Abstract Rationale aPAP is a rare chronic lung disease caused by autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) and is characterized by surfactant accumulation in the alveoli, resulting in impaired oxygen transfer. Routine laboratory tests are typically normal in aPAP patients; however, an association has been observed between elevations in serum lactate dehydrogenase (LDH) and disease severity. Additionally, elevations in serum concentrations of cytokeratin 19 fragments (CYFRA21-1) and Krebs von den Lungren protein-6 (KL-6) have been observed in aPAP, with the degree of increase correlated with disease severity. Molgramostim inhalation solution, an investigational recombinant human GM-CSF, is being evaluated for the treatment of aPAP in a Phase 3 clinical trial (IMPALA-2). Here we report serum biomarker levels from IMPALA-2. Methods IMPALA-2 is a global, randomized, double-blind, placebo-controlled trial conducted in aPAP patients receiving nebulized molgramostim 300 µg (n = 81) or placebo (n = 83) once daily for 48 weeks. Blood samples were collected at baseline and at Weeks 4, 12, 24, and 48 for biomarker analysis, which included measurement of levels of KL-6, CYFRA 21-1, carcinoembryonic antigen (CEA), LDH, hemoglobin (Hb), and hematocrit (Hct). Spearman’s rank correlation coefficients were calculated post-hoc between changes from baseline in percent predicted diffusing capacity of the lungs for carbon monoxide adjusted for hemoglobin (DLco%) and changes from baseline in biomarker levels for all patients. Results Molgramostim significantly improved pulmonary gas transfer as measured by change from baseline in DLco% at Week 24 (P = 0.0007) and Week 48 (P = 0.0008) compared with placebo. At baseline, all biomarker levels were similar between the molgramostim and placebo groups. At Weeks 24 and 48, results from post-hoc analyses showed that mean LDH, CYFRA 21-1, and KL-6 levels were decreased more from baseline in the molgramostim group compared with the placebo group; LDH (Week 24, P = 0.0150; Week 48, P = 0.0051), CYFRA 21-1 (Week 24, P = 0.0036; Week 48 , P = 0.0017), and KL-6 (Week 24, P = 0.0016; Week 48, P = 0.0022). Mean changes from baseline in Hb, Hct and CEA at Weeks 24 and 48 were similar between the treatment groups. Strong negative correlations were observed between changes in DLco% and LDH (Week 24, r=-0.5154, P 0.0001; Week 48, r=-0.6266, P 0.0001), DLco% and CYFRA 21-1 (Week 24, r=-0.6414, P 0.0001; Week 48, r=-0.6908, P 0.0001), and DLco% and KL-6 (Week 24, r=-0.7286, P 0.0001; Week 48, r=-0.6864, P 0.0001) at 24 and 48 weeks. Conclusions Patients in the molgramostim group had improvements in gas transfer (DLco%) and decreased levels of biomarkers associated with aPAP disease severity. This abstract is funded by: Savara Inc.
Inoue et al. (Fri,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: