(137) Tobacco smoke exposure reduces the clinical efficacy of ivacaftor: Results from the G551D observational trial (GOAL)

Background: Cigarette smoke causes acquired CFTR dysfunction and may exacerbate CF lung disease by reducing protein expression and function. We used urinary biomarkers of second-hand smoke exposure to examine its effect on ivacaftor response among participants in the G551D Observational Trial (GOAL). We hypothesized that exposure to smoke lessens the clinical efficacy of ivacaftor in GOAL study subjects.

Methods: Smoke exposure was quantified with LC-MS/MS of urinary NNAL, a nicotine metabolite used in studies of second-hand smoke exposure, and 3-HPMA, a metabolite of acrolein that affects CFTR channel gating. Specimens were categorized as exposed (NNAL ≥10 pg/ml or HPMA ≥75^th percentile of the sample distribution), not exposed (NNAL< 10 and 3-HPMA < 50^th percentile), or undetermined (NNAL< 10 and 3-HPMA 50^th-75^thpercentile). Primary outcome was change in sweat chloride from baseline (pre-ivacaftor) to 6 months post-ivacaftor initiation. Secondary outcomes were change in ppFEV₁ and CFQ-R respiratory scale.

Results: A total of 142 individuals, mean age 20.8 (SD 11.4), range 6-59 years, contributed urinary specimens. About a third (N=41, 29%) were smoke-exposed, 71 (50%) were unexposed, and 30 (21%) were undetermined. After 6 months of ivacaftor treatment, sweat chloride decreased by 59.2 mmol/L (95%CI -64.1, -54.3) in unexposed subjects vs 44.0 (95%CI -53.0, -35.0) in smoke-exposed subjects (p< 0.01). At 6 months, the mean absolute sweat chloride value was 42.3 vs 58.5 mmol/L (p< 0.01) in unexposed vs exposed subjects (Fig 1). In multivariable models controlling for age and baseline clinical characteristics, smoke-exposed subjects had 4.5-point less improvement in ppFEV₁ (95%CI -8.8, -0.2; p< 0.01) and 6.8-point less improvement in CFQ-R respiratory scale (95%CI -13.1, -0.5; p< 0.01) compared to unexposed counterparts.

Conclusions: Tobacco smoke exposure, assessed by urinary biomarkers, limits the therapeutic efficacy of ivacaftor in subjects with G551D CFTR. Sweat chloride declined by an additional 15 mmol/L in unexposed subjects, with consequent improvement in lung function and respiratory quality of life. Cessation of smoke exposure may optimize the therapeutic benefit of highly effective CFTR modulators.

Acknowledgements: This work was supported by grants from the National Institutes of Health (P30DK72482) and the CF Foundation (OATES20AO-I).

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