Mechanism, Clinical Evidence, and Therapeutic Role of Nerandomilast in Fibrotic Lung Diseases

Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) are chronic, progressive interstitial lung diseases associated with poor prognosis and few effective treatment options. Nintedanib and pirfenidone remain the cornerstones of antifibrotic therapy, yet both are limited by their tolerability issues and fail to stop the disease progression in many patients. Nerandomilast (Jascayd ® ; BI 1015550) is an oral, preferential PDE4B inhibitor designed to suppress pro-fibrotic inflammation, with an acceptable and generally manageable safety profile. This structured narrative review examines its mechanism of action, clinical evidence, and place in the management of fibrotic lung diseases. Preclinical work demonstrated consistent anti-inflammatory and antifibrotic activity across several experimental models. In a 12-week Phase 2 IPF trial, nerandomilast stabilized forced vital capacity (FVC) regardless of background antifibrotic use. Both Phase 3 trials, FIBRONEER-IPF and FIBRONEER-ILD, met their primary endpoint, with nerandomilast 9 mg and 18 mg twice daily significantly reducing FVC decline at 52 weeks versus placebo. In IPF, the 18 mg and 9 mg doses reduced FVC decline by 68.8 mL ( p < 0.001) and 44.9 mL ( p = 0.02); in PPF, reductions reached 67.2 mL (18 mg) and 81.1 mL (9 mg) (both p < 0.001). The key secondary composite endpoint was not met in IPF and did not reach significance in PPF, and patient-reported outcomes were similar between groups. Diarrhea was the most frequent adverse event, causing discontinuation in up to 6.1% of patients, while no imbalance in depression, suicidality, or potential drug-induced liver injury was observed and no photosensitivity was reported. Overall, nerandomilast represents an additional treatment option for IPF and PPF. Longer-term data, head-to-head trials, and biomarker-guided studies will be essential to fully define its role in clinical practice.