Abstract Rationale Nerandomilast, an oral phosphodiesterase-4 (PDE4) inhibitor, has shown promise in slowing the progression of pulmonary fibrosis by modulating pro-inflammatory and profibrotic signaling. We conducted a meta-analysis to evaluate the efficacy and safety of nerandomilast in preserving lung function among patients with pulmonary fibrosis. Methods We systematically searched MEDLINE (via PubMed), Embase, the Cochrane Library, and ClinicalTrials.gov for randomized controlled trials (RCTs) comparing nerandomilast with placebo in adults with pulmonary fibrosis. Two reviewers independently screened records, extracted data, and assessed study quality using the revised Cochrane Risk of Bias tool (RoB 2.0). Analyses were performed in RevMan 5.4 with random-effects models. Continuous outcomes were summarized as mean difference (MD), and dichotomous outcomes as risk ratio (RR), each with 95% confidence intervals (CI). Prespecified outcomes included change in forced vital capacity (FVC), change in diffusing capacity for carbon monoxide (DLco % predicted), all-cause mortality, any adverse events (AEs), and serious AEs. Results Four RCTs encompassing 1,730 participants were included. Compared with placebo, nerandomilast was associated with a smaller decline in FVC from baseline to follow-up (MD, 72.76 mL; 95% CI, 50.10-95.41), indicating attenuation of disease-related lung function loss. By contrast, there was no significant difference in change in DLco % predicted (MD, 1.01%; 95% CI, −0.51 to 2.53). Nerandomilast reduced all-cause mortality (RR, 0.60; 95% CI, 0.40-0.92). Safety outcomes were neutral: there was no increase in any AEs (RR, 1.01; 95% CI, 0.98-1.03) or serious AEs (RR, 0.94; 95% CI, 0.73-1.13) relative to placebo. Overall study quality by RoB 2.0 was acceptable; most trials reported adequate randomization and outcome assessment, with typical limitations related to attrition and missing data reporting. Conclusion Across four RCTs, nerandomilast slowed FVC decline and lowered all-cause mortality without increasing overall or serious adverse events in patients with pulmonary fibrosis. These findings support nerandomilast as a promising therapeutic option—either as an adjunct to established antifibrotics or as a standalone alternative when standard agents are not tolerated. To refine clinical use, future RCTs should adopt standardized, patient-centered endpoints (e.g., absolute FVC change, ≥10% FVC decline, respiratory-related hospitalizations, and quality-of-life measures), evaluate durability of benefit beyond one year, and explore subgroup effects by baseline severity and radiographic phenotype. Trials testing nerandomilast in combination with nintedanib or pirfenidone, with rigorous safety monitoring and harmonized outcome definitions, are particularly warranted to clarify potential additive or synergistic effects. This abstract is funded by: None
Afzaal et al. (2026) studied this question.