LPA1 antagonist BMS-986278 may slow IPF lung function decline
Findings derived from a Phase 2 clinical trial that tested therapy on 278 people
An experimental oral medication Bristol Myers Squibb is developing did better than a placebo at slowing lung function decline for up to 26 weeks, slightly more than six months, in people with idiopathic pulmonary fibrosis (IPF).
The effect was seen when the therapy, BMS-986278, was given at a dose of 60 mg twice a day, but not at 30 mg. It was well tolerated, with about as many side effects as seen with the placebo. The company plans to move the therapy into Phase 3 clinical testing.
The findings came from an international Phase 2 clinical trial (NCT04308681) that tested how safe BMS-986278 is and how well it works to slow IPF progression. The trial is ongoing for a group with progressive pulmonary fibrosis.
“These Phase 2 data give us the confidence to initiate our global Phase 3 clinical trial program where we will continue exploring BMS-986278 as a potentially new and meaningful therapeutic option for people with pulmonary fibrosis,” Samit Hirawat, MD, Bristol Myers Squibb’s chief medical officer, said in a company press release.
IPF occurs when fibrosis, or tissue scarring, occurs in the lungs for unknown reasons. This can worsen over time, often causing symptoms like shortness of breath and a persistent dry, hacking cough.
Lysophosphatidic acid (LPA) is a type of fat involved in multiple functions in the body. One is tissue fibrosis. LPA can interact with many receptor proteins, but LPA1 receptors appear to be most abundant in the lungs of people with IPF.
This means blocking LPA1 receptors may be a viable strategy for treating IPF. With this in mind, Bristol Myers Squibb designed BMS-986020, a first-generation LPA1 antagonist that disrupts LPA1 function.
In a Phase 2 trial (NCT01766817), it slowed IPF lung function decline over a placebo, but caused liver enzyme levels to rise, a sign it may be inflamed or damaged. The trial was halted after three participants developed cholecystitis, an inflammation of the gallbladder.
BMS-986278 is a second-generation LPA1 antagonist. Unlike BMS-986020, it’s not expected to cause side effects on the liver or gallbladder, at least according to earlier work on cells and animal models of IPF. A Phase 1 trial (NCT03429933) in healthy volunteers indicated it may lower blood pressure, however.
Testing safety, efficacy of BMS-986278
A Phase 2 trial was set up to test BMS-986278’s safety and effectiveness in 278 people with IPF. They were randomly assigned to receive it at 30 or 60 mg, or a placebo, by mouth twice daily for 26 weeks. This was followed by an optional 26-week active extension period and a four-week follow-up. Two-thirds of the patients continued taking their anti-fibrotic medication for the duration of the trial.
Some were at risk of low blood pressure and received 10 mg of BMS-986278 twice daily or a matching placebo, as per the trial’s protocol. The proportion of patients who met the criteria for a dose reduction was about the same in the 30 mg (8%), 60 mg (6%), and placebo (5%) groups.
The study’s primary goal was to evaluate the rate of change in percent predicted forced vital capacity (ppFVC), a measure of lung function, from the trial’s beginning (baseline) to week 26.
Before the dose reduction, 60 mg of BMS-986278 reduced the rate of change in ppFVC by 62% over a placebo. When the researchers looked at all data regardless of the dose reduction, the rate of change in ppFVC was reduced by 54%.
They estimated a probability greater than 95% of 60 mg that BMS-986278 was superior to a placebo at slowing ppFVC decline, based on a statistical method called Bayesian analysis. The 30 mg dose didn’t do better than the placebo.
The proportion of patients who reported side effects and serious side effects was similar across the three groups. The most common side effects were diarrhea, cough, and orthostatic hypotension, which occurs when there’s a sudden drop in blood pressure when a person stands from a sitting or lying position.
“As a treating physician, I am acutely aware of the urgent need for new pulmonary fibrosis treatment options that can improve symptoms, address the underlying cause of disease and are well tolerated by patients,” said Tamera J. Corte, a trial investigator and director of interstitial lung disease in the department of Respiratory Medicine at Royal Prince Alfred Hospital in Sydney, Australia. “These Phase 2 data for this potential first-in-class oral LPA1 antagonist represent important progress for patients and physicians alike, who are eager for a new standard of care that can mitigate the decline of lung function.”
Corte presented the data at the American Thoracic Society 2023 International Conference, May 19-24, in Washington, D.C.
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