Approval in Japan for sargramostin to treat aPAP (autoimmune pulmonary alveolar proteinosis)

PTx licensed rights for certain indications in Japan to Nobelpharma in 2022. Leukine is a glycosylated recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) produced by recombinant DNA technology in yeast. Leukine is not approved outside Japan for aPAP or as an inhalation therapy. Partner Therapeutics will manufacture Sargmalin for Nobelpharma at its manufacturing facility in Lynnwood, WA.

Investigation of inhaled sargramostim, a recombinant human GM-CSF, in aPAP is based on knowledge that the disease is a progressive lung disorder driven by blockage of GM-CSF signaling due to the production of GM-CSF autoantibodies. The deficiency of GM-CSF in aPAP patients inhibits their ability to differentiate monocytes into alveolar macrophages, which causes aPAP patients to accumulate surfactant in their lungs. This dysfunction leads to low oxygen levels, difficulty breathing, innate immune deficiency, and, in some cases, serious infection, pulmonary fibrosis, respiratory failure, and death. GM-CSF improves lung function by directly acting on alveolar macrophages to promote their maturation and the breakdown of pulmonary surfactant by mature macrophages.

To date, the standard treatment for aPAP has been Whole Lung Lavage (WLL), a lengthy and invasive procedure where saline is used to wash the lungs of excess surfactant. WLL requires hospitalization, general anesthesia, and mechanical ventilation. While effective in providing short term symptomatic relief, WLL can also have serious complications and does not treat alveolar macrophage dysfunction, the underlying cause of aPAP.

The Sargmalin approval is based on data from the PAGE trial, a phase II multicenter, randomized, double-blind, placebo-controlled study to evaluate Leukine in 64 patients with mild to moderate aPAP led by Sponsor-Investigator Koh Nakata MD, PhD, Project Professor, Division of Pioneering Advanced Therapeutics, Center for Medical Innovation of Niigata University Medical Dental Hospital. Patients were randomly assigned 1:1 to receive either 125 micrograms of Leukine or placebo twice per day for seven days and then off for seven days for twelve two–week cycles. There was a significant improvement (p=0.02) in the primary endpoint of improvement in alveolar–arterial oxygen gradient (A-aDO2) between baseline and week 25. Greater improvements in serum biomarker secondary endpoints KL-6, CEA, and monocyte chemoattractant protein-1 (MCP-1) were observed with Leukine.