FIBRONEER-ILD

NEJM 2025

the coarse crackle

FIBRONEER-ILD was a phase 3, double-blind, randomized, placebo-controlled trial evaluating nerandomilast 18 mg twice daily or 9 mg twice daily for progressive pulmonary fibrosis (PPF), stratified by background nintedanib use and CT pattern. Nerandomilast attenuated FVC decline versus placebo (−98.6 mL for 18 mg and −84.6 mL for 9 mg vs −165.8 mL). Benefits were consistent with or without background nintedanib.

fine crackles

  • Nerandomilast slowed FVC decline by roughly 70–80 mL versus placebo over 52 weeks in PPF, with early separation of FVC curves after randomization.

  • Efficacy was observed both with and without background nintedanib; however, the composite of acute exacerbation, respiratory hospitalization, or death was not statistically different.

  • Diarrhea was the most frequent adverse event and occurred more often with concurrent nintedanib; dose reduction or interruption of nintedanib was recommended to manage adverse events.

  • FIBRONEER-ILD’s entry definition is not identical to the 2022 ATS/ERS/JRS/ALAT guideline definition of PPF. The trial allowed progression documented over the preceding 24 months using INBUILD-like combinations of relative FVC decline, symptoms, and imaging, rather than requiring documentation within 12 months. This is not unreasonable, especially since the guideline authors noted that they blended several slightly different trial definitions to settle on the guideline's 2022 definition.

  • Nintedanib use itself was not randomized. Therefore, the greater FVC loss among patients taking nintedanib than among those not taking it should not be used to infer nintedanib is ineffective or harmful. Patients receiving background nintedanib had somewhat longer-standing and more impaired disease; the trial authors even suggest they may have had more aggressive disease.

  • Approximately 70% of participants had a UIP or UIP-like radiographic pattern. Autoimmune ILD accounted for only about 28% of the population. Thus, the study was etiologically broad, based on the enrollment of patients with a variety of diagnoses, but may still be heavily weighted toward a UIP-like fibrotic morphology.

  • For SARD-ILD, mycophenolate, rituximab, tocilizumab, and cyclophosphamide were not permitted at enrollment; prednisone above 15 mg daily was also prohibited. Some of these therapies could be introduced after six months for systemic worsening, but the trial did not evaluate the common contemporary situation of adding nerandomilast to established mycophenolate, rituximab, or tocilizumab. This was highlighted in a subsequent correspondence.

  • 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.)

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