Use of Trikafta medication found to improve mucus clearance in CF

Improvements may lead to better lung function for CF patients: Study

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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Improvements in mucus clearance with the approved medication Trikafta — evident among patients within a month after starting treatment, according to researchers — may contribute to better lung function in people with cystic fibrosis (CF), per a new U.S. study.

Mucus clearance mechanisms are meant to keep the airways healthy by removing potential disease-causing agents that can become trapped in the abnormally thick and sticky mucus that’s a hallmark of CF.

According to the researchers, this study supports “the concept that improved epithelial function and mucus clearance contributes to the significant clinical lung health benefits conferred by [CFTR modulators].” Epithelial cells line the airways and their functions include protection and regulation of airway innate immunity.

The study, “Longitudinal improvements in clinical and functional outcomes following initiation of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis,” was published in the journal Heliyon.

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Seeking to better understand the mechanisms underlying CFTR modulators

CF is caused by mutations in the CFTR gene that lead to the production of mucus that accumulates in the body’s organs, most notably the lungs, but also the pancreas, digestive tract, and reproductive system.

This sticky mucus can lead to organ damage and cause symptoms of CF. Inadequate mucus clearance, therefore, is a key process driving lung disease in people with CF.

Highly effective CFTR modulators, including Trikafta (elexacaftor/tezacaftor/ivacaftor), are meant to increase the functioning of the CFTR protein, whose production or activity is disrupted in CF. However, existing methods have indicated little correlation between changes in CFTR activity and the lung function improvements associated with Trikafta therapy.

“Hence, there is an imperative need to improve our understanding of the functional response of the respiratory epithelium — a key biological target of ETI [Trikafta] therapy which is critical to addressing the prolonged pulmonary effects of ETI therapy and to appreciate aspects of altered epithelial function that are not directly treated by [CFTR modulators],” the scientists wrote.

A team in the U.S. previously had developed micro-optical coherence tomography (micro-OCT), an imaging approach for monitoring nasal mucus clearance in CF patients. To further determine if micro-OCT can be used to analyze the impact of Trikafta, the researchers analyzed 24 CF patients with at least one F508del mutation in the CFTR gene.

Participants were recruited for a micro-OCT sub-study at the University of Alabama at Birmingham. The parent study was called PROMISE (NCT04038047) and assessed the biological and clinical effects of treatment with Trikafta. Enrolled patients had an average age of 27 and 92% identified as white individuals; one-third were female.

Half were receiving treatment with other CFTR modulators, and 54% carried F508del mutations in both CFTR copies. Micro-OCT imaging was performed before the study’s start, known as baseline, and at one month after starting Trikafta treatment. A total of 22 participants were assessed at both timepoints.

Within one month on Trikafta, the results showed a significant improvement in lung function. Specifically, a 10.9% increase was seen in percent predicted forced expiratory volume in one second (ppFEV1), which is a commonly used measure based on how much air a person can forcibly exhale in one second. This benefit persisted at six months, the data showed.

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CFTR activity also improved, as indicated by a significant decrease of sweat chloride levels at both one and six months. This test involves measuring levels of chloride ions in a person’s sweat, which are abnormally high in people with CF.

Patients had a mean of 0.71 CF exacerbations — periods of acute symptom worsening — requiring hospital admission, and 3.08 exacerbations requiring treatment with antibiotics in the year before starting treatment with Trikafta. Exacerbation rates fell to zero inpatient stays and 0.8 outpatient antibiotic treatments in the year after starting treatment.

Regarding micro-OCT data, patients experienced a significant improvement in their mucociliary transport rate (MCT), from 2.8 mm/min at baseline to 4 mm/min one month into Trikafta therapy.

The … significant increase in MCT [mucociliary transport rate] within one month of [Trikafta] therapy suggests that MCT improvement may directly contribute to … improvement in lung function.

“Our data supports the unparalleled improvements previously reported in clinical outcomes up to 6 months following ETI therapy. The corresponding significant increase in MCT within one month of ETI therapy suggests that MCT improvement may directly contribute to this improvement in lung function,” the researchers wrote.

The study’s small sample size was noted as a limitation by the scientists, who noted that further studies using micro-OCT for longer follow-up periods may contribute to a better understanding of the effects of CFTR modulators.

Overall, however, the team concluded that this work “suggests improved mucociliary transport as a probable mechanism of action underlying the clinical benefits” seen with the use of Trikafta medication.