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Effect of ivacaftor in patients with advanced cystic fibrosis and a G551D-CFTR mutation: Safety and efficacy in an expanded access program in the United States

Open ArchivePublished:February 11, 2015DOI:https://doi.org/10.1016/j.jcf.2015.01.008

      Abstract

      Background

      Ivacaftor is the first therapeutic agent approved for the treatment of cystic fibrosis (CF) that targets the underlying molecular defect. Patients with severe lung disease were excluded from the randomized Phase 3 trials. This open-label study was designed to provide ivacaftor to patients in critical medical need prior to commercial product availability.

      Methods

      CF patients aged ≥6 years with a G551D-CFTR mutation and FEV1 ≤ 40% predicted or listed for lung transplant received ivacaftor 150 mg every 12 h. The primary endpoint was safety as determined by adverse events. Secondary endpoints included assessment of lung function and weight.

      Results

      The rate of serious adverse events was consistent with disease severity. At 24 weeks of treatment with ivacaftor, there was a mean absolute increase in percent predicted FEV1 of 5.5 percentage points and a 3.3 kg mean absolute increase in weight from baseline.

      Conclusions

      In patients with severe lung disease, ivacaftor was well tolerated and was associated with improved lung function and weight gain.

      Abbreviations:

      AE (Adverse Event), SAE (Serious Adverse Event), CF (Cystic Fibrosis), CFF (Cystic Fibrosis Foundation), CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), FDA (Federal Drug Administration), FEV1 (Forced expiratory volume in 1s)

      Keywords

      1. Introduction

      Mutations in the cystic fibrosis transmembrane regulator (CFTR) gene can lead to a lack of adequate production and/or function of the CFTR chloride channel at the cell membrane [
      • Welsh M.J.
      • Smith A.E.
      Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis.
      ]. In the lungs, the resultant abnormal ion transport causes dysregulation of the airway surface liquid layer and the presence of thickened mucus that can prevent airway clearance of microbes and toxins [
      • Knowles M.R.
      • Boucher R.C.
      Mucus clearance as a primary innate defense mechanism for mammalian airways.
      ]. Cystic fibrosis (CF) is a progressive disease, and the ultimate consequence of CFTR dysfunction in the lungs is progressive bronchiectasis and early death [
      • Gibson R.L.
      • Burns J.L.
      • Ramsey B.W.
      Pathophysiology and management of pulmonary infections in cystic fibrosis.
      ,
      • MacKenzie T.
      • Gifford A.H.
      • Sabadosa K.A.
      • Quinton H.B.
      • Knapp E.A.
      • Goss C.H.
      • et al.
      Longevity of patients with cystic fibrosis in 2000 to 2010 and beyond: survival analysis of the cystic fibrosis foundation patient registry.
      ]. Although lung disease is the primary cause of morbidity and mortality in CF, related pathophysiologic processes adversely affect multiple other organs.
      Since the first description of CF in 1938, survival for patients born with CF has improved as a result of coordinated care and the development of therapeutic agents that affect the secondary consequences of CFTR dysfunction [
      • Andersen D.H.
      Cystic fibrosis of the pancreas and its relation to celiac disease.
      ,
      ]. Despite these gains, the life expectancy for an individual with CF remains significantly shorter than that of healthy individuals. The median predicted age of survival for a patient with CF is 41, and the median age at death is currently in the mid-20s [
      ].
      Ivacaftor, a CFTR potentiator, is the first therapeutic agent for the treatment of CF designed to address an underlying cause of CF by targeting of the gating function of CFTR, and was first approved for use in patients ≥6 years of age in the US in January 2012. The G551D-CFTR mutation affects approximately 4% of the CF population and leads to decreased chloride transport through the CFTR channel [
      ,
      • Van Goor F.
      • Hadida S.
      • Grootenhuis P.D.
      • Burton B.
      • Cao D.
      • Neuberger T.
      • et al.
      Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770.
      ]. In vitro, ivacaftor increases the channel open probability (gating) and total chloride transport of cell surface localized CFTR, including mutated forms of the protein, such as G551D-CFTR. Ivacaftor restored up to 50% of normal CFTR chloride transport for G551D-CFTR in vitro, a level thought likely sufficient to mitigate the CF phenotype; this hypothesis was confirmed in the clinical studies [
      • Van Goor F.
      • Hadida S.
      • Grootenhuis P.D.
      • Burton B.
      • Cao D.
      • Neuberger T.
      • et al.
      Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770.
      ,
      • Yu H.
      • Burton B.
      • Huang C.J.
      • Worley J.
      • Cao D.
      • Johnson Jr., J.P.
      • et al.
      Ivacaftor potentiation of multiple CFTR channels with gating mutations.
      ,
      • Amaral M.D.
      Processing of CFTR: traversing the cellular maze—how much CFTR needs to go through to avoid cystic fibrosis?.
      ,
      • Accurso F.J.
      • Rowe S.M.
      • Clancy J.P.
      • Boyle M.P.
      • Dunitz J.M.
      • Durie P.R.
      • et al.
      Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation.
      ,
      • Ramsey B.W.
      • Davies J.
      • McElvaney N.G.
      • Tullis E.
      • Bell S.C.
      • Drevinek P.
      • et al.
      A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.
      ,
      • Davies J.C.
      • Wainwright C.E.
      • Canny G.J.
      • Chilvers M.A.
      • Howenstine M.S.
      • Munck A.
      • et al.
      Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation.
      ]. The results of a Phase 2 study of patients with FEV1 ≥ 40% of predicted were consistent with the in vitro results: chloride transport across cell membranes improved, as demonstrated by the change in nasal potential difference and sweat chloride. Improvements in lung function were also observed [
      • Accurso F.J.
      • Rowe S.M.
      • Clancy J.P.
      • Boyle M.P.
      • Dunitz J.M.
      • Durie P.R.
      • et al.
      Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation.
      ]. Moreover, Phase 3 randomized, placebo-controlled trials demonstrated that in patients with the G551D mutation, treatment with ivacaftor provided a significant clinical benefit, with improvements observed in FEV1, nutritional measures, and for patients ≥12 years of age, a decrease in the rate of pulmonary exacerbations over 24 weeks [
      • Ramsey B.W.
      • Davies J.
      • McElvaney N.G.
      • Tullis E.
      • Bell S.C.
      • Drevinek P.
      • et al.
      A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.
      ,
      • Davies J.C.
      • Wainwright C.E.
      • Canny G.J.
      • Chilvers M.A.
      • Howenstine M.S.
      • Munck A.
      • et al.
      Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation.
      ].
      As with most new CF therapies, the ivacaftor clinical trials excluded patients with severe lung disease (FEV1 < 40% of predicted). Since this patient population requires a great deal of medical intervention and is at high risk for serious complications and a rapid decline in health, it is important to understand tolerance and potential responsiveness to ivacaftor in these patients. This study was initiated prior to commercial availability of ivacaftor and reports the safety profile and clinical response to ivacaftor in a prospective cohort of patients with severe CF lung disease.

      2. Materials and methods

      2.1 Study design and participants

      This ivacaftor expanded access program (EAP) study was an open-label, non-randomized, single-group, assigned treatment study designed to provide ivacaftor to patients in critical medical need who were not eligible for participation in other Vertex-sponsored studies, and who might benefit from treatment prior to commercial product availability. Patients were eligible for inclusion if they were aged 6 years or older with a confirmed diagnosis of CF, had at least one G551D-CFTR gene mutation, and had an FEV1 ≤ 40% of predicted (highest value in the 6 months prior to screening) or were actively on a lung transplant wait list. Patients with abnormal liver function at screening, patients requiring invasive mechanical ventilation, and patients with a history of solid organ or hematological transplantation were excluded.
      The study was reviewed and approved by the relevant Ethics Committee or Institutional Review Board at participating centers. Written informed consent was obtained from patients, or a parent or guardian of children.
      All patients were assigned to receive ivacaftor 150 mg every 12 h. Safety and efficacy data were collected throughout the entire study period, which lasted until marketing approval when ivacaftor became commercially available. Safety is reported for all available data. However, spirometry and weight gain results are reported here for the initial 24 weeks of treatment as the number of patients with assessments beyond this time point was limited because patients exited the study as commercial drug became available. Not all patients had data through 24 weeks; for each time point, results are reported for all available data.

      2.2 Assessments

      The primary endpoint was safety, as determined by adverse events (AEs) throughout the study. Secondary endpoints included changes in percent predicted FEV1 and weight, and incidence of pulmonary exacerbations throughout the time in the study. Pulmonary exacerbations were defined at the discretion of the investigator. Spirometry was evaluated in the subset of patients who had a baseline spirometry assessment ≤31 days prior to treatment initiation. Percent predicted values were derived using Knudson standards [
      • Knudson R.J.
      • Lebowitz M.D.
      • Holberg C.J.
      • Burrows B.
      Changes in the normal maximal expiratory flow-volume curve with growth and aging.
      ]. Changes in FEV1 (L) and FEF25–75% were also evaluated.

      2.3 Statistical analysis

      The analysis set for this study included all enrolled patients who received at least one dose of study drug. Analyses for efficacy and safety were summarized with descriptive statistics. The pulmonary exacerbation event rate was calculated as the total number of events/the total number of patients in the full analysis set.

      3. Results

      3.1 Patients

      The study population consisted of 44 patients who received at least one dose of ivacaftor. Baseline characteristics and demographics are summarized in Table 1. At baseline, the mean age of the patients was 33.1 years, and the mean FEV1 was 29.6% of predicted. A variety of CFTR genotypes were represented on the non-G551D-CFTR allele; the vast majority of patients had the F508del mutation (36 patients, 81.8%). Among the 44 patients, 35 had optional baseline spirometry assessments within 1 month (≤31 days) prior to study drug initiation; spirometry results are reported only for this subset of patients. Nine patients (20.5%) discontinued from the program; the reasons for discontinuation in these patients were lung transplant (4 patients), AEs (2 patients), or death (3 patients). Discontinuation for lung transplant ranged from 82 to 287 days after initiation of therapy.
      Table 1Baseline characteristics and demographics.
      CharacteristicAll subjects (N = 44)
      Gender, female; n (%)18 (40.9)
      Age, years33.1 (11.9)

      [10–61]
      Weight, kg58.9 (15.4)

      [32.4–104.5]
      BMI, kg/m221.2 (4.4)

      [15.1–38.3]
      FEV1
      Spirometry subset: includes only patients with baseline spirometry assessed ≤31days prior to first dose of study drug (n=35).
      percent predicted, percentage points
      29.6 (6.3)

      [17.2–45.2]
      FEV1
      Spirometry subset: includes only patients with baseline spirometry assessed ≤31days prior to first dose of study drug (n=35).
      , L
      0.99 (0.27)

      [0.5–1.6]
      FEF25–75%
      Spirometry subset: includes only patients with baseline spirometry assessed ≤31days prior to first dose of study drug (n=35).
      , L/s
      0.37 (0.14)

      [0.1–0.7]
      All data reported are mean (SD) [range] unless otherwise noted.
      a Spirometry subset: includes only patients with baseline spirometry assessed ≤31 days prior to first dose of study drug (n = 35).

      3.2 Safety & adverse event profile

      During the course of the study, AEs were reported in 38 (86.4%) patients (Table 2). The most frequently reported AEs were consistent with those that would be expected in patients with advanced CF lung disease; pulmonary exacerbation was the most commonly reported AE (19 patients, 43.2%). Adverse events occurring in >2 patients are summarized in Table 2.
      Table 2Adverse event summary for the overall study period.
      Adverse eventNumber of patients (%) (N = 44)
      Any adverse event38 (86.4)
      Serious adverse event14 (31.8)
      Adverse events leading to death3 (6.8)
      Adverse events reported in >2 patients, number of patients (%)
      Pulmonary exacerbation19 (43.2)
      Hemoptysis7 (15.9)
      Increased sputum7 (15.9)
      Cough6 (13.6)
      Upper respiratory tract infection6 (13.6)
      Headache5 (11.4)
      Rash4 (9.1)
      Dyspnea3 (6.8)
      Respiration abnormal3 (6.8)
      Respiratory tract congestion3 (6.8)
      Serious adverse events (SAEs) were reported in 14 (31.8%) patients (Table 2); SAEs included pulmonary exacerbation, pneumothorax, upper respiratory tract infection, hemoptysis, gastroenteritis, acute respiratory failure, secondary adrenocortical insufficiency, syncope, abdominal pain, and abnormal liver test. Pulmonary exacerbation was the most common SAE (10 patients, 22.7%). Two patients discontinued due to an AE (one due to severe abdominal pain, one due to dizziness and tinnitus). There were 3 deaths in the study. All were the result of pulmonary exacerbations (onset of exacerbation at Day 11, 26, or 80 after first ivacaftor dose) and all were considered unrelated to study drug by the physician.

      3.3 Clinical efficacy

      For the patients in the spirometry subset, at Week 24 of treatment with ivacaftor (n = 19) there was a mean absolute increase from baseline in the percent of predicted FEV1 of 5.5 percentage points (Fig. 1, Table 3). Although the study was not powered for statistical comparisons, an increase in percent predicted FEV1 was observed as early as Week 2 (mean absolute change, 2.3 percentage points), and the magnitude of this change continued to increase at Weeks 4, 12, and 24 (Fig. 1, Table 3). Individual responses in FEV1 from baseline to Week 24 are reported in Fig. 1; the majority of individuals experienced an improvement in FEV1. Based on a post-hoc analysis, of the 19 patients with available spirometry data at Week 24, 7 (36.8%) had an absolute improvement in percent predicted FEV1 of >5 percentage points. The relative change in percent predicted FEV1 at Week 24 was 18.9%. At Week 24, the mean improvement in FEV1 (L) was 0.19 L. The absolute change from baseline in FEF25–75% was 0.09 L/s at Week 24.
      Figure thumbnail gr1
      Fig. 1Change from baseline in percent predicted FEV1 and weight. Panels A and C: mean change. Panel B, individual patient responses.
      Table 3Summary of efficacy results at Weeks 2, 4, 12, and 24.
      FEV1 and FEF reported for spirometry subset: includes only patients with baseline spirometry assessed ≤31days prior to first dose of study; weight reported for all patients with available data.
      AssessmentAbsolute change from baseline at Week 2
      Mean (SD) [range].
      Absolute change from baseline at Week 4
      Mean (SD) [range].
      Absolute change from baseline at Week 12
      Mean (SD) [range].
      Absolute change from baseline at Week 24
      Mean (SD) [range].
      FEV1n = 20n = 23n = 26n = 19
      FEV1% predicted, percentage points2.3 (4.5)

      [−9.5–10.2]
      3.6 (4.9)

      [−3.8–16.4]
      4.8 (7.5)

      [−13.1–22.7]
      5.5 (5.3)

      [−2.6–18.4]
      FEV1, L0.07 (0.17)

      [−0.4–0.3]
      0.12 (0.18)

      [−0.2–0.6]
      0.17 (0.26)

      [−0.4–0.8]
      0.19 (0.21)

      [−0.1–0.8]
      FEF25–75%, L/s0.05 (0.10)

      [−0.1–0.3]
      0.07 (0.11)

      [−0.2–0.3]
      0.10 (0.14)

      [−0.1–0.6]
      0.09 (0.13)

      [−0.1–0.4]
      Weightn = 28n = 36n = 38n = 25
      Weight, kg0.3 (1.9)

      [−5.5–4.1]
      0.9 (1.8)

      [−4.3–4.3]
      2.2 (2.7)

      [−3.3–10.0]
      3.3 (4.0)

      [−2.3–14.4]
      a FEV1 and FEF reported for spirometry subset: includes only patients with baseline spirometry assessed ≤31 days prior to first dose of study; weight reported for all patients with available data.
      b Mean (SD) [range].
      A total of 20 out of 44 patients experienced a pulmonary exacerbation, as defined by the investigator, during the course of the study. Of these patients, 12 required IV antibiotics and 10 required hospitalizations (Table 4). Thirty-nine total events of pulmonary exacerbation were reported, with an event rate of (0.9) for the study period, which translates into an annualized rate of 2.1 events per year (Table 4).
      Table 4Assessment of pulmonary exacerbation through Week 24.
      Pulmonary exacerbation as defined by physician judgment on report log.
      AssessmentNumber of patients with events (N = 44)Number of events (event rate)Annualized event rate
      Annualized event rate is calculated as the total number of events divided by the total number of years on study.
      Pulmonary exacerbations2039 (0.9)2.1
      Pulmonary exacerbations requiring IV antibiotics1222 (0.5)1.2
      Pulmonary exacerbations requiring hospitalizations1017 (0.4)0.9
      a Pulmonary exacerbation as defined by physician judgment on report log.
      b Annualized event rate is calculated as the total number of events divided by the total number of years on study.
      An improvement in weight was reported, with a mean absolute increase from baseline of 3.3 kg at Week 24. Again, although the study was not powered for statistical analysis, weight gain was observed as early as Week 2 (mean change, 0.3 kg) and continued to increase through Week 24. Based on a post-hoc threshold analysis, 18 (72%) of patients with available data at Week 24 (n = 25) had a weight gain of >1 kg.

      4. Discussion

      Ivacaftor is the first approved therapy that modulates a disease-causing CFTR protein. In the pivotal Phase 3 studies in patients aged 6 and older with a G551D mutation, ivacaftor improved lung function and nutrition, and in patients aged 12 years and older, significantly reduced the frequency of pulmonary exacerbations [
      • Ramsey B.W.
      • Davies J.
      • McElvaney N.G.
      • Tullis E.
      • Bell S.C.
      • Drevinek P.
      • et al.
      A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.
      ,
      • Davies J.C.
      • Wainwright C.E.
      • Canny G.J.
      • Chilvers M.A.
      • Howenstine M.S.
      • Munck A.
      • et al.
      Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation.
      ]. As with most new CF therapies, the safety and efficacy of ivacaftor was first established in patients with percent predicted FEV1 ≥ 40. Descriptive analyses of a small subset of patients from the Phase 3 study of adults/adolescents who had FEV1 that fell below 40% of predicted between screening and baseline showed that the majority of patients who received ivacaftor experienced improvements in clinical parameters over time and that the response was much more variable for the patients in this subset who received placebo [
      • Bell S.
      • Rodriguez S.
      • Lubarsky B.
      Effect of ivacaftor in patients with cystic fibrosis and the G551D-CFTR mutation who have severe lung dysfunction or lung function in the normal range [abstract P8].
      ]. This study was conducted to provide ivacaftor to patients in critical medical need and to evaluate the effect of ivacaftor in patients with more severe lung disease.
      The combination of the in vitro and clinical trial results provided the rationale for this program; it was thought that treatment with ivacaftor might improve epithelial ion transport and potentially improve pulmonary function and nutrition in patients with G551D-CFTR and severe lung disease. In addition, while the AEs reported in the Phase 3 studies were similar in the ivacaftor and placebo groups [
      • Ramsey B.W.
      • Davies J.
      • McElvaney N.G.
      • Tullis E.
      • Bell S.C.
      • Drevinek P.
      • et al.
      A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.
      ,
      • Davies J.C.
      • Wainwright C.E.
      • Canny G.J.
      • Chilvers M.A.
      • Howenstine M.S.
      • Munck A.
      • et al.
      Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation.
      ], safety in patients with end stage CF could not be assumed. Given the significant effects of ivacaftor on pulmonary and nutritional outcomes in patients with a wide spectrum of lung function, from 40% to 105% predicted FEV1 in patients age 6 years and older, ivacaftor was made available in an early access program for patients with severe lung disease and a G551D mutation.
      In this study, adverse events were frequent, but occurred at a rate consistent with what may be expected for a population of patients with limited pulmonary reserve. Pulmonary adverse events, such as increased cough and hemoptysis, are typical for a population of patients with severe disease. The non-pulmonary adverse events appeared comparable to those reported in the Phase 3 ivacaftor studies of patients with less severe disease, and the dropout frequency was also comparable. There were three deaths in this cohort of patients with end stage disease; in all cases, the physician considered treatment with ivacaftor unrelated to death. While the frequency of death within 24 weeks in patients with severe CF lung disease has not been determined, the rate observed in this cohort does not appear excessive compared with that in other multi-center studies of CF therapies [
      • McCoy K.
      • Hamilton S.
      • Johnson C.
      Effects of 12-week administration of dornase alfa in patients with advanced cystic fibrosis lung disease. Pulmozyme Study Group.
      ,
      • Scheinberg P.
      • Shore E.
      A pilot study of the safety and efficacy of tobramycin solution for inhalation in patients with severe bronchiectasis.
      ]. These observations suggest that ivacaftor appears to be well tolerated in patients with very severe disease.
      Patients with severe obstructive lung disease from CF uniformly have significant bronchiectasis and airway fibrosis. The effects of advanced bronchiectasis (historically thought to be irreversible) may be hypothesized to limit the effectiveness of ivacaftor or any new therapy. However, as in patients with milder disease, improvements in FEV1 were observed following 24 weeks of ivacaftor treatment in the expanded access cohort (change in percent predicted FEV1: mean relative change of 18.9% vs. 17.2% and mean absolute change of 5.5 vs. 10.4 percentage points in the EAP vs. Phase 3 randomized study, respectively) [
      • Ramsey B.W.
      • Davies J.
      • McElvaney N.G.
      • Tullis E.
      • Bell S.C.
      • Drevinek P.
      • et al.
      A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.
      ]. These results suggest that, even in patients with severe lung disease, treatment with ivacaftor may provide clinical benefit. In the studies of ivacaftor in patients with mild disease, the increase in FEV1 was rapid and sustained, but showed a plateau effect [
      • Ramsey B.W.
      • Davies J.
      • McElvaney N.G.
      • Tullis E.
      • Bell S.C.
      • Drevinek P.
      • et al.
      A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.
      ,
      • Davies J.C.
      • Wainwright C.E.
      • Canny G.J.
      • Chilvers M.A.
      • Howenstine M.S.
      • Munck A.
      • et al.
      Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation.
      ]. In our study, we showed a slowly progressive increase in lung function without plateau. The differences between the response observed in the group of patients with mild lung disease in the previous studies and those in our group of severe patients are likely related to the differences in baseline lung function. In other words, in subjects with near normal or normal baseline lung function, a maximum benefit may be rapidly achieved and sustained, whereas in those with more severe disease, reversal of chronic damage may take more time to reach. The maximal achievable benefit in this group of patients may not be answered in a 6-month study.
      In addition to the improvement in the mean percent predicted FEV1, weight gain at 24 weeks of treatment was observed in the majority of patients with available data (at 24 weeks: mean gain 3.3 kg; 72% had weight gain >1 kg). In patients with CF, defective CFTR in the gastrointestinal tract leads to impaired digestion and resultant caloric malabsorption. In addition, as lung disease in CF progresses, the majority of patients suffer from refractory malnutrition related to the imbalance among increased resting energy expenditure, hypercatabolism, and decreased caloric intake [
      • Buchdahl R.M.
      • Cox M.
      • Fulleylove C.
      • Marchant J.L.
      • Tomkins A.M.
      • Brueton M.J.
      • et al.
      Increased resting energy expenditure in cystic fibrosis.
      ]. Despite increased resting energy expenditure, ivacaftor use in this open-label study was associated with weight gain comparable to that observed in the ivacaftor Phase 3 randomized trials. The mechanism for the consistent observation of weight gain after initiation of ivacaftor treatment in patients with a G551D mutation has not been defined but may relate to a partial restoration of bicarbonate and/or fluid secretion in the intestine that may promote pancreatic enzyme activity and improved nutrient absorption [
      • Rowe S.M.
      • Heltshe S.L.
      • Gonska T.
      • Donaldson S.H.
      • Borowitz D.
      • Gelfond D.
      • et al.
      Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in g551d-mediated cystic fibrosis.
      ].
      Although there was limited information on the effects of ivacaftor in patients with advanced lung disease at the outset of this program, there have since been a few reports in patients with severe lung function. In two such studies, CF patients with severe lung dysfunction showed significant improvements in clinical outcomes following ivacaftor treatment [
      • Barry P.J.
      • Plant B.J.
      • Nair A.
      • Bicknell S.
      • Simmonds N.J.
      • Bell N.J.
      • et al.
      Effects of Ivacaftor in cystic fibrosis patients carrying the G551D mutation with severe lung disease.
      ,
      • Hebestreit H.
      • Sauer-Heilborn A.
      • Fischer R.
      • Kading M.
      • Mainz J.G.
      Effects of ivacaftor on severely ill patients with cystic fibrosis carrying a G551D mutation.
      ]. In the study performed in the UK/Ireland, 21 patients with severe CF lung disease eligible for an ivacaftor compassionate use program were matched with controls. Patients receiving ivacaftor had an increase in mean percent predicted FEV1 (from 26.5 to 30.7, p = 0.01) and median weight (from 49.8 kg to 51.6 kg, p = 0.006), and a decrease in median total inpatient intravenous antibiotic days per year (74 days to 38 days, p = 0.002) [
      • Barry P.J.
      • Plant B.J.
      • Nair A.
      • Bicknell S.
      • Simmonds N.J.
      • Bell N.J.
      • et al.
      Effects of Ivacaftor in cystic fibrosis patients carrying the G551D mutation with severe lung disease.
      ]. Hebestreit and colleagues reported the results of a retrospective review of 14 patients with very severe lung dysfunction receiving ivacaftor [
      • Hebestreit H.
      • Sauer-Heilborn A.
      • Fischer R.
      • Kading M.
      • Mainz J.G.
      Effects of ivacaftor on severely ill patients with cystic fibrosis carrying a G551D mutation.
      ]. Although 1 patient discontinued ivacaftor as a result of side effects (increased bronchial secretions leading to hospitalization for pulmonary exacerbation), as in the case of the European study, patients showed an average increase of 5.2 ± 5.6 percentage points in percent predicted FEV1 (p < 0.01). Similarly, in a report of patients with severe lung disease who received compassionate access to ivacaftor prior to registration in Australia, significant improvements in FEV1, weight, and BMI were observed [
      • Wainwright C.
      • Bell S.
      • Morton J.
      • Ryan G.
      • Serisier D.
      • et al.
      The effect of ivacaftor in individuals with CF and severe lung disease [abstract 442].
      ]. Two independent case reports have also described improvements following ivacaftor treatment in patients with advanced lung disease who have the G551D mutation [
      • Harrison M.J.
      • Murphy D.M.
      • Plant B.J.
      Ivacaftor in a G551D homozygote with cystic fibrosis.
      ,
      • Polenakovik H.M.
      • Sanville B.
      The use of ivacaftor in an adult with severe lung disease due to cystic fibrosis (DeltaF508/G551D).
      ]. As with all clinical study findings, these case examples may not be generalizable to the general CF population.
      A number of patients in this cohort had been listed for lung transplant prior to initiation of ivacaftor. Among other factors, lung function and weight are key aspects of lung transplant evaluation. Although we did not collect data regarding whether patients were able to be deactivated on the lung transplant list subsequent to initiation of ivacaftor treatment, there is an individual case study reported in the literature [
      • Harrison M.J.
      • Murphy D.M.
      • Plant B.J.
      Ivacaftor in a G551D homozygote with cystic fibrosis.
      ]. Some transplant centers will not offer lung transplant to patients with BMI < 18. Thus, improvements in body mass following ivacaftor treatment in patients with very severe lung disease may allow such patients to meet minimum lung transplant criteria. Moreover, since survival after lung transplant is higher for patients with normal body mass index than for underweight patients [
      • Lederer D.J.
      • Wilt J.S.
      • D'Ovidio F.
      • Bacchetta M.D.
      • Shah L.
      • Ravichandran S.
      • et al.
      Obesity and underweight are associated with an increased risk of death after lung transplantation.
      ], adding ivacaftor to other therapies in patients with severe lung disease awaiting lung transplant may be associated with better post-transplant outcomes for those patients.

      4.1 Limitations

      Together, the results presented here are encouraging; however, caution should be taken when interpreting the data as there are a number of limitations to this study. First, the observational, open-label study design limited our ability to make statistical comparisons. Statistical analyses were further limited by the small number of patients treated with ivacaftor, and in particular the limited number with follow-up outcomes at 24 weeks. Second, no quality of life measures were included in the outcomes, precluding any assessment of respiratory and other symptoms before and after initiation of ivacaftor.

      5. Conclusions

      Despite the study limitations, the observations in this early access program suggest that ivacaftor treatment was well tolerated and may benefit patients with the G551D mutation and advanced lung disease, as the majority of patients had clinically relevant improvements in lung function and/or body weight.

      Disclosures and acknowledgments

      This study was sponsored by Vertex Pharmaceuticals Incorporated. The sponsor, with consultation from the investigators, designed the study, performed the statistical analysis, and was involved in interpreting the data. JTC and JP were involved in collection of and interpretation of the data.
      The first draft of the Introduction was written by JTC; the first draft of the Discussion was written by JP. A professional medical writer developed the first draft of the 2, 3 sections based on a detailed outline agreed upon by JTC, GG, and JP. All authors as well as the study sponsor contributed to subsequent revision and approval of the manuscript. The final decision to submit for Publication was made by JTC, JP, and the study sponsor.
      JTC has served as an investigator for Vertex Pharmaceuticals Incorporated, N30 Pharmaceuticals Incorporated, and Gilead Pharmaceuticals Incorporated, and has participated in advisory boards for Vertex Pharmaceuticals Incorporated, Novartis Pharmaceuticals Incorporated and Gilead Pharmaceuticals Incorporated. MK is an employee of Vertex Pharmaceuticals Incorporated who may own stock or options in that company. GG is a former employee of Vertex Pharmaceuticals Incorporated who may own stock or options in that company. JP has served as an investigator for Vertex Pharmaceuticals Incorporated, Calaboose, PTC Therapeutics, and Prion Sciences and has participated in advisory boards for Vertex Pharmaceuticals Incorporated.
      Medical writing and editorial coordination and support were provided by Elizabeth Dorn, PhD. Graphic Design support was provided by Jonathan Kirk. ED and JK are employees of Vertex Pharmaceuticals Incorporated who may own stock or options in that company.

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