Nerandomilast in Patients with Progressive Pulmonary Fibrosis

Background: Nerandomilast (BI 1015550) is an orally administered preferential inhibitor of phosphodiesterase 4B with antifibrotic and immunomodulatory properties. Nerandomilast has been shown to slow the progression of idiopathic pulmonary fibrosis, but an assessment of its effects in other types of progressive pulmonary fibrosis is needed. Methods: In a phase 3, double-blind trial, we randomly assigned patients with progressive pulmonary fibrosis in a 1:1:1 ratio to receive nerandomilast at a dose of 18 mg twice daily, nerandomilast at a dose of 9 mg twice daily, or placebo, with stratification according to background therapy (nintedanib vs. none) and fibrotic pattern on high-resolution computed tomography (usual interstitial pneumonia-like pattern vs. other patterns). The primary end point was the absolute change from baseline in the forced vital capacity (FVC), measured in milliliters, at week 52. Results: A total of 1176 patients received at least one dose of nerandomilast or placebo, of whom 43.5% were taking background nintedanib therapy at baseline. The adjusted mean change in the FVC at week 52 was -98.6 ml (95% confidence interval [CI], -123.7 to -73.4) in the nerandomilast 18-mg group, -84.6 ml (95% CI, -109.6 to -59.7) in the nerandomilast 9-mg group, and -165.8 ml (95% CI, -190.5 to -141.0) in the placebo group. The adjusted difference between the nerandomilast 18-mg group and the placebo group was 67.2 ml (95% CI, 31.9 to 102.5; P<0.001), and the adjusted difference between the nerandomilast 9-mg group and the placebo group was 81.1 ml (95% CI, 46.0 to 116.3; P<0.001). The most frequent adverse event was diarrhea, reported in 36.6% of the patients in the nerandomilast 18-mg group, 29.5% of those in the nerandomilast 9-mg group, and 24.7% of those in the placebo group. Serious adverse events occurred in similar percentages of patients in the trial groups. Conclusions: In patients with progressive pulmonary fibrosis, treatment with nerandomilast led to a smaller decline in the FVC than placebo over a period of 52 weeks. (Funded by Boehringer Ingelheim; FIBRONEER-ILD ClinicalTrials.gov number, NCT05321082.).