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Long-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)

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Summary

Background

Ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, is approved for the treatment of patients with cystic fibrosis aged 6 years or older with Gly551Asp-CFTR. We assessed the safety and efficacy of ivacaftor during 96 weeks of PERSIST in patients with cystic fibrosis who completed a previous 48-week, placebo-controlled trial of the drug (STRIVE or ENVISION).

Methods

In this phase 3, open-label extension study, patients received ivacaftor 150 mg every 12 h in addition to their prescribed cystic fibrosis therapies. Patients who received placebo in their previous study initiated ivacaftor in this extension study. Patients were eligible if they had a Gly551Asp-CFTR mutation on at least one allele. The primary objective was to assess the long-term safety profile of ivacaftor as assessed by adverse events, clinical laboratory assessments, electrocardiograms, vital signs, and physical examination; secondary measures included change in forced expiratory volume in one second (FEV1), weight, and pulmonary exacerbations. This study is registered with ClinicalTrials.gov, number NCT01117012 and EudraCT, number 2009-012997-11.

Findings

Between July 8, 2010, and April 8, 2013, 144 adolescents/adults (≥12 years) from STRIVE and 48 children (6–11 years) from ENVISION were enrolled. Across both trials, 38 (20%) patients had a serious adverse event during the first 48 weeks and 44 (23%) during the subsequent 48 weeks. Two adults (1%) and one child (<1%) discontinued because of adverse events. The most common adverse events were pulmonary exacerbation, cough, and upper respiratory tract infection. Patients previously treated with ivacaftor had sustained improvements in FEV1, weight, and rate of pulmonary exacerbations for up to 144 weeks of treatment. Among adolescents/adults and children who previously received ivacaftor, absolute change in FEV1 at week 96 (144 weeks ivacaftor) was 9·4 and 10·3 % points and absolute increase in weight was 4·1 kg and 14·8 kg, respectively. For adolescents/adults only, the pulmonary exacerbation rate remained suppressed compared with that of patients who received placebo in the placebo-controlled study.

Interpretation

At 144 weeks of treatment, ivacaftor was well tolerated, with no new safety concerns. Ivacaftor also provided durable effects for 144 weeks in patients who had received active treatment in the placebo-controlled study. Those patients who previously received placebo had improvements comparable to those of patients treated with ivacaftor in the placebo-controlled study.

Funding

Vertex Pharmaceuticals Inc.

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

References (29)

  • Cystic Fibrosis Foundation. Patient Registry 2012 Annual Data Report, Bethesda, MD, USA;...
  • ECFS Patient Registry Annual Data Report 2008–09,...
  • JL Bobadilla et al.

    Cystic fibrosis: a worldwide analysis of CFTR mutations--correlation with incidence data and application to screening

    Hum Mutat

    (2002)
  • F Van Goor et al.

    Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770

    Proc Natl Acad Sci USA

    (2009)
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