SAN FRANCISCO -- The investigational oral agent nerandomilast was superior to placebo at slowing the decline in forced vital capacity (FVC) among patients with progressive pulmonary fibrosis (PF), results of the phase 3 randomized FIBRONEER-ILD trial showed.
Among 1176 patients, the mean decline from baseline in FVC at 1 year was significantly greater for those assigned to receive a placebo than those assigned to receive nerandomilast at either of two doses, reported Marlies S. Wijsenbeek, MD, PhD, from Erasmus Medical Center in Rotterdam, the Netherlands.
"I think, personally, that these results are really a major step forward. After a decade of failed phase 3, we have now a positive trial which is really important for treatment of people with IPF [idiopathic PF]," she said in oral abstract session at American Thoracic Society (ATS) 2025 International Conference.
The study was also published online in The New England Journal of Medicine to coincide with the presentation.
Nerandomilast is an oral preferential inhibitor of PDE-4B that has shown both antifibrotic and immunomodulatory effects in preclinical models.
In a phase 3 follow-on trial of this agent in patients with IPF (FIBRONEER-IPF), nerandomilast was associated with a smaller decline in FVC compared with placebo over 1 year.
In FIBRONEER-ILD, which was conducted at 403 sites in 44 countries, patients with fibrosing interstitial lung disease (ILD) other than IPF were enrolled. After stratification by prior nintedanib (OFEV) use and high-resolution CT pattern (either usual interstitial pneumonia [UIP] or UIP-like fibrotic pattern vs other fibrotic patterns), patients were randomized in a 1:1:1 ratio to receive either nerandomilast twice daily at doses of 18 or 9 mg or placebo. Approximately 44% of patients in each study arm were on nintedanib background therapy.
The adjusted mean change in FVC at week 52, the primary endpoint, was -98.6 mL for patients assigned to nerandomilast 18 mg, -84.6 mL for those assigned to nerandomilast 9 mg, and -165.8 mL for those assigned to placebo.
The adjusted difference between 9-mg nerandomilast and placebo groups was 81.1 mL (P < .001), and the adjusted difference between 18-mg and placebo groups was 67.2 mL (P < .001).
The effect of nerandomilast was generally consistent across ILD subtypes, Wijsenbeek said.
At the time of data cutoff, a first acute exacerbation of ILD, hospitalization for a respiratory cause, or death -- a key composite secondary endpoint -- occurred in 95 patients on the 18-mg dose, 110 on the 9-mg dose, and 122 patients on placebo. These differences did not reach statistical significance, however.
A total of 24 patients in the 18-mg group (6.1%), 33 in the 9-mg group (8.4%), and 50 in the placebo group (12.8%) died during the study. The hazard ratio for death among patients in the 18-mg vs placebo group was 0.48 (95% CI, 0.30-0.79), and the hazard ratio for the 9-mg vs placebo group was 0.60 (95% CI, 0.38-0.95).
Diarrhea, the most common adverse event, was reported in 36.6% of patients taking 18 mg nerandomilast twice daily, 29.5% of those taking 9 mg twice daily, and 24.7% of those on placebo. Diarrhea leading to discontinuation was also higher in both the nerandomilast dosing groups than in the placebo group.
In the question and answer following her talk, Gisli Jenkins, MD, PhD, from Imperial College London, London, England, asked Wijsenbeek whether slowing absolute decline in FVC was the best endpoint for the trial.
"I think there is a lot of debate [about] what is the best endpoint. I think it's the best endpoint we currently have," she replied.
Ganesh Raghu, MD, from the University of Washington in Seattle, commented that FIBRONEER-ILD efficacy data were similar to those seen a decade ago with nintedanib and asked Wijsenbeek whether she could put the new data in context with existing therapies.
She replied that although the efficacy of the agents are similar, patients appear to tolerate nerandomilast better than nintedanib, "so that's a gain, in my opinion."
She added that any additional clinical benefit, even if it's only incremental, is better for patients, and she noted that although the study was not powered to detect a decrease in acute exacerbations, hospitalizations, or deaths, the data pointed to a benefit for nerandomilast.
In an editorial accompanying the study in NEJM, Joyce S. Lee, MD, from the University of Colorado Anschutz Medical Campus in Aurora, Colorado, commented that the FIBRONEER-IPF and FIBRONEER-ILD trials "represent a meaningful advancement in the treatment landscape for persons living with IPF and progressive ILD other than IPF. Important issues that our community of clinicians will need to address moving forward nonetheless remain -- decisions regarding the choice of first-line therapy, indications for up-front combination therapy as compared with add-on therapy, and the role of immunosuppression in patients with non-IPF ILD and a PPF phenotype."
The study was supported by Boehringer Ingelheim.
Wijsenbeek reported serving on a scientific advisory board and receiving speaker fees and unrestricted grants, all paid to her institution and not her personally. Lee and Jenkins reported having financial relationships with Boehringer Ingelheim and others. Raghu disclosed advisory board/consulting activities for various companies, not including Boehringer Ingelheim.