FIBRONEER-ILD Extended Follow-Up: What Nerandomilast Means for PPF Care

Executive Takeaways¹ 

• Nerandomilast led to a reduction in FVC decline that was maintained through Week 76.  

• Patients receiving nerandomilast experienced a 22-23% reduction in exacerbations, hospitalizations, and death.  

• Nerandomilast led to a ~50% relative reduction in mortality.  

• Nerandomilast exhibited comparable discontinuation rates to placebo.  

• Treatment with nerandomilast has potential implications for health care utilization and treatment persistence.  

Progressive pulmonary fibrosis (PPF) is a devastating clinical phenotype that can emerge across multiple fibrosing interstitial lung diseases (ILDs), including connective tissue disease-associated ILD, hypersensitivity pneumonitis, and idiopathic nonspecific interstitial pneumonia.^1,2 Regardless of the underlying diagnosis, PPF is characterized by relentless fibrosis, worsening respiratory symptoms, declining lung function, and a heightened risk of hospitalization and premature death.^1,2 Despite advances in disease recognition and management, many patients continue to experience progressive deterioration that significantly impairs quality of life and survival. 

While the antifibrotic nintedanib has long been considered the standard of care option, tolerability challenges—particularly gastrointestinal adverse events—have limited treatment persistence for many patients.^3,4 According to Dr Toby Maher, director of the Interstitial Lung Disease Program at Keck Medicine of USC, these real-world limitations have created a substantial unmet need for therapies that can both slow disease progression and be well-tolerated over long-term treatment. 

Extended follow-up from the Phase III FIBRONEER-ILD trial demonstrates that nerandomilast, a preferential phosphodiesterase 4B (PDE4B) inhibitor, delivers durable benefits on lung function and clinically meaningful outcomes, reinforcing its potential to reshape the treatment landscape for PPF.⁴  

The primary analysis of FIBRONEER-ILD demonstrated that nerandomilast 9 mg and 18 mg twice daily met the primary endpoint, significantly reducing forced vital capacity (FVC) decline over 52 weeks versus placebo.⁵ The extended follow-up analysis provides additional evidence of durability, showing that the treatment effect on lung function was maintained through week 76.⁴ At the final database lock, adjusted mean (SE) changes in FVC were −224.9 mL (15.5) with placebo, compared with −119.7 mL (15.5) and −140.6 mL (15.5) with nerandomilast 9 mg and 18 mg, respectively.⁴ Importantly, the FVC benefit was observed in patients both with and without background nintedanib, demonstrating that nerandomilast can provide benefit as either monotherapy or add-on therapy.⁵ Dr Maher noted that patients receiving background nintedanib continued to experience substantial lung function decline, underscoring the ongoing burden of disease despite currently available antifibrotic treatment.5 The ability of nerandomilast to further reduce FVC decline while receiving nintedanib suggests that PDE4B inhibition may provide incremental antifibrotic benefit beyond that achieved with existing therapy alone.  

These findings are particularly meaningful because FVC decline remains one of the most validated surrogate markers for disease progression and mortality in fibrosing ILDs.⁵ The sustained effect on FVC through week 76 provides further evidence that nerandomilast may be influencing the underlying disease trajectory rather than simply delaying physiologic decline. Dr Maher emphasized that the durability of the FVC benefit, including among patients already receiving antifibrotic therapy, supports the potential of nerandomilast to play an important role in long-term disease management for patients with PPF. 

One of the most notable aspects of the FIBRONEER-ILD design was its extended blinded follow-up period, which allowed investigators to evaluate clinically meaningful outcomes beyond lung function alone.⁴ By the final database lock, nerandomilast reduced the risk of the composite endpoint of acute exacerbation of ILD, respiratory hospitalization, or death by 22% and 23% with the 9 mg and 18 mg doses, respectively, compared with placebo (hazard ratio 0.78 and 0.77).⁴ Additional benefits were observed across several clinically important endpoints, including a 30% and 41% reduction in the risk of acute exacerbation or death, a 26% and 24% reduction in the risk of respiratory hospitalization or death, and a 31% and 29% reduction in the risk of a >10% decline in FVC or death with the 9 mg and 18 mg doses, respectively.⁴  

Perhaps most compelling was the survival signal observed during extended follow-up. Mortality rates were 16.3% in the placebo group compared with 9.2% and 8.7% among patients receiving nerandomilast 9 mg and 18 mg, respectively, corresponding to a 49% reduction in the risk of death across the two dose groups versus placebo (hazard ratio 0.51 for each dose).⁴ Notably, this difference was driven primarily by reductions in respiratory-related deaths, which accounted for nearly two-thirds of all deaths observed during the trial.⁴  

For clinicians, these findings help connect improvements in FVC with outcomes directly relevant to patients. Acute exacerbations and respiratory hospitalizations are often major inflection points in disease course, frequently leading to irreversible functional decline, worsening quality of life, and increased mortality risk.^1,5,6 As Dr Maher noted, reducing these events may be just as meaningful to patients as slowing lung function decline itself, reinforcing the potential value of nerandomilast as a therapy that addresses both disease progression and its downstream clinical consequences.  

The safety and tolerability profile of nerandomilast may ultimately prove to be one of its most clinically meaningful attributes. Across the extended follow-up period, discontinuation rates due to adverse events were comparable between placebo and nerandomilast treatment groups, and between those receiving background nintedanib versus without background therapy. Among patients receiving background nintedanib, treatment discontinuation due to adverse events occurred in 12.9% of the placebo group, 12.7% of the nerandomilast 9 mg group, and 15.2% of the nerandomilast 18 mg group.⁴ Among patients not receiving background nintedanib, discontinuation rates were similarly low at 12.2%, 11.4%, and 10.0%, respectively.⁴ Serious adverse events, psychiatric events, vasculitis, and potential drug-induced liver injury were balanced across treatment arms, providing reassurance to clinicians and patients regarding the long-term safety of PDE4B inhibition.⁴  

Diarrhea remained the most frequently reported adverse event, particularly among patients receiving background nintedanib, but treatment discontinuations due to diarrhea were uncommon.⁴ According to Dr Maher, the similarity in discontinuation rates between nerandomilast and placebo is particularly noteworthy in a disease area where tolerability challenges have historically limited long-term antifibrotic use.  

Improved tolerability has the potential to translate into improved disease control, fewer hospitalizations, and greater real-world effectiveness. When considered alongside the efficacy findings from FIBRONEER-ILD, the favorable safety profile of nerandomilast strengthens its potential role as a long-term treatment option for PPF. 

For patients with progressive pulmonary fibrosis, disease progression is often marked by acute exacerbations, respiratory hospitalizations, and accelerating functional decline—events that can have profound consequences for both patients and health care systems.⁶ Acute exacerbations frequently result in hospitalization, prolonged recovery, irreversible loss of lung function, and increased mortality risk.¹ Real-world analyses have shown that these events are among the most significant drivers of health care utilization and costs in fibrosing interstitial lung diseases.⁷  

Against this backdrop, the extended follow-up findings from FIBRONEER-ILD provide a broader perspective on the potential impact of nerandomilast beyond lung function preservation alone. In addition to sustained reductions in FVC decline, nerandomilast was associated with lower risks of acute exacerbations, respiratory hospitalizations, and mortality during long-term follow-up.⁴ Collectively, these outcomes reflect disease events that are clinically meaningful to patients and highly relevant to health care systems. 

Treatment persistence may also be an important consideration. Historically, tolerability challenges have limited long-term use of antifibrotic therapies for some patients with PPF.⁸ In FIBRONEER-ILD, discontinuation rates due to adverse events remained low and were generally comparable between nerandomilast and placebo, regardless of background nintedanib use.⁴ As Dr Maher noted, a therapy that patients can remain on over time may ultimately be better positioned to deliver sustained clinical benefit. 

Although formal health economic analyses are still needed, the combination of durable efficacy, reduced disease-related events, and favorable long-term tolerability suggests that nerandomilast could have implications beyond clinical outcomes alone. For payers and health care decision-makers evaluating emerging therapies in PPF, these findings may be particularly relevant as they consider the potential impact of treatment on disease burden, health care utilization, and long-term patient management. 

One of the most important themes noted by Dr Maher is that nerandomilast may change how clinicians approach treatment conversations in PPF. Historically, some clinicians have delayed antifibrotic therapy because of concerns about tolerability, gastrointestinal adverse events, monitoring requirements, and the practical burden of long-term treatment. By demonstrating durable efficacy with low discontinuation rates, nerandomilast may help lower one of the barriers to earlier intervention once progression is identified. 

While important questions remain regarding optimal sequencing, combination therapy, and long-term real-world outcomes, the extended follow-up results from FIBRONEER-ILD provide compelling evidence that PDE4B inhibition represents a meaningful new therapeutic approach in PPF. 

For a disease historically defined by limited treatment options and poor outcomes, nerandomilast may represent more than just another antifibrotic. It introduces a novel mechanism of action, demonstrates sustained efficacy, and offers the possibility of improved treatment persistence—all factors that could influence the future management of progressive pulmonary fibrosis.⁴  

1. Strykowski R, Adegunsoye A. Idiopathic pulmonary fibrosis and progressive pulmonary fibrosis. Immunol Allergy Clin North Am. 2023;43(2): doi:10.1016/j.iac.2023.01.010.  

2. Liu GY, Budinger GRS, Dematte JE. Advances in the management of idiopathic pulmonary fibrosis and progressive pulmonary fibrosis. BMJ. 2022;377:e066354. doi:10.1136/bmj-2021-066354.  

3. Naqvi M, Hannah J, Lawrence A, Myall K, West A, Chaudhuri N. Antifibrotic therapy in progressive pulmonary fibrosis: a review of recent advances. Expert Rev Respir Med. 2024;18(6):397-407. doi:10.1080/17476348.2024.2375420  

4. Wijsenbeek MS, Assassi S, Azuma A, et al. Nerandomilast in progressive pulmonary fibrosis: data from the whole follow-up period of the FIBRONEER-ILD trial. Eur Respir J. 2026; in press. doi: https://doi.org/10.1183/13993003.01899-2025 

5. Maher TM, Assassi S, Azuma A, et al. Nerandomilast in patients with progressive pulmonary fibrosis. N Engl J Med. 2025;392(22):2203-2214. doi:10.1056/NEJMoa2503643  

6. Yang J, Sadowski K, Mercer D, Zeldow B, Gomez Manjarres D. Health care utilization and costs associated with acute exacerbation of fibrosing interstitial lung disease in the United States: a retrospective administrative claims database analysis. J Manag Care Spec Pharm. 2026;32(3):374-389: doi: 10.18553/jmcp.2026.32.3.374  

7. Dempsey TM, Thao V, Moriarty JP, Borah BJ, Limper AH. Cost-effectiveness of the anti-fibrotics for the treatment of idiopathic pulmonary fibrosis in the United States. BMC Pulm Med. 2022;22:18. doi:10.1186/s12890-021-01811-0. 

8. Onyilmaz T, Baris SA, Ozturk B, et al. Evaluation of factors affecting mortality in patients with idiopathic pulmonary fibrosis: a 10-year single-center experience. Diagnostics (Basel). 2026;16(1):74. doi:10.3390/diagnostics16010074.