-- In the Largest Clinical Trial Conducted in Autoimmune PAP, Molgramostim Inhalation Solution (Molgramostim) Reduced Surfactant Burden and Improved Pulmonary Gas Transfer, Respiratory Health-Related Quality of Life, and Patient Functionality --
Savara Inc. (Nasdaq: SVRA) (the Company), a clinical stage biopharmaceutical company focused on rare respiratory diseases, announced that the results from the Phase 3 IMPALA-2 clinical trial will be published online in NEJM. The manuscript, titled “A Phase 3 Trial of Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis” will appear in the August 21, 2025, online version of the publication and can be found at www.nejm.org. Following the online publication in NEJM, the manuscript will be available on the Congresses & Publications page of the Company’s corporate website.
“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, University of Cincinnati College of Medicine and Lead Clinical Investigator of the IMPALA-2 trial. “Treatment with molgramostim improved the cardinal manifestations of autoimmune PAP, namely it reduced pulmonary surfactant burden and improved pulmonary gas transfer, respiratory health-related quality of life, and patient functionality. Additionally, molgramostim was well tolerated with no notable safety concerns.”
IMPALA-2 achieved statistical significance on its primary endpoint, change from baseline in the hemoglobin-adjusted percent predicted diffusing capacity of the lungs for carbon monoxide (DLco%) at Week 24. Molgramostim significantly improved pulmonary gas transfer as measured by DLco% at Week 24 compared with placebo (9.8% vs. 3.8%; estimated treatment difference, 6.0%; P<0.001 by comparison of least-squares means [LSMs]). The beneficial effect of molgramostim on pulmonary gas transfer was maintained to Week 48 as shown by the difference in LSM change from baseline in DLco% at Week 48 between molgramostim and placebo groups (11.6% vs. 4.7%; estimated treatment difference, 6.9%; P<0.001). The mean improvements in DLco% from baseline for molgramostim (9.8% at Week 24 and 11.6% at Week 48) are similar to the minimal clinically meaningful difference (MCID) in DLco% of 10% reported for pulmonary fibrosis.1
Molgramostim improved respiratory health-related quality of life as measured by the St. George’s Respiratory Questionnaire (SGRQ) Total and Activity scores. The magnitude of LSM reduction from baseline in SGRQ Total score was significantly greater in the molgramostim group than placebo at Week 24 (-11.5 points vs. -4.9 points, estimated difference, -6.6 points; P=0.007) and remained numerically greater at Week 48 (-10.7 points vs. -5.9 points, estimated difference, -4.9 points [95% confidence interval, -10.8, 1.0]). The LSM change from baseline in SGRQ Activity score was greater for molgramostim compared with placebo at Week 24 (-13.0 points vs. -5.2 points, estimated difference, -7.8 points [95% confidence interval, -14.1, -1.5]) and at Week 48 (-13.4 vs. -7.4 points, estimated difference, -6.0 points [95% confidence interval, -13.6, 1.6]).
Molgramostim improved patient function as measured by exercise capacity (expressed as peak metabolic equivalents [METs]). A MET is a unit of resting oxygen uptake which measures energy expenditure. The LSM change from baseline in peak-METs was greater at Week 48 for molgramostim than placebo (1.1 vs. 0.6; estimated treatment difference, 0.6; [95% confidence interval, 0.1, 1.0]). Peak-METs is a clinically useful unit of measure reflecting exercise capacity, prognosis, and mortality in cardiovascular disease for which a 0.5-MET increase comprises a clinically useful measure of rehabilitation.2 Using the treadmill test in IMPALA-2, the LSM change in peak-METs from baseline to Week 48 was 1.1 in molgramostim-treated patients and the between-group difference observed at Week 48 was 0.6 peak-METs.
Molgramostim reduced surfactant burden as measured by ground glass opacity (GGO) score, an exploratory endpoint in IMPALA-2; GGO scores were determined by two blinded radiologists from a chest CT scan, with scores ranging from 0 to 15 (higher scores are worse). The mean reduction from baseline in GGO score was greater in the molgramostim group than the placebo group at Week 24 (-2.1 vs -1.1). Further, the number of patients who received ≥1 whole lung lavage as rescue therapy during the double-blind intervention period was lower with molgramostim than placebo (6 [7%] vs. 11 [13%]).
In IMPALA-2, molgramostim was well tolerated. Most treatment-emergent adverse events (AEs) were mild or moderate, and few led to discontinuation, with 98% of patients in the molgramostim group and 96% of patients in the placebo group completing the 48-week double-blind period on treatment.
About IMPALA-2
IMPALA-2 was a global, pivotal, Phase 3, 48-week, randomized, double-blind, placebo-controlled clinical trial designed to compare the efficacy and safety of molgramostim 300 mcg self-administered once daily by inhalation with matching placebo in patients with autoimmune PAP. The trial was conducted at 43 clinical trial sites across 16 countries, including the U.S., Canada, Japan, South Korea, Australia, and countries in Europe, including Turkey. The primary efficacy assessment was hemoglobin-adjusted percent predicted diffusing capacity of the lungs for carbon monoxide (DLco%), a gas transfer measure, and the primary endpoint was change from baseline to Week 24 in percent predicted DLco%, with a secondary endpoint of change from baseline to Week 48 in percent predicted DLco%. Three additional secondary efficacy variables evaluated clinical measures of patient benefit: St. George’s Respiratory Questionnaire (SGRQ) Total score, SGRQ Activity score, and exercise capacity using a treadmill test, with each endpoint measured at Weeks 24 and 48. The primary time point for efficacy assessments was at Week 24; however, efficacy was assessed through Week 48 to evaluate durability of effect. Safety was assessed through Week 48. All patients who completed the 48-week double-blind treatment period continued into a 96-week open-label period during which molgramostim 300 mcg is administered once daily.
About Autoimmune Pulmonary Alveolar Proteinosis (Autoimmune PAP)
Autoimmune PAP is a rare lung disease characterized by the abnormal build-up of surfactant in the alveoli of the lungs. Surfactant consists of proteins and lipids and is an important physiological substance that lines the alveoli to prevent them from collapsing. In a healthy lung, excess surfactant is cleared and digested by immune cells called alveolar macrophages. Alveolar macrophages need to be stimulated by granulocyte-macrophage colony-stimulating factor (GM-CSF) to function properly in clearing surfactant, but in autoimmune PAP, GM-CSF is neutralized by antibodies against GM-CSF, rendering macrophages unable to adequately clear surfactant. As a result, an excess of surfactant accumulates in the alveoli, causing impaired gas transfer, resulting in clinical symptoms of shortness of breath, often with cough and frequent fatigue. Patients may also experience episodes of fever, chest pain, or coughing up blood, especially if secondary infection develops. In the long term, the disease can lead to serious complications, including lung fibrosis and the need for a lung transplant.
Savara is a clinical stage biopharmaceutical company focused on rare respiratory diseases. Our lead program, molgramostim inhalation solution (molgramostim), is a recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) in Phase 3 development for autoimmune pulmonary alveolar proteinosis (autoimmune PAP). Molgramostim is delivered via an investigational eFlow® Nebulizer System (PARI Pharma GmbH) specifically developed for inhalation of a large molecule. Our management team has significant experience in rare respiratory diseases and pulmonary medicine, identifying unmet needs, and effectively advancing product candidates to approval and commercialization. More information can be found at www.savarapharma.com and LinkedIn.
1 Raghu G, et al. Am J Respir Crit Care Med 2022;205:e18-e47.
2 Ross R, et al. Circulation 2016;134:e653-e99; Grace SL, et al. Can J Cardiol 2014;30:945-8; Kehler DS, et al. J Cardiopulm Rehabil Prev 2017;37:250-6.
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ir@savarapharma.com