(20) Impact of Elexacaftor/Tezacaftor/Ivacaftor therapy on older patients with Cystic Fibrosis

Background: Survival for CF patients has increased over the past few decades and is projected to rise further with the use of effective CFTR modulator therapy. We aimed to assess clinical response of CF patients aged ≥40 years to Elexacaftor/Tezacaftor/Ivacaftor (Elx/Tez/Iva) therapy, and explore the impact of Elx/Tez/Iva therapy on liver function tests (LFTs), cardiovascular risk factors including serum markers of inflammation, lipid profiles, blood pressure (BP) and non-invasive measurements of central arterial stiffness; including pulse wave velocity (PWV) and augmentation index (AI).

Methods: We conducted a single-centre, prospective, observational study between August 2020 and December 2021 of CF patients aged ≥40 years who were prescribed Elx/Tez/Iva following licensing of this CFTR modulator in the UK. Measurements of C-reactive protein (CRP), LFTs, serum iron, lipid profiles, spirometry, sweat tests, BP, PWV and AI were taken at times of clinical stability before commencing Elx/Tez/Iva therapy and 3 to 6 months thereafter. All permanent and temporary discontinuations of Elx/Tez/Iva were recorded.

Results: 73 adults over the age of 40 years old commenced Elx/Tez/Iva, of whom 65 patients (including 31 Phe508del homozygotes) were studied. We found the mean percentage predicted FEV₁ improved from 54.6 ± 22.9% to 61.0 ± 22.8% (p< 0.001). Mean weight increased by 1.9kg (p< 0.001) and sweat chloride was reduced by 41.4mmol/L (p< 0.001) with the greatest decrease seen in the minimal function group. There was an increase in serum iron levels from 11.9 ± 6.1 mmol/l to 15.7 ± 7 mmol/l (p=0.009). CRP decreased from a median of 3 mg/l [1.0-59] to 1 mg/l[1.0-11.0] (p=0.001). A change in lipid profiles was observed with increases in triglycerides (p=0.006) and apolipoprotein A1 (p=0.006). No change statistically significant change was found in serum total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein, cholesterol/HDL ratio, apolipoprotein B or apolipoprotein B/A1 ratio. There were also no significant changes in BP or AI however, PWV increased from 8.6 ± 1.2m/s to 9.3 ± 2.4 m/s (p=0.022). A rise in LFTs was noted with aspartate aminotransferase 22.6 ± 8.8 IU/l to 23.8 ± 10.7 IU/l (p=0.006) and bilirubin 7.5 ± 6.0umol/L to 9.3 ± 5.8umol/L (p< 0.001).

Conclusions: Our study highlights CF patients aged ≥40 years had a similar response to Elx/Tez/Iva therapy, measured by sweat chloride, spirometry and weight to that seen in younger CF patients in phase III trials. Further research is required in establishing the longer-term impact of CFTR modulation on co-morbidities including dyslipidaemia and other potential risk factors of cardiovascular disease.

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