Sweat study finds room for improvement in CFTR modulators

Sweat tests show high chloride levels in patients on treatment

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Some people with cystic fibrosis (CF) have levels of sweat chloride above the cut-off for a diagnosis of the disease despite being on CFTR modulators, suggesting there is room for improving treatment, a study found.

The study, “Heterogeneity of CFTR modulator-induced sweat chloride concentrations in people with cystic fibrosis,” was published in the Journal of Cystic Fibrosis.

CF patients have higher levels of chloride in their sweat because the CFTR protein, a channel that transports chloride ions into and out of cells, is faulty or missing. Higher levels of sweat chloride usually mean more severe symptoms of CF.

CFTR modulators, a type of medication that targets the causes of CF, can increase the functionality of the CFTR protein and help ease CF symptoms. But they may not always bring sweat chloride down to normal levels.

While the findings suggest there is room for improving treatment with CFTR modulators, “it remains to be determined whether additional CFTR restoration would improve clinical outcomes” for patients with higher levels of sweat chloride, the researchers wrote.

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CFTR modulators lowered sweat chloride, but levels still high

The CHEC-SC study (NCT03350828) looked at how the levels of sweat chloride varied in 3,131 people with CF, 4 months and older, based on the disease-causing mutations they carried and the CFTR modulators they used. CHEC-SC stands for Characterizing CFTR Modulated Changes in Sweat Chloride and their Association with Clinical Outcomes.

Researchers used a sweat test to measure the amount of chloride in the patients’ sweat. They obtained 3,787 measurements from patients who had been on Trikafta (elexacaftor, tezacaftor, and ivacaftor), Kalydeco (ivacaftor), Orkambi (lumacaftor and ivacaftor), or Symdeko (tezacaftor and ivacaftor) for at least 90 days.

Most patients carried two copies (63.7%) or one copy (30.8%) of F508del, the most common CF-causing mutation. The remaining 5.5% had CF that wasn’t caused by a F508del mutation.

Sweat chloride dropped from a median 100 mmol/L before treatment to levels ranging from a median 42 mmol/L after treatment with Trikafta to 91 mmol/L after treatment with Symdeko. A level of 60 mmol/L or greater means that a person likely has CF.

After treatment with Trikafta, 79.1% of patients’ measurements were below 60 mmol/L, with 460, or 26%,  falling below 30 mmol/L. Fewer measurements were below 60 mmol/L after treatment with Kalydeco (64.2%), Orkambi (10.8%), or Symdeko (6.9%).

However, even after treatment with Trikafta, 370, or 21%, of the measurements were at or above the cut-off level of 60 mmol/L. More patients who carried one copy of F508del and one minimal function mutation had measurements of at least 60 mmol/L compared with those who carried two copies of F508del (31% vs. 18%).

Sweat chloride levels were 7.4 mmol/L lower in female patients with two copies of F508del than in males with two copies. In 6- to 11-year-old patients in the same group, the levels were 6 mmol/L lower than in those 26 and older; and in patients 18-25, they were 6 mmol/L higher.