A phase 3 study of inhaled molgramostim therapy found the drug resulted in greater improvements in pulmonary gas transfer and functional health status than placebo in patients with Autoimmune Pulmonary Alveolar Proteinosis (aPAP), according to data published online in the New England Journal of Medicine.
Pulmonary alveolar proteinosis (PAP) is a rare lung disease caused by a build-up of material (surfactant) in the air sacs, resulting in shortness of breath, The Cleveland Clinic reports. Autoimmune pulmonary alveolar proteinosis is the most common form and occurs in 90% of PAP patients.
The Phase 3 IMPALA study, published online in the NEJM, was a 24-week, double-blind, placebo-controlled study that evaluated molgramostim nebulizer solution (an inhaled granulocyte-macrophage colony-stimulating factor).
Patients were randomized to one of three arms:
- molgramostim 300 µg continuous daily dosing,
- molgramostim 300 µg daily dosing intermittently every other week, or
- placebo.
The double-blind period was followed by a 24/48-week open-label period where all arms received molgramostim 300 µg daily dosing intermittently every other week. The A-aDO2 gradient was the primary endpoint in the study. Key secondary endpoints included the SGRQ total score, six-minute walk distance, and time-to-requirement for whole lung lavage.
According to the manufacturer Savara Inc, IMPALA did not meet the primary endpoint of A-aDO2 in the primary analysis. However, replacement (by imputation) of invalid A-a DO2 data for four severely affected patients who required continuous nasal oxygen therapy resulted in a change in A-aDO2 from baseline to week 24 that was greater in patients receiving continuous administration of molgramostim compared to placebo.
Oxygen therapy during arterial blood gas measurement was permitted by protocol for ethical reasons (n=1 in each molgramostim arm, n=2 in the placebo arm). The estimated treatment difference was -6.2 mmHg, p=0.03. Additionally, improvement in A-aDO2 was supported by another secondary measure of pulmonary gas transfer called diffusing capacity for carbon monoxide (DLCO). The mean change from baseline at week 24 in DLCO was greater in patients receiving continuous administration of molgramostim compared to placebo, with an estimated treatment difference of 7.8 percent predicted (95% CI 2.3 to 13.3). Regarding the key secondary endpoints, in the full analysis set, SGRQ total score showed improvement with continuous administration of molgramostim compared to placebo, with an estimated treatment difference of -7.4, p=0.012.
Results in the six-minute walk distance and time-to-requirement for whole lung lavage were numerically in favor of patients receiving molgramostim but did not demonstrate statistically significant differences compared to placebo. 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.
“IMPALA was the largest treatment trial ever conducted in aPAP patients and demonstrated that daily administration of inhaled molgramostim led to greater improvement than placebo in outcomes that reflect physiological, radiological, biochemical, and clinical manifestations of aPAP,” said Bruce Trapnell, MD, lead investigator of the IMPALA study in the US. “Importantly, molgramostim was well tolerated with no notable safety concerns. I believe that the drug will be a significant improvement to the care of aPAP patients.”
“With no other drugs on the market to treat this rare lung disease, and data from the IMPALA study that indicates the drug has effect, we believe molgramostim has the potential to transform the standard-of-care for aPAP patients,” said Badrul Chowdhury, Chief Medical Officer, Savara. “At the end of last year, the FDA granted molgramostim Breakthrough Therapy Designation for the treatment of aPAP and advancing this program is our highest priority. We now have a finalized study design for IMPALA 2, the Phase 3 confirmatory study required for regulatory approval, that incorporates the key learnings from the first IMPALA study as well as feedback from regulatory agencies. We look forward to initiating it in the first quarter of next year.”
