LPA1 Receptor Affects Biomarkers in Pulmonary Fibrosis

VIENNA — Treatment with a novel lysophosphatidic acid receptor 1 (LPA1) antagonist was associated with significant changes in baseline biomarkers of disease in adults with pulmonary fibrosis, based on data from more than 300 individuals.

“Lysophosphatidic acid receptor signaling is central to the pathogenesis of fibrotic lung diseases,” said Toby M. Maher, MD, of the University of Southern California, Los Angeles, in a presentation at the European Respiratory Society (ERS) 2024 International Congress.

In a phase 2 study, Maher and colleagues recruited 278 adults aged 40 years or older with idiopathic pulmonary fibrosis (IPF) and 125 with progressive pulmonary fibrosis (PPF). Participants were randomized 1:1:1 to receive 30 mg or 60 mg of oral admilparant (BMS-986278) or a placebo twice daily for 26 weeks.

The primary outcome was change from baseline in percent of predicted forced vital capacity (ppFVC). In the original study, treatment with admilparant vs placebo significantly reduced the rate of ppFVC decline over 26 weeks in both patients with IPF and PPF, with an acceptable safety profile, Maher said in his presentation. Those data were presented at the American Thoracic Society 2023 International Conference, according to a press release from manufacturer Bristol Myers Squibb.

In this exploratory analysis, the researchers examined the change in biomarkers of lung fibrosis after treatment with admilparant vs placebo.

At 26 weeks, patients with IPF in the admilparant groups showed significant improvement from baseline compared with those in the placebo group. Those treated with 60 or 30 mg of admilparant vs placebo demonstrated significantly increased levels of adiponectin (P < .0001 and P < .001, respectively), and those receiving 60 mg admilparant showed decreased epithelial injury and fibrosis compared with those receiving placebo (P < .05).

Among patients with PPF, those treated with 60 mg of admilparant showed significant decreases in periostin, ferritin, and multiple inflammatory markers. The findings were consistent with data from a 2018 study published in Chest involving a different LPA1 antagonist, Maher said.

Additional research is needed, but the current results suggest that the biomarkers in patients with IPF and PFF may be used to monitor treatment response and disease progression in future trials for pulmonary fibrosis treatments, Maher said in his presentation.

The current research is important because of the significant need for new and improved therapies for pulmonary fibrosis that slow disease progression, are well tolerated, and help patients manage their disease while they continue to perform daily activities, said Edgar Charles, MD, Vice President and Senior Global Program Lead, early/late development immunology, at Bristol Myers Squibb, the manufacturer of admilparant, in an interview.

“Specifically, it is important to evaluate the impact of therapies that block lysophosphatidic acid receptor 1 and their potential to address the altered fibrotic processes in pulmonary fibrosis,” said Charles, who was not among the authors on the current study. “The findings of this analysis provide insight into admilparant’s mechanism of action across diverse forms of pulmonary fibrosis,” he said.

The findings of the current secondary analysis were consistent with effective antagonism of the LPA1 pathway, and they built upon the study’s primary results, Charles told Medscape Medical News. “Of note, we observed increased levels of adiponectin, a protein with anti-inflammatory and antifibrotic properties, in patients with IPF when treated with admilparant; this observation was consistent with results from a previous trial with a different LPA1 antagonist,” he said.

The new analysis supports admilparant’s potential as a first-in-class, oral, small molecule lysophosphatidic acid receptor 1 antagonist and “a new and meaningful therapeutic option for people living with pulmonary fibrosis,” Charles said. “In terms of additional research, the biomarkers analyzed in this study may have potential value to monitor treatment response, as well as the progression or regression of disease, in future pulmonary fibrosis clinical trials,” he added.

Meeting a Need

“Safer, more effective novel treatments are greatly needed to help our IPF and PPF patients,” said Anoop M. Nambiar, MD, professor of medicine and founding director of The University of Texas Health San Antonio Center for Interstitial Lung Diseases, in an interview.

“In addition, there is a lack of available validated biomarkers to monitor treatment response and disease progression,” he said.

“Available approved antifibrotics may help slow down progressive decline in lung function and reduce the risk of sudden deadly acute exacerbations, but do not stop or improve a patient’s symptoms, quality of life, or lung function and may be difficult to tolerate due to side effects, as well as cost-prohibitive for many,” said Nambiar, who was not involved in the study.

After admilparant treatment reduced the rate of decline in ppFVC compared with placebo, the current exploratory analysis focused on the changes in biomarkers of lung fibrosis, Nambiar said.

“I was pleasantly surprised to see a consistent signal of effective LPA1 pathway antagonism by admilparant that may correlate with the reduced FVC decline at 26 weeks,” Nambiar said. “Unfortunately, based on many past promising phase 2 studies followed by failed phase 3 studies, I think we need to remain cautiously optimistic about the durability of treatment response using both promising biomarkers that are blood-based, physiologic, and radiologic, as well as safety and tolerability over a longer follow-up period,” he told Medscape Medical News.

Despite this caution, “the future remains bright in the field of IPF and PPF,” Nambiar emphasized. “New tools, including blood-based biomarkers to aid in monitoring treatment response and progression and potentially accurate diagnosis and prognostication are coming soon,” he said.

Limitations of the current study included the relatively small sample size and short treatment duration, Nambiar said. “Additional studies should be aimed at further investigation in larger prospective phase 3 trials, and much-needed correlation of these promising blood-based biomarkers with PFTs [pulmonary function tests], quantitative CT, and important outcomes such as health-related quality of life, respiratory-related hospitalizations, and survival,” he noted.

The study was supported by Bristol Myers Squibb. Maher disclosed receiving honoraria or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, FibroGen, Galapagos, Galecto, GlaxoSmithKline, IQVIA, Merck, Pliant, Pfizer, Qureight, Roche, Sanofi-Aventis, Structure Therapeutics, Trevi, and Veracyte.

Charles is employed by Bristol Myers Squibb. Nambiar disclosed receiving institutional research grants from Boehringer Ingelheim, Bristol Myers Squibb, DaeWoong, Nitto Denko, and Galapagos and serving on speaker’s bureaus for Boehringer Ingelheim and Veracyte.