The first major advance in over a decade slows disease progression and expands treatment options.
Investigational drug nerandomilast has shown promise in phase 3 trials, offering new hope for idiopathic pulmonary fibrosis and secondary fibrotic lung disease patients.
The results, presented at the American Thoracic Society (ATS) International Conference 2025 in San Francisco, could reshape the standard of care for patients facing a condition with a median survival of only three to five years after diagnosis.
For more than a decade, all potential new drugs for pulmonary fibrosis have failed in phase 2 or phase 3 trials.
The success of nerandomilast represents the first major therapeutic breakthrough in over 10 years, according to researchers.
Results from the FIBRONEER-IPF and FIBRONEER-ILD trials have been published in the New England Journal of Medicine.
Nerandomilast is an orally administered preferential inhibitor of phosphodiesterase 4B with antifibrotic and immunomodulatory effects. In a phase 2 trial involving patients with idiopathic pulmonary fibrosis, treatment with nerandomilast stabilised lung function over a period of 12 weeks.
In the latest phase 3, double-blind trial, researchers randomly assigned patients with idiopathic pulmonary fibrosis in a 1:1:1 ratio to receive nerandomilast at a dose of 18mg twice daily; nerandomilast at a dose of 9mg twice daily; or placebo, with stratification according to background antifibrotic therapy (nintedanib or pirfenidone vs none).
The primary end point was the absolute change from baseline in forced vital capacity (FVC), measured in millilitres, at week 52.
A total of 1177 patients underwent randomisation, of whom 77.7% were taking nintedanib or pirfenidone at enrolment.
Adjusted mean changes in FVC at week 52 were −114.7 ml (95% confidence interval [CI], −141.8 to −87.5) in the nerandomilast 18mg group; −138.6 ml (95% CI, −165.6 to −111.6) in the nerandomilast 9mg group; and −183.5 ml (95% CI, −210.9 to −156.1) in the placebo group.
“The adjusted difference between the nerandomilast 18mg group and the placebo group was 68.8 ml (95% CI, 30.3 to 107.4; P<0.001), and the adjusted difference between the nerandomilast 9mg group and the placebo group was 44.9 ml (95% CI, 6.4 to 83.3; P=0.02),” the researchers wrote.
“The most frequent adverse event in the nerandomilast groups was diarrhea, reported in 41.3% of the 18mg group and 31.1% of the 9mg group, as compared with 16.0% in the placebo group. Serious adverse events were balanced across trial groups.”
Professor Luca Richeldi, professor of diseases of the respiratory system at the Catholic University of the Sacred Heart and director of the UOC of Pneumology at Fondazione Policlinico Gemelli IRCCS, was the global principal investigator and first author of the study.
He said the phase 2 and 3 studies represented “a breakthrough for the disease, because it opens up a new generation of drugs for these patients, who have so far had very limited therapeutic options available to them and from now on will also be able to benefit from combined treatments with several drugs”.
“Nerandomilast has shown clear efficacy in slowing the progression of IPF used alone, and has fewer side effects than previous therapies,” Professor Richeldi said.
“In IPF, the drug reduced disease progression by more than 50% over the 52-week trial duration; and in non-idiopathic forms of fibrosis, it was also shown to produce a reduction in mortality.
“This dual indication (for both idiopathic and secondary forms of fibrosis) represents a novelty because it will allow the treatment of a broader spectrum of pathologies, compared to the narrow spectrum of IPF.
“Non-idiopathic forms include, for example, pulmonary diseases secondary to autoimmune diseases or exposure or drug-related diseases”.
Professor Richeldi said the findings represented a major step forward for the treatment of this condition.
“It is also important to have reached another endpoint: the new drug delays the start of oxygen therapy, which, in my experience, is extremely disabling for these patients, to the point of limiting (and sometimes wiping out) their social life, leading to significant negative effects on their quality of life,” he said.
He said the next step was a two-year study in patients with the earliest form of the disease, known as ILA (interstitial lung abnormalities), treated with nerandomilast in order to understand whether treating preclinical or subclinical phases of disease can further slow down its progression and even prevent the emergence of pulmonary fibrosis symptoms.
