Mechanism of hepatobiliary toxicity of the LPA1 antagonist BMS-986020 developed to treat idiopathic pulmonary fibrosis: Contrasts with BMS-986234 and BMS-986278

Gill, Michael; Murphy, Brian J.; Cheng, Peter; Sivaraman, Lakshmi; Davis, Myrtle; Lehman‐McKeeman, Lois D.

doi:10.1016/j.taap.2022.115885

Cited by 16 publications

(15 citation statements)

References 47 publications

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“…This may be determined by ongoing studies of other autotaxin inhibitors with different pharmacological characteristics to those of ziritaxestat (such as BBT-877) or lysophosphatidic acid receptor antagonists (such as BMS-986278). Of note, the lysophosphatidic acid receptor antagonist BMS-986020 was discontinued due to hepatobiliary toxicity; however, this was found to be unrelated to lysophosphatidic acid antagonism and, indeed, no such safety issues were identified in the ISABELA trials.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

Maher

Ford

Brown

et al. 2023

JAMA

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“…Synthesis of (S)-7-Methyl-N- (1-(4-(phenylsulfonyl)piperazin-1yl)propan-2-yl)thieno [3,2-d]pyrimidin-4-amine (12). Intermediate 84 (37 mg, 0.13 mmol) and benzenesulfonyl chloride 85a (42 mg, 0.24 mmol) were reacted according to the general procedure H. The crude residue was purified on a C18 cartridge (eluent: H 2 O/ACN + 0.1% HCOOH from 95/5 to 0/100) to afford compound 12 (30 mg, 0.07 mmol, 54% yield) as a white solid.…”

Section: Synthesis Of Tert-butyl 4-((1-(((benzyloxy)carbonyl)amino)cy...mentioning

confidence: 99%

“…10 The role of LPA 1 receptors in modulating lung fibrotic processes is well established in the clinic. Bristol Myers Squibb (among others) is studying the LPA 1 receptor antagonist BMS-986278 11 in phase 2 clinical trials for IPF and PF-ILD, while BMS-986020, 12 although discontinued in a phase 2 clinical trial in IPF patients for its hepatobiliary toxicity, showed a statistically significant reduction in the change from baseline of forced vital capacity compared to placebo.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of a Potent, Selective, and Orally Bioavailable Tool Compound for Probing the Role of Lysophosphatidic Acid Type 2 Receptor Antagonists in Fibrotic Disorders

et al. 2023

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Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by lung fibrosis leading to an irreversible decline of lung function. Current antifibrotic drugs on the market slow down but do not prevent the progression of the disease and are associated with tolerability issues. The involvement of lysophosphatidic acid receptor 2 (LPA 2 ) in IPF is supported by LPA 2 knockdown studies. To further validate the role of LPA 2 receptors in modulating IPF and potentially other fibrotic processes, a potent and selective LPA 2 receptor antagonist with a good pharmacokinetic (PK) profile is needed. Herein, we report the medicinal chemistry exploration that led to the discovery of a new class of highly potent and selective LPA 2 antagonists. Among them, compound 58 exhibits excellent potency, selectivity, and oral PK profile, making it a suitable tool for probing the involvement of LPA 2 receptors in IPF and other fibrotic processes.

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“…This could be looked into by continuing research on other autotaxin inhibitors, such as BBT‐87723, or LPA receptor antagonists, such as BMS‐98627824, which have different pharmacological properties from those in ziritaxestat. It should be noted that the LPA receptor antagonist (BMS‐986020) was halted because of the resultant hepatobiliary toxicity, but it was later determined that this was unrelated to LPA antagonism 81,82 in fact, no such safety concerns were detected in the ISABELAs.…”

Section: Potential and Futuristic Drugs In The Management Of Idiopath...mentioning

confidence: 99%

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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Mechanism of hepatobiliary toxicity of the LPA1 antagonist BMS-986020 developed to treat idiopathic pulmonary fibrosis: Contrasts with BMS-986234 and BMS-986278

Cited by 16 publications

References 47 publications

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

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

Discovery of a Potent, Selective, and Orally Bioavailable Tool Compound for Probing the Role of Lysophosphatidic Acid Type 2 Receptor Antagonists in Fibrotic Disorders

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

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