Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor

Abstract

Background: Ivacaftor is the first cystic fibrosis transmembrane conductance regulator (CFTR) modulator demonstrating clinical benefit in patients with cystic fibrosis (CF). As ivacaftor is intended for chronic, lifelong use, understanding long-term effects is important for patients and healthcare providers.

Objective: This ongoing, observational, postapproval safety study evaluates clinical outcomes and disease progression in ivacaftor-treated patients using data from the US and the UK CF registries following commercial availability.

Methods: Annual analyses compare ivacaftor-treated and untreated matched comparator patients for: risks of death, transplantation, hospitalisation, pulmonary exacerbation; prevalence of CF-related complications and microorganisms and lung function changes in a subset of patients who initiated ivacaftor in the first year of commercial availability. Results from the 2014 analyses (2 and 3 years following commercial availability in the UK and USA, respectively) are presented here.

Results: Analyses included 1256 ivacaftor-treated and 6200 comparator patients from the USA and 411 ivacaftor-treated and 2069 comparator patients from the UK. No new safety concerns were identified based on the evaluation of clinical outcomes included in the analyses. As part of safety evaluations, ivacaftor-treated US patients were observed to have significantly lower risks of death (0.6% vs 1.6%, p=0.0110), transplantation (0.2% vs 1.1%, p=0.0017), hospitalisation (27.5% vs 43.1%, p<0.0001) and pulmonary exacerbation (27.8% vs 43.3%, p<0.0001) relative to comparators; trends were similar in the UK. In both registries, ivacaftor-treated patients had a lower prevalence of CF-related complications and select microorganisms and had better preserved lung function.

Conclusions: While general limitations of observational research apply, analyses revealed favourable results for clinically important outcomes among ivacaftor-treated patients, adding to the growing body of literature supporting disease modification by CFTR modulation with ivacaftor.

Eu pas registration number: EUPAS4270.

Keywords: cystic fibrosis; rare lung diseases; respiratory infection; systemic disease and lungs.

Figure 1

Hospitalisations and pulmonary exacerbations, 2014 ivacaftor and comparator cohorts, (A) USA and (B) UK. ªHospitalisation due to any reason in the US CFFPR and for PEx in the UK CFR. ^bIn the UK CFR, PEx were defined as the requirement of intravenous antibiotic use at home or in the hospital. CFFPR, Cystic Fibrosis Foundation Patient Registry; CFR, Cystic Fibrosis Registry; PEx, pulmonary exacerbations; RR, relative risk.

Figure 2

(A) Hospitalisations and (B) PEx by age and lung function, 2014 ivacaftor and comparator cohorts, USA and UK. Error bars indicate 95% CIs. *P=0.23; ^†p=0.12. Hospitalisation due to any reason in the US CFFPR and for PEx in the UK CFR; PEx were defined as the requirement of intravenous antibiotic use at home or in the hospital. CFFPR, Cystic Fibrosis Foundation Patient Registry; CFR, Cystic Fibrosis Registry; PEx, pulmonary exacerbations; ppFEV₁, per cent predicted FEV ₁. Refer to online supplementary tables S1-S4 for tables corresponding to figure 2.

Figure 3

Death and organ transplantation, 2014 ivacaftor and comparator cohorts, (A) US CFFPR and (B) UK CFR. *Fisher’s exact p values are shown when the expected value is <5 in at least one cell of the contingency table. CFFPR, Cystic Fibrosis Foundation Patient Registry; CFR, Cystic Fibrosis Registry; NR, not reported; RR, relative risk.

Figure 4

CF complications, 2014 ivacaftor and comparator cohorts, (A) US CFFPR and (B) UK CFR Direct comparisons between the US and the UK data on the prevalence of complications cannot be made because of the differences in complication screening and data capture between countries. ^aIncludes distal intestinal obstruction syndrome, fibrosing colonopathy/colonic stricture, gastro-oesophageal reflux disease, gastrointestinal bleed (non-variceal) requiring hospitalisation, peptic ulcer disease and rectal prolapse. ^bIncludes allergic bronchopulmonary aspergillosis, asthma, massive haemoptysis and pneumothorax requiring a chest tube. ^cIncludes arthritis/arthropathy, bone fracture, osteopaenia and osteoporosis. ^dThe US CFFPR includes gallstones, gallstones requiring surgery/procedure, liver disease (cirrhosis), cirrhosis complications (oesophageal varices, gastric varices, gastrointestinal bleed, splenomegaly, hypersplenism and ascites), liver disease (non-cirrhosis), hepatic steatosis and liver disease (other); the UK CFR also includes abnormal liver enzymes. CF, cystic fibrosis; CFFPR, Cystic Fibrosis Foundation Patient Registry; CFR, Cystic Fibrosis Registry; CFRD, cystic fibrosis-related diabetes; RR, relative risk.

Figure 5

Summary of lung function changes over time for ivacaftor and comparator patients, (A) US CFFPR and (B) UK CFR. *Within-group; ^†Between-group. ^aIncludes all patients followed from 2011 through 2014 (regardless of availability of ppFEV₁ values in a given analysis year). ^bCalculations of change from baseline performed on patients with non-missing ppFEV₁ values in 2011 and 2014 (n=636 for ivacaftor; n=2854 for comparator). ^cIncludes all patients followed from 2012 through 2014. ^dCalculations of change from baseline performed on patients with non-missing ppFEV₁ values in 2012 and 2014 (n=250 for ivacaftor; n=1211 for comparator). CFFPR, Cystic Fibrosis Foundation Patient Registry; CFR, Cystic Fibrosis Registry; ppFEV₁, per cent predicted FEV₁.