Nerandomilast slows decline in FVC in idiopathic pulmonary fibrosis

1. In this randomized trial, among patients with idiopathic pulmonary fibrosis (IPF), nerandomilast slowed the decline in the forced vital capacity (FVC) after 52 weeks compared to placebo.

2. Nerandomilast was associated with a dose-dependent increased rate of diarrhea, which occurred more commonly in those taking background nintedanib.

Evidence Rating Level: 1 (Excellent)

Study Rundown: IPF is a progressive fibrosing interstitial lung disease resulting in declining lung function and heightened risk of death. Current first-line antifibrotic agents, nintedanib and pirfenidone, slow this decline but do not stop disease progression. Furthermore, they are associated with gastrointestinal adverse effects, which compromise adherence. Nerandomilast is an oral phosphodiesterase 4B (PDE4) inhibitor with antifibrotic and immunomodulatory effects. This trial investigated the use of nerandomilast in patients with IPF, including those already receiving first-line antifibrotics. At 52 weeks, nerandomilast resulted in a dose-dependent slowing of FVC decline compared to placebo. This effect was also observed in those already receiving background antifibrotics. Pirfenidone interacted with nerandomilast and reduced its serum concentration by approximately 50%. Nerandomilast was associated with diarrhea and was more common in those concurrently taking nintedanib. The study was limited by an underpowered subgroup analysis and a lack of long-term mortality outcomes. Nevertheless, these results demonstrated additional benefits of this novel antifibrotic in patients with IPF beyond those offered by current standard treatments.

Click here to read the study in NEJM

Relevant Reading: Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmonary Fibrosis

In-Depth [randomized controlled trial]: This was a placebo-controlled trial assessing the efficacy and safety of nerandomilast in treating IPF. Patients 40 years of age or older who had a diagnosis of IPF, a FVC ≤45% of predicted value, and a diffusing capacity of the lungs for carbon monoxide (DLCO) ≤25% of predicted value were eligible for inclusion. In total, 1,177 patients were assigned in a 1:1:1 ratio to receive nerandomilast 18mg, nerandomilast 9mg, or placebo taken orally twice daily. The primary outcome was the absolute change in FVC from baseline to week 52. At 52 weeks, the decline in FVC from baseline was smallest in the nerandomilast 18mg group. The adjusted mean change in FVC was -114.7ml for the nerandomilast 18mg group (95% Confidence Interval [CI], -141.8 to -87.5), -138.6ml for the placebo nerandomilast 9mg group (95% CI, -165.6 to -111.6), and -183.5ml for the placebo group (95% CI, -210.9 to -156.1). This translated to an adjusted difference (compared to placebo) of 68.8ml (95% CI, 30.3-107.4; p<0.001) for the nerandomilast 18mg group and 44.9ml (95% CI, 6.4-83.3; p=0.02) for the nerandomilast 9mg group. Changes in patient-reported outcomes (dyspnea, cough, and fatigue scores) were also similar across all three groups. Diarrhea was the most common adverse event associated with nerandomilast, observed in 41.3% of patients in the 18mg group and 31.1% in the 9mg group, compared to 16.0% in the placebo group. The incidence of diarrhea was higher for those concurrently on background nintedanib. This led to discontinuation of the trial regimen in 6.1% of the 18-mg group, 1.8% of the 9-mg group, and 0.5% of the placebo group. Serious adverse events occurred at similar rates across all groups, and adverse events of special interest for this class of drug (PDE4 inhibitors) were balanced across the groups. In summary, the study results suggest that nerandomilast slows FVC decline in patients with IPF.

Image: PD

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