Real-World Outcomes of Ivacaftor Treatment in People with Cystic Fibrosis: A Systematic Review.

Jamie Duckers,Beth Lesher,Eleanor Lucas,Fosca De Iorio,Teja Thorat,Keval Chandarana,Lisa J Mcgarry

doi:10.3390/jcm10071527

Abstract

Cystic fibrosis (CF) is a rare, progressive, multi-organ genetic disease. Ivacaftor, a small-molecule CF transmembrane conductance regulator modulator, was the first medication to treat the underlying cause of CF. Since its approval, real-world clinical experience on the use of ivacaftor has been documented in large registries and smaller studies. Here, we systematically review data from real-world observational studies of ivacaftor treatment in people with CF (pwCF). Searches of MEDLINE and Embase identified 368 publications reporting real-world studies that enrolled six or more pwCF treated with ivacaftor published between January 2012 and September 2019. Overall, 75 publications providing data from 57 unique studies met inclusion criteria and were reviewed. Studies reporting within-group change for pwCF treated with ivacaftor consistently showed improvements in lung function, nutritional parameters, and patient-reported respiratory and sino-nasal symptoms. Benefits were evident as early as 1 month following ivacaftor initiation and were sustained over long-term follow-up. Decreases in pulmonary exacerbations, Pseudomonas aeruginosa prevalence, and healthcare resource utilization also were reported for up to 66 months following ivacaftor initiation. In studies comparing ivacaftor treatment to modulator untreated comparator groups, clinical benefits similarly were reported as were decreases in mortality, organ-transplantation, and CF-related complications. The safety profile of ivacaftor observed in these real-world studies was consistent with the well-established safety profile based on clinical trial data. Our systematic review of real-world studies shows ivacaftor treatment in pwCF results in highly consistent and sustained clinical benefit in both pulmonary and non-pulmonary outcomes across various geographies, study designs, patient characteristics, and follow-up durations, confirming and expanding upon evidence from clinical trials.

Highlights

Results from the LTSS for the US disease progression cohort showed a significantly lower risk of all-cause hospitalizations for the ivacaftor-treated than the modulator untreated comparator cohort beginning at Year 1 (25.5% vs. 37.4%; rate ratio (RR) 0.68; 95% confidence interval (CI) 0.59, 0.79)
The GOAL study in people with CF (pwCF) with a G551D gating mutation reported no significant difference in the odds of a positive methicillin-sensitive S. aureus (MSSA) (p = 0.59) or methicillin-resistant S. aureus (MRSA) (p = 0.44) culture from 24 months pre- to 12 months post-ivacaftor initiation [44]
Results from one study of pediatric pwCF (n = 26) noted that MRSA persisted in 80% of pwCF after 12 months of ivacaftor therapy [67], while another study showed no change in MSSA and a significant increase in the odds of positive

Summary

Introduction

CF results from mutations in the CF transmembrane conductance regulator (CFTR) gene, which impact on CFTR protein expression and/or function at the epithelial cell surface [2]. This leads to defective transport of chloride and sodium ions across the epithelial cell membrane of multiple organs, including the lungs, pancreas, gallbladder, intestine, and reproductive system [3]. Lung function is negatively affected by pulmonary exacerbations (PEx), an acute worsening of signs and symptoms that may require hospitalization and treatment with intravenous (IV) antibiotics [5,6]. Following a PEx, many pwCF do not recover baseline lung function and experience sustained decreases in ppFEV1 [6]. CF is associated with damage to the endocrine pancreas over time, leading to the development of CF-related diabetes (CFRD)

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