Elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and rare mutations.

Introduction: The triple combination of elexacaftor/tezacaftor/ivacaftor (ETI) has dramatically improved the outcome of people with Cystic Fibrosis (pwCF) with at least one F508del mutation. However, carriers of rare cystic fibrosis transmembrane conductance regulator (CFTR) variants are not candidates for this innovative treatment.

Methods: In this observational study, we report the results of the compassionate use of ETI in 10 pwCF carriers of rare mutations after 2 months of treatment. Rectal organoids and short-term cultures of nasal epithelium obtained from rectal suction biopsies and nasal brushing were obtained from four subjects.

Results: After 2 months of ETI, all patients (4 males, mean age 30.1 ± 13.3 years) showed a significant increase of FEV₁% predicted values [+8.0 (3.5-12.7) %, p < 0.010], body mass index [+0.85 (0-1.22) kg/m², p < 0.020] and cystic fibrosis questionnaire-revised [+19.5 (6.3-29.2) points, p < 0.009]. A significant decrease of sweat chloride concentration [-11.2 (-1.7 to -34.0) mmol/L, p < 0.020] and exacerbations [-1.5 (-2 to -1), p < 0.008] was also recorded. Overall, 7 out of 10 participants were considered full responders. All patients reported cough disappearance (n = 3) or reduction (n = 7). Long-term oxygen was discontinued in two out of three patients and one also stopped noninvasive ventilation and was removed from the lung transplantation waiting list.

Conclusions: Despite the limited number of cases, our results support the use of CFTR modulators in patients with rare CFTR variants that are not currently approved for ETI in Europe.