Nerandomilast lowers FVC decline in progressive pulmonary fibrosis at 52 weeks

Key takeaways:

• Oral nerandomilast doses of 9 mg and 18 mg were evaluated against placebo.
• Both dose groups had significantly smaller degrees of FVC decline vs. placebo.
• The safety and tolerability profile was deemed favorable.

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

This research on oral nerandomilast (BI 1015550, Boehringer Ingelheim) was simultaneously presented at the American Thoracic Society International Conference.

Results from the FIBRONEER-IPF trial investigating nerandomilast in patients with idiopathic pulmonary fibrosis was also published in The New England Journal of Medicine and presented at the ATS International Conference.

“In patients with progressive pulmonary fibrosis, nerandomilast slows FVC decline,” Toby M. Maher, MD, PhD, professor of medicine and director of interstitial lung disease at Keck School of Medicine, University of Southern California, Los Angeles, said during the ATS presentation. “It also appeared to have a very favorable effect on mortality and had a trend on the key secondary endpoint. And overall, I think the take-home message on safety and tolerability is that it was very well tolerated with no concerning safety signals.”

In the multicenter, double-blind, randomized, placebo-controlled phase 3 FIBRONEER-ILD trial, Maher and colleagues assessed 1,176 adults (mean age, 66.4 years; 55.6% men; mean FVC, 70.1% predicted) with progressive pulmonary fibrosis (PPF; mean time since ILD diagnosis, 4.2 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 February.

When divided by ILD diagnosis, researchers found that 27.6% had autoimmune ILDs, 19.8% had hypersensitivity pneumonitis, 19.6% had unclassifiable idiopathic interstitial pneumonia, 19.4% had idiopathic non-specific interstitial pneumonia and 13.5% had other ILDs.

At baseline, 43.7% (n = 514) of patients reported background antifibrotic therapy use, and all but two of these patients used nintedanib over pirfenidone.

The 18 mg nerandomilast group included 391 patients (mean age, 66 years; 56.3% men; mean FVC, 70.4% predicted), the 9 mg nerandomilast group included 393 patients (mean age, 66.5 years; 51.7% men; mean FVC, 70.3% predicted) and the placebo group included 392 patients (mean age, 66.6 years; 58.9% men; mean FVC, 69.7% predicted).

Results

Between baseline and week 52, researchers found that patients receiving 18 mg nerandomilast had a significantly smaller degree of FVC decline vs. patients receiving placebo (adjusted mean change, –98.6 mL vs. –165.8 mL; adjusted difference, 67.2 mL; 95% CI, 31.9-102.5).

Similarly, a significantly smaller FVC reduction was found in those receiving 9 mg nerandomilast vs. placebo (–84.6 mL vs. –165.8 mL; adjusted difference, 81.1 mL; 95% CI, 46-116.3), according to the study.

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. Compared with patients receiving placebo, patients receiving 18 mg nerandomilast had a smaller degree of FVC decline (adjusted mean change, –95.2 mL vs. –154.1 mL; adjusted difference, 58.9 mL; 95% CI, 12.1-105.8), and this was also true for those receiving the 9 mg dose (–82.3 mL vs. –154.1 mL; adjusted difference, 71.8 mL; 95% CI, 24.9-118.8).

Smaller FVC reductions with nerandomilast vs. placebo between baseline and week 52 were also observed in the subgroup of patients who used nintedanib. According to the study, patients receiving 18 mg nerandomilast had less FVC decline vs. placebo (adjusted mean change, –102.9 mL vs. –180.9 mL; adjusted difference, 78 mL; 95% CI, 24.2-131.8), as did patients receiving 9 mg nerandomilast (–87.8 mL vs. –180.9 mL; adjusted difference, 93.1 mL; 95% CI, 39.9-146.3).

Notably, researchers reported results similar to the overall population when divided based on ILD diagnosis.

Researchers additionally noted that lower proportions of patients receiving nerandomilast experienced a first acute ILD exacerbation, a respiratory cause hospitalization or death vs. patients receiving placebo (18 mg, 24.3%; 9 mg, 28% vs. 31.1%), but this did not reach significance.

When evaluating death by itself, Maher and colleagues also found this outcome in a smaller proportion of patients in both nerandomilast groups vs. the placebo group (18 mg, 6.1%; 9 mg, 8.4% vs. 12.8%).

“I think unequivocally, we are seeing a benefit in terms of mortality in these patients,” Maher said.

Another outcome measured in this study was 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.

Safety

In the nerandomilast groups, researchers observed that 92.6% of patients receiving the 18 mg dose and 92.1% of patients receiving the 9 mg dose reported an adverse event, which was comparable to the proportion in the placebo group (91.8%).

The study also noted this pattern when comparing patients who experienced serious adverse events (18 mg, 33.2%; 9 mg, 31.8% vs. 35.2%).

Notably, researchers found a higher proportion of patients receiving either dose of nerandomilast vs. placebo reporting diarrhea (18 mg, 36.6%; 9 mg, 29.5% vs. 24.7%). When divided based on background nintedanib, the proportion of patients reporting diarrhea was greater in the subgroup with vs. without this therapy in each treatment group (18 mg, 49.1%; 9 mg, 48%; placebo, 36.5% vs. 26.8%; 15%; 15.8%).

“From experience in the trial, this is not qualitatively the same sort of diarrhea problem that we see with nintedanib,” Maher said. “In general, it is much milder, and that translates into very few discontinuations due to diarrhea.”

A similar proportion of patients in each group had to permanently discontinue treatment due to an adverse event (18 mg, 10%; 9 mg, 8.1%; placebo, 10.2%). According to the study, two adverse events were commonly behind these discontinuations: aggravated condition (1%; 1.5%; 3.1%) and diarrhea (2.6%; 1.3%; 0.5%).

In the subgroups with and without nintedanib use, researchers reported “generally similar” proportions of patients who discontinued treatment due to an adverse event.

The adverse events of interest in the trial included vasculitis, depression and suicidality, and the study noted similar rates of each event across the treatment groups.

“We’re very proud about the data presented at ATS from the two phase 3 FIBRONEER clinical studies because results show that nerandomilast met the primary endpoint — the absolute change from baseline in FVC at week 52 vs. placebo, which included patients with and without background IPF and PPF treatments — in not one, but two trials,” Leticia Orsatti, MD, vice president of clinical development and medical affairs at Boehringer Ingelheim, told Healio.

Looking ahead, Orsatti said a new drug application for nerandomilast in PPF has been filed with the FDA.

“Boehringer Ingelheim has long been committed to patients living with respiratory diseases, and we value opportunities like ATS to connect with the broader scientific community to share the latest learnings from our research,” Orsatti told Healio. “Our hope is that the learnings from these trials will inspire continued investigation into new options for clinicians and their patients.”

Reference:

• Richeldi L, et al. B2 NEJM, AJRCCM, JAMA: Discussions on the edge: Reports of recently published pulmonary research. Presented at: American Thoracic Society International Conference; May 16-21, 2025; San Francisco.