Nerandomilast Reduces Mortality Risk in Pulmonary Fibrosis Analysis

Pooled data from the phase 3 FIBRONEER-IPF and FIBRONEER-ILD trials showed nerandomilast (Jascayd) reduced the risk of death by 33% at the 9 mg twice-daily dose and by 43% at the 18 mg twice-daily dose compared with placebo in patients with idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF), according to results published in the European Respiratory Journal.¹

Nerandomilast, a preferential phosphodiesterase 4B (PDE4B) inhibitor, received its first regulatory approvals for IPF and PPF based on the FIBRONEER trials, in which both doses reduced the primary endpoint of forced vital capacity (FVC) decline at week 52 versus placebo.¹ The key secondary composite endpoint, time to first acute exacerbation, respiratory hospitalization, or death, was not met in either trial at the first database lock, meaning downstream analyses of individual components, including mortality, are considered exploratory.¹ Because hierarchical testing stopped once the composite endpoint missed significance, all mortality p-values reported are nominal rather than confirmatory.¹

Justin M Oldham, MD, Clinical Associate Professor, University of Michigan Health, and colleagues wrote that “over the whole trial, there was a numerical reduction of 34% in the risk of death with nerandomilast 18 mg bid versus placebo in FIBRONEER-IPF and a nominally significant reduction in the risk of death of 49% with both doses of nerandomilast versus placebo in FIBRONEER-ILD. We performed additional analyses to investigate the effect of nerandomilast on mortality in the FIBRONEER trials.”

What Did Pooled Survival Data From FIBRONEER Trials Show?

The analysis pooled data from FIBRONEER-IPF and FIBRONEER-ILD, in which patients with IPF or an ILD other than IPF with a progressive fibrosing phenotype were randomized 1:1:1 to nerandomilast 9 mg twice daily, 18 mg twice daily, or placebo.¹ Across both trials, 2353 patients received at least 1 dose of trial medication, with mean exposure of approximately 15 months and mean observation time of approximately 17 months.¹ The primary analysis of time to death used a Cox proportional hazards model adjusted for background antifibrotic therapy, age, and lung function, based on all deaths except those after lung transplant.¹

In the pooled analysis, deaths occurred in 106 patients (13.5%) on placebo, 72 patients (9.2%) on nerandomilast 9 mg twice daily (HR, 0.67; 95% CI, 0.49-0.90; P = .009), and 60 patients (7.7%) on nerandomilast 18 mg twice daily (HR, 0.57; 95% CI, 0.41-0.78; P <.001).¹ The mortality benefit reached significance in FIBRONEER-ILD alone, where both doses reduced the hazard ratio to 0.51 (95% CI, 0.34-0.78) versus placebo, but not in FIBRONEER-IPF alone, where the hazard ratio for the 18 mg dose was 0.66 (95% CI, 0.41-1.08).¹ The number needed to treat with the 18 mg dose to prevent 1 death over a median exposure of approximately 16.5 months was 13 in FIBRONEER-ILD and 43 in FIBRONEER-IPF.¹

What Was Nerandomilast Dosing and Analysis Limitations?

Sensitivity analyses adjusting for additional covariates and supplementary analyses censoring deaths at various points after treatment discontinuation were consistent with the primary mortality findings.¹ Two tipping-point analyses found the mortality benefit would only lose statistical significance under extreme, implausible assumptions about missing vital-status data, such as an 8% yearly mortality rate in the placebo group with missing data rising to 78% in the nerandomilast 18 mg missing-data group before the effect disappeared.¹ In FIBRONEER-ILD, no significant treatment-by-subgroup interaction was found across ILD diagnoses, though small numbers of deaths in each subgroup produced wide, overlapping confidence intervals.¹

Exposure-response analyses found higher trough plasma concentrations of nerandomilast were associated with a lower risk of death, with median exposure roughly twice as high at the 18 mg dose as the 9 mg dose.¹ The study authors noted patients taking background pirfenidone should not use the 9 mg twice-daily dose, since a drug interaction reduces nerandomilast plasma levels by approximately 50% and renders the 9 mg dose ineffective in this population.¹ The trials were not powered to assess mortality as an endpoint, and the study authors noted all analyses besides the primary time-to-death analysis were conducted post hoc.¹

Nerandomilast received FDA approval for IPF in October 2025 and for PPF in December 2025, based on the FVC data from the FIBRONEER trials rather than the mortality analyses reported here.² The study authors called for further research into the drivers of mortality in pulmonary fibrosis and the mechanisms behind nerandomilast's survival signal.¹

References

1. Oldham JM, Assassi S, Azuma A, et al. Effect of nerandomilast on survival in patients with pulmonary fibrosis. Eur Respir J. 2026; in press. doi:10.1183/13993003.00338-2026

2. FDA approves new treatment option for adults with PPF. Boehringer Ingelheim. Published December 2025. Accessed July 30, 2026. https://www.boehringer-ingelheim.com/us/human-health/lung-diseases/pulmonary-fibrosis/fda-approves-new-treatment-option-adults-ppf