The science team at Spyryx has recently published an open-access article in the Journal of Cystic Fibrosis, supporting the stability of SPX-101 in the protease-rich environment of cystic fibrosis airways. Here, we demonstrate SPLUNC1, the natural allosteric regulator of ENaC, is degraded by multiple proteases present in sputum of CF patients. SPX-101 is stable in CF sputum and after exposure, retains functionality to internalize ENaC, raise the apical hydration of CF cells, and promote the survival of a mouse model of CF. This is not the case for the natural sequence of the ENaC-regulatory fragment of SPLUNC1, which is rapidly degraded under the same conditions.
Read the full open-access article here: https://www.cysticfibrosisjournal.com/article/S1569-1993(18)30627-1/fulltext
This comprehensive manuscript details functional activity of SPX-101 in both cell lines and animal models of cystic fibrosis (CF). SPX-101 promotes internalization of the epithelial sodium channel (ENaC), thereby reducing the total number of functional channels on the surface of cells and generating a durable inhibition of sodium absorption by respiratory epithelia. SPX-101 enhances mucus movement in the trachea of both mouse and sheep models of CF, rescuing survival of the mouse model of CF which normally dies from mucus plugging in the lower airways. These data present SPX-101 as novel promoter of ENaC internalization with a more durable mechanism of action as compared to traditional ENaC inhibitors.
Follow this link to the AJRCCM website to view the full article: https://www.atsjournals.org/doi/abs/10.1164/rccm.201612-2445OC
This article describes 28-day inhalation toxicology experiments in rats and dogs to assess the safety of SPX-101. In contrast to previously-developed ENaC inhibitors, SPX-101 did not achieve significant systemic circulation, and did not induce hyperkalemia or weight loss at even the highest doses. SPX-101 did not cause any adverse events throughout the preclinical study, indicating a superior safety profile compared to channel blockers such as amiloride and its derivatives.
This article can be accessed via the Inhalation Toxicology website here: https://www.tandfonline.com/doi/full/10.1080/08958378.2017.1366602