Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis
Bruce C Trapnell1, Yoshikazu Inoue1, Francesco Bonella1
1From the Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center, Cincinnati (B.C.T.); National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka (Y.I.), Aichi Medical University Hospital, Nagakute, Aichi (E.Y.), and Kanagawa Cardiovascular and Respiratory Center, Yokohama (T.B.) - all in Japan; Outpatients Clinic for Interstitial and Rare Lung Disease, Ruhrlandklinik University Hospital, Essen (F.B.), and Center for Interstitial and Rare Lung Diseases, Pulmonology, Thoraxklinik, Heidelberg University Hospital, and German Center for Lung Research, Heidelberg (M.K.) - all in Germany; the Departments of Critical Care and Respiratory Medicine, Royal Brompton Hospital, London (C.M.); Respiratory Diseases Department, Pontchaillou Hospital, IRSET UMR 1085, Rennes 1 University, Rennes, France (S.J.); the Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus (E.B.), and Savara, Horsholm (C.G., I.T.) - both in Denmark; the Pneumology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (I.C.); the 2nd Pulmonary Medicine Department, General University Hospital "Attikon," Medical School, National and Kapodistrian University of Athens, Athens (S.A.P.); University of Health Sciences Turkey, Yedikule Chest Diseases and Thoracic Surgery Education and Research Hospital, Istanbul (E.C.); Pulmonary Clinic of St. Petersburg Pavlov State Medical University, St. Petersburg, Russia (M.M.I.); Institute of Pulmonary and Allergy Medicine, Rabin Medical Center, Petah Tikva, Israel (M.R.K.); ILD Center of Excellence, Department of Pulmonology, St. Antonius Hospital, Nieuwegein, the Netherlands (M.V.); the University of Western Australia, Royal Perth Hospital, Perth, Australia (G.W.); and Savara, Austin, TX (T.J.).
Background:
Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia. It is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant. Recently, inhaled GM-CSF was shown to improve the partial pressure of arterial oxygen in patients with aPAP.
Methods:
In a double-blind, placebo-controlled, three-group trial, we randomly assigned patients with aPAP to receive the recombinant GM-CSF molgramostim (300 μg once daily by inhalation), either continuously or intermittently (every other week), or matching placebo. The 24-week intervention period was followed by an open-label treatment-extension period. The primary end point was the change from baseline in the alveolar-arterial difference in oxygen concentration (A-aDo2) at week 24.
Results:
In total, 138 patients underwent randomization; 46 were assigned to receive continuous molgramostim, 45 to receive intermittent molgramostim, and 47 to receive placebo. Invalid A-aDo2 data for 4 patients (1 in each molgramostim group and 2 in the placebo group) who received nasal oxygen therapy during arterial blood gas measurement were replaced by means of imputation. For the primary end point - the change from baseline in the A-aDo2 at week 24 - improvement was greater among patients receiving continuous molgramostim than among those receiving placebo (-12.8 mm Hg vs. -6.6 mm Hg; estimated treatment difference, -6.2 mm Hg; P = 0.03 by comparison of least-squares means). Patients receiving continuous molgramostim also had greater improvement than those receiving placebo for secondary end points, including the change from baseline in the St. George's Respiratory Questionnaire total score at week 24 (-12.4 points vs. -5.1 points; estimated treatment difference, -7.4 points; P = 0.01 by comparison of least-squares means). For multiple end points, improvement was greater with continuous molgramostim than with intermittent molgramostim. The percentages of patients with adverse events and serious adverse events were similar in the three groups, except for the percentage of patients with chest pain, which was higher in the continuous-molgramostim group.
Conclusions:
In patients with aPAP, daily administration of inhaled molgramostim resulted in greater improvements in pulmonary gas transfer and functional health status than placebo, with similar rates of adverse events. (Funded by Savara Pharmaceuticals; IMPALA ClinicalTrials.gov number, NCT02702180.).
Insights
Daily inhaled molgramostim improved oxygen levels and health status in autoimmune pulmonary alveolar proteinosis (aPAP) patients. Continuous treatment showed greater benefits than intermittent or placebo, with similar safety profiles.
Area of Science:
- Pulmonary Medicine
- Rare Diseases
- Immunology
Background:
- Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare condition causing surfactant buildup and low oxygen levels.
- It stems from impaired granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, crucial for lung macrophage function.
- Inhaled GM-CSF has emerged as a potential therapeutic for aPAP.
Purpose of the Study:
- To evaluate the efficacy and safety of inhaled molgramostim in patients with aPAP.
- To compare continuous versus intermittent inhaled molgramostim administration.
- To assess the impact on gas exchange and quality of life.
Main Methods:
- A 24-week, double-blind, placebo-controlled trial with three arms: continuous molgramostim, intermittent molgramostim, and placebo.
- Patients received inhaled molgramostim (300 μg daily) or placebo.
- The primary endpoint was the change in alveolar-arterial oxygen difference (A-aDo₂).
Main Results:
- Continuous molgramostim significantly improved the A-aDo₂ compared to placebo (estimated treatment difference: -6.2 mm Hg, P=0.03).
- Patients on continuous molgramostim also showed greater improvements in the St. George's Respiratory Questionnaire score (estimated treatment difference: -7.4 points, P=0.01).
- Adverse event rates were similar across groups, though chest pain was more frequent with continuous molgramostim.
Conclusions:
- Daily inhaled molgramostim effectively enhances pulmonary gas exchange and functional health status in aPAP patients.
- Continuous administration appears more beneficial than intermittent therapy.
- The treatment is generally well-tolerated, with a manageable safety profile.
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