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
Reddy et al. (Fri,) studied this question.