Effect of nerandomilast on survival in patients with pulmonary fibrosis

Background In the placebo-controlled FIBRONEER-IPF and FIBRONEER-ILD trials in patients with idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF), the key secondary endpoint was not met but numerical benefits of nerandomilast on time to death (a secondary endpoint) were observed. We further investigated the robustness of the effect of nerandomilast on survival. Methods In both trials, the primary analysis of time to death was based on all deaths except those after lung transplant, using a Cox proportional hazards model. We performed sensitivity analyses of the impact of covariates, tipping point analyses, and supplementary analyses of deaths during and shortly after treatment and the impact of intercurrent events. We assessed time to death by exposure to nerandomilast (trough concentration at steady state). Results Based on pooled data from both trials, over the whole follow-up period (mean:16.7 months), the risk of death versus placebo was reduced by 33% (hazard ratio: 0.67 [95% CI: 0.49, 0.90]; p=0.009) with nerandomilast 9 mg bid and by 43% (hazard ratio: 0.57 [95% CI: 0.41, 0.78]; p<0.001) with nerandomilast 18 mg bid. Sensitivity analyses and supplementary analyses were consistent with the primary analysis of time to death. Tipping point analyses demonstrated a very low likelihood that the benefit of nerandomilast on mortality was due to missing data. Exposure–response analyses indicated that a higher plasma exposure to nerandomilast was associated with a lower risk of death. Conclusion These analyses support the use of nerandomilast 18 mg bid to improve survival in patients with IPF and PPF.