Background: Elexacaftor/tezacaftor/ivacaftor (ETI) treatment is showing remarkable beneficial effects in people with Cystic Fibrosis (pwCF) harboring the F508del mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. Although this therapy is generally well tolerated in pwCF, some adverse events (AEs) have been recently described both in controlled studies and in post-marketing observations. Methods: We followed 414 pwCF carrying F508del CFTR that initiated ETI treatment, recording AEs for a period of 5 years. Results: A total of 142 AEs were reported. The most frequent AEs in the whole cohort were liver marker elevation, skin rush, epigastric pain, headache, and depression. Considering pediatric subjects, psychiatric and gastrointestinal disorders were the most frequent AEs. Only one patient reported a severe AE, leading to treatment discontinuation. In case of AEs, different decisions on ETI treatment were made, including temporary interruption and temporary or permanent dosage modification. Conclusions: Throughout the long-term observational period, almost 21% of pwCF experienced at least one AE. Psychiatric disorders, in particular attention deficit, were the most prevalent issue in our pediatric cohort, whereas adult patients mainly reported depression, anxiety and sleep disorders. This study therefore strengthen the recommendation of screening for changes in mental health during ETI treatment. AEs led to the permanent reduction of ETI dosage in 32% of cases, raising the issue of safety in relation to dosage reduction, efficacy, and minimum ETI levels. Eventually, this study highlights the need for a longitudinal monitoring of ETI safety since a significant number of AEs occurred after one year of treatment.

Background: Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a therapy approved for cystic fibrosis (CF) that has given improved clinical outcomes in patients carrying the F508del mutation. There are few published data regarding ETI’s effects on patients’ quality of life (QoL). This study aims to (fill the data gap in current literature by assessing) evaluate the long-term effects of ETI on QoL. Methodology: A prospective observational study was conducted with thirty-seven severe patients that received ETI for compassionate use (group A), 184 received it for on-label use (group B). All carried one F508del mutation. Patients were assessed using the CFQ-R (Cystic Fibrosis Questionnaire-Revised). The evaluation time-points were pre-treatment (T0), and after 12 (T1) and 24 months (T2); group A was also assessed after 36 months (T3). Twenty-five patients completed 3 years of treatment and 65 patients completed 2 years of treatment, in groups A and B respectively. Results: At T1, median values for almost all areas of CFQ-R statistically significant increased in group A, particularly Physical Functioning (+ 25.0), Respiratory (+ 22.2) and Health Perception (+ 22.2).The Social Functioning area statistically significant increased at T2 (+ 5.6). At T3, these improvements remained stable. At T1, all areas of CFQ-R statistically significant increased in group B, particularly the Health Perception (+ 22,2) heading. At T2, these improvements remained stable. For both groups, the changes identified at the last follow-up showed no major differences by gender, age or genetic status. Conclusions: Treatment with ETI significantly improved patients’ QoL in both groups at 12–24 months, these improvements remaining stable in patients tested at 36 months.

Background: Cystic Fibrosis is an inherited disorder caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene, encoding a chloride and bicarbonate channel widely expressed in epithelia. Loss of CFTR function leads to dehydration of the epithelium surface with thicker mucus secretions from tissues. The lungs, pancreas, liver, intestines, and sweat glands are the most common affected organs. However, pulmonary disease remains the main cause of morbidity and mortality. Fortunately, elexacaftor/tezacaftor/ivacaftor (ETI) therapy is showing unprecedented clinical benefits in patients with Cystic Fibrosis (CF) carrying at least one F508del mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. However, almost 35% of the CF population living in the Mediterranean area still lacks effective CFTR modulator therapies because of the elevated incidence of patients with (pw)CF harboring CFTR rare mutations (RMs), different from F508del. Methods: Twenty-three pwCF harboring RM including the N1303K underwent off-label ETI treatment for 6-12 months. Respiratory function in terms of FEV1 and FVC was measured after 3, 6, and 12 months of treatment. In addition, we analyzed sweat chloride concentration, body mass index (BMI), and quality of life before and after treatment. Possible adverse effects were recorded. Results: All patients included in this off-label program displayed a substantial improvement in respiratory function. In particular, patients carrying the N1303K mutation showed an improvement in FEV1 and FVC similar to that observed in subjects harboring the F508del mutation, although sweat chloride concentration was not significantly decreased. No severe adverse effect was reported. Conclusions: This study strengthens the clinical efficacy of ETI in pwCF harboring the N1303K and other CFTR rare variants. Since these CFTR RMs have not been approved for ETI therapy in Europe, this study may promote the inclusion of these variants in the list of CFTR mutations responsive to ETI.

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) treatment is showing remarkable beneficial effects in patients with Cystic Fibrosis (pwCF) harboring the F508del mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. Although this therapy is generally well tolerated in pwCF, some adverse events (AEs) have been recently described both in controlled studies and in post-marketing observations. Methods: We followed 414 pwCF carrying F508del CFTR that initiated ETI treatment, recording AEs for a period of 5 years. Results: A total of 142 AEs were reported. The most frequent AEs in the whole cohort were liver marker elevation, skin rush, epigastric pain, headache, and depression. Considering pediatric subjects, psychiatric and gastrointestinal disorders were the most frequent AEs. Only one patient reported a severe AE, leading to treatment discontinuation. In case of AEs, different decisions on ETI treatment were made, including temporary interruption and temporary or permanent dosage modification. Conclusions: Throughout the long-term observational period, almost 21% of pwCF experienced at least one AE. Psychiatric disorders, in particular attention deficit, were the most prevalent issue in our pediatric cohort, whereas adult patients mainly reported depression, anxiety and sleep disorders. This study therefore strengthen the recommendation of screening for changes in mental health during ETI treatment. AEs led to the permanent reduction of ETI dosage in 32% of cases, raising the issue of safety in relation to dosage reduction, efficacy, and minimum ETI levels. Eventually, this study highlights the need for a longitudinal monitoring of ETI safety since a significant number of AEs occurred after one year of treatment.