WS15.03Elevated sweat chloride concentrations in people with cystic fibrosis with at least one N1303K, 2789+5G>A or R334W treated with elexacaftor/tezacaftor/ivacaftor

Objectives

Data from the French Compassionate Program have shown that people with CF (pwCF) and no F508del variant but at least one N1303K, 2789+5G>A or R334W treated with elexacaftor-tezacaftor-ivacaftor showed clinical improvement with no or small decrease in sweat chloride concentration. We sought to characterize the sweat chloride concentration with ETI in people with CF with these variants, according to the second CFTR variant.

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 were described according the second CFTR variant.

Results

Among 163 participants with at least one N1303K, 2789+5G>A or R334W variants, 55 had an F508del, 19 had a non-F508del responsive variant, 20 had two N1303K, 2789+5G>A or R334W variants and in 69 participant the other variant was non-responsive to ETI. In these subgroups, median [IQR] sweat chloride concentrations were 48 [37; 65] mmol/l, 28 [22; 50] mmol/l, 88 [79; 95] mmol/l, and 90 [84;100] mmol/l, respectively (P<0.0001). All participants with two N1303K, 2789+5G>A or R334W variants or with one of these variants and a non-ETI responsive variant had sweat chloride concentrations with ETI ≥60 mmol/l; in those with at least one F508del or another non-F508del responsive variant, only 42.6% had sweat chloride concentrations ≥60 mmol/l.

Conclusion

These data confirm that sweat chloride concentrations are often elevated in people with CF with N1303K, 2789+5G>A or R334W variants treated with ETI. Only those with another ETI-responsive variant may show sweat chloride concentration <60 mmol/l.