Trikafta, Kaftrio in EU, helps to thin mucus and harmful bacteria in lungs
Positive changes in airways with cystic fibrosis seen over year of use
Kaftrio, sold as Trikafta in the U.S., continues to thin mucus and to reduce the number of harmful bacteria in the airways when taken for over a year by people with cystic fibrosis (CF), according to an observational study in Germany.
While long-term use of Vertex Pharmaceuticals’ triple-combination therapy helped these patients, all with at least one copy of the common CF-causing F508del mutation, it did not restore their airways to the level of healthy individuals.
“This is a major step forward in treating cystic fibrosis,” Marcus Mall, MD, who led the study, said in a press release. Mall directs the Department of Pediatric Respiratory Medicine, Immunology, and Critical Care Medicine at Charité – Universitätsmedizin Berlin.
“At the same time, it would be premature to say that patients have been normalized, let alone cured. Chronic lung changes arising over many years of living with the disease cannot be reversed, unfortunately,” added Mall, who also heads the CF center at Charité.
One year of Trikafta/Kaftrio ‘shifted the CF sputum proteome towards healthy’
The study, “Longitudinal Effects of Elexacaftor/Tezacaftor/Ivacaftor on Sputum Viscoelastic Properties, Airway Infection and Inflammation in Patients with Cystic Fibrosis,” was published in the European Respiratory Journal.
CF is caused by mutations in the CFTR gene, which provides instructions for making a protein of the same name. This protein helps to regulate the movement of chloride into and out of cells, which is needed for the production of thin, easily flowing mucus.
The mutations lead either to no protein or to a protein that doesn’t work properly. “This results in thick, sticky mucus, which clogs the airways, making it harder for patients to breathe and leading to chronic bacterial infection and inflammation of the lungs,” Mall said.
F508del, the most common CFTR mutation, causes the protein to fold into a wrong shape. Kaftrio, a combination of elexacaftor, tezacaftor, and ivacaftor, works by enabling the protein to fold correctly and then holds it open to allow more chloride, an element of salt, to pass through. This eases the symptoms of CF.
Mall was part of a team that showed the medication can aid lung function and patients’ quality of life. Now, he and other researchers in Germany looked at how Kaftrio changes mucus in the airways and whether it can reduce inflammation and the spread of bacteria.
Their study included 79 people with CF, ages 12 and older. Sputum samples were collected before treatment and again at one, three, and 12 months after its start. Ten healthy individuals were used as controls.
Treatment led to mucus becoming less elastic and viscous three and 12 months later. Usually, “the mucus in the airways [of people with CF] is very sticky because it doesn’t contain enough water and the mucins, the molecules that form mucus, adhere too much due to their chemical properties,” Mall said.
At the three-month mark, a lesser number of Pseudomonas aeruginosa, a type of bacteria that often causes lung infections in people with CF, was evident. Greater alpha diversity, a measure of the relative abundance of bacteria living in the airways, also was seen.
Moreover, three months of Kaftrio’s use reduced the level of interleukin-8, a molecule that signals inflammation. Free neutrophil elastase activity, another biomarker of inflammation, also fell over the 12 months.
Over time, treatment with Kaftrio “shifted the CF sputum proteome towards healthy,” the researchers wrote. The proteome refers to the entire set of proteins that can be found in a cell, tissue, or organism at a certain time point.
“What’s more, the effects lasted over the entire one-year study period. This is really important because previous medications caused a rebound in the bacterial load in the airways,” said Simon Gräber, MD, a clinician scientist working in the same department at Charité as Mall.
However, noted improvements were observed “without reaching levels close to healthy,” the researchers wrote.
The team is working toward a better understanding of changes in mucus with CF, with a goal of developing new mucolytics, medications that can thin and loosen mucus.
“We plan to forge ahead with our research on how to make treatments that address cystic fibrosis via the molecular defects that cause the disease — like the triple medication combination studied here — even more effective. This includes starting treatment in early childhood with the goal of preventing chronic lung changes wherever possible,” Mall said.
“Aside from that, this therapy is not available to about ten percent of our patients right now due to their genetic conditions,” Gräber added. “That’s why we are also hard at work on … new molecular treatments so we can treat all people with cystic fibrosis effectively.”