(443) Elexacaftor/Tezacaftor/Ivacaftor treatment promotes inflammation resolution in people with CF

Background: Excessive and persistent inflammation is a major cause of lung damage in people with CF (pwCF). Several studies have demonstrated an improvement in measurements of inflammation in pwCF with G551D mutations taking Ivacaftor, but little is known of how CFTR modulators will impact inflammation in pwCF now able to benefit from the highly effective CFTR modulator combination Elexacaftor/Tezacaftor/Ivacaftor (Elex/Tez/Iva). Inflammation resolution is an essential feature in the process of tissue repair and we wanted to investigate whether treatment of pwCF with Elex/Tez/Iva promotes a “pro-repair” environment.

Methods: Eligible adults were selected by genotype and recruited when commencing or switching from a different modulator to Elex/Tez/Iva. Additionally, 10 modulator naïve patients were recruited to undergo high resolution CT chest scans prior to commencing Elex/Tez/Iva and after 1 year of treatment, to assess for evidence of improvement in inflammatory lung damage. Serum samples were collected prior to commencing modulator, and consecutively at 3 months and 1 year of therapy. Inflammatory biomarkers including calprotectin, IL-6, IL-8, IL-10 and CRP were measured. In a sub-group of patients nasal cells were collected at the same time points and selected basal cells subject to RNA sequencing.

Results: 77 adult pwCF were recruited. There was a significant reduction in C-reactive protein in the initial 3 months after commencing Elex/Tez/Iva treatment (p=0.0021, n=73). IL-6 was significantly reduced at 3 months of Elex/Tez/Iva (p=0.0023, n=49) and correlated with CRP reduction, however, there was no significant change seen in circulating levels of IL-8 or IL-10. Calprotectin, a biomarker of exacerbation risk, was significantly reduced (p=0.0028, n=38) after 3 months of Elex/Tez/Iva in patients who had not been on a previous modulator. pwCF who were previously treated with Tez/Iva and switched to Elex/Tez/Iva at the start of the study had lower levels of calprotectin at baseline. Biomarker analysis after 1 year of therapy is on-going. CT imaging after 1 year of Elex/Tez/Iva therapy showed improvements in bronchial wall thickening and associated bronchiectasis. Gene ontology enrichment analysis of basal cells from pwCF (n=9) before and after 3 months of Elex/Tez/Iva treatment demonstrated that pathways associated with tissue repair were enriched following treatment.

Conclusions: Our study shows that treatment with Elex/Tez/Iva improves systemic markers of inflammation. Elex/Tez/Iva is also associated with improvements in CF related changes on chest CT scans and the development of gene signatures in basal cells associated with repair. Together these data suggest that treatment with Elex/Tez/Iva promotes inflammation resolution and is associated with basal cell changes that favour lung repair pathways.

Acknowledgements: This work was supported by the Scottish Adult Cystic Fibrosis Unit, Edinburgh; the Medical Research Council; Warren's Wish Charitable Foundation; and the Cystic Fibrosis Trust.

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