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ERS Data Could Position Nerandomilast as Anti-Fibrotic of Choice
Nerandomilast's tolerability and dual antifibrotic/immunomodulatory mechanism directly address the critical non-adherence issue with current therapies, positioning it as a potential first-line treatment for IPF and PPF despite remaining questions about very long-term efficacy and the need for biomarkers.
The emergence of nerandomilast, a new anti-fibrotic agent, represents a potential paradigm shift in the management of idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF), according to Steven Nathan, MD, medical director of the advanced lung disease and lung transplant program at Inova Health System, Fairfax Hospital. Nathan’s commentary focused on data from the European Respiratory Society Congress 2025, particularly highlighting the drug’s novel mechanism and superior tolerability profile—key advantages over the current standard-of-care therapies.
The most significant barrier to the effective use of existing anti-fibrotics, nintedanib and pirfenidone, is their poor tolerability and resulting patient non-adherence. Although these established drugs effectively slow the decline in forced vital capacity (FVC) and enhance survival, severe adverse events—like the significant gastrointestinal upset and diarrhea associated with nintedanib—often lead to patient discontinuation within one year. Nathan stressed that efficacy is nullified by non-adherence, limiting the real-world impact of current treatments.
Nerandomilast is an oral medication with a distinctive mechanism: it is a preferential phosphodiesterase 4B (PDE4B) inhibitor. This selective action increases intracellular cyclic AMP (cAMP), producing a beneficial dual mechanism of action with both antifibrotic and immunomodulatory (anti-inflammatory) properties. Nathan pointed out that this dual action is especially promising for PPF, as many of its underlying conditions, such like hypersensitivity pneumonitis, involve inflammation. The initial slight "bump up" in FVC observed in the FIBRONEER trial data is hypothesized to stem from this anti-inflammatory effect.
The FIBRONEER trials for IPF and PPF confirmed nerandomilast's efficacy, showing a significant reduction in FVC decline at 52 weeks and sustained benefit up to 76 weeks.1,2 Crucially, its favorable safety profile and adverse event-related discontinuation rates, which were similar to placebo, directly address the adherence crisis. Nerandomilast was FDA-approved for IPF in October 2025, with PPF approval anticipated in early 2026. Nathan believes this superior tolerability will make nerandomilast the medication of choice, potentially positioning it as the first-line therapy for both conditions, as physicians and patients will logically favor the drug most likely to be taken long-term to maximize survival benefits.
Despite the breakthrough, Nathan noted that key unanswered questions remain, primarily regarding the drug's very long-term efficacy (beyond 76-96 weeks) and the lack of biomarkers in the field. He emphasized the critical need for biomarkers to accurately predict which of the three anti-fibrotic therapies—nerandomilast, nintedanib, or pirfenidone—would best suit an individual patient’s phenotype.
