CFTR modulators need to lower sweat chloride levels, study finds
Greater benefits seen in people whose levels fell with treatment in trials
Among cystic fibrosis (CF) patients treated with CFTR modulators in pivotal clinical trials, those who achieved lower sweat chloride levels — a standard assessment for diagnosing and monitoring CF — saw greater clinical improvements, according to a pooled analysis of trial data.
Sweat chloride levels in patients also correlated with a measure of CFTR function in cell studies. CFTR is the protein whose problems underlie CF.
Altogether, the scientists believe that restoring sweat chloride to near normal levels is an important goal when developing more effective disease treatments.
“These findings support the therapeutic goal of CFTR modulator therapy to restore CFTR function to normal as early in life as possible … to reverse the abnormal physiology of underlying CF disease and to optimize therapeutic benefit,” they wrote.
CFTR mutations affect the movement of water and salt molecules in cells
The study, “Sweat chloride reflects CFTR function and correlates with clinical outcomes following CFTR modulator treatment,” was published in the Journal of Cystic Fibrosis. It was funded by Vertex Pharmaceuticals, which markets all currently available CFTR modulator therapies, and a number of its employees contributed to the study.
CF is caused by mutations in the CFTR gene, which encodes the production of the CFTR protein involved in regulating the movement of water and salt molecules, particularly chloride, in and out of cells.
Different CF-causing mutations affect CFTR in various ways. But the end result is always an inability to appropriately regulate the water and chloride flow in cells, leading to the buildup of thick and sticky mucus that damages organs and tissues.
Measuring chloride concentrations in a person’s sweat is a gold-standard way of establishing a CF diagnosis, and these concentrations are thought to generally reflect the degree of CFTR dysfunction. People with CF have abnormally high levels of the salt ions in their sweat, and corresponding sweat chloride levels of at least 60 millimoles per liter (mmol/L). A normal level is less than 30 mmol/L.
The sweat test, as it’s known, also can be used to monitor disease severity and treatment responses. Among CF patients, higher sweat chloride levels, generally associated with poorer residual CFTR function, link with more severe disease symptoms. Treatments seen in clinical trials to lower sweat chloride levels — reflecting an improvement in CFTR function — generally are considered to be showing clinical benefit, like better lung health and nutritional status.
While a number of CFTR modulators are available, ongoing research aims at developing new ones that further improve CFTR function.
But to fully understand the potential value of more effective modulator therapies — and their potential added benefits — it’s important to determine how well measures of CFTR function, such as sweat chloride, actually correlate with clinical improvements in patients.
Trial patients had average sweat chloride levels of 101.5 mmol/L
Scientists examined pooled data from more than 1,300 CF patients treated with CFTR modulators — and more than 600 others given a placebo — in Phase 3 trials. These included studies of Symdeko (ivacaftor/tezacaftor) and Trikafta (ivacaftor/tezacaftor/elexacaftor), two modulators that went on to be approved, as well as the VX-659/tezacaftor/ivacaftor, an experimental CFTR modulator. Patients’ average sweat chloride levels at the start of these studies was 101.5 mmol/L.
Analyses showed that, in general, sweat chloride levels that fell with treatment associated with better clinical outcomes.
Treated patients who achieved sweat chloride levels below the 60 mmol/L diagnostic cutoff for CF showed numerically greater improvements in lung function and nutritional status relative to those whose levels remained at or above that threshold. They also reported greater reductions in respiratory symptoms and fewer pulmonary exacerbations, acute bouts of worsening lung function.
Likewise, they had slower annual rates of lung function decline. Overall, patients with sweat chloride levels lower than the cutoff showed no significant declines in lung function, whereas those above the cutoff exhibited a significant decline.
Still, lung function declines in people with higher sweat chloride levels occurred “at a slower rate than might be expected,” the scientists wrote. Treated patients with the highest sweat chloride levels also exhibited better clinical outcomes than those given a placebo.
“Clinical benefit was seen in all groups treated with CFTR modulators relative to placebo, even those with sweat chloride [greater than or equal to] 80 mmol/L,” the scientists wrote.
In additional experiments, measures of chloride transport in lab-grown lung cells — an indicator of CFTR function — showed a linear correlation with sweat chloride levels in people. The scientists considered these findings to support the idea that sweat chloride levels reflect underlying CFTR function.
“Results from the current study both confirm and expand upon the relationship between CFTR function, sweat chloride, and clinical outcomes shown in natural history studies,” they wrote.
The team noted that larger and longer studies aiming to further understand the relationship between sweat chloride and clinical outcomes in CF “could further evaluate the clinical benefits of normalizing versus simply improving CFTR function.”
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