ArticlesLong-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST)
Introduction
Cystic fibrosis is an autosomal recessive genetic disorder characterised by chronic pulmonary infection, bronchiectasis, pancreatic exocrine insufficiency, and elevated sweat chloride.1 Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) that affect CFTR-dependent ion transport. More than 1900 mutations in CFTR have been identified, with the most common mutation being Phe508del-CFTR. About 85% of patients with cystic fibrosis worldwide carry at least one Phe508del-CFTR mutation, with 50% homozygous for the mutation.2, 3, 4, 5 Although many of the mutations are rare, the disease-causing Gly551Asp-CFTR mutation is fairly common and is identified in about 4% of patients with cystic fibrosis worldwide.2, 3, 4
Gly551Asp-CFTR is expressed on the surface of epithelial cells but, compared with normal CFTR channels, has reduced function due to low channel open probability compared with normal CFTR (ie, defective gating). This leads to a severe reduction in CFTR chloride transport activity6 and cystic fibrosis disease. Ivacaftor is a novel CFTR potentiator that increases chloride transport by potentiating the channel open probability of the CFTR protein, including Gly551Asp-CFTR.6, 7, 8 In-vitro studies of ivacaftor have shown significant improvements in CFTR chloride channel opening time, with improved chloride transport approaching 50% of normal CFTR.6, 7 Two phase 3 studies (STRIVE and ENVISION) examined the effects of ivacaftor in patients with cystic fibrosis who had at least one copy of Gly551Asp-CFTR. STRIVE assessed ivacaftor in patients aged 12 years and older with moderate cystic fibrosis lung disease (forced expiratory volume in one second [FEV1] from 40–90% predicted) during a 48-week period.9 ENVISION was a similar study but recruited paediatric patients aged 6–11 years (FEV1 from 40–105% predicted).10 In STRIVE, ivacaftor improved lung function, weight, and patient-reported respiratory symptoms, reduced the frequency of pulmonary exacerbations, and reduced sweat chloride levels to below the diagnostic threshold.9 Similar improvements in lung function and nutrition were seen with ivacaftor in ENVISION.10 These studies helped to establish the safety and tolerability profile of ivacaftor in patients with cystic fibrosis with a Gly551Asp mutation. The results of these studies led to the approval of ivacaftor in North America, Australia, New Zealand, and Europe as a chronic therapy for patients with cystic fibrosis aged 6 years and older with at least one copy of Gly551Asp-CFTR.
Although these trials have shown the benefit-risk profile of ivacaftor during 48 weeks, the long-term safety and efficacy of ivacaftor is not known. The aims of PERSIST were to identify whether long-term use of ivacaftor was safe and well tolerated in patients with cystic fibrosis and whether the beneficial effects of ivacaftor seen in STRIVE and ENVISION were sustained. We present results from PERSIST and the experience so far in patients with cystic fibrosis who have received up to 144 weeks of daily ivacaftor therapy.
Section snippets
Study design and participants
PERSIST was an open-label clinical trial of ivacaftor in eligible patients who completed 48 weeks of treatment or placebo in STRIVE or ENVISION. Patients were eligible if they had the Gly551Asp-CFTR mutation on at least one allele and had completed either the STRIVE9 or ENVISION study.10 Further inclusion criteria were that women who could bear children must have had a negative urine pregnancy test and met requirements for contraception if sexually active; males who could father a child also
Results
Between July 8, 2010, and April 8, 2013, PERSIST enrolled 192 patients: 144 adolescents/adults from STRIVE and 48 children from ENVISION (figure 1). Table 1 shows the demographic and baseline characteristics at roll-over into PERSIST. At entrance into PERSIST, baseline percentage predicted FEV1, weight, BMI, weight-for-age z-scores, and BMI-for-age z-scores were higher in the groups that had received ivacaftor than those that had received placebo in STRIVE or ENVISION. 173 (90%) of 192 patients
Discussion
Our findings show that the benefits of ivacaftor on lung function, weight, and patient-reported respiratory symptoms noted in the earlier STRIVE and ENVISION studies were sustained for up to 144 weeks of therapy. Patients who previously received placebo showed responses to ivacaftor treatment similar to those who received ivacaftor in the original randomised controlled trials. In adults/adolescents, the beneficial effect of long-term ivacaftor on pulmonary exacerbations continued throughout the
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