Background

Alveolar macrophages require granulocyte-macrophage colony-stimulating factor (GM-CSF) to maintain normal function. aPAP, a rare lung disease caused by autoantibodies to GM-CSF, is characterised by surfactant accumulation in the alveoli resulting in impaired oxygen transfer. Molgramostim nebuliser solution is an investigational inhaled non-glycosylated recombinant human GM-CSF. In a Phase 2/3 clinical trial (IMPALA), daily administration of inhaled molgramostim for 24 weeks resulted in greater mean improvements in pulmonary gas exchange and functional health status compared with placebo.

Objective

Report primary results from IMPALA-2, a Phase 3 clinical trial being conducted to investigate the efficacy and safety of inhaled molgramostim for the treatment of aPAP.

Methods

IMPALA-2 is a global, randomised, double-blind, placebo-controlled Phase 3 trial of molgramostim conducted in adult aPAP patients who received nebulised molgramostim 300 µg or placebo once daily for 48 weeks. The primary endpoint was mean change in haemoglobin-adjusted percent predicted diffusing capacity of the lungs for carbon monoxide (DLco%) from baseline to Week 24. Secondary endpoints were mean changes from baseline in DLco% at Week 48, St. George's Respiratory Questionnaire (SGRQ) total score, SGRQ Activity score, and exercise capacity (EC) expressed as peak metabolic equivalents (METs) at Weeks 24 and 48.

Results

A total of 164 patients received molgramostim (n=81) or placebo (n=83). Molgramostim significantly improved DLco% compared with placebo at Week 24 (difference in least squares mean change 6.0%, p=0.0007) and at Week 48 (6.9%, 95% CI 2.9, 10.9). Molgramostim treated patients had greater mean improvements than placebo patients at Week 24 and at Week 48 in SGRQ total score (difference in least squares mean change at Week 24: -6.59 points, 95% CI -11.4, -1,79; Week 48: -4.87 points, 95% CI -10.76, 1.01) and EC (Week 24: 0.41 METs, 95% CI -0.06, 0.89; Week 48: 0.55 METs, 95% CI 0.07, 1.03). SGRQ Activity was also improved at Week 24. Molgramostim was well tolerated; most adverse events were mild or moderate in severity. All patients who completed double-blind treatment continued in the open-label period.

Conclusions

Molgramostim was well tolerated and improved pulmonary gas exchange, respiratory health-related quality of life, and EC of patients with aPAP.