Precision Modulation of the PDE4 Pathway: The Emerging Role of Nerandomilast in Pulmonary Fibrosis

Objective: To review the emerging evidence supporting the use of nerandomilast (Jascayd), a selective phosphodiesterase-4B (PDE4B) inhibitor, for the treatment of idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). The review aims to summarize its mechanism of action, efficacy, safety, and potential role as monotherapy or in combination with existing antifibrotic therapies. Data Sources: A literature search was conducted using PubMed, Embase, ClinicalTrials.gov, and relevant conference proceedings from January 2018 through December 2025. Search terms included nerandomilast, BI 1015550, Jascayd, phosphodiesterase-4B inhibitor, idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, interstitial lung disease, FIBRONEER-IPF, and FIBRONEER-ILD. Human studies published in English were included. Study Selection and Data Extraction: Original clinical studies, phase II and phase III trials, subgroup analyses, and regulatory publications evaluating nerandomilast in patients with IPF or PPF were reviewed. Studies were selected based on relevance to efficacy, safety, mechanism of action, and clinical outcomes. Data regarding study design, patient population, forced vital capacity (FVC) outcomes, adverse events, and concomitant antifibrotic use were extracted and qualitatively synthesized. Data Synthesis: Nerandomilast was approved in October 2025 for the treatment of IPF and PPF, representing the first PDE4B inhibitor approved for fibrotic lung disease. By inhibiting PDE4B, nerandomilast increases intracellular cyclic adenosine monophosphate (cAMP) levels, resulting in reduced inflammatory cytokine production and decreased fibroblast activation. Clinical trials, including the phase III FIBRONEER-IPF study, demonstrated a significant reduction in the rate of FVC decline compared with placebo, indicating attenuation of disease progression. Benefits were observed both in patients receiving nerandomilast alone and in those receiving background antifibrotic therapy with pirfenidone or nintedanib. Overall, nerandomilast demonstrated a favorable benefit-risk profile and offers a mechanistically distinct approach compared with currently available antifibrotic agents. Conclusions: Nerandomilast provides a novel anti-inflammatory and antifibrotic treatment option for patients with IPF and PPF. Available evidence suggests meaningful reductions in lung function decline with acceptable tolerability, including use alongside established antifibrotic therapies. As longer-term and real-world data emerge, nerandomilast may become an important component of the therapeutic strategy for progressive fibrotic lung diseases.