CYSTIC FIBROSIS

Preserving Lung Function in Cystic Fibrosis (CF)

Cystic Fibrosis (CF) is an inherited chronic disease that affects the lungs and digestive system of about 70,000 children and adults worldwide (30,000 in the US). The average expected lifespan for a CF patient born today is about 37 years of age.

CF is caused by the mutation of the CF transmembrane conductance regulator (CFTR) gene, causing the body to produce unusually thick mucus that clogs small airways leading to persistent lung inflammation and increasing risk of lung infections. The result of lung inflammation is permanent degradation of lung function over time. Lung disease remains the major cause of hospitalizations and premature death in CF.

CF lung inflammation is driven by immune system cells called neutrophils. The lungs of CF patients are flooded by excessive amounts of neutrophils, which upon entering the lungs release their DNA out into the airways. The neutrophils and their DNA add onto the thick and sticky mucus, further restricting the flow of air through the small airways. This is important because small airways are the channels through which air from outside the lung must pass in order to get to the final cul-de-sacs (alveoli) where oxygen is absorbed into the blood. The result is that not enough oxygen is absorbed in the lungs of CF patients.

In addition to releasing their DNA into the lung, neutrophils also release an enzyme called elastase (NE). In a healthy lung, elastase is a tool that neutrophils use to help them clear away debris and kill bacteria. Excessive amounts of elastase in the lungs of a CF patient begin to erode the very processes that neutrophils are intended to protect.

First, and best known, excess elastase degrades healthy lung tissue by breaking down the collagen matrix that provides the flexibility that allows the lungs to expand and contract. The result is that over time, the lung becomes too weak to pull in air. Second, excess elastase erodes the ability of neutrophils to find and kill bacteria, the very thing neutrophils are called to do in the first place. Elastase does this by shaving off the receptors that enable neutrophils to locate bacteria (the opsonizing receptors), in effect turning off the cellular GPS. This explains why even in the presence of excessive neutrophils, the lungs of CF patients are chronically infected with bacteria. Finally, and least known, excess elastase inactivates CFTR, the protein at the heart of CF disease.

Taken together, lung inflammation in CF results in progressive deterioration of lung function over time. By tuning down the excessive neutrophil response and thus reducing DNA and elastase in the lungs of CF patients, acebilustat aims to potentially preserve lung function in CF patients.

Acebilustat is currently undergoing a Phase 2 clinical trial testing 48-weeks of treatment in CF patients in the US and EU to further assess its efficacy and safety. For more information about the trial, please visit our Patient Trials page.