Lysophosphatidic acid receptor 1 antagonist slows lung function decline in progressive PF

Key takeaways:

• Treatment with an oral lysophosphatidic acid receptor 1 antagonist resulted in smaller decreases in percent predicted FVC at 26 weeks vs. placebo.
• Use of background antifibrotics did not change this finding.

Receiving an oral lysophosphatidic acid receptor 1 antagonist for 26 weeks lowered the rate of percent predicted FVC decline in progressive pulmonary fibrosis, according to a European Respiratory Society International Congress presentation.

“Lysophosphatidic A and its receptor, LPA₁, are involved in wound healing and have been implicated now in the pathogenesis of fibrotic diseases overall but also in the pathogenesis of pulmonary fibrosis,” Tamera J. Corte, BSc, MBBS, FRACP, PhD, clinical trial investigator and consultant respiratory physician and director of interstitial lung disease in the department of respiratory medicine at Royal Prince Alfred Hospital, said during the presentation.

In a phase 2 randomized controlled trial, Corte and colleagues analyzed 123 adults with progressive pulmonary fibrosis to evaluate the efficacy and safety of BMS-986278 (Bristol Myers Squibb) given either in a 30 mg (n = 40; mean age, 71.4 years; 57.5% men; 67.5% white) or 60 mg (n = 42; mean age, 67.9 years; 52.4% men; 76.2% white) dose two times a day compared with placebo (n = 41; mean age, 68.8 years; 48.8% men; 75.6% white) over 26 weeks.

Notably, researchers previously presented results from this study among a cohort of patients with idiopathic pulmonary fibrosis.

“We showed that the BMS-986278 was effective in reducing the rate of decline of FVC percent predicted at 26 weeks,” Corte said during the presentation.

The current cohort included 38% of patients using background nintedanib (Ofev, Boehringer Ingelheim), pirfenidone and/or select immunosuppressives (mycophenolate mofetil, mycophenolic acid, azathioprine and/or tacrolimus). Also, 27% of patients had unclassifiable ILD and 52% had usual interstitial pneumonia (UIP) pattern, with a baseline mean percent of predicted FVC (ppFVC) of 66.7%.

During the study, more patients in the BMS-986278 arms required a dose reduction to 10 mg compared with patients in the placebo arm (30 mg, n = 6; 60 mg, n = 5 vs. placebo, n = 1).

No patients from the 60 mg group discontinued treatment due to an adverse event, whereas one patient from the 30 mg group and five patients from the placebo group stopped treatment for this reason.

Compared with both doses of BMS-986278, researchers found greater decreases in ppFVC among patients receiving placebo at 26 weeks (placebo, –4.3% vs. 30 mg, –2.7% vs. 60 mg, –1.1%), revealing a treatment difference of 1.6% (95% CI, –1 to 4.1) between 30 mg and placebo and 3.2% (95% CI, 0.7-5.6) between 60 mg and placebo.

These findings equated to relative reductions of 37% for the 30 mg dose and 74% for the 60 mg dose compared with placebo, according to the abstract.

Researchers found comparable results for ppFVC when evaluating all data before patients received a lower dose of treatment, with a relative reduction of 69% between the 60 mg dose and placebo.

Patients assigned BMS-986278 continued to show less decline in ppFVC compared with the placebo group regardless of use of background antifibrotics and the presence or absence of a UIP pattern.

Among the three treatment groups, the rate of treatment-related adverse events was highest among patients receiving the 30 mg dose (82.5%), followed by patients receiving placebo (78%) and patients receiving the 60 mg dose (66.7%). Several similar adverse events occurred within the placebo, 30 mg and 60 mg groups: diarrhea (14.6% vs. 15% vs. 7.1%), COVID-19 (4.9% vs. 15% vs. 14.3%) and cough (9.8% vs. 7.5% vs. 11.9%). Notably, dyspnea occurred in 14.6% of patients receiving placebo and 5% of patients receiving the 30 mg dose of BMS-986278.

Researchers reported no deaths due to treatment-related adverse events in either of the BMS-986278 arms, whereas three patients from the placebo arm died.

“[BMS-986278] was safe and well tolerated, with very few treatment discontinuations, and these findings together with the findings from the idiopathic pulmonary fibrosis parallel cohort give us confidence in data going forward into phase 3 clinical trials,” Corte said during the presentation.

Reference:

• Bristol Myers Squibb’s investigational LPA1 antagonist reduces rate of lung function decline in progressive pulmonary fibrosis cohort of phase 2 study. https://news.bms.com/news/corporate-financial/2023/Bristol-Myers-Squibbs-Investigational-LPA1-Antagonist-Reduces-Rate-of-Lung-Function-Decline-in-Progressive-Pulmonary-Fibrosis-Cohort-of-Phase-2-Study/default.aspx. Published Sept. 9, 2023. Accessed Sept. 11, 2023.