmonary fibrosis (IPF) and non-IPF, progressive fibrotic interstitial lung diseases (PF-ILD), are associated with a progressive loss of lung function and a poor prognosis. Treatment with antifibrotic agents can slow, but not halt, disease progression, and treatment discontinuation because of adverse events is common. Fibrotic diseases such as these can be mediated by lysophosphatidic acid (LPA), which signals via six LPA receptors (LPA1–6). Signalling via LPA1 appears to be fundamental in the pathogenesis of fibrotic diseases. BMS-986278, a second-generation LPA1 antagonist, is currently in phase 2 development as a therapy for IPF and PF-ILD.Methods and analysisThis phase 2, randomised, double-blind, placebo-controlled, parallel-group, international trial will include adults with IPF or PF-ILD. The trial will consist of a 42-day screening period, a 26-week placebo-controlled treatment period, an optional 26-week active-treatment extension period, and a 28-day post-treatment follow-up. Patients in both the IPF (n=240) and PF-ILD (n=120) cohorts will be randomised 1:1:1 to receive 30 mg or 60 mg BMS-986278, or placebo, administered orally two times per day for 26 weeks in the placebo-controlled treatment period. The primary endpoint is rate of change in per cent predicted forced vital capacity from baseline to week 26 in the IPF cohort.Ethics and disseminationThis study will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles, and local ethical and legal requirements. Results will be reported in a peer-reviewed publication.Trial registration numberNCT04308681.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phase 2 trial design of BMS-986278, a lysophosphatidic acid receptor 1 (LPA₁) antagonist, in patients with idiopathic pulmonary fibrosis (IPF) or progressive fibrotic interstitial lung disease (PF-ILD)

et al. 2021

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Idiopathic pulmonary fibrosis: Addressing the current and future therapeutic advances along with the role of Sotatercept in the management of pulmonary hypertension

Hadi,

Marsool,

Marsool

et al. 2023

Immunity Inflam & Disease

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BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive and debilitating lung disease characterized by irreversible scarring of the lungs. The cause of IPF is unknown, but it is thought to involve a combination of genetic and environmental factors. There is no cure for IPF, and treatment is focused on slowing disease progression and relieving symptoms.AimsWe aimed in this review to investigate and provide the latest insights into IPF management modalities, including the potential of Saracatinibas a substitute for current IPF drugs. We also investigated the therapeutic potential of Sotatercept in addressing pulmonary hypertension associated with IPF.Materials and MethodsWe conducted a comprehensive literature review of relevant studies on IPF management. We searched electronic databases, including PubMed, Scopus, Embase, and Web of science.ResultsThe two Food and Drug Administration‐approved drugs for IPF, Pirfenidone, and Nintedanib, have been pivotal in slowing disease progression, yet experimental evidence suggests that Saracatinib surpasses their efficacy. Preclinical trials investigating the potential of Saracatinib, a tyrosine kinase inhibitor, have shown to be more effective than current IPF drugs in slowing disease progression in preclinical studies. Also, Sotatercept,a fusion protein, has been shown to reduce pulmonary vascular resistance and improve exercise tolerance in patients with PH associated with IPF in clinical trials.ConclusionsThe advancements discussed in this review hold the promise of improving the quality of life for IPF patients and enhancing our understanding of this condition. There remains a need for further research to confirm the efficacy and safety of new IPF treatments and to develop more effective strategies for managing exacerbations.

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Lysophosphatidic acid (LPA) receptor modulators: Structural features and recent development

Bhagyalalitha

Pujar

Kumar

et al. 2021

European Journal of Medicinal Chemistry

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BMS-986278, an LPA₁ Receptor Antagonist for Idiopathic Pulmonary Fibrosis: Preclinical Assessments of Potential Hepatobiliary Toxicity

Cited by 9 publications

References 0 publications

Phase 2 trial design of BMS-986278, a lysophosphatidic acid receptor 1 (LPA₁) antagonist, in patients with idiopathic pulmonary fibrosis (IPF) or progressive fibrotic interstitial lung disease (PF-ILD)

Phase 2 trial design of BMS-986278, a lysophosphatidic acid receptor 1 (LPA₁) antagonist, in patients with idiopathic pulmonary fibrosis (IPF) or progressive fibrotic interstitial lung disease (PF-ILD)

Idiopathic pulmonary fibrosis: Addressing the current and future therapeutic advances along with the role of Sotatercept in the management of pulmonary hypertension

Lysophosphatidic acid (LPA) receptor modulators: Structural features and recent development

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BMS-986278, an LPA1 Receptor Antagonist for Idiopathic Pulmonary Fibrosis: Preclinical Assessments of Potential Hepatobiliary Toxicity

Cited by 9 publications

References 0 publications

Phase 2 trial design of BMS-986278, a lysophosphatidic acid receptor 1 (LPA1) antagonist, in patients with idiopathic pulmonary fibrosis (IPF) or progressive fibrotic interstitial lung disease (PF-ILD)

Phase 2 trial design of BMS-986278, a lysophosphatidic acid receptor 1 (LPA1) antagonist, in patients with idiopathic pulmonary fibrosis (IPF) or progressive fibrotic interstitial lung disease (PF-ILD)

Idiopathic pulmonary fibrosis: Addressing the current and future therapeutic advances along with the role of Sotatercept in the management of pulmonary hypertension

Lysophosphatidic acid (LPA) receptor modulators: Structural features and recent development

Contact Info

Product

Resources

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BMS-986278, an LPA₁ Receptor Antagonist for Idiopathic Pulmonary Fibrosis: Preclinical Assessments of Potential Hepatobiliary Toxicity

Phase 2 trial design of BMS-986278, a lysophosphatidic acid receptor 1 (LPA₁) antagonist, in patients with idiopathic pulmonary fibrosis (IPF) or progressive fibrotic interstitial lung disease (PF-ILD)

Phase 2 trial design of BMS-986278, a lysophosphatidic acid receptor 1 (LPA₁) antagonist, in patients with idiopathic pulmonary fibrosis (IPF) or progressive fibrotic interstitial lung disease (PF-ILD)