Introduction
Idiopathic pulmonary fibrosis, or IPF, and progressive pulmonary fibrosis, or PPF, are both associated with a high risk of death. PPF can occur in many interstitial lung diseases, or ILDs, and autoimmune ILD is an important part of this group. During the 2026 Chinese Thoracic Society Congress, or CTS 2026, several datasets on nerandomilast were presented. They focused on survival benefit with nerandomilast in patients with IPF and PPF, while also examining safety and tolerability in PPF related to autoimmune ILD, with special attention to the safety risk when nerandomilast is combined with immunomodulatory therapy. This article reviews those data and their meaning.
Multiple analyses of pooled FIBRONEER trial data show that nerandomilast 18 mg twice daily reduces the risk of death in patients with IPF and PPF
A pooled analysis of the FIBRONEER program presented at the congress used complete follow up data from FIBRONEER IPF and FIBRONEER ILD to further evaluate the effect of nerandomilast on mortality in patients with IPF and PPF. The analysis included 2353 patients. Mean exposure to study drug was 15.0 months, and mean observation duration was 16.7 months.
The primary analysis showed that, compared with placebo, nerandomilast 18 mg twice daily reduced the risk of death by 43 percent, with HR 0.57, 95% CI 0.41 to 0.78, and P less than 0.001. Nerandomilast 9 mg twice daily reduced the risk of death by 3 percent, with HR 0.67, 95% CI 0.49 to 0.90, and P equal to 0.009.
Beyond the primary analysis, the study used multiple sensitivity analyses to assess robustness. When treatment regimen was the only covariate, death risk in the nerandomilast 18 mg twice daily group was reduced by 44%. When sex and height were added on top of treatment regimen as the main covariates, death risk was reduced by 42%. Both results were consistent with the primary analysis.
Supplementary analyses also showed broadly consistent results. During nerandomilast 18 mg twice daily treatment and within 7, 30, 60, and 90 days after stopping treatment, death risk was reduced by 61%, 52% 53%, and 50%. After excluding deaths occurring after starting nintedanib or pirfenidone, death risk was reduced by 41%. When lung transplantation or death was used as the endpoint, the 18 mg twice daily group had a 39% lower risk. In the respiratory related death analysis, death risk was reduced by 49%.
Tipping point analysis further assessed the impact of missing survival status data. The results suggested that the probability of missing vital status data materially changing the primary result was very low.
In addition, although the 9 mg twice daily and 18 mg twice daily doses had similar effects on FVC decline, exposure response analysis showed that higher nerandomilast exposure was associated with lower death risk. The median steady state trough concentration, or Cmin ss, for nerandomilast 18 mg twice daily was 173 nM. At this exposure level, the death risk was reduced by 39% compared with placebo, with HR 0.61 and 95% CI 0.44 to 0.77. For nerandomilast 9 mg twice daily, the median Cmin ss was 86.1 nM, and death risk was reduced by 24% compared with placebo, with HR 0.76 and 95% CI 0.61 to 0.87. These findings suggest that the improvement in death risk with nerandomilast may not be fully mediated by its effect on lung function.
Taken together, the analyses show that nerandomilast can reduce the risk of death in patients with IPF and PPF, with good robustness. The exposure response analysis further indicates that higher exposure is associated with lower death risk, supporting use of nerandomilast 18 mg twice daily to improve survival in patients with IPF and PPF.
Parametric survival models predict potential long term survival benefit with nerandomilast 18 mg twice daily in patients with PPF
Another study presented at the congress used FIBRONEER ILD data and a parametric model to evaluate the long term effect of nerandomilast 18 mg twice daily on survival in patients with PPF. This result was similar to the ATS 2026 analysis based on FIBRONEER IPF, which used a parametric model to estimate long term survival benefit with nerandomilast 18 mg twice daily in patients with IPF.
Using survival data from the final database lock, the study fitted seven parametric models. Combining model fit statistics and clinical plausibility, the Weibull model was selected. It simulated 30 year survival trends for patients who did not receive background nintedanib and for those who did, and estimated median survival. The analysis assumed that the effect of nerandomilast 18 mg twice daily on survival and the rate of treatment discontinuation remained consistent with the trial period.
In patients without background nintedanib, median survival was estimated at 3.9 years in the control group, with Q1 and Q3 of 2.9 and 4.9 years, and 7.2 years in the nerandomilast 18 mg twice daily group, with Q1 and Q3 of 4.6 and 11.2 years. The model estimated a 3.3 year extension in median survival, an increase to 1.8 times the control value.
In patients receiving background nintedanib, median survival was estimated at 3.4 years in the nintedanib group, with Q1 and Q3 of 2.3 and 4.3 years, and 4.4 years in the nerandomilast 18 mg twice daily plus nintedanib group, with Q1 and Q3 of 2.8 and 6.2 years. The model estimated a 1.0 year extension in median survival, an increase to 1.3 times the nintedanib value.
These model analyses further support survival benefit with nerandomilast 18 mg twice daily in patients with PPF and add long term evidence for its survival value. As FIBRONEER ON and real world data accumulate, further evidence is expected to confirm its long term survival effect.
In PPF related to autoimmune disease, the safety and tolerability of nerandomilast are consistent with the overall population whether or not immunomodulatory drugs are used together
The congress also presented a FIBRONEER ILD subgroup analysis examining safety and tolerability of nerandomilast in patients with autoimmune ILD plus PPF.
In FIBRONEER ILD, autoimmune ILD accounted for 27.6% of patients, or 325 patients. The placebo group, nerandomilast 9 mg twice daily group, and nerandomilast 18 mg twice daily group included 100, 112, and 113 patients. Mean exposure to study drug was 15.8 months. This analysis assessed adverse events in the overall population and in the autoimmune ILD subgroup up to the final database lock. It further stratified patients with autoimmune ILD by baseline use of immunomodulatory drugs and nintedanib.
In the overall FIBRONEER ILD population, by baseline nintedanib use, adverse events leading to treatment discontinuation in patients not using nintedanib occurred in 12.2%, 11.4%, and 10.0% of the placebo, nerandomilast 9 mg twice daily, and nerandomilast 18 mg twice daily groups. In patients using nintedanib, the corresponding rates were 12.9%, 12.7%, and 15.2%.
In patients with autoimmune ILD, safety and tolerability were consistent with the overall trial population. By baseline immunomodulatory drug use, among patients not using immunomodulatory drugs, diarrhea occurred in 20.9%, 24.5%, and 25.9% of the placebo, nerandomilast 9 mg twice daily, and nerandomilast 18 mg twice daily groups, while adverse events leading to treatment discontinuation occurred in 14.0%, 6.1%, and 11.1%. Among patients using immunomodulatory drugs, diarrhea occurred in 26.3%, 31.7%, and 35.6 percent, while adverse events leading to treatment discontinuation occurred in 12.3%, 9.5%, and 10.2%.
By baseline nintedanib use, among patients not using nintedanib, diarrhea occurred in 19.2% and 22.9% in the groups shown, and adverse events leading to treatment discontinuation occurred in 12.7%, 6.8%, and 8.6%. Among patients using nintedanib, diarrhea occurred in 34.5%, 46.2%, and 44.2%, while adverse events leading to treatment discontinuation occurred in 13.8%, 10.3%, and 14.0%.
These safety analyses show that in FIBRONEER ILD, patients with PPF related to autoimmune disease treated with nerandomilast had favorable safety and tolerability whether or not they used immunomodulatory drugs or nintedanib. The results were consistent with the overall trial population and support use of nerandomilast for PPF, including PPF related to autoimmune disease.
Summary
The data presented at CTS 2026 enrich the evidence base for nerandomilast from the perspectives of death risk benefit and safety in patients with PPF related to autoimmune disease. Overall, the results support the clinical benefit of nerandomilast in improving survival outcomes in patients with pulmonary fibrosis and its important value across different clinical use scenarios. In the future, as FIBRONEER ON and real world research data continue to accumulate, long term survival evidence for nerandomilast is expected to become richer, and its application value in more pulmonary fibrosis clinical practice settings may be further clarified.
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