Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis

Abstract

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.).

Copyright © 2020 Massachusetts Medical Society.

Figures

Figure 1.. Changes in Alveolar-Arterial Difference in Oxygen Concentration (A-aDO2).

The figure shows the change in A-aDO2 from baseline to week 24 in the continuous molgramostim group (46 patients) and placebo group (47 patients) during the 24-week randomized intervention period analyzed using the revised full analysis set. Each symbol represents the results for one patient; data for one patient in the molgramostim and two patients in the placebo group were invalid, treated as missing, and replaced using multiple imputation (see text for details).

Figure 2.. Changes in the Primary Endpoint and Selected Secondary Endpoints Over Time.

Panels A-D show the mean change from baseline during the blinded intervention period (white regions) and open-label treatment period (grey regions) for patients who received continuous molgramostim (n=46, green circles) or placebo (n=47, grey squares) from week 0 to week 24 and intermittent molgramostim from week 24 to week 72 for the following end points: alveolar-arterial difference in oxygen concentration (A-aDO2) (Panel A), diffusing capacity for carbon monoxide (DLCO percent of predicted) (Panel B), Saint George Respiratory Questionnaire (SGRQ) Total Score (Panel C), and distance covered in a six-minute walk test (6MWT) (Panel D). The number of patients for whom results were available at each time point is shown; data missing during the double-blind period were replaced using multiple imputation. The difference in numbers of patients included between weeks 24 – 48 and weeks 48 – 72 was due to a protocol amendment permitting use of a longer open-label period for some patients. T bars indicate standard errors.