Heterogeneity of CFTR modulator-induced sweat chloride concentrations in people with cystic fibrosis

Abstract

Background: Sweat chloride (SC) concentrations in people with cystic fibrosis (PwCF) reflect relative CF transmembrane conductance regulator (CFTR) protein function, the primary CF defect. Populations with greater SC concentrations tend to have lesser CFTR function and more severe disease courses. CFTR modulator treatment can improve CFTR function within specific CF genotypes and is commonly associated with reduced SC concentration. However, SC concentrations do not necessarily fall to concentrations seen in the unaffected population, suggesting potential for better CFTR treatment outcomes. We characterized post-modulator SC concentration variability among CHEC-SC study participants by genotype and modulator.

Methods: PwCF receiving commercially approved modulators for ≥90 days were enrolled for a single SC measurement. Clinical data were obtained from chart review and the CF Foundation Patient Registry (CFFPR). Variability of post-modulator SC concentrations was assessed by cumulative SC concentration frequencies.

Results: Post-modulator SC concentrations (n = 3787) were collected from 3131 PwCF; most (n = 1769, 47 %) were collected after elexacaftor/tezacaftor/ivacaftor (ETI) treatment. Modulator use was associated with lower SC distributions, with post-ETI concentrations the lowest on average. Most post-ETI SC concentrations were <60 mmol/L (79 %); 26 % were <30 mmol/L. Post-ETI distributions varied by genotype. All genotypes containing at least one F508del allele had individuals with post-ETI SC ≥60 mmol/L, with the largest proportion being F508del/minimal function (31 %).

Conclusions: Post-modulator SC concentration heterogeneity was observed among all genotypes and modulators, including ETI. The presence of PwCF with post-modulator SC concentrations within the CF diagnostic range suggests room for additional treatment-associated CFTR restoration in this population.

Keywords: CFTR function; CFTR modulators; Epidemiology; Sweat chloride.

Figure 1.. Area-proportional diagrams of CFTR modulator enrollments among CHEC-SC enrollees.

Plots highlight numbers of individual CHEC-enrollees for which sweat chloride data are available for only one versus for multiple CFTR modulators during CHEC-SC. Individual participants could re-enroll in CHEC-SC if their modulator prescription changed.

Figure 2.. Cumulative distribution of CHEC-SC participant sweat chloride concentrations by CFTR modulator.

Sweat chloride was obtained prior to modulator use and at CHEC enrollment (post-modulator). For each modulator, the vertical axis represents the percentage of participants with sweat chloride (mmol/L) measured at or below the corresponding x-axis value. Individuals who re-enrolled in CHEC on a different modulator were included once for each applicable distribution.

Figure 3.. Cumulative distribution of CHEC-SC participant sweat chloride concentrations on ELE/TEZ/IVA by genotype.

Sweat chloride was obtained prior to modulator use and at CHEC enrollment (post-modulator). For each genotype, the vertical axis represents the percentage of participants with sweat chloride (mmol/L) measured at or below the corresponding x-axis value.

Figure 4.. Cumulative distribution of CHEC-SC participant sweat chloride concentrations on ELE/TEZ/IVA by genotype, pre- and post-modulator.

Sweat chloride was obtained prior to modulator use and at CHEC enrollment (post-modulator). For each modulator, the vertical axis represents the percentage of participants with sweat chloride (mmol/L) measured at or below the corresponding x-axis value.