Anti-Fibrotic Nerandomilast Proves Tolerable Compared With Other IPF/PPF Drugs

Steven Nathan, MD, medical director of the advanced lung disease and lung transplant program at Inova Health System at Fairfax Hospital in Falls Church, Virginia, offered commentary on the significance of nerandomilast, a novel anti-fibrotic agent, in the context of existing treatments for idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF), with data presented at the European Respiratory Society Congress 2025. Current FDA-approved anti-fibrotics, nintedanib and pirfenidone, are effective in slowing forced vital capacity (FVC) decline and improving survival.

However, their major drawback is poor tolerability, leading to high patient discontinuation rates. Nintedanib is often associated with significant gastrointestinal adverse effects (diarrhea), and pirfenidone also carries gastrointestinal and other systemic issues, limiting their real-world effectiveness since a drug is only as effective as long as a patient takes it.

Nerandomilast is an oral medication that acts as a preferential inhibitor of phosphodiesterase 4B, granting it both antifibrotic and immunomodulatory properties. The drug was studied in two large trials: FIBRONEER-IPF and FIBRONEER-ILD (for PPF).^1,2 FIBRONEER-ILD was a randomized, placebo-controlled trial in adults with progressive ILD (not IPF) who showed evidence of disease progression. Participants (n = 785) were stratified based on background nintedanib use and randomized 1:1:1 to receive nerandomilast (9 mg twice daily), nerandomilast (18 mg twice daily), or placebo. The primary endpoint for both studies was the absolute decline in FVC at 52 weeks.

Both FIBRONEER trials met the primary end point, showing that nerandomilast significantly reduced the decline in FVC at 52 weeks compared to placebo. A pooled analysis showed this positive impact on lung function was sustained over 76 weeks and also reduced key clinical events and mortality. Notably, in the IPF study, nerandomilast worked in patients regardless of whether they were on existing background anti-fibrotic therapy. The drug was FDA-approved for IPF in October 2025, with PPF approval expected in early 2026.³

Nathan noted that nerandomilast was shown to work both as a monotherapy and in combination with background anti-fibrotic therapies in the IPF study. While a drug-drug interaction with pirfenidone restricts combination use to the 18 mg twice-daily dose of nerandomilast, the improved tolerability signal, even with background nintedanib, is key. Nathan predicted that physicians and patients will naturally steer towards the medication that is best tolerated and most likely to be taken long-term.