A39-34 Positioning Nerandomilast Within the Evolving Antifibrotic Landscape: A Comprehensive Network Meta- Analysis of Efficacy and Safety in Fibrosing Lung Disease

Abstract Introduction Idiopathic pulmonary fibrosis and progressive fibrosing interstitial lung diseases continue to progress despitestandard antifibrotic therapy. In October 2025, the U.S. FDA approved Nerandomilast, a first-in-class selectivePDE4B inhibitor, expanding the therapeutic landscape. Assessing its comparative efficacy and safety againstexisting antifibrotics is essential to define its role in fibrosing lung disease management. Methods A systematic search was conducted across various databases to identify randomized controlled trials evaluatingantifibrotic therapies in fibrosing lung disease. Network meta-analysis was performed in R, and pairwise meta-analysis in Stata. Risk of bias was assessed using RoB 2.0. Results Six phase 3 randomized controlled trials comprising 5,883 patients (Nerandomilast 2,353; Pirfenidone 1,801;Nintedanib 1,729; Placebo 1,762) were analyzed over 52 weeks. All agents significantly attenuated decline inforced vital capacity (FVC) versus placebo. Pooled mean differences in FVC (mL 95 % CI) were +118(84-152) for Nintedanib, +102 (68-136) for Pirfenidone, and +83 (61-105) for Nerandomilast. The relative risk(RR) for ≥10 % FVC decline or death was 0.69 (0.57-0.83), 0.73 (0.61-0.88), and 0.71 (0.59-0.85),respectively. SUCRA ranking for efficacy: Nintedanib 0.89, Pirfenidone 0.74, Nerandomilast 0.62, Placebo0.05. For safety, pooled RRs for any adverse event were 1.14 (1.08-1.21) for Nintedanib, 1.10 (1.03-1.18) forPirfenidone, and 1.07 (1.01-1.14) for Nerandomilast. Discontinuation due to adverse events occurred with RRsof 1.54 (1.32-1.80), 1.41 (1.18-1.68), and 1.29 (1.10-1.51), respectively. Serious adverse events were similar toplacebo (RR 1.12 0.92-1.36, 1.09 0.88-1.33, 1.03 0.85-1.25). Safety ranking (SUCRA) favoredNerandomilast 0.81, followed by Pirfenidone 0.68 and Nintedanib 0.42. Conclusion Nerandomilast demonstrated comparable antifibrotic efficacy with superior safety and tolerability, positioning italongside Nintedanib and Pirfenidone as a viable therapeutic option in fibrosing lung disease. This abstract is funded by: none