Treatment effects of elexacaftor/tezacaftor/ivacaftor on people with cystic fibrosis heterozygous for 3849+10kbC->T and a class I variant

Background: The splice variant 3849+10kbC->T (c.3717+12191C>T) (3849 variant) is a residual function CFTR variant, characterized by insertion of an in-frame stop codon into most CFTR transcripts. Both ivacaftor (Iva) and tezacaftor/ivacaftor (Tez/Iva) have been approved for people with CF (pwCF) carrying the 3849 variant. In-vitro studies for elexacaftor/tezacaftor/ivacaftor (ETI) did not include the 3849 variant as responsive to ETI. We present the clinical effectiveness of ETI in pwCF homozygous for the 3849 variant or heterozygous for 3849 and class I variants previously treated with Iva or Tez/Iva. Methods: We conducted a multi-center observational study of pwCF homozygous for the 3849 variant or heterozygous for 3849 and class I variants who were transitioned from Iva or Tez/Iva to ETI. We collected clinical data, including sweat chloride concentrations, pulmonary function tests, BMI and intravenous antibiotic treatments. Results: We identified nine pwCF heterozygous for 3849 and class I variants and one pwCF homozygous for the 3849 variant. Prior to transitioning to ETI, nine pwCF were treated with Tez/Iva and one with Iva. Compared to baseline, median sweat chloride concentration declined from 48 to 35 mEq/L (p = 0.009). Median FEV₁ increased from 53 % to 65 % (p = 0.006). Pulmonary exacerbations requiring intravenous antibiotics declined from mean 1.4 to 0.6 in the twelve months before and after ETI. Conclusions: We demonstrate the clinical effectiveness of ETI in pwCF carrying the 3849 variant, in excess of the response to Iva or Iva/Tez. Our results provide preliminary support for clinical use of ETI in pwCF carrying the 3849+10kbC->T variant.