FIBRONEER-IPF

NEJM 2025

the coarse crackle

FIBRONEER-IPF was a phase 3, double‑blind, randomized, placebo‑controlled trial evaluating nerandomilast 18 mg twice daily, 9 mg twice daily, or placebo, stratified by background therapy (with nintedanib or pirfenidone) for the treatment of idiopathic pulmonary fibrosis. Nerandomilast reduced FVC decline versus placebo, yielding treatment differences of 68.8 mL and 44.9 mL for the 18mg twice daily and 9mg twice daily groups, respectively.

fine crackles

  • Nerandomilast, a preferential PDE4B inhibitor, produced a statistically significant and clinically meaningful preservation of FVC over 52 weeks versus placebo in IPF, without improving time-to-event outcomes (e.g., composite of first acute exacerbation, respiratory hospitalization, or death) within one year.

  • Diarrhea was the most common adverse event (41.3% at 18 mg; 31.1% at 9 mg; 16.0% with placebo), and was more frequent with background nintedanib. Diarrhea lead to permanent discontinuation in <4%.

  • Co-administration with pirfenidone approximately halved nerandomilast plasma concentrations, diminishing effect at 9 mg twice daily. Nerandomilast 18 mg twice daily is therefore the recommended dose for patients on concurrent pirfenidone.

  • Background

    Nerandomilast (BI 1015550) is an orally administered preferential inhibitor of phosphodiesterase 4B with antifibrotic and immunomodulatory effects. In a phase 2 trial involving patients with idiopathic pulmonary fibrosis, treatment with nerandomilast stabilized lung function over a period of 12 weeks.

    Methods

    In this phase 3, double-blind trial, we randomly assigned patients with idiopathic 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 antifibrotic therapy (nintedanib or pirfenidone vs. none). The primary end point was the absolute change from baseline in forced vital capacity (FVC), measured in milliliters, at week 52.

    Results

    A total of 1177 patients underwent randomization, of whom 77.7% were taking nintedanib or pirfenidone at enrollment. Adjusted mean changes in FVC at week 52 were −114.7 ml (95% confidence interval [CI], −141.8 to −87.5) in the nerandomilast 18-mg group, −138.6 ml (95% CI, −165.6 to −111.6) in the nerandomilast 9-mg group, and −183.5 ml (95% CI, −210.9 to −156.1) in the placebo group. The adjusted difference between the nerandomilast 18-mg group and the placebo group was 68.8 ml (95% CI, 30.3 to 107.4; P<0.001), and the adjusted difference between the nerandomilast 9-mg group and the placebo group was 44.9 ml (95% CI, 6.4 to 83.3; P=0.02). The most frequent adverse event in the nerandomilast groups was diarrhea, reported in 41.3% of the 18-mg group and 31.1% of the 9-mg group, as compared with 16.0% in the placebo group. Serious adverse events were balanced across trial groups.

    Conclusions

    In patients with idiopathic pulmonary fibrosis, treatment with nerandomilast resulted in a smaller decline in the FVC than placebo over a period of 52 weeks. (Funded by Boehringer Ingelheim; FIBRONEER-IPF ClinicalTrials.gov number, NCT05321069.)