Abstract Rationale aPAP is a rare chronic lung disease caused by autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) characterized by surfactant accumulation in the alveoli, impairing oxygen transfer and reducing exercise capacity. Molgramostim inhalation solution (molgramostim) is an investigational recombinant human GM-CSF that is being evaluated for the treatment of aPAP in a Phase 3 clinical trial (IMPALA-2). IMPALA-2 achieved statistical significance on its primary endpoint and other secondary endpoints; a greater improvement in the molgramostim group in exercise capacity expressed as peak metabolic equivalents (METs) was observed at 48 weeks. Here we report the effects of molgramostim on exercise-related exploratory endpoints - exercise distance and duration. Methods IMPALA-2 is a global, randomized, double-blind, placebo-controlled Phase 3 trial conducted in adults with aPAP who received nebulized molgramostim 300 µg or placebo once daily for 48 weeks. Exploratory endpoints included change from baseline in distance walked and change from baseline in duration of exercise at 24 and 48 weeks during a conservative, symptom-limited, exercise treadmill test. Results A total of 164 patients received molgramostim (n = 81) or placebo (n = 83). Greater mean improvements in distance walked were observed in the molgramostim-treated patients compared with placebo, with an associated P-value 0.05 at Week 48. The least-squares mean (LSM) change in distance walked from baseline to Week 48 was 167.0 m (95% confidence interval CI, 112.1 to 221.8) in the molgramostim group and 86.4 m (95% CI, 32.4 to 140.4) in the placebo group; the estimated treatment difference based on LSM changes was 80.6 m (P = 0.0301). Molgramostim patients were also able to exercise for longer periods of time compared with patients who received placebo. At Week 48, the LSM change in duration of exercise from baseline to Week 48 was 2.0 minutes (95% CI, 1.3 to 2.7) in the molgramostim group and 1.0 minute (95% CI, 0.3 to 1.6) in the placebo group; the estimated treatment difference based on LSM changes was 1.0 minute (P = 0.0262). Conclusions IMPALA-2 is the first clinical trial in patients with aPAP to assess exercise capacity using an exercise treadmill test. Consistent with improvements in peak METs, molgramostim improved distance walked and duration of exercise at Week 48 compared with placebo. This abstract is funded by: Savara Inc.
Mccarthy et al. (Fri,) studied this question.