44 An alginate oligomer (OligoG) developed as a dry powder for inhalation in cystic fibrosis demonstrates an excellent safety profile, similar to a nebulised solution used in a phase 2a trial

Abstract

Objectives: An alginate oligosaccharide (OligoG) solution for nebulisation has completed phase 2a for treatment of cystic fibrosis. The objective of the current study was to assess the systemic and local toxic potential of a newly developed OligoG dry powder for inhalation (DPI) in a 4-week inhalation study in rats. Methods: Conscious rats (n = 142) were dosed once daily for 28 days in a snout-only flow-past inhalation exposure chamber with test aerosols delivered by a Rotating Brush Generator providing OligoG doses up to 467mg/kg/day. Serial investigations were performed to monitor any treatment related effects. Results: No clinical signs or treatment related effects were observed on bodyweight, food consumption, ophthalmoscopy or haematology. Dose related findings included high lung weights, pale areas and alveolar macrophages/macrophage debris in the lungs, and enlarged tracheobronchial lymph nodes with increased cellularity in some rats in all treated groups. After 4 weeks of recovery for high dose animals, previously slightly elevated blood phosphorous and urinary pH values, were normalised. Furthermore, all animals fully recovered from the findings in the lymph nodes and partially recovered from the findings in the lungs. Similar to the nebulised solution, all histology findings were considered to be consequences of normal clearance mechanisms and therefore not adverse. Toxicokinetic data demonstrated low uptake and efficient plasma clearance of the OligoG. Conclusion: Inhalation of OligoG DPI up to for 28 days was well tolerated without signs of adverse toxicity. Based on this study, 467mg OligoG/kg/day is considered to be the No Observed Adverse Effect Level (NOAEL).