Molgramostim Nebulizer Solution Expanded Access Program Protocol

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease mediated by autoantibodies targeting granulocyte macrophage colony-stimulating factor (GM-CSF), resulting in malfunctioning macrophages with impaired surfactant catabolism. The latter causes accumulation of surfactant in the alveoli, which has a negative impact on gas exchange between lung and blood. The clinical course of autoimmune PAP varies among patients with continuously slowly progressive disease in most patients, spontaneous improvement in a small percentage (5-7%), and rapid progression and/or pulmonary fibrosis, respiratory failure, and death in others. The most common cause of death is respiratory failure followed by secondary pulmonary bacterial infections. Estimated 5-year mortality rates vary between 10-30%, with overall disease-specific survival rates at 5 years exceeding 80%. There are currently no approved pharmacological treatments for aPAP in most of the world. Whole lung lavage (WLL) is the primary treatment option currently available for most aPAP patients. However, its invasive nature, limited access, and the variable effect of WLLs due to lack of standardization emphasize that there is an unmet need for a non-invasive, safe and well-tolerated, easily accessible and effective treatment for aPAP patients. The rationale for treating aPAP patients with molgramostim nebulizer solution is based on the capacity of GM-CSF to promote differentiation and mobilization of different myeloid leukocyte subsets including neutrophils, tissue macrophages/dendritic cells or their circulating precursors. It is crucially involved in anti-microbial pulmonary host defense and ameliorates lung injury by increasing the size and activation of the alveolar macrophage pool. GM-CSF also contributes to the proliferation of megakaryocytic and erythroid progenitors and plays a key role in surfactant homeostasis, by maturation of alveolar macrophages. Molgramostim is a non-glycosylated recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) produced by using recombinant DNA technology via a bacterial (E. coli) expression system. Molgramostim is formulated in a sterile nebulizer solution (molgramostim nebulizer solution) which is supplied in vials containing 300 µg of molgramostim in 1.2 mL solution and is administered by inhalation via an investigational eFlow Nebulizer System (PARI Pharma GmbH). Results of a completed randomized, placebo-controlled clinical trial support the safety, tolerability, and efficacy of inhaled molgramostim nebulizer solution as a treatment for autoimmune PAP patients.