Nerandomilast achieved the primary endpoints in both the Phase III FIBRONEER-ILD (NCT05321082) and FIBRONEER-IPF (NCT05321069) trials by producing significant lung function preservation in patients with idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF).^1-3

Phase III Trials Show Nerandomilast Significantly Slows Lung Function Decline in IPF and PPF

Data from both trials published by The New England Journal of Medicine (NEJM) show a statistically significant reduction in lung function decline at both tested doses of nerandomilast over 52 weeks, demonstrating potential as both a monotherapy or in combination with current antifibrotics.^4,5

"After several challenges in the scientific community to bring forward new clinical data, IPF and PPF continue to take a devastating toll on patients,” Toby Maher, MD, PhD, professor of Clinical Medicine, Keck School of Medicine, USC Los Angeles, said in a press release. “Having two Phase III trials meet the primary endpoint is a major breakthrough for the scientific community, highlighting nerandomilast’s potential to have a meaningful impact on patients’ unmet needs, being studied as mono therapy or in combination with current treatments.”¹

Currently, nintedanib (Ofev and Vargatef) is the only FDA-approved treatment for PPF. The small molecule tyrosine kinase inhibitor attaches to growth factor receptors to slow the proliferation of fibroblasts and lower ongoing fibrotic processes to delay the progression to long-lasting damage.⁶

However, investigators noted that patients taking the drug have experienced gastrointestinal adverse effects (AEs) that frequently cause treatment discontinuation. They added that many patients with PPF are not currently taking a medication that is effective in slowing disease progression.³

“Two antifibrotic drugs, nintedanib and pirfenidone, slow decline in lung function in patients with IPF and have become the standard of care,” the NEJM study authors wrote. “However, these drugs do not halt progression, and their gastrointestinal side effects often prevent treatment initiation or result in discontinuation.”⁵

Nerandomilast Delivers Consistent Efficacy and Safety Across FIBRONEER-IPF and FIBRONEER-ILD Studies

Nerandomilast is an investigational, oral, preferential inhibitor of phosphodiesterase 4B (PDE4B), representing the first molecule in a new class of PDE4B inhibitors.

The double-blind, randomized, placebo-controlled FIBRONEER-ILD trial analyzed the efficacy and safety of nerandomilast across a minimum of 52 weeks in patients with IPF. Investigators randomly assigned 1,177 patients in a 1:1:1 ratio to receive nerandomilast 9 mg twice-daily (n=392), nerandomilast 18 mg twice-daily (n=392), or placebo twice-daily (n=393). Investigators stratified randomization by background antifibrotic therapy use, as 77.7% of patients received nintedanib or pirfenidone at enrollment.

The trial’s primary endpoint was absolute change from baseline in the forced vital capacity (FVC), measured in milliliters, at week 52. The trial’s composite key secondary endpoint was time to first acute IPF exacerbation, first hospitalization for respiratory cause, or death.

Among the 1176 patients administered a minimum of one dose of nerandomilast or placebo, 43.5% were using background nintedanib therapy at baseline.

Results show an adjusted mean change in FVC at week 52 of −98.6 ml (95% confidence interval [CI], −123.7 to −73.4) among patients administered nerandomilast 18 mg, −84.6 ml (95% CI, −109.6 to −59.7) among patients administered nerandomilast 9 mg, and −165.8 ml (95% CI, −190.5 to −141.0) among patients administered the placebo. These results translated to an adjusted difference of 67.2 ml (95% CI, 31.9 to 102.5; P<0.001) between the nerandomilast 18-mg cohort and the placebo group cohort, and an adjusted difference of 81.1 ml (95% CI, 46.0 to 116.3; P<0.001) between the nerandomilast 9 mg cohort and the placebo cohort. The drug did not achieve the trial’s key composite secondary endpoint.

In terms of safety, the most frequently reported AE was diarrhea, which occurred in 36.6% of patients in the nerandomilast 18 mg cohort, 29.5% in the nerandomilast 9 mg cohort, and 24.7% in the placebo cohort.

“In the FIBRONEER-ILD trial involving patients with progressive pulmonary fibrosis, treatment with nerandomilast resulted in a smaller decline in the FVC than placebo over a period of 52 weeks,” the study authors concluded.⁴

FIBRONEER-IPF and FIBRONEER-ILD Trial Designs Support Broad Clinical Relevance

The double-blind, randomized, placebo-controlled FIBRONEER-IPF trial was conducted at 403 sites in 44 countries. Investigators randomly assigned 1,176 patients in a 1:1:1ratio to receive nerandomilast 9 mg twice-daily (n=393), nerandomilast 18 mg twice-daily (n=391), or placebo twice-daily (n=392). Investigators stratified randomization was stratified by background antifibrotic therapy use, with 43.5% of patients using nintedanib.

The primary endpoint was absolute change from baseline in FVC milliliters at week 52, with a composite key secondary endpoint of time to first acute exacerbation, hospitalization for a respiratory cause, or death.

At week 52, the results show adjusted mean changes in FVC of −114.7 ml (95% confidence interval [CI], −141.8 to −87.5) among patients administered nerandomilast 18 mg group, −138.6 ml (95% CI, −165.6 to −111.6) among patients administered nerandomilast 9 mg, and −183.5 ml (95% CI, −210.9 to −156.1) among patients administered placebo.

This translates to adjusted difference of 68.8 ml between the nerandomilast 18 mg cohort and the placebo cohort (95% CI, 30.3 to 107.4; P<0.001), while the adjusted difference was 44.9 ml between the nerandomilast 9 mg cohort and the placebo cohort (95% CI, 6.4 to 83.3; P=0.02). Like the FIBRONEER-ILD trial, the composite key secondary endpoint in this trial fell short of statistical significance.

The most common AE in the nerandomilast cohort was diarrhea, reported in 41.3% of patients in 18 mg cohort and 31.1% in the 9 mg cohort compared to 16.0% in the placebo cohort.

New Data Reinforce Unmet Need for Additional IPF and PPF Treatment Options

“Idiopathic pulmonary fibrosis and progressive pulmonary fibrosis are devastating conditions, with one in two people dying within five years of IPF diagnosis. Despite this stark reality, ongoing research may provide new possibilities for patients, as there remains a need for additional therapies,” Shashank Deshpande, head of Human Pharma and member of the Board of Managing Directors at Boehringer Ingelheim, said in the release. “The latest efficacy, safety and tolerability data on nerandomilast points to its potential in addressing the needs of those impacted by IPF and PPF.”¹

References

1. Global phase III trials demonstrate that nerandomilast slowed lung function decline in IPF and PPF, with similar discontinuation rates to placebo. News release. Boehringer Ingelheim. May 19, 2025. Accessed May 22, 2025. https://www.boehringer-ingelheim.com/human-health/lung-diseases/pulmonary-fibrosis/phase-3-trials-nerandomilast-slowed-lung-function-decline-ipf-and-ppf

2. A Study to Find Out Whether BI 1015550 Improves Lung Function in People With Progressive Fibrosing Interstitial Lung Diseases (PF-ILDs). ClinicalTrials.gov. Updated May 13, 2025. Accessed May 22, 2025. https://clinicaltrials.gov/study/NCT05321082.

3. A Study to Find Out Whether BI 1015550 Improves Lung Function in People With Idiopathic Pulmonary Fibrosis (IPF). ClinicalTrials.gov. Updated March 10, 2025. Accessed May 22, 2025. https://clinicaltrials.gov/study/NCT05321069

4. Maher T., Nerandomilast in Patients with Progressive Pulmonary Fibrosis. N Engl J Med 2025; https://www.nejm.org/doi/full/10.1056/NEJMoa2503643

5. Richeldi L., Nerandomilast in Patients with Idiopathic Pulmonary Fibrosis. N Engl J Med 2025; https://www.nejm.org/doi/full/10.1056/NEJMoa2414108 

6. Gole S, Bankole A. Nintedanib. [Updated 2024 Aug 17]. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from https://www.ncbi.nlm.nih.gov/books/NBK585049/