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Key takeaways
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Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy improves CFTR protein function in individuals with cystic fibrosis (CF) with certain responsive genetic variants.
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Sweat chloride (SC) concentrations, typically high in people with CF, are a marker of CFTR protein function; SC decreases with CFTR modulator treatment.
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Post-modulator SC levels decreased for all participants but were lowest in those who received elexacaftor/tezacaftor/ivacaftor (ETI).
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After treatment, many patients still had SC levels above the diagnostic range, suggesting the need for additional therapies and further research.
Research study background
An ongoing multicenter study is examining the effect of cystic fibrosis transmembrane conductance regulator (CFTR) therapies on sweat chloride (SC) levels. Cystic fibrosis (CF) is diagnosed when SC concentrations exceed 60 mmol/L. Individuals with higher SC concentrations are likely to have less CFTR function and more severe disease. CFTR modulators improve CFTR protein function in individuals with responsive genotypes and are associated with decreased post-modulator SC levels. However, treatment doesn’t always lower SC concentrations to levels seen in populations not affected by CF.
Edith Zemanick, MD, a physician-scientist in the Mike McMorris Cystic Fibrosis Research and Care Center at Children’s Hospital Colorado, contributed to the design of the Characterizing CFTR Modulated Changes in Sweat Chloride and Their Association with Clinical Outcomes (CHEC-SC) study. She co-authored a recent report of phase 2 findings from 51 enrollment sites between 2018 and 2022. Participants, both pediatric and adult, were treated with a commercially available CFTR modulator for at least three months and categorized by modulator type and CF genotype. Investigators used cumulative incidence plots to determine the distribution of SC values and proportion of individuals with values above the diagnostic threshold and within the normal range.
“We do not know the amount of CFTR protein function people with CF need to remain healthy and prevent disease. However, we think a post-modulator SC below the diagnostic range, or even below the normal range of 30 mmol/L, may indicate that there is enough CFTR protein function to prevent many complications of CF.”
- EDITH ZEMANICK, MD
All modulators lowered SC concentrations, but individual SC values were wide-ranging. Nearly half of study participants were taking elexacaftor/tezacaftor/ivacaftor (ETI), the most effective modulator available. ETI elicited the lowest chloride levels in sweat tests of those treated — 79% had values <60 mmol/L, including 26% with values in the normal range — consistent with earlier clinical trial results. In comparison, the modulators lumacaftor/ivacaftor and tezacaftor/ivacaftor were associated with smaller improvements in SC levels, lung function and clinical symptoms.
The study also revealed that the proportion of individuals with SC levels above 60 mmol/L differed by CF genetic variant, likely because only certain genetic variants respond to ETI. More individuals with two copies of the F508del, an ETI responsive variant, had SC less than 60mmol/L compared to individuals with one F508del variant. However, there was a wide range of responses in all genotype groups.
Clinical implications
To date, this is the largest study of post-modulator SC values in people with CF. Clinical trial findings thus far indicate that CFTR modulators, particularly ETI, can result in positive changes in people with CF by reducing SC levels and improving lung function. However, researchers have not yet determined if lower SCL levels correlate with better clinical outcomes. Next, the CHEC-SC study will analyze data from the CF Foundation patient registry to assess whether SC levels are linked to improvements in lung function and illness frequency over time. If confirmed, additional CFTR-enhancing therapies could offer further benefits.
Featured researcher
Edith Zemanick, MD
Associate Director of the Cystic Fibrosis Research Center
Children's Hospital Colorado
Professor
Pulmonary Medicine - Department of Pediatrics
University of Colorado
