Savara Inc. has announced that its inhaled molgramostim therapy achieved statistically significant improvements in lung function for patients with autoimmune pulmonary alveolar proteinosis (PAP) in the pivotal Phase 3 IMPALA-2 trial. The results, set to be published in the New England Journal of Medicine on August 21, 2025, represent the largest and longest clinical trial ever conducted in this rare respiratory disease.
Primary Endpoint Success Demonstrates Clinical Efficacy
The trial met its primary endpoint with molgramostim significantly improving pulmonary gas transfer as measured by hemoglobin-adjusted percent predicted diffusing capacity of the lungs for carbon monoxide (DLco%) at Week 24. Patients receiving molgramostim showed a 9.8% improvement compared to 3.8% with placebo, resulting in an estimated treatment difference of 6.0% (P<0.001).
The therapeutic benefit was sustained through 48 weeks, with molgramostim-treated patients demonstrating an 11.6% improvement in DLco% versus 4.7% for placebo (estimated treatment difference, 6.9%; P<0.001). According to the study data, these improvements approach the minimal clinically meaningful difference of 10% reported for pulmonary fibrosis.
"IMPALA-2, the largest and longest Phase 3 clinical trial conducted in patients with autoimmune PAP, demonstrated that 48 weeks of once daily administration of inhaled molgramostim addresses the underlying pathophysiology of this chronic rare lung disease," said Bruce Trapnell, M.D., Professor of Medicine and Pediatrics at the University of Cincinnati College of Medicine and Lead Clinical Investigator of the IMPALA-2 trial.
Quality of Life and Functional Improvements
Beyond lung function, molgramostim demonstrated meaningful improvements in patient-reported outcomes. The St. George's Respiratory Questionnaire (SGRQ) Total score showed significantly greater improvement with molgramostim compared to placebo at Week 24 (-11.5 points vs. -4.9 points, estimated difference, -6.6 points; P=0.007). The SGRQ Activity score also favored molgramostim at Week 24 (-13.0 points vs. -5.2 points, estimated difference, -7.8 points).
Exercise capacity, measured as peak metabolic equivalents (METs), improved more substantially with molgramostim treatment. At Week 48, the change from baseline in peak-METs was 1.1 for molgramostim versus 0.6 for placebo (estimated treatment difference, 0.6). This 0.6 peak-MET difference exceeds the 0.5-MET increase considered clinically meaningful for cardiovascular rehabilitation.
Reduction in Disease Burden and Rescue Interventions
Molgramostim reduced surfactant burden as measured by ground glass opacity (GGO) scores on chest CT scans. The mean reduction from baseline in GGO score was greater in the molgramostim group than placebo (-2.1 vs -1.1) at Week 24. Importantly, fewer patients required whole lung lavage as rescue therapy during the study period with molgramostim compared to placebo (6 patients [7%] vs. 11 patients [13%]).
Safety Profile and Trial Completion
The treatment demonstrated a favorable safety profile, with most adverse events being mild or moderate. High completion rates were observed, with 98% of molgramostim patients and 96% of placebo patients completing the 48-week double-blind treatment period.
Global Trial Design and Patient Population
IMPALA-2 was conducted at 43 clinical trial sites across 16 countries, including the United States, Canada, Japan, South Korea, Australia, and European nations. The randomized, double-blind, placebo-controlled trial evaluated molgramostim 300 mcg administered once daily via inhalation using an investigational eFlow® Nebulizer System developed specifically for large molecule inhalation.
The study design included a primary efficacy assessment at Week 24, with durability evaluated through Week 48. All patients completing the double-blind period continued into a 96-week open-label extension phase.
Addressing Unmet Medical Need
Autoimmune PAP is characterized by abnormal surfactant accumulation in lung alveoli due to neutralizing antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). This impairs alveolar macrophage function, leading to surfactant buildup that causes impaired gas transfer and symptoms including shortness of breath, cough, and fatigue. Long-term complications can include lung fibrosis and the potential need for lung transplantation.
Molgramostim, a recombinant human GM-CSF, directly addresses this underlying pathophysiology by providing functional GM-CSF to restore macrophage activity and surfactant clearance.
