Spyryx Biosciences recently presented preclinical data supporting the clinical benefits of its cystic fibrosis (CF) treatment candidate SPX-101, intended to improve lung function in all patients regardless of their underlying disease-causing mutation.
The data, presented in four posters at the recent North American Cystic Fibrosis Conference (NACFC) in Indianapolis, demonstrated how the inhaled drug works — data that support the HOPE-1 Phase 2 clinical trial of SPX-101 in adults with CF, which is currently recruiting participants.
SPX-101 targets epithelial sodium channels (ENaC) in the lungs, making them leave the cell surface.
One of the consequences of a faulty CFTR channel (the cause of CF) is that ENaCs become hyperactive, absorbing more sodium from the airway surface than normal. Researchers believe this further worsens the lack of airway liquid that makes CF patients’ mucus thick and sticky.
“The strong preclinical data presented at NACFC highlight the novel mechanism of action of channel internalization achieved by SPX-101 and fully differentiates the peptide from traditional small molecule ENaC inhibitors,” David Scott, senior principal scientist at Spyryx, said in a press release.
Other attempts to block ENaC have not been entirely successful. Small inhaled molecules, such as amiloride, did block the channel and increased the amount of airway liquid. But the molecules are washed away as the process takes place.
SPX-101 is a small peptide, or protein fragment, that uses a different approach to prevent ENaCs from taking up too much sodium. In a poster presentation, Spyryx’s Matthew Walker showed that SPX-101 makes all three subunits of the channel’s receptor become internalized in the cell in tiny vesicles. This allows for more durable effects.
Researchers could observe a lowering of surface ENaC numbers in lab-grown CF cells, derived from patients with various mutations.
Timothy Stuhlmiller further added to the data in his poster and workshop presentations. He showcased data demonstrating that the height of airway surface liquid was increased on lab-grown cells — again derived from CF patients with different mutations — after SPX-101 treatment.
SPX-101 also prevented the reduction in airway surface liquid seen when researchers treated normal cells with a blocker of CFTR to mimic CF conditions.
While the team noted significant increases in airway liquid height in all cells tested, the quantity of the increase differed among cells. Nonetheless, Stuhlmiller underscored that they also observed a treatment effect in cells from patients with Class I CFTR mutations. Such mutations cause a total lack of functional CFTR protein.
In a set of experiments exploring the biophysical properties of mucus produced by human lab-grown lung cells, researchers also noted that SPX-101 treatment improved the ability of other molecules to diffuse within the mucus layer — indicating that it became less thick and sticky.
Using the drug in a sheep CF model, researchers could demonstrate that mucus traveled faster in airways treated with SPX-101. Higher doses gave better results, and the effect of SPX-101 was stable during all eight hours it was measured.
Importantly, the team noted that hypertonic saline further improved the impact of SPX-101 on the speed of mucus movement in the sheep airways.
This data was supported by additional experiments. Bryant Wu demonstrated that SPX-101 makes mucus in a mouse model of faulty ENaC travel faster and in a more directional manner in the airways.
The research team also compared SPX-101 to a combination of compounds VX-770/VX-809 — also known as ivacaftor and lumacaftor (approved for CF treatment under the brand name Orkambi). They demonstrated that in lab-grown human bronchial epithelial cells, SPX-101 gave rise to a larger airway surface liquid height than the VX-770/VX-809 combination. Adding SPX-101 to the combination did not improve the airway surface liquid content further.
Finally, Juliana Sesma examined the safety and efficacy of the treatment in various animals. She showed that in a CF mouse model with increased ENaC activity, SPX-101 treatment given at two days after birth improved survival.
After 15 days, about half of untreated control mice were dead, while 90 percent of mice given the highest SPX-101 dose were alive. The treatment also reduced the infiltration of inflammatory cells into the animals’ lungs.
Researchers also exposed dogs to high single doses of SPX-101 or extended treatment with high doses. A single high dose did not give rise to any breathing or heart problems, and 28 days of treatment with higher doses did not impact the dogs’ serum or urinary sodium or potassium levels, suggesting that the drug has a good safety profile.
“We believe these findings demonstrate that SPX-101 targeting reduction of ENaC density represents a unique opportunity to bring clinically meaningful benefit to all CF patients regardless of CFTR mutation by promoting airway hydration and increasing mucociliary clearance,” said Scott.
The HOPE-1 trial (NCT03229252) is currently recruiting about 78 patients in Canada, France, Italy, Portugal, and the U.K. More information, including locations and contact details, can be found on the trial registration page here.