Nerandomilast reduces FVC decline, has ‘manageable’ adverse events in IPF at 52 weeks

Key takeaways:

• Two differing nerandomilast doses were assessed against placebo.
• Both groups had significantly smaller degrees of FVC decline vs. placebo.
• A greater proportion of patients receiving nerandomilast had diarrhea.

SAN FRANCISCO — Two doses of 52-week nerandomilast, a phosphodiesterase 4B inhibitor, reduced FVC decline vs. placebo in patients with idiopathic pulmonary fibrosis, according to results published in the New England Journal of Medicine.

These data on oral nerandomilast (BI 1015550, Boehringer Ingelheim) were simultaneously presented at the American Thoracic Society International Conference.

“I think, personally, that these results really are a major step forward,” Marlies S. Wijsenbeek, MD, of the Center of Expertise for Interstitial Lung Diseases in the department of respiratory medicine at the Erasmus MC University Medical Centre, said during her ATS presentation. “After a decade of failed phase 3 trials, we have now a positive trial, which is really important to the treatment of people with IPF.”

In the multicenter, double-blind, randomized, placebo-controlled phase 3 FIBRONEER-IPF trial, Wijsenbeek and colleagues assessed 1,177 adults aged 40 years or older (mean age, 70.2 years; 83% men; mean FVC, 78.2% predicted) with IPF (mean time since diagnosis, 3.5 years) to determine the impact of two different twice-daily doses of oral nerandomilast vs. placebo on FVC after 52 weeks of treatment.

Healio previously reported on topline results from this trial in September 2024.

Within this set of patients, use of background antifibrotic therapy at enrollment was common, as 77.7% (n = 915) reported nintedanib (n = 535) or pirfenidone (n = 380) use. Wijsenbeek highlighted during her presentation that those with vs. without background use of nintedanib/pirfenidone had a lower FVC (77.1% predicted vs. 82.2% predicted) and more time since diagnosis (3.7 years vs. 2.8 years) at baseline.

The 18 mg nerandomilast group included 392 patients (mean age, 70.3 years; 82.4% men; mean FVC, 78.4% predicted), the 9 mg nerandomilast group included 392 patients (mean age, 70.5 years; 80.9% men; mean FVC, 79% predicted) and the placebo group included 393 patients (mean age, 69.9 years; 85.8% men; mean FVC, 77.3% predicted).

Results

Between baseline and week 52, researchers observed that patients receiving 18 mg nerandomilast had a significantly smaller degree of FVC decline vs. patients receiving placebo (adjusted mean change, –114.7 mL vs. –183.5 mL; adjusted difference, 68.8 mL; 95% CI, 30.3-107.4; P < .001).

Similarly, a significantly smaller FVC reduction was found in those receiving 9 mg nerandomilast vs. placebo (–138.6 mL vs. –183.5 mL; adjusted difference, 44.9 mL; 95% CI, 6.4-83.3; P = .02), according to the study.

“If you look at these data over time, you see that the curves already very early split, and that they continue to diverge over the trajectory over time, which is very encouraging,” Wijsenbeek said. “And you even see that better if you have longer follow-up to 76 weeks.”

Researchers continued to report less FVC decline with both nerandomilast doses by week 52 in the subgroup of patients who did not use background antifibrotic therapy. In the 18 mg and 9 mg nerandomilast groups, FVC went down by 79.2 mL and 70.4 mL, respectively, whereas this measure of lung function dropped by 148.7 mL in the placebo group.

This pattern also held true in the subgroup of patients who used nintedanib, with smaller FVC reductions in those receiving nerandomilast vs. placebo (18 mg, –118.5 mL; 9 mg, –130.7 mL vs. –191.6 mL).

“It’s important to realize that despite that these patients are on an effective drug, they still have this decline, so this illustrates that we really need additional drugs,” Wijsenbeek said.

Patients in the pirfenidone subgroup receiving 18 mg nerandomilast also had a smaller degree of FVC decline between baseline and week 52 vs. patients receiving placebo (–133.7 mL vs. –197 mL), but this was not the case when researchers compared the 9 mg nerandomilast group with the placebo group (–201.8 mL vs. –197 mL).

“We think that the reason for this lack of effect with pirfenidone is probably in the plasma concentrations,” Wijsenbeek said.

“[With] pirfenidone … the plasma concentration levels of nerandomilast are about 50% of what they are in the nintedanib and no background group, so we believe that that explains it,” she continued.

In addition to changes in FVC, the study captured changes in three scores on the Living with Pulmonary Fibrosis questionnaire: dyspnea score, cough score and fatigue score. Between baseline and week 52, patients receiving the nerandomilast doses had comparable changes in these three scores to patients receiving placebo.

Researchers also noted that similar proportions of patients receiving nerandomilast and patients receiving placebo experienced a first acute exacerbation, a respiratory cause hospitalization or death (18 mg, 21.7%; 9 mg, 20.2% vs. 20.4%).

When looking at death alone, Wijsenbeek highlighted that “there are numerically fewer deaths in the 18 mg group twice a day compared to placebo.”

Notably, a greater proportion of patients receiving placebo vs. nerandomilast who did not use supplemental oxygen at enrollment received supplemental oxygen during the trial (19.5% vs. 18 mg, 16%; 9 mg, 12.1%), according to the study.

Safety

In the nerandomilast groups, 95% of patients receiving the 18 mg dose and 93% of patients receiving the 9 mg dose reported an adverse event, and this was comparable to the 94% of patients in the placebo group.

Researchers highlighted that this pattern continued when evaluating the proportions of patients who experienced a serious adverse event (18 mg, 30%; 9 mg, 31% vs. 33%).

A greater proportion of patients receiving either dose of nerandomilast vs. placebo reported diarrhea (18 mg, 41.3%; 9 mg, 31.1% vs. 16%), according to the study. This finding held true across each background antifibrotic subgroup, with the highest proportions of patients reporting diarrhea in the nintedanib group (18 mg, 62%; 9 mg, 49% vs. placebo, 27%).

Slightly more patients receiving 18 mg nerandomilast had to permanently discontinue treatment due to an adverse event vs. patients receiving the 9 mg dose or placebo (14% vs. 11.7% or 10.7%). Additionally, researchers found that diarrhea was the adverse event commonly behind these discontinuations (6.1% vs. 1.8% or 0.5%).

The adverse events of interest in the trial included depression, suicidality, insomnia, nervousness combined with anxiety, vasculitis, potential drug-induced liver injury and severe/serious infections, and Wijsenbeek noted similar rates of each event across the 18 mg nerandomilast group, the 9 mg nerandomilast group and the placebo group.

“Safety data suggested that the adverse events that were associated with nerandomilast are manageable,” Wijsenbeek and colleagues wrote in the study.

When broken down into the three background antifibrotic therapy subgroups, researchers observed that a higher proportion of patients using nintedanib vs. pirfenidone or no therapy had to discontinue treatment due to an adverse event.

“These findings serve as the basis of regulatory filings worldwide,” Leticia Orsatti, MD, vice president of clinical development and medical affairs at Boehringer Ingelheim, told Healio. “The U.S. FDA recently granted priority review to the [new drug application] for nerandomilast in IPF, with an anticipated action date in the fourth quarter of 2025.”

Reference:

• Wijsenbeek MS. A82 Breaking news: 2025 clinical trial results in pulmonary medicine. Presented at: American Thoracic Society International Conference; May 16-21, 2025; San Francisco.