INHALED therapy improved gas transfer and respiratory health in adults with autoimmune pulmonary alveolar proteinosis.
Autoimmune pulmonary alveolar proteinosis is a rare lung disease in which surfactant accumulates in the alveoli and causes progressive hypoxemia driven by autoantibodies against granulocyte macrophage colony stimulating factor. In this Phase III double blind and placebo-controlled trial, investigators assessed whether once daily inhaled recombinant human GM CSF, molgramostim, could improve pulmonary gas transfer and patient reported outcomes compared with placebo.
Inhaled Therapy for Autoimmune PAP in Phase III Trial
A total of 164 adults with autoimmune pulmonary alveolar proteinosis were randomly assigned to receive inhaled molgramostim 300 micrograms or matching placebo once daily for 48 weeks. The primary end point was change from baseline to Week 24 in hemoglobin adjusted diffusing capacity of the lungs for carbon monoxide. Secondary end points included diffusing capacity at Week 48 and change in St George Respiratory Questionnaire total and activity scores and exercise capacity, with lower questionnaire scores indicating better health related quality of life.
Improved Gas Transfer and Respiratory Health Status
Inhaled GM CSF therapy produced greater improvements in diffusing capacity than placebo. From baseline to Week 24, the least squares mean change in diffusing capacity was 9.8 percentage points with molgramostim and 3.8 percentage points with placebo, yielding an estimated treatment difference of 6.0 percentage points with a 95% confidence interval of 2.5 to 9.4 and P<0.001. At week 48, the corresponding changes were 11.6 and 4.7 percentage points, respectively, with P<0.001. The least squares mean change in St George Respiratory Questionnaire total score at week 24 was minus 11.5 points with molgramostim and minus 4.9 points with placebo, with P=0.007. No significant between group difference was seen for the activity score at 24 weeks, so no formal statistical inference was made for subsequent secondary end points.
Safety Profile and Clinical Implications for aPAP Care
The proportions of patients with at least one adverse event and at least one serious adverse event were similar in the molgramostim and placebo groups. These findings indicate that once daily inhaled GM CSF therapy can enhance pulmonary gas transfer in adults with autoimmune pulmonary alveolar proteinosis while providing meaningful improvements in respiratory health status. For pulmonologists and other clinicians who manage this rare autoimmune lung disease, the trial offers evidence supporting inhaled therapy that targets the granulocyte macrophage colony stimulating factor dependent pathway underlying impaired surfactant clearance.
Reference: Trapnell B et al. Phase 3 Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis. N Engl J Med. 2025;393(8):764-773.
