(253) Change in liver biomarkers after introduction of elexacaftor/tezacaftor/ivacaftor: Results from a 12-month follow-up study in the national CF-cohort in Denmark

Background: Elexacaftor/tezacaftor/ivacaftor improves lung function and nutrition status in people with cystic fibrosis (CF), whereas its hepatic impact remains poorly characterized as advanced CF liver disease was an exclusion criterion in clinical trials. Increased liver enzymes were shown in 5-10% of patients in safety studies, but almost all cases returned to habitual levels when treatment was discontinued prompting the

recommendation for routine monitoring of liver function tests. Elexacaftor/tezacaftor/ivacaftor was approved for CF patients ≥12 years in Denmark in September 2020 and extensive data has been systematically collected by the CF team before and after initiation. The objective of this study was to assess changes in liver biomarkers in the nationwide Danish cohort of patients with CF after the introduction of highly effective CF transmembrane conductance regulator modulators (CFTRm).

Methods: The study includes all patients with CF ≥12 years started on elexacaftor/tezacaftor/ivacaftor before September 2021 in Denmark. Patients with previous solid organ transplantation are excluded. Demographic and clinical characteristics, incl. gender, age, pulmonary function, CF mutation, chronic pulmonary infection, co-morbidities, nutritional status are collected at treatment initiation. Measurements of biochemical markers including hemoglobin, leucocytes, platelets, alanine aminotransferase, aspartate aminotransferase, alkaline phosphate, gamma glutamyl transferase, and bilirubin are collected at baseline and at months 1, 3, 6, 9 and 12 after initiation of elexacaftor/tezacaftor/ivacaftor. The last 12-month patient visit is scheduled in September 2022. Changes are assessed using a longitudinal mixed-effects model. Subgroup effect is assessed for patients previously treated with and patients naïve to CFTRm treatment at initiation of elexacaftor/tezacaftor/ivacaftor.

Results:

Preliminary results
A total of 300 patients (48.3% males) were included. The median age was 26 years [IQR 18;35], mean percent predicted FEV1 was 74.9% (SD±25.3) and mean body mass index was 21.4 (SD±3.6). All patients are homozygous (73.7%) or heterozygous (26.3%) for the delta 508 mutation. 106 (35.3%) patients were naïve to treatment with other CFTR modulators. Results on changes in liver biomarkers will be available after data collection is completed in September 2022.

Conclusions:

Discussion
Given the success of CFTRm in improving life expectancy and pulmonary status, the focus of care will include other causes of morbidity and mortality, such as CFLD. The findings from this study may improve insight into the impact on liver biomarkers after initiating treatment with triple CFTRm. Considering that we now treat patients with triple CFTRm, including patients with advanced CF liver disease, it is critical to study the hepatic impact to foresee patients at risk of developing hepatobiliary complications.

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