Real

Introduction Elexacaftor, Tezacaftor, Ivacaftor (ETI) became available in the UK in August 2020 to treat people with Cystic Fibrosis (CF) aged > 12 years. We report a real-world study of clinical outcomes in young people treated with ETI at our CF centre within the first two years of its availability.

Methods Participants aged 12-17 were identified within our clinic, with demographic data supplemented by the UK CF registry. Comprehensive outcome data spanning two years pre- and two years post-initiation of CFTR modulators were compiled from various local sources, including patient records, medication delivery logs, and clinical notes.

Results Of the 62 patients started on ETI (32 male, mean age 13.3 years), most (76%) were homozygous for the F508del mutation. Three discontinuations occurred: one pregnancy, two related to side effects. Adherence was high (Proportion of Days covered >90% both years). Following ETI initiation there was a significant increase in mean FEV1% (+11.7 units; 95% CI 7.4 – 15.6), sustained throughout the two-year treatment period. There was no association between baseline lung function and the degree of improvement or rate of decline post-treatment. Improvements were similar for all treatable genotypes. There was a small increase in BMI z-score at four months of treatment, returning to baseline by 24 months. There was a marked reduction in the need for intravenous antibiotics.

Conclusions ETI use in adolescents in a real-world setting led to sustained improvements in health outcomes, consistent with those seen in open trial extension studies

What is already known on this topic - Clinical trials have demonstrated the efficacy of the highly effective CFTR modulator ETI in improving health outcomes for CF patients. However, there is a significant gap in understanding its real-world impact, particularly in young patients where adherence to optimise long-term outcomes is crucial.

What this study adds - ETI provides sustained real-world benefits in young people with CF, including better lung function and reduced need for intravenous antibiotic treatment. High adherence likely plays a role.

How this study might affect research, practice or policy - These findings support the widespread adoption of ETI in eligible CF patients and emphasise the need for further research to assess its long-term benefits and optimal integration into CF treatment protocols.

JPL and GJC have both served as principal investigators on Vertex-sponsored studies evaluating the use of ETI in patients with cystic fibrosis.

SM was funded by an NIHR Pre-Doctoral Fellowship (NIHR302776). RHK was funded by UK Research and Innovation (Future Leaders Fellowship MR/X015017/1).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This work used anonymised data from the UK Cystic Fibrosis Registry, which has Research Ethics Approval (REC ref: 07/Q0104/2). The use of the data was approved by the Registry Research Committee (Data Request Reference 382). Data are available following application to the Registry Research Committee. https://www.cysticfibrosis.org.uk/the-work-we-do/uk-cf-registry/apply-for-data-fromthe-uk-cf-registry. This work was also approved by the London School of Hygiene & Tropical Medicine Research Ethics Committee (Ref 21866).

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