WS15.02Impact of one versus two responsive CFTR variants on sweat chloride and FEV1 responses to elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis: a real-world study

Abstract

Objectives

It remains unknown whether responses to elexacaftor-tezacaftor-ivacaftor (ETI) vary according to the number of ETI-responsive CFTR variants in people with cystic fibrosis (pwCF).

Methods

Data from pwCF treated with ETI were obtained using the French adult ETI-real world study and the French Compassionate program. CFTR variants were classified according to their ETI-responsiveness, as determined in the French Compassionate Program. Sweat chloride concentrations with ETI and absolute change in sweat chloride and in ppFEV₁ following ETI initiation were described, comparing pwCF with one vs. two ETI-responsive variants.

Results

Among 1266 participants, 834 had two ETI-responsive variants and 432 had only one. Median [IQR] sweat chloride concentrations were lower in participants with two vs. one ETI-responsive variants; 36 [24; 50] mmol/l and 53 [26; 72] mmol/l, respectively (P<0.0001). The proportion of participants with sweat chloride concentration <30 mmol/l was 35.7% vs. 15.0% in those with two vs. one ETI-responsive variants, respectively (Chi-square, P<0.00001). In multivariable analyses, the number of ETI-responsive variants was a determinant of sweat chloride concentration with ETI (P<0.0001) but not of absolute change in ppFEV₁ following ETI initiation (P=0.80).

Conclusion

PwCF with two responsive CFTR variants have better correction of CFTR function than those with one responsive CFTR variant when treated with ETI, but sweat chloride response is not predictive of the change in ppFEV₁. These data suggest that maximal improvement in lung function is already obtained with current CFTR modulators and that no further lung function improvement may be expected from newer modulators with more potent restoration of CFTR function.