Oral BMS-986278 slows lung decline in progressive PF, Phase 2 trial finds

Phase 3 testing planned for people with idiopathic and progressive disease

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by Steve Bryson, PhD |

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The experimental oral therapy BMS-986278, taken at 60 mg twice daily for 26 weeks, resulted in a 69% reduction in the rate of lung function decline in adults with progressive pulmonary fibrosis taking part in a Phase 2 trial.

These findings are consistent with previously reported data from a group of idiopathic pulmonary fibrosis (IPF) patients also participating in the clinical trial, whose lung function decline decreased by 62% with treatment at that dose.

Study results support moving BMS-986278 into global Phase 3 testing in a trial program being called ALOFT, according to the therapy’s developer, Bristol Myers Squibb.

“Our industry-leading drug discovery and development capabilities and collective results from this Phase 2 study provide us the expertise and confidence to support continued development of BMS-986278 in our global Phase 3 ALOFT program in idiopathic and progressive pulmonary fibrosis,” Jonathan Sadeh, MD, Bristol Myers Squibb’s senior vice president of immunology development, said in a company press release.

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Phase 2 trial data were presented at the European Respiratory Society (ERS) 2023 International Congress, held Sept. 9-13 in Italy.

Pulmonary fibrosis (PF) is characterized by scarring — or fibrosis — of the lungs, resulting in shortness of breath, a dry and hacking cough, fatigue, and shallow breathing. While IPF marks a disease type whose cause is unknown, progressive PF refers to patients with signs of worsening fibrosis, which is challenging to treat and associated with poorer outcomes.

“People living with pulmonary fibrosis are in urgent need of new treatment options for this devastating disease, which has a median overall survival of 3-5 years,” said Tamera J. Corte, MD, a trial investigator and consultant physician in the department of respiratory medicine at Royal Prince Alfred Hospital​, in Australia.

BMS-986278 is an orally available small molecule designed to block the action of the lysophosphatidic acid receptor 1 (LPA1), a protein in the lungs linked to PF development. Blocking LPA1 in cells and animal models showed promise in treating lung injury and fibrosis.

The global Phase 2 clinical trial (NCT04308681) tested BMS-986278’s safety and efficacy in 278 people with IPF or progressive PF. Participants were randomly assigned to a 30 or 60 mg dose of the therapy, or to a placebo, both taken twice a day for 26 weeks (about six months). The study’s protocol included an optional 26-week extension period and a four-week follow-up.

Antifibrotic and/or select immunosuppressive therapies were allowed during the study, and about two-thirds of people in the IPF group and one-third of those with progressive PF used such background medications.

A dose reduction, to 10 mg of BMS-986278 or a placebo twice daily, also was allowed if specific blood pressure changes were met. Lower dosing was reported across all three progressive PF arms: six people in the 30 mg group, five in the 60 mg group, and one placebo patient.

The study’s main outcome was the rate of change in lung function in IPF patients, as measured by the percent predicted forced vital capacity (ppFVC) after 26 weeks of treatment.

Treatment led to an over 60% drop in patients’ rate of lung function decline

Data from the IPF group showed the 60 mg dose of BMS-986278 lowered the rate of change in ppFVC by 62% over a placebo. In this group, the rate of change in ppFVC lowered by 54% when all data, regardless of the dose reduction, were included in the analysis. In the 30 mg group, no significant change in ppFVC was noted.

A key secondary outcome was the rate of ppFVC change in those with progressive PF, defined as evidence of progressive lung disease within the two years of the study.

Among these patients, the 60 mg dose of BMS-986278 led to a 69% relative reduction in the rate of change in ppFVC versus a placebo prior to dose reduction, and a 74% relative decrease when dose-reduction cases were included.

The 30 mg progressive PF group saw a 42% relative reduction in the rate of ppFVC change before dose reduction and a 37% relative reduction when dose adjustments were included in the analyses as part of the treatment regimen.

Treatment efficacy was not affected by the presence or absence of antifibrotic medication and usual interstitial pneumonia pattern, or areas of fibrosis in the lungs.

BMS-986278 was well tolerated at both doses in progressive PF patients, with rates of adverse events (AEs) similar to placebo and low discontinuation rates. The most frequent AEs included diarrhea, COVID-19, cough, and shortness of breath. Treatment discontinuation due to AEs was highest among patients on a placebo.

“Pulmonary fibrosis is a chronic, life threatening interstitial lung disease with significant need for new and improved therapies that are well tolerated and slow disease progression,” Sadeh wrote in an email to Pulmonary Fibrosis News.

“The Phase 2 study results show that it may be possible to use BMS-986278 alone or in combination with established pulmonary fibrosis therapies to reduce the rate of decline in lung function,” Sadeh added. “Our progressive pulmonary fibrosis findings, along with the previously reported idiopathic pulmonary fibrosis cohort results, support the initiation of our global Phase 3 ALOFT program.”