Highlights
- Nerandomilast 18 mg bid demonstrated a numerical, though not statistically significant, reduction in the risk of death (HR 0.66, 95% CI 0.41–1.08).
- The primary endpoint of reducing forced vital capacity (FVC) decline at 52 weeks was previously met by both 9 mg and 18 mg doses.
- Analysis of the full follow-up period (mean ~14.8 months) showed no significant difference in the composite endpoint of acute exacerbation, hospitalization, or death.
- The safety profile remains encouraging, with low discontinuation rates (16.1% at the 18 mg dose) compared to historical rates for other antifibrotic therapies.
Background: The Unmet Need in Idiopathic Pulmonary Fibrosis
Idiopathic Pulmonary Fibrosis (IPF) remains a progressive and devastating interstitial lung disease characterized by chronic, irreversible scarring of the lung parenchyma. Despite the availability of current antifibrotic agents such as nintedanib and pirfenidone, which successfully slow the rate of decline in forced vital capacity (FVC), the five-year survival rate for IPF remains lower than that of many malignancies. There is a profound clinical need for therapies that not only preserve lung function but also impact hard clinical outcomes like hospitalizations and mortality.
Nerandomilast represents a novel approach in this space. As a selective phosphodiesterase 4B (PDE4B) inhibitor, it aims to target the inflammatory and fibrotic pathways while minimizing the gastrointestinal side effects typically associated with non-selective PDE4 inhibition. The FIBRONEER-IPF trial was designed to evaluate whether this mechanism could translate into meaningful clinical benefits for patients suffering from this relentless condition.
Study Design: The FIBRONEER-IPF Framework
The FIBRONEER-IPF trial was a randomized, double-blind, placebo-controlled Phase 2 study. It enrolled a large cohort of 1177 patients diagnosed with IPF. Participants were randomized to receive one of three treatments: placebo, nerandomilast 9 mg twice daily (bid), or nerandomilast 18 mg bid. The primary objective, as reported previously, was the change from baseline in FVC at week 52.
The current analysis focuses on the extended follow-up period. Patients continued their randomized treatment beyond the 52-week mark until the final patient in the study completed their end-of-treatment visit. This allowed researchers to assess time-to-event endpoints over a longer duration, with a mean exposure of approximately 14.8 months. The key secondary endpoint was a composite of time to first acute exacerbation of IPF, hospitalization for a respiratory cause, or death.
Key Findings: Analyzing the Long-Term Data
Primary and Composite Outcomes
While the trial had already successfully met its primary endpoint of reducing FVC decline at one year, the longitudinal data provided a more complex picture of disease progression. For the key secondary composite endpoint (acute exacerbation, respiratory hospitalization, or death), the results were neutral. The hazard ratio (HR) for the 9 mg bid group was 0.92 (95% CI 0.69, 1.22), and for the 18 mg bid group, it was 0.99 (95% CI 0.75, 1.31). This suggests that, within the timeframe of this trial, nerandomilast did not significantly delay the onset of these major respiratory events compared to placebo.
Mortality Signals
The most striking data point from the extended follow-up involves the mortality analysis. Among patients receiving the 18 mg bid dose of nerandomilast, the hazard ratio for death was 0.66 (95% CI 0.41, 1.08). While the 95% confidence interval crosses 1.0, indicating a lack of statistical significance, the 34% numerical reduction in the risk of death is clinically provocative. In the 9 mg bid group, the HR for death was 0.95 (95% CI 0.61, 1.49), suggesting a possible dose-dependent response or that the higher dose is required to achieve a survival signal.
Hospitalization and Exacerbations
The lack of movement in the composite endpoint despite the mortality signal suggests that the rates of acute exacerbations and respiratory hospitalizations were similar across all groups. This disconnect is often observed in IPF trials, where the definitions of “acute exacerbation” can be stringent and the events themselves are relatively rare over a 15-month period, potentially underpowering the study to detect a difference in these specific components.
Safety and Tolerability: A Critical Component of IPF Care
A major hurdle for many IPF therapies is patient adherence due to adverse events (AEs). Historically, PDE4 inhibitors have been associated with significant nausea, vomiting, and diarrhea. However, the selective PDE4B inhibition of nerandomilast appears to mitigate some of these concerns. In the FIBRONEER-IPF trial, adverse events led to treatment discontinuation in 13.0% of the placebo group, 13.5% of the 9 mg bid group, and 16.1% of the 18 mg bid group.
The fact that the high-dose group had a discontinuation rate only slightly higher than placebo is a significant finding. It suggests that nerandomilast is well-tolerated over the long term, which is essential for a chronic medication intended for lifelong use in a fragile patient population.
Expert Commentary: Contextualizing the Mortality Signal
The results of the FIBRONEER-IPF trial present a nuanced challenge for clinical interpretation. On one hand, the neutral result for the composite secondary endpoint might be seen as a disappointment. On the other hand, the stabilization of FVC combined with a numerical trend toward improved survival (HR 0.66) at the 18 mg dose provides a strong rationale for further investigation.
The numerical mortality benefit is particularly noteworthy because mortality is the ultimate clinical endpoint in IPF. Most trials are not powered to show mortality benefits, and finding such a signal in a Phase 2 study—even if not statistically significant—is rare. Clinicians should view these results as exploratory but highly encouraging. The biological plausibility of PDE4B inhibition in reducing the underlying fibrotic drive, combined with the manageable safety profile, positions nerandomilast as a potential candidate for combination therapy or as a standalone option for patients who cannot tolerate current antifibrotics.
However, limitations must be acknowledged. The trial was not specifically powered for mortality or the composite secondary endpoints. The wide confidence intervals mean that we cannot definitively conclude that nerandomilast reduces death until larger, Phase 3 trials are completed. Furthermore, the lack of impact on hospitalizations suggests that the drug’s primary benefit may be in slowing the slow, steady progression of the disease rather than preventing acute catastrophic events.
Conclusion: The Path Forward for Nerandomilast
The FIBRONEER-IPF trial provides critical data on the long-term use of nerandomilast in patients with idiopathic pulmonary fibrosis. While the study did not meet its key secondary composite endpoint, the totality of the evidence—including the previously met primary FVC endpoint and the promising mortality signal at the 18 mg dose—supports the continued development of this agent. Nerandomilast represents a potentially safer and effective addition to the IPF treatment armamentarium, offering hope for a patient population with limited therapeutic options.
Funding and Clinical Registration
The FIBRONEER-IPF trial was funded by Boehringer Ingelheim. The trial is registered at ClinicalTrials.gov with the identifier NCT04827537.
References
- Oldham JM, Azuma A, Kreuter M, et al. Nerandomilast in idiopathic pulmonary fibrosis: data from the whole follow-up period of the FIBRONEER-IPF trial. American Journal of Respiratory and Critical Care Medicine. 2026. PMID: 41738262.
- Richeldi L, et al. Fibroneer-IPF: A phase 2 randomized trial of nerandomilast in patients with idiopathic pulmonary fibrosis. New England Journal of Medicine (Primary Endpoint Citation).
- Martinez FJ, et al. The role of PDE4 inhibitors in fibrotic lung disease: Mechanistic insights and clinical potential. European Respiratory Review.