Response to Elexacaftor/Tezacaftor/Ivacaftor in people with cystic fibrosis with the N1303K mutation: Case report and review of the literature

Cystic fibrosis (CF) is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Thousands of CFTR mutations have been identified, but only a fraction are known to cause CF, with the most common being the prototypical class II CFTR mutation F508del. Elexacaftor-Tezacaftor-Ivacaftor (ETI) is a CFTR modulator that significantly increases ppFEV1 and reduces exacerbation frequencies. It is indicated for people with CF (pwCF) 2 years or older with at least one copy of F508del or one copy of the other 177 CFTR mutations that are responsive to ETI based on clinical or in vitro data. N1303K is the second most common class II mutation in the U.S. but is not yet FDA-approved for CFTR modulator therapy. However, N1303K is very similar to the F508del mutation and reveals variable in vitro responses to ETI.Theratyping provides an opportunity to consider ETI therapy for pwCF with mutations currently not approved by the FDA. We describe the case of an adult CF patient with W1282X and N1303K CFTR mutations and advanced CF lung disease (ACFLD) and declining lung function in which ETI was started after theratyping of nasal cells showed a meaningful response to ETI (current enhanced to over 10% of WT CFTR). The patient experienced clinical improvement with a 5% improvement in ppFEV1 and 10% increase in weight. However, there was no change in sweat chloride and the increase in ppFEV1 was less than what has been described for ACFLD patients with more typical ETI-amenable mutations. However, the response was in line with a few other cases described in the literature. This suggests a partial functional CFTR rescue like first-generation modulators for F508del. Thus, pwCF with N1303K CFTR variant could be considered for ETI eligibility.