Trikafta shown to halve sweat chloride levels in real-world study
Still, some treated patients had levels outside the normal range
Treatment with Trikafta (elexacaftor/tezacaftor/ivacaftor) cut sweat chloride levels in half among people with cystic fibrosis (CF), according to a real-world Danish study.
Still, sweat chloride levels — a known biomarker of treatment responses in CF — were variable, and some treated patients still had levels out of the normal range.
“These real-world data confirm a substantial decrease in sweat chloride concentration during modulator treatment, especially [with Trikafta], where mean concentrations halved. However, large variation remained, including persistently high concentrations,” the researchers wrote.
According to the team, “these findings emphasize the potential of sweat chloride concentration as a treatment response biomarker and the need to explore its heterogeneity [variability] and relationship with clinical outcomes.”
The study, “Real-world data confirm elexacftor/tezacaftor/ivacaftor modulators halves sweat chloride concentration in eligible people with cystic fibrosis,” was published in the journal APMIS. It was funded by Vertex Pharmaceuticals, which markets Trikafta and other CFTR modulators.
Investigating Trikafta use in the real world
In CF, mutations in the CFTR gene lead to faulty or deficient CFTR protein. CFTR normally resides on the surface of cells and acts as a gate to regulate the movement of water and salt molecules, particularly chloride, in and out of cells.
An imbalance in salt and water affects various tissues, including the sweat glands, and people with CF have unusually high amounts of chloride in their sweat.
A sweat test to measure chloride is thus a gold standard way of diagnosing the disease and monitoring treatment responses. A reduction in these levels generally indicates a beneficial effect of a given treatment and correlates with other clinical measures.
Trikafta is a triple combination CFTR modulator therapy that works to help faulty CFTR proteins be more functional.
Its availability — the therapy was initially approved in the U.S. in 2019 — has significantly improved clinical outcomes for people with CF, with better lung function and higher life quality seen for patients. Clinical trial data indicate reductions in sweat chloride levels, often by around 50%, that correspond with these improvements, according to the researchers.
In this study, a team of scientists in Copenhagen aimed to collect real-world data to support clinical trial findings related to Trikafta and sweat chloride levels.
Their analysis included 430 people with CF who had at least one copy of F508del, the most common CF-causing mutation, and an available sweat test. All were included in the national Danish CF Cohort, a registry for CF patients from Denmark, Greenland, and the Faroe Islands.
Nearly three-quarters of the patients had two copies of F508del, and thus were considered homozygous, while the remaining had one, and were heterozygous.
Study reveals areas for further research into sweat chloride levels
From these individuals, 977 sweat tests were collected. These comprised 359 collected when patients were not on CFTR modulators, 304 with a CFTR modulator other than Trikafta, and 314 with Trikafta.
Among untreated homozygous patients, sweat chloride levels were a mean of 104 millimoles per liter (mmol/L), which significantly dropped by 59% (to 60 mmol/L) for measures taken while on Trikafta. Likewise, heterozygous patients saw an average 48% drop from 82 mmol/L to 39 mmol/L.
Other CFTR modulators led to smaller decreases in these levels.
Still, regardless of treatment status, there was a high variation in sweat chloride levels. Seven heterozygous patients had normal levels without treatment.
Even with Trikafta, 27% of heterozygous and 23% of homozygous patients still had levels that were considered elevated.
“These non-responders, in terms of sweat chloride concentration, may serve as candidates for future studies, especially in the development of improved modulators,” the researchers wrote.
Our study provides real-world evidence of the beneficial effect of [Trikafta] treatment in [people with CF].
Age was associated with higher concentrations, and men tended to have higher concentrations than did women.
Overall, “our study provides real-world evidence of the beneficial effect of [Trikafta] treatment in [people with CF],” the researchers wrote, noting that the real-world results offer data from a broader population than that included in clinical studies.
The findings leave a few areas for additional research.
“Future studies should explore the relationship between sweat chloride concentration and clinically relevant outcomes in greater detail,” the scientists wrote.
According to the team, such studies will offer information about whether sweat chloride can be used as a proxy indicator of benefits in other organ systems when monitoring patients for a treatment response.
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