Inhaled molgramostim shows benefit in autoimmune pulmonary alveolar proteinosis
In patients with autoimmune pulmonary alveolar proteinosis, daily administration of inhaled molgramostim for 24 weeks had beneficial effects on pulmonary gas transfer and functional health status compared with placebo.
The randomized, double-blind, placebo-controlled IMPALA trial assessed administration of inhaled molgramostim in 138 patients with autoimmune pulmonary alveolar proteinosis. Patients were randomly assigned to receive recombinant inhaled granulocyte-macrophage colony-stimulating factor molgramostim 300 g once daily (Savara Pharmaceuticals; n = 46; mean age, 54 years), molgramostim 300 g every other week (n = 45; mean age 49.2 years) or placebo (n = 47; mean age, 46.1 years). The 24-week treatment period was followed by an open-label extension period out to 72 weeks.
At 24 weeks, the primary endpoint of change from baseline in alveolar-arterial difference in oxygen concentration was greater among patients assigned continuous molgramostim compared with placebo (–12.8 mm Hg vs. –6.6 mm Hg; estimated treatment difference, –6.2 mm Hg; P = .03). In addition, patients assigned continuous molgramostim had a greater change in the prespecified outcome of mean change from baseline in percent of predicted diffusing capacity of the lung for carbon monoxide at 24 weeks compared with placebo (12 percentage points vs. 4.2 percentage points; estimated treatment difference, 7.8 percentage points; 95% CI, 2.3-13.3).
Patients in the continuous molgramostim group had greater improvement from baseline to 24 weeks in change in the St. George’s Respiratory Questionnaire total score compared with placebo (–12.4 points vs. –5.1 points; estimated treatment difference, –7.4 points; P = .01).
There was no difference in change in 6-minute walk test distance from baseline to 24 weeks between the continuous molgramostim or placebo groups.
In other results, the researchers reported a change from baseline in chest CT scan ground-glass opacification score with continuous molgramostim compared with placebo (–3.6 points vs. –1.1 points; estimated treatment difference, –2.5 points; 95% CI, –3.7 to –1.2).
Use of whole lung lavage was not different after 24 weeks, but continued to decline in the molgramostim group during an open-label treatment extension period, Bruce C. Trapnell, MS, MD, professor of medicine and pediatrics at the University of Cincinnati College of Medicine and director of the Transitional Pulmonary Science Center at Cincinnati Children’s Hospital Medical Center, said during a presentation at the virtual European Respiratory Society International Congress.
Other improvements observed during the blinded intervention period continued to occur during the open-label treatment period, he said.
“Therapeutic benefit was greater when molgramostim was administered every day than on alternating weeks,” Trapnell said during the presentation.
Rates of adverse events and serious adverse events were similar among the three treatment groups. Twenty-two percent of patients in the continuous molgramostim group experienced chest pain compared with 4% in the intermittent molgramostim group and 2% in the placebo group.
“Compared to placebo, daily administration of inhaled molgramostim ... in patients with autoimmune [pulmonary alveolar proteinosis] resulted in greater improvement in outcomes reflecting the physiologic, radiologic, biochemical and clinical manifestations of [pulmonary alveolar proteinosis],” Trapnell said.
Inhaled molgramostim is an Escherichia coli-produced recombinant granulocyte-macrophage colony-stimulating factor that is formulated as a nebulizer solution. Currently, there is no approved therapy for autoimmune pulmonary alveolar proteinosis. Autoimmune pulmonary alveolar proteinosis is treated by whole-lung lavage.
According to the researchers, the IMPALA trial results are similar to those reported in other studies that evaluated granulocyte-macrophage colony-stimulating factor molgramostim therapy for patients with autoimmune pulmonary alveolar proteinosis.
“Further studies are needed to define the duration of treatment required to achieve maximal therapeutic benefit and the potential utility of differential dosing for induction and maintenance therapy,” Trapnell said.
Reference:
Trapnell BC, et al. NEJM. 2020;doi:10.1056/NJEMoa1913590.