Phase 3 Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis.

Summary

In a 48-week, double-blind phase 3 RCT in autoimmune PAP (n=164), inhaled molgramostim significantly improved DLCO versus placebo at 24 weeks (difference 6.0 percentage points; P<0.001) and 48 weeks, and improved SGRQ total score at 24 weeks. Adverse events and serious adverse events were similar between groups.

Key Findings

• Primary endpoint: LS mean DLCO change at week 24 was 9.8% with molgramostim vs 3.8% with placebo (difference 6.0 pp; 95% CI 2.5–9.4; P<0.001).
• Week 48 DLCO improvement persisted: 11.6% with molgramostim vs 4.7% with placebo (P<0.001).
• SGRQ total score improved at week 24 (−11.5 vs −4.9; P=0.007); safety and serious adverse events were similar between groups.

Clinical Implications

Inhaled molgramostim may become a disease-directed therapy for aPAP, potentially reducing reliance on whole lung lavage and improving gas transfer and quality of life.

Limitations

• Primary outcome is a physiological surrogate (DLCO) rather than hard clinical endpoints such as need for whole lung lavage or survival
• No significant difference in SGRQ activity at 24 weeks; subsequent secondary endpoints not inferentially tested after hierarchal gate

Future Directions

Evaluate long-term clinical outcomes (e.g., frequency of whole lung lavage, oxygen requirement, exacerbations) and biomarkers to guide patient selection and dosing; assess comparative effectiveness versus lavage.