In patients with autoimmune pulmonary alveolar proteinosis (aPAP), once-daily inhaled molgramostim significantly improved pulmonary gas transfer compared with placebo in a phase 3 randomized, placebo-controlled trial.1
“To those who are familiar with aPAP and the use of inhaled granulocyte-macrophage colony-stimulating factor (GM-CSF) to treat it, this is validation that once-daily administration of inhaled molgramostim may address the underlying pathophysiology of this chronic and rare lung disease,” said author Brian Robinson, MD, Executive Vice-President and Head of Global Medical Affairs at Savara Inc.
For the Clinical Trial of Inhaled Molgramostim Nebulizer Solution in Autoimmune Pulmonary Alveolar Proteinosis (aPAP) (IMPALA-2) study, researchers at 43 sites in 16 countries randomly assigned 164 patients with aPAP to receive molgramostim at a dose of 300 μg or placebo once daily for 48 weeks. The primary end point was the change in hemoglobin-adjusted diffusing capacity of the lung for carbon monoxide (Dlco), expressed as a percentage of the predicted value, from baseline to week 24.
Secondary end points, adjusted for multiplicity, included the change from baseline in Dlco at 48 weeks; changes in St. George’s Respiratory questionnaire total (SGRQ-T) and activity scores (range 0-100, with lower scores indicating better quality of life); and changes in exercise capacity measured using peak metabolic equivalents (METs), a measurement that reflects the body’s oxygen consumption, all at 24 and 48 weeks.
Participants in the molgramostim group were marginally older than those in the placebo group (a mean of 50.8 vs 48.4 years, respectively) and included a higher proportion of women (46% vs 35%). At week 24, the least-squares mean change from baseline in Dlco was 9.8 percentage points (95% CI, 7.3-12.3) with molgramostim and 3.8 percentage points (95% CI, 1.4-6.3) with placebo. This yielded an estimated treatment difference of 6.0 percentage points (95% CI, 2.5-9.4; P < .001).
At week 48, patients receiving molgramostim had a least-squares mean increase in Dlco of 11.6 percentage points (95% CI, 8.7-14.5) compared with 4.7 points (95% CI, 1.8-7.6) in the placebo group (P < .001). At week 24, the least-squares mean improvement in the SGRQ-T score was -11.5 points (95% CI, -15.0 to -8.0) with molgramostim and -4.9 points (95% CI, -8.3 to -1.5) with placebo (P = .007).
In other findings, exercise capacity increased by 1.1 MET (95% CI, 0.8-1.5) at week 24 in the molgramostim group and by 0.7 MET (95% CI, 0.3-1.1) in the placebo group, with an estimated treatment difference of 0.4 MET (95% CI, -0.1 to 0.9). At week 48, the increases were 1.1 MET (95% CI, 0.8-1.5) and 0.6 MET (95% CI, 0.2-0.9), respectively, yielding a difference of 0.6 MET (95% CI, 0.1-1.0).
Overall adverse event (AE) rates and serious AEs were similar between groups in the blinded period. Additionally, while Dlco is a biological end point for aPAP, relevant hard outcomes—like time to whole lung lavage and hospitalization rates—were not published.
“While there have been previous smaller trials that have looked at the use of inhaled GM-CSF for aPAP, this is the first trial that addresses safety and efficacy at 48 weeks, whereas previous trials looked only as far as 24 weeks,” Dr. Robinson said. “In addition, this was the first trial in aPAP to show improvements in patient functionality (exercise capacity) in addition to gas transfer, respiratory health-related quality of life, and surfactant burden, all with no notable safety concerns.”
He acknowledged certain limitations of the study, including the fact that 48 weeks may not capture the maximal treatment effect of molgramostim for patients with aPAP. “There are no medicines approved in either the United States or Europe to treat aPAP,” Dr. Robinson added. “If molgramostim were to become available in these regions, it would be interesting to understand how this may affect the natural history of the disease. In addition, there is an ongoing 96-week, open-label period of the IMPALA-2 trial that is designed to shed light on long-term safety and efficacy of molgramostim in aPAP.” Including both the double-blind and open-label periods, IMPALA-2 will have a total duration of 144 weeks.
References
1. Trapnell BC, Inoue Y, Bonella F, et al. Phase 3 trial of inhaled molgramostim in autoimmune pulmonary alveolar proteinosis. N Engl J Med. 2025;393(8):764-773. doi:10.1056/NEJMoa2410542
