Real-World Outcomes Among Patients with Cystic Fibrosis Treated with Ivacaftor: 2012–2016 Experience

Abstract

Introduction: In this long-term, postapproval, observational study, data from the US Cystic Fibrosis Foundation Patient Registry and the UK Cystic Fibrosis Registry were used to evaluate the impact of ivacaftor treatment on cystic fibrosis (CF) by comparing outcomes in ivacaftor-treated patients with those in matched untreated comparator patients. Registry data from up to 5 years of ivacaftor availability in the US and up to 4 years of availability in the UK were evaluated. Methods: Starting in the first year of ivacaftor availability, ivacaftor-treated patients in each registry were matched 1:5 to comparator patients who never received ivacaftor. Clinical endpoints were evaluated in annual cross-sectional safety analyses. The key endpoints were death, organ transplants, pulmonary exacerbation, and hospitalization. Relative risks and 95% CIs were calculated to compare the ivacaftor and comparator cohorts in each registry. Results: Here, we report the complete and final results of the annual cross-sectional safety analyses across the duration of the study, with up to 5 years of follow-up. Data show a pattern of lower risk of death, transplant, pulmonary exacerbation, and hospitalization among ivacaftor-treated patients in both registries. Conclusions: Ivacaftor-treated patients had consistently favorable clinical outcomes relative to untreated comparators, and no new safety concerns were identified. While general limitations of observational research apply, these findings support disease modification by CF transmembrane conductance regulator (CFTR) modulator therapy with ivacaftor. Future research of novel CFTR modulators will need to explore alternative methods for comparator selection for evaluation of clinical data given the evolving landscape of CF treatment.

Cystic fibrosis with non‐G551D gating mutations in Italy: Epidemiology and clinical characteristics

“…Both cross‐sectional and longitudinal studies showed the favorable long‐term outcomes of ivacaftor treatment, both in terms of patients' annual experience during each year of treatment and considering their cumulative experience over time. These data support the conclusion that effective CFTR modulation with ivacaftor leads to disease modification 16–18 …”

“…Thus, we believe that the observed favorable trends in Italian patients with GMs could probably be explained by widespread ivacaftor treatment. Regarding death and transplantation, no variations were shown in the observed period, but, as in the United Kingdom, 16,18 the low number of events made this evaluation unreliable.…”

“…T A B L E 3 Death and organ transplantation across annual analyses of the gating mutation (GM) versus F/F groups We examined the GM patients' data in the years before and These data support the conclusion that effective CFTR modulation with ivacaftor leads to disease modification. [16][17][18] Unfortunately were shown in the observed period, but, as in the United Kingdom, 16,18 the low number of events made this evaluation unreliable.…”

“…No conclusions of a cause-effect relationship between improvement of non-G551D GM patients and ivacaftor treatment can be drawn until accurate data about the use of CFTR modulators are collected by the ICFR. In particular, as demonstrated in the subjects with the G551D mutation by the United Kingdom and the United States registries, [16][17][18] longitudinal trends showing a significant decrease in FEV 1 decline are needed to thoroughly define the long-term clinical effects of CFTR modulation in non-G551D patients.…”

In silico drug repositioning on F508del-CFTR: A proof-of-concept study on the AIFA library

“…These new therapies resulted in significant benefits for CF patients as described both in Randomized Controlled Trials (RCTs) and studies on data from national CF registries [13,14], but also some adverse events mainly consisting in cough, nasopharyngitis, oropharyngeal pain, and upper respiratory tract infection [15]. In addition, depression, anxiety, sleep paralysis with hypnopompic hallucinations [16] and testicular pain [17] have been reported after initiation of Trikafta therapy.…”