SPX-101, a mutation-agnostic therapeutic for Cystic Fibrosis

What happens in the lungs of people with Cystic Fibrosis?

Healthy vs CF Lung

In healthy lungs, airway hydration is controlled by the balanced action of ion channels present on the surface of the cell. The epithelial sodium channel, ENaC, allows sodium to enter the cell and the cystic fibrosis transmembrane conductance regulator, CFTR, allows chloride to leave the cell. The proper balance of sodium and chloride ensures that airways remain hydrated and that cilia are able to clear mucus from the lungs and keep them free from infection.

Both ENaC and CFTR are dysfunctional in CF. Cystic Fibrosis results when mutations in CFTR cause the protein to lose function or not be expressed at all. In addition, there is an increased density of hyperactivated ENaC. This hyperabsorption of sodium and reduced/absent release of chloride leads to dehydration of the airway, the accumulation of thick sticky mucus, decreased mucociliary clearance, and infection with bacteria such as Pseudomonas aeruginosa and Staphylococcus aureus.

What goes wrong with ENaC in CF?

Airway cells secrete a protein called SPLUNC1 that regulates ENaC in healthy lungs but it is lost in CF. SPLUNC1 binds to ENaC and causes it to be internalized (moved inside the cell). In CF, SPLUNC1 is broken down by proteases before it can bind to ENaC. Without SPLUNC1 present in the airway, ENaC accumulates on the cell surface, leading to airway dehydration.

How does Spyryx approach this problem and how is it different from what has been done before?

With its important role in controlling airway hydration, scientists and clinicians have attempted to target ENaC using small molecule inhibitors such as amiloride and later derivatives. These molecules block the pore of ENaC like a plug that fits into a drain. However, these inhibitors only have a transient effect, potentially because they can be rapidly washed away when the airway is rehydrated. Thus, ENaC hyperactivation quickly resumes and the mucus remains dehydrated. Spyryx has approached this problem differently, seeking to address the lost function of SPLUNC1 and reduce the number of ENaC channels on the surface of airway cells. Spyryx has developed a novel ENaC regulatory peptide, called SPX-101, which mimics the regulatory activity of SPLUNC1 and removes ENaC from the cell surface instead of just inhibiting ENaC.

Short-Term and Long-Term CF Treatment

What do we expect to happen when lungs are treated with SPX-101?

SPX-101 replaces SPLUNC1 in CF to restore airway hydration. Like SPLUNC1, SPX-101 is able to bind to ENaC causing the channels to be removed from the surface of cells. Since SPX-101 has removed ENaC from the surface, this effect cannot be washed away when the airway is rehydrated. Due to this mechanism of action, we expect SPX-101 to have a long-lasting, durable effect on airway hydration. Unlike SPLUNC1, SPX-101 can resist breakdown by proteases and will remain available to decrease ENaC on cell surfaces in the diseased lung. Decreased ENaC activity should lead to mucus hydration and promote mucociliary clearance and ultimately increase lung function in people with CF. Furthermore, since SPX-101 targets ENaC, we expect this therapeutic approach to provide clinical benefit agnostic to CFTR mutation.

SPX-101 A New Approach