ARINA-1, a nebulized therapy being developed by Renovion for cystic fibrosis (CF) and other chronic inflammatory lung diseases, may be better than currently available options for clearing mucus in CF patients with the most common CFTR mutation, results of a study in cell models of CF showed.
The investigative treatment significantly improved mucus transport when used alone, and worked even better in combination with approved CFTR modulators, its researchers found, adding data supported moving ARINA-1 into clinical testing in people.
One of the hallmark symptoms of CF is the accumulation of thick, viscous mucus in the lungs. This leads to problems, as the mucus cannot be properly moved and cleared by the body. The exact reasons that CF mucus is so thick are still being worked out, though lack of water, increased acidity, and imbalances in various molecules likely all play a role.
ARINA-1 is a combination of three compounds that may make CF mucus easier to clear. The first is bicarbonate, which is deficient in CF mucus and may help to control its acidity, among other effects. The second, glutathione, is also lacking in CF mucus. Glutathione could help break apart mucus proteins, reducing the viscosity.
ARINA-1 was designated an orphan drug by the U.S. Food and Drug Administration for the treatment of people with lung transplants and CF. Renovion recently secured $8.1 million in funding to speed its clinical development.
Researchers evaluated the effects of ARINA-1 on human lung cells in dishes. These cells came from CF patients with the common F508del mutation, and were treated with ARINA-1 at concentrations thought to be reflective of what could realistic for a human lung.
Using advanced imaging technology, the researchers then calculated how quickly the mucus could be moved by the cells (the mucociliary transport rate, or MCT).
Compared to cells treated with saline, a standard approach for clearing out mucus, those treated with ARINA-1 had a significantly higher peak MCT (2.8 vs. 0.2 mm/min). Other parameters, such as how deep the mucus was or how the lung cells themselves moved, were not affected.
CFTR modulators are a class of CF therapies that work by increasing the activity of CFTR — the protein whose deficit causes CF.
Treatment with two approved CFTR modulators, lumacaftor and ivacaftor (marketed in combination as Orkambi, by Vertex Pharmaceuticals), did not significantly increase MCT. However, treatment with both ARINA-1 and Orkambi significantly increased MCT at six hours, more than ARINA-1 alone (3.0 vs. 2.3 mm/min).
“These results suggest the potential of ARINA-1 as an efficacious approach to improving mucus clearance, both as a monotherapy and in addition to approved combination CFTR modulator therapy,” the researchers wrote.
Additional experiments measured mucus reflectivity, which is an indirect way of measuring its viscosity (higher reflectivity indicates more viscous mucus). Mucus reflectivity was significantly lower for cells treated with ARINA-1, compared to those given saline (12.7 vs. 18.1).
“Together, these data indicate that ARINA-1 reduces the viscosity of CF mucus, suggesting a mechanistic pathway for its impact on mucus transport,” the researchers wrote.
Cells where then treated with various components of ARINA-1, alone or in combinations, to fully understand the effects of each component. Results showed that the combination of bicarbonate and glutathione only had almost the same effect on MCT as the triple combination.
“These data indicate that the combination of bicarbonate with glutathione contributes significantly to the effect of ARINA-1 on MCT rates,” the researchers wrote.
ARINA-1’s other component, ascorbic acid, was able to increase the activity of the CFTR protein, but only in cells producing a fully functional protein. In cells producing a mutated form CFTR, ascorbic acid had no effect on its activity, even after treatment with CFTR corrector lumacaftor.
“Overall, these results indicate that the improvements in MCT induced by ARINA-1 … are largely independent of CFTR channel activity,” the team wrote.
This study was supported by grants from the Cystic Fibrosis Foundation and the National Institute of Diabetes and Digestive and Kidney Diseases. Two of this study’s 13 researchers are Renovion employees, and hold patents on ARINA-1.
“These research results demonstrate the significant impact that ARINA-1 has on restoring mucus transport in primary human bronchial epithelial cells from dF508 CF patients,” study co-author Steven M. Rowe, MD, of the University of Alabama at Birmingham, said in a press release.
“Based on our studies demonstrating that ARINA-1 is more effective than hypertonic saline for mucus clearance in CF cells, the potential for ARINA-1 helping people with CF improve clinically is promising,” he added. “These results support the importance of advancing the clinical program for ARINA-1 in CF patients … and possibly in other chronic lung diseases characterized by excess mucus.”
We are sorry that this post was not useful for you!
Let us improve this post!
Tell us how we can improve this post?