Nerandomilast slows IPF progression in patients already on antifibrotic therapy

The novel oral PDE4B* inhibitor nerandomilast slows the progression of idiopathic pulmonary fibrosis (IPF) in patients receiving antifibrotic treatment, as shown in the phase III FIBRONEER-IPF trial.

Treatment with nerandomilast led to a smaller decline in forced vital capacity (FVC) compared with placebo over 52 weeks. Adjusted mean changes from baseline in FVC were –114.7 mL and –138.6 mL with nerandomilast 18 mg and 9 mg doses, respectively, compared with –183.5 mL with placebo (adjusted differences, p<0.001 and p=0.02).

The adjusted difference between nerandomilast 18 mg and placebo was 68.8 mL (p<0.001), and it was 44.9 mL (p=0.02) between nerandomilast 9 mg and placebo.

FVC decline is a surrogate for mortality. “If we can slow the decline, survival would be better for patients. And that is what we saw when we looked at patients beyond the 52-week endpoint,” said Dr Marlies Wijsenbeek from the Erasmus Medical Center in Rotterdam, the Netherlands, at ATS 2025. “However, in the subgroup of patients already taking pirfenidone, only the higher dose demonstrated an additional effect.”

She noted that the loss of FVC observed over 52 weeks in the placebo group, despite more than three-quarters of patients already receiving antifibrotic therapy, underscores the need for additional treatments for IPF.

Difference with other antifibrotics

Preferentially targeting the PDE4B with nerandomilast may induce anti-inflammatory and antifibrotic effects by increasing cAMP levels while also enhancing tolerability. The mechanism differs from approved antifibrotic treatments, such as pirfenidone and nintedanib, which primarily work by inhibiting the migration, activation, and differentiation of fibroblasts. [Inflamm Regen 2024;44:34]

In the FIBRONEER-IPF trial, 1,177 IPF patients aged 40 years and older were randomly assigned to receive either nerandomilast 18 mg or 9 mg twice daily, or a placebo for 52 weeks. Nearly 78 percent were taking nintedanib or pirfenidone at enrolment. [N Engl J Med 2025;392:2193-2202]

At Week 52, nerandomilast slowed the FVC decline in both patients with and without background antifibrotic therapy. In those on background antifibrotic therapy, the FVC decline was –79.2 mL with nerandomilast 18 mg vs –148.7 mL with placebo. Among patients on nintedanib, the decline was –118.5 mL vs –191.6 mL, respectively. However, in patients on pirfenidone, only the 18-mg dose of nerandomilast showed benefit.

“The interaction between nerandomilast and pirfenidone reduced plasma concentrations of nerandomilast by about 50 percent in patients taking pirfenidone,” said Wijsenbeek. “This meant that only nerandomilast 18 mg appeared to be effective in these patients.”

Looking at the overall results, the FVC curves separated early after randomization, suggesting a rapid effect of nerandomilast, which continued to diverge up to Week 52.

Patient-reported outcomes such as dyspnoea, cough, and fatigue did not vary significantly between groups. Time to first acute exacerbation, hospitalization for a respiratory cause, or death occurred at similar rates across all groups, with no statistically significant differences.

The most common adverse event reported in the nerandomilast groups was diarrhoea, occurring in 41.3 percent of the high-dose group, 31.1 percent of the low-dose group, and 16 percent in the placebo group.

The results mark a significant advancement in IPF treatment, as current options mainly include nintedanib and pirfenidone for slowing disease progression. An open-label extension study will continue monitoring patients.