Nerandomilast slows FVC decline in progressive pulmonary fibrosis

1. In this randomized controlled trial, treatment with nerandomilast led to slower declines in forced vital capacity (FVC) in patients with progressive pulmonary fibrosis over 52 weeks

2. The occurrence of serious adverse events was similar between the nerandomilast group and the placebo group.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Progressive pulmonary fibrosis is an interstitial lung disease that results in progressive inflammation and/or fibrosis of the alveolar interstitium. The only approved therapy is nintedanib, which slows the decline of FVC. However, it is associated with gastrointestinal side effects, which often lead to its discontinuation. Nerandomilast is an oral preferential inhibitor of phosphodiesterase 4B that has shown antifibrotic and immunomodulatory effects in preclinical models. This phase three, randomized controlled trial aimed to investigate the efficacy and safety of nerandomilast at the dose of 18 mg twice daily (BID) or 9 mg BID in patients with progressive pulmonary fibrosis. Patients who met inclusion criteria were randomly assigned in a 1:1:1 ratio to receive nerandomilast at a dose of 18 mg BID, nerandomilast 9 mg BID, or placebo. Patients were stratified based on their background therapy and fibrotic pattern on high-resolution computed tomography (CT). The primary end point for this study was the absolute change from baseline in the FVC at week 52. Results from this study found that treatment with nerandomilast led to a smaller decline in FVC at week 52 in patients with progressive pulmonary fibrosis. The percentage of adverse events that occurred was similar between treatment groups and placebo. Limitations of this study include that it was not powered to evaluate nerandomilastin specific subgroups, including those based on interstitial lung disease diagnosis. Further, patients taking certain medications were excluded from the trial.

Click here to read the study in NEJM

In-Depth [randomized controlled trial]: This phase three, randomized controlled trial investigated the efficacy and safety of nerandomilast at a dose of 18 mg BID or 9 mg BID in patients with progressive pulmonary fibrosis. Adult patients with a diagnosis of interstitial lung disease other than idiopathic pulmonary fibrosis and a fibrotic lung disease extent of more than 10% based on a high-resolution CT scan obtained no more than 12 months before screening were eligible for the study. Patients were required to have an FVC of at least 45% of predicted value and a diffusion capacity for carbon monoxide of at least 25% of predicted value. The primary endpoint for this study was the absolute change from baseline in the FVC at week 52. A total of 1176 patients were recruited and underwent randomization in a 1:1:1 ratio to receive nerandomilast at a dose of 18 mg BID, nerandomilast 9 mg BID, or placebo. Of these patients, 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. Between the 18 mg nerandomilast and the placebo group, the adjusted difference was was 67.2 ml (95% CI, 31.9 to 102.5; P<0.001), and the adjusted difference between the 9 mg nerandomilast group and the placebo group was 81.1 ml (95% CI, 46.0 to 116.3; p<0.001). The most frequently cited adverse event was diarrhea. The percentage of patients reporting serious adverse events was similar across groups. Overall, the results from this study found that treatment with nerandomilast led to a smaller decline in FVC at week 52 in patients with progressive pulmonary fibrosis.

Image: PD

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