Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele.

BACKGROUND: Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes. METHODS: We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4. RESULTS: A total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor-tezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group. CONCLUSIONS: Elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.).

VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles.

BACKGROUND: VX-445 is a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector designed to restore Phe508del CFTR protein function in patients with cystic fibrosis when administered with tezacaftor and ivacaftor (VX-445-tezacaftor-ivacaftor). METHODS: We evaluated the effects of VX-445-tezacaftor-ivacaftor on Phe508del CFTR protein processing, trafficking, and chloride transport in human bronchial epithelial cells. On the basis of in vitro activity, a randomized, placebo-controlled, double-blind, dose-ranging, phase 2 trial was conducted to evaluate oral VX-445-tezacaftor-ivacaftor in patients heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-MF) and in patients homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del) after tezacaftor-ivacaftor run-in. Primary end points were safety and absolute change in percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline. RESULTS: In vitro, VX-445-tezacaftor-ivacaftor significantly improved Phe508del CFTR protein processing, trafficking, and chloride transport to a greater extent than any two of these agents in dual combination. In patients with cystic fibrosis, VX-445-tezacaftor-ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. The treatment also resulted in an increased percentage of predicted FEV1 of up to 13.8 points in the Phe508del-MF group (P<0.001). In patients in the Phe508del-Phe508del group, who were already receiving tezacaftor-ivacaftor, the addition of VX-445 resulted in an 11.0-point increase in the percentage of predicted FEV1 (P<0.001). In both groups, there was a decrease in sweat chloride concentrations and improvement in the respiratory domain score on the Cystic Fibrosis Questionnaire-Revised. CONCLUSIONS: The use of VX-445-tezacaftor-ivacaftor to target Phe508del CFTR protein resulted in increased CFTR function in vitro and translated to improvements in patients with cystic fibrosis with one or two Phe508del alleles. This approach has the potential to treat the underlying cause of cystic fibrosis in approximately 90% of patients. (Funded by Vertex Pharmaceuticals; VX16-445-001 ClinicalTrials.gov number, NCT03227471 ; and EudraCT number, 2017-000797-11 .).

Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation. METHODS: This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV1) of 40-90%, inclusive. After a 4-week tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548. FINDINGS: Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV1 (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], p<0·0001) and the key secondary outcomes of sweat chloride concentration (LSM treatment difference -45·1 mmol/L [95% CI -50·1 to -40·1], p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points [95% CI 11·8 to 23·0], p<0·0001) compared with the tezacaftor plus ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus ivacaftor and in one (2%) receiving tezacaftor plus ivacaftor. INTERPRETATION: Elexacaftor plus tezacaftor plus ivacaftor provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation. FUNDING: Vertex Pharmaceuticals.

Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR.

BACKGROUND: Cystic fibrosis is a life-limiting disease that is caused by defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Phe508del is the most common CFTR mutation. METHODS: We conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator, in patients 12 years of age or older who had cystic fibrosis and were homozygous for the Phe508del CFTR mutation. In both studies, patients were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary end point was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24. RESULTS: A total of 1108 patients underwent randomization and received study drug. The mean baseline FEV1 was 61% of the predicted value. In both studies, there were significant improvements in the primary end point in both lumacaftor-ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV1 ranged from 2.6 to 4.0 percentage points (P<0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (P<0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the lumacaftor-ivacaftor groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor-ivacaftor groups as well. The incidence of adverse events was generally similar in the lumacaftor-ivacaftor and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor-ivacaftor versus 1.6% among those who received placebo. CONCLUSIONS: These data show that lumacaftor in combination with ivacaftor provided a benefit for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation. (Funded by Vertex Pharmaceuticals and others; TRAFFIC and TRANSPORT ClinicalTrials.gov numbers, NCT01807923 and NCT01807949.).

Lumacaftor/Ivacaftor in Patients Aged 6-11 Years with Cystic Fibrosis and Homozygous for F508del-CFTR.

RATIONALE: Combination lumacaftor/ivacaftor has been shown to improve lung function and other endpoints in patients aged 12 years and older with cystic fibrosis and homozygous for F508del-CFTR, but it has not been assessed in younger patients. OBJECTIVES: In this open-label phase III trial, we evaluated the safety, tolerability, pharmacodynamics, and efficacy of lumacaftor/ivacaftor combination therapy in patients aged 6-11 years with cystic fibrosis who were homozygous for F508del-CFTR. METHODS: Patients (N = 58) received 200 mg lumacaftor/250 mg ivacaftor orally every 12 hours for 24 weeks in addition to their existing cystic fibrosis medications. MEASUREMENTS AND MAIN RESULTS: Lumacaftor/ivacaftor was well tolerated; the safety profile was generally similar to that observed in larger lumacaftor/ivacaftor trials with older patients. Four patients discontinued (two because of drug-related adverse events: elevated liver transaminases, n = 1; rash, n = 1). No safety concerns were associated with spirometry. No significant changes in percent predicted FEV1 were observed (change from baseline at Week 24, +2.5 percentage points; 95% confidence interval [CI], -0.2 to 5.2; P = 0.0671). At Week 24, significant improvements from baseline were observed in sweat chloride (-24.8 mmol/L; 95% CI, -29.1 to -20.5; P < 0.0001), body mass index z score (+0.15; 95% CI, 0.08 to 0.22; P < 0.0001), Cystic Fibrosis Questionnaire-Revised respiratory domain score (+5.4; 95% CI, 1.4 to 9.4; P = 0.0085), and lung clearance index based on lung volume turnover required to reach 2.5% of starting N2 concentration (-0.88; 95% CI, -1.40 to -0.37; P = 0.0018). CONCLUSIONS: Lumacaftor/ivacaftor was well tolerated in this young population; no new safety concerns were identified. Improvements in lung clearance index, sweat chloride, nutritional status, and health-related quality of life were observed after 24 weeks of treatment. Clinical trial registered with www.clinicaltrials.gov (NCT01897233).

Active albuterol or placebo, sham acupuncture, or no intervention in asthma.

BACKGROUND: In prospective experimental studies in patients with asthma, it is difficult to determine whether responses to placebo differ from the natural course of physiological changes that occur without any intervention. We compared the effects of a bronchodilator, two placebo interventions, and no intervention on outcomes in patients with asthma. METHODS: In a double-blind, crossover pilot study, we randomly assigned 46 patients with asthma to active treatment with an albuterol inhaler, a placebo inhaler, sham acupuncture, or no intervention. Using a block design, we administered one each of these four interventions in random order during four sequential visits (3 to 7 days apart); this procedure was repeated in two more blocks of visits (for a total of 12 visits by each patient). At each visit, spirometry was performed repeatedly over a period of 2 hours. Maximum forced expiratory volume in 1 second (FEV(1)) was measured, and patients' self-reported improvement ratings were recorded. RESULTS: Among the 39 patients who completed the study, albuterol resulted in a 20% increase in FEV(1), as compared with approximately 7% with each of the other three interventions (P<0.001). However, patients' reports of improvement after the intervention did not differ significantly for the albuterol inhaler (50% improvement), placebo inhaler (45%), or sham acupuncture (46%), but the subjective improvement with all three of these interventions was significantly greater than that with the no-intervention control (21%) (P<0.001). CONCLUSIONS: Although albuterol, but not the two placebo interventions, improved FEV(1) in these patients with asthma, albuterol provided no incremental benefit with respect to the self-reported outcomes. Placebo effects can be clinically meaningful and can rival the effects of active medication in patients with asthma. However, from a clinical-management and research-design perspective, patient self-reports can be unreliable. An assessment of untreated responses in asthma may be essential in evaluating patient-reported outcomes. (Funded by the National Center for Complementary and Alternative Medicine.).

Exhaled breath condensate eicosanoid levels associate with asthma and its severity.

BACKGROUND: The relationship between anti-inflammatory lipoxins and proinflammatory leukotrienes might be important in the pathobiology and severity of asthma. OBJECTIVE: We sought to investigate whether exhaled breath condensate (EBC) lipoxin and leukotriene measurements can noninvasively characterize the asthmatic diathesis and its severity. METHODS: We measured lipoxin A4 (LXA4) and leukotriene B4 (LTB4) levels in EBC collected from patients with asthma of different severities and from healthy control subjects. RESULTS: EBC LXA4 and LTB4 levels are increased in asthmatic patients compared with those seen in healthy control subjects (LXA4: 31.40 vs 2.41 pg/mL EBC, respectively [P < .001]; LTB4: 45.62 vs 3.82 pg/mL EBC, respectively [P < .001]). Although levels of both eicosanoids are increased in asthmatic patients, the LXA4/LTB4 ratio decreases with increasing asthma severity. It is 41% lower in patients with severe versus moderate asthma (0.52 vs 0.88, P = .034). EBC LXA4 levels correlate with the degree of airflow obstruction measured by using FEV1 (r = 0.28, P = .018). An LXA4 cutoff value of 7 pg/mL EBC provides 90% sensitivity and 92% specificity for the diagnosis of asthma (area under the curve, 0.96; P < .001). An LTB4 cutoff value of 11 pg/mL EBC provides 100% sensitivity and 100% specificity for the diagnosis of asthma (area under the curve, 1; P < .001). CONCLUSIONS: Proresolving and proinflammatory eicosanoids are generated in the airways of all asthmatic patients. The proportion of proresolving compounds decreases with asthma severity. These findings support the role for EBC eicosanoid measurements in the noninvasive diagnosis of asthma and suggest that proresolving eicosanoid pathways are dysregulated in patients with severe asthma.

Mepolizumab as a steroid-sparing treatment option in patients with Churg-Strauss syndrome.

BACKGROUND: Treatments for Churg-Strauss syndrome (CSS), a rare eosinophilic vasculitis characterized by asthma, sinusitis, peripheral eosinophilia, pulmonary infiltrates, and tissue infiltration, are limited by toxicity or poor efficacy. Levels of IL-5, a cytokine regulating eosinophils, can be increased in patients with CSS. Mepolizumab, a humanized monoclonal anti-IL-5 antibody, decreases steroid requirements in patients with non-CSS hypereosinophilic syndromes. OBJECTIVE: The purpose of this study was to assess whether mepolizumab would safely allow corticosteroid tapering in patients with steroid-dependent CSS while decreasing serum markers of disease activity. METHODS: This open-label pilot study treated 7 patients with 4 monthly doses of mepolizumab to assess whether it safely decreased CSS disease activity and permitted tapering of systemic corticosteroids. RESULTS: Mepolizumab was safe and well tolerated in patients with CSS. Mepolizumab reduced eosinophil counts and allowed for safe corticosteroid reduction in all 7 subjects. On cessation of mepolizumab, CSS manifestations recurred, necessitating corticosteroid bursts. CONCLUSION: Mepolizumab is a safe and well-tolerated therapy in patients with CSS, offering clinical benefit by enabling corticosteroid tapering while maintaining clinical stability.

Airway lipoxin A4 generation and lipoxin A4 receptor expression are decreased in severe asthma.

RATIONALE: Airway inflammation is common in severe asthma despite antiinflammatory therapy with corticosteroids. Lipoxin A(4) (LXA(4)) is an arachidonic acid-derived mediator that serves as an agonist for resolution of inflammation. OBJECTIVES: Airway levels of LXA(4), as well as the expression of lipoxin biosynthetic genes and receptors, in severe asthma. METHODS: Samples of bronchoalveolar lavage fluid were obtained from subjects with asthma and levels of LXA(4) and related eicosanoids were measured. Expression of lipoxin biosynthetic genes was determined in whole blood, bronchoalveolar lavage cells, and endobronchial biopsies by quantitative polymerase chain reaction, and leukocyte LXA(4) receptors were monitored by flow cytometry. MEASUREMENTS AND MAIN RESULTS: Individuals with severe asthma had significantly less LXA(4) in bronchoalveolar lavage fluids (11.2 +/- 2.1 pg/ml) than did subjects with nonsevere asthma (150.1 +/- 38.5 pg/ml; P < 0.05). In contrast, levels of cysteinyl leukotrienes were increased in both asthma cohorts compared with healthy individuals. In severe asthma, 15-lipoxygenase-1 mean expression was decreased fivefold in bronchoalveolar lavage cells. In contrast, 15-lipoxgenase-1 was increased threefold in endobronchial biopsies, but expression of both 5-lipoxygenase and 15-lipoxygenase-2 in these samples was decreased. Cyclooxygenase-2 expression was decreased in all anatomic compartments sampled in severe asthma. Moreover, LXA(4) receptor gene and protein expression were significantly decreased in severe asthma peripheral blood granulocytes. CONCLUSIONS: Mechanisms underlying pathological airway responses in severe asthma include lipoxin underproduction with decreased expression of lipoxin biosynthetic enzymes and receptors. Together, these results indicate that severe asthma is characterized, in part, by defective lipoxin counterregulatory signaling circuits.

Measuring recovery in health-related quality of life during and after pulmonary exacerbations in patients with cystic fibrosis.

BACKGROUND: We explored the time-dependent impact of pulmonary exacerbations (PEx) on health-related quality of life (HRQoL) using Cystic Fibrosis Questionnaire-Revised (CFQ-R) data from 2 large cystic fibrosis (CF) trials. METHODS: This exploratory post-hoc analysis evaluated the impact of PEx on CFQ-R domains of functioning in 80 patients with CF (homozygous for F508del-CFTR), aged ≥14 years randomized to placebo in the TRAFFIC and TRANSPORT trials who experienced 1 PEx. RESULTS: Scores on the CFQ-R were significantly lower within 1 week of PEx start in 8 out of 12 domains (Respiratory Symptoms, Physical Functioning, Emotional Functioning, Health Perceptions, Role Functioning, Social Functioning, Eating, and Vitality). Patients whose PEx was treated with hospitalization or intravenous antibiotics had greater reductions in some domains of HRQoL compared with those treated with oral antibiotics. In the immediate weeks post-PEx, improvement was seen on Emotional Functioning, Respiratory Symptoms, and Health Perceptions, while further decline was seen for Eating, Physical Functioning, Role Functioning, Vitality, and Weight. For some measures (Physical Functioning, Vitality), full recovery to pre-PEx levels took several weeks. CONCLUSIONS: Pulmonary exacerbations have significant effects on multiple domains of HRQoL, and recovery across multiple domains post-PEx can take several weeks. These findings provide insight into the impact of PEx on patient HRQoL and recovery post-PEx. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT01807923 and NCT01807949.

Safety, pharmacokinetics, and pharmacodynamics of lumacaftor and ivacaftor combination therapy in children aged 2-5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study.

BACKGROUND: The efficacy, safety, and tolerability of lumacaftor and ivacaftor are established in patients aged 6 years and older with cystic fibrosis, homozygous for the F508del-CFTR mutation. We assessed the safety, pharmacokinetics, pharmacodynamics, and efficacy of lumacaftor and ivacaftor in children aged 2-5 years. METHODS: In this multicentre, phase 3, open-label, two-part study, we enrolled children aged 2-5 years, weighing at least 8 kg at enrolment, with a confirmed diagnosis of cystic fibrosis who were homozygous for the F508del-CFTR mutation. Children received lumacaftor 100 mg and ivacaftor 125 mg (bodyweight <14 kg) or lumacaftor 150 mg and ivacaftor 188 mg (bodyweight ≥14 kg) orally every 12 h for 15 days in part A (to assess pharmacokinetics and safety) and for 24 weeks in part B (to assess safety, pharmacokinetics, pharmacodynamics, and efficacy). Children could participate in part A, part B, or both. Children were enrolled into part A at five sites in the USA and into part B at 20 sites in North America (USA, 17 sites; Canada, three sites). The primary endpoints of the study were the pharmacokinetics (part A) and safety (part B) of lumacaftor and ivacaftor; all analyses were done in children who received at least one dose of lumacaftor and ivacaftor. Secondary endpoints in part A were safety and pharmacokinetics of the metabolites of lumacaftor and ivacaftor, and in part B included pharmacokinetics in children who received at least one dose of lumacaftor and ivacaftor and absolute changes from baseline in sweat chloride concentration, growth parameters, and markers of pancreatic function. This study is registered with ClinicalTrials.gov, number NCT02797132. FINDINGS: The study was done from May 13, 2016, to Sept 8, 2017. 12 children enrolled in part A, 11 of whom completed the 15-day treatment period and enrolled in part B. 60 children enrolled in part B, 56 of whom completed the 24-week treatment period. Safety and pharmacokinetics were consistent with the well characterised safety profile of lumacaftor and ivacaftor. In part B, most children (59 [98%] of 60 children) had one or more treatment-emergent adverse events; most events were mild to moderate in severity. The most common adverse events were cough (38 [63%] of 60), vomiting (17 [28%]), pyrexia (17 [28%]), and rhinorrhoea (15 [25%]). Serious adverse events occurred in four children: infective pulmonary exacerbation of cystic fibrosis (n=2), gastroenteritis viral (n=1), and constipation (n=1). Three (5%) of 60 children discontinued treatment because of elevated serum aminotransferase concentrations. Mean sweat chloride concentrations decreased by 31·7 mmol/L, biomarkers of pancreatic function improved (fecal elastase-1 concentrations increased and serum immunoreactive trypsinogen concentrations decreased), and growth parameters increased at week 24. INTERPRETATION: Lumacaftor and ivacaftor were generally safe and well tolerated in children aged 2-5 years with cystic fibrosis for 24 weeks. Efficacy findings also suggest that early intervention with lumacaftor and ivacaftor has the potential to modify the course of disease. FUNDING: Vertex Pharmaceuticals Incorporated.

Lumacaftor/Ivacaftor reduces pulmonary exacerbations in patients irrespective of initial changes in FEV1.

BACKGROUND: Improved lung function and fewer pulmonary exacerbations (PEx) were observed with lumacaftor/ivacaftor (LUM/IVA) in patients with cystic fibrosis homozygous for F508del. It is unknown whether PEx reduction extends to patients without early lung function improvement. METHODS: Post hoc analyses of pooled phase 3 data (NCT01807923, NCT01807949) categorized LUM/IVA-treated patients by percent predicted forced expiratory volume in 1 s (ppFEV1) change from baseline to day 15 into threshold categories (absolute change ≤0 vs >0; relative change <5% vs ≥5%) and compared PEx rates vs placebo. RESULTS: LUM (400 mg q12h)/IVA (250 mg q12h)-treated patients (n = 369) experienced significantly fewer PEx vs placebo, regardless of threshold category. With LUM/IVA, PEx rate per patient per year was 0.60 for those with absolute change in ppFEV1 > 0 and 0.85 for those with absolute change ≤0 (respective rate ratios vs placebo [95% CI]: 0.53 [0.40-0.69; P < .0001], 0.74 [0.55-0.99; P = .04]). CONCLUSIONS: LUM/IVA significantly reduced PEx, even in patients without early lung function improvement.

Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator gene (CFTR) that result in diminished quantity and/or function of the CFTR anion channel. F508del-CFTR, the most common CF-causing mutation (found in ∼90% of patients), causes severe processing and trafficking defects, resulting in decreased CFTR quantity and function. CFTR modulators are medications that increase the amount of mature CFTR protein (correctors) or enhance channel function (potentiators) at the cell surface. Combinations of CFTR correctors and potentiators (i.e. lumacaftor/ivacaftor, tezacaftor/ivacaftor) have demonstrated clinical benefit in subsets of patients. However, none are approved for patients with CF heterozygous for F508del-CFTR and a minimal function mutation, i.e. a mutation that produces either no protein or protein that is unresponsive to currently approved CFTR modulators. Next-generation CFTR correctors VX-659 and VX-445, each in triple combination with tezacaftor and ivacaftor, improve CFTR processing, trafficking and function in vitro and have demonstrated clinical improvements in phase 2 studies in patients with CF with one or two F508del-CFTR alleles. Here, we present the rationale and design of four randomised phase 3 studies, and their open-label extensions, evaluating VX-659 (ECLIPSE) or VX-445 (AURORA) plus tezacaftor and ivacaftor in patients with one or two F508del-CFTR alleles.

Lumacaftor/ivacaftor in patients with cystic fibrosis and advanced lung disease homozygous for F508del-CFTR.

OBJECTIVE: Evaluation of the safety, tolerability, and efficacy of lumacaftor/ivacaftor in patients with cystic fibrosis (CF) with severe lung disease. METHODS: Patients with CF 12 years of age and older, homozygous for F508del-CFTR, with percent predicted forced expiratory volume in 1 second (ppFEV1) <40 received lumacaftor 400 mg/ivacaftor 250mg every 12h (full dose) for 24weeks in an open-label, prospective study (NCT02390219). Dose modification to half dose for 1-2weeks (including at initiation) was permitted. Safety and tolerability were the primary outcome measures; clinical outcomes were also assessed. RESULTS: Of 46 patients (initiated on full dose: n=28; initiated on half dose: n=18), 35 (76%) completed 24weeks of treatment. The most common adverse events included infective pulmonary exacerbation, abnormal respiration, cough, and dyspnea. Compared with patients initiating on full dose, patients initiating at half dose had less frequent respiratory events (56% vs 71%) of shorter median duration (4 vs 9days). No dose modifications or discontinuations as a result of respiratory events occurred in patients initiating on half dose who were then increased to the full dose over 2weeks (versus three each for patients on full dose). Following an initial reduction, ppFEV1 was similar to baseline from week 4 throughout the remainder of the study (least squares mean [95% confidence interval] at week 24: -0.4 [-1.9, 1.1]; p=0.6249). Compared with the 24weeks prior to study, the annualized hospitalization rate was lower (rate ratio: 0.41; p=0.00026) and the duration of intravenous antibiotics was shorter (mean [standard deviation] difference: -8.52 [24.91] days; p=0.0369) through study week 24. CONCLUSIONS: Compared with patients with higher lung function, respiratory events were more common in patients with ppFEV1<40; aside from these events, the lumacaftor/ivacaftor safety profile was consistent with previous studies. Results suggest that patients with ppFEV1<40 may benefit from treatment initiation at a lower dose with augmented monitoring before increasing to the full dose.

Effect of bronchodilators in healthy individuals receiving lumacaftor/ivacaftor combination therapy.

In an open-label, single-center phase 1 pharmacokinetic study in healthy subjects who received lumacaftor (LUM) in combination with ivacaftor (IVA), review of spirometry data showed a transient decline in percent predicted forced expiratory volume in 1s (ppFEV1) within 4h of drug administration. An additional cohort of healthy subjects with normal baseline ppFEV1 values was studied to evaluate the ppFEV1 response to LUM/IVA administration and assess the effect of long-acting bronchodilators (LABDs) and short-acting bronchodilators (SABDs) on ppFEV1 response. The ppFEV1 decline observed at 4h was attenuated following administration of an LABD and reversed following administration of an SABD. Concomitant administration of LUM/IVA with bronchodilators was well tolerated. These data show that a transient decline in ppFEV1 was observed in healthy subjects following administration of LUM/IVA combination therapy, which can be ameliorated with LABDs or SABDs.

Lumacaftor/Ivacaftor Treatment of Patients with Cystic Fibrosis Heterozygous for F508del-CFTR.

RATIONALE: In a prior study, lumacaftor/ivacaftor treatment (≤28 d) in patients with cystic fibrosis (CF) heterozygous for F508del-CFTR did not improve lung function. OBJECTIVES: To evaluate an optimized lumacaftor/ivacaftor dosing regimen with a longer duration in a cohort of patients heterozygous for F508del-CFTR. METHODS: Patients aged 18 years or older with a confirmed CF diagnosis and percent predicted FEV1 (ppFEV1) of 40 to 90 were randomized to lumacaftor/ivacaftor (400 mg/250 mg every 12 h) or placebo daily for 56 days. Primary outcomes were change in ppFEV1 at Day 56 and safety. Other disease markers were evaluated. MEASUREMENTS AND MAIN RESULTS: Of 126 patients, 119 (94.4%) completed the study. Lumacaftor/ivacaftor was well tolerated, although chest tightness and dyspnea occurred more frequently with active treatment than with placebo (27.4% vs. 14.3% and 14.5% vs. 6.3%, respectively). Mean (SD) ppFEV1 values at baseline were 62.9 (14.3) in the active treatment group and 60.1 (14.0) in the placebo group. Absolute changes in ppFEV1 (least squares mean [SE]) at Day 56 were -0.6 (0.8) percentage points in the active treatment group and -1.2 (0.8) percentage points in the placebo group (P = 0.60). CF respiratory symptom scores in the active treatment group improved by a mean of 5.7 points versus a decrease of -0.8 in the placebo group (P < 0.01). No changes in body mass index occurred. Changes from baseline in sweat chloride (least squares mean [SE]) at Day 56 were -11.8 (1.3) mmol/L in the active treatment group and -0.8 (1.2) mmol/L in the placebo group (P < 0.0001). CONCLUSIONS: Sweat chloride and respiratory symptom scores improved with lumacaftor/ivacaftor, though no meaningful benefit was seen in ppFEV1 or body mass index in patients heterozygous for F508del-CFTR. Clinical trial registered with www.clinicaltrials.gov (NCT01225211).

Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial.

BACKGROUND: Lumacaftor and ivacaftor combination treatment showed efficacy in patients aged 12 years or older with cystic fibrosis homozygous for F508del-cystic fibrosis transmembrane conductance regulator (CFTR) in placebo-controlled studies and patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR in an open-label study. We report efficacy and safety of lumacaftor and ivacaftor in patients with cystic fibrosis aged 6-11 years homozygous for F508del-CFTR. METHODS: In this phase 3, randomised, double-blind, placebo-controlled, multicentre study, patients were enrolled at 54 hospitals and medical centres in nine countries (the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK). Eligible patients weighed at least 15 kg, with a confirmed diagnosis of cystic fibrosis, percent predicted forced expiratory volume in 1 s (FEV1) of 70 or more, and lung clearance index2·5 (LCI2·5) of 7·5 or more at screening (values less than these thresholds were permitted at day 1). All patients were tested for CFTR genotype at screening; eligible patients had to have the F508del-CFTR mutation on both alleles. Exclusion criteria included any comorbidity or laboratory abnormality that might confound the study results or pose additional risk to the patient. Patients were stratified by weight (<25 kg vs ≥25 kg) and ppFEV1 severity (<90 vs ≥90) determined at the screening visit, and randomly assigned 1:1 to treatment using an interactive web response system to receive 200 mg lumacaftor and 250 mg ivacaftor every 12 hours or placebo for 24 weeks. Patients, all site personnel including the investigator and the site monitor, and the study team were blinded, with the exception of site personnel needing this information in the event of medical emergency or pregnancy and patient safety and regulatory affairs personnel to meet serious adverse event reporting requirements. The primary endpoint was the mean absolute change in LCI2·5 from all on-treatment study visits up to and including week 24. All randomly assigned patients who were exposed to any amount of study drug, with treatment assignment as assigned were included in primary and other efficacy analyses. All patients who were exposed to any amount of study drug, with treatment assignment as treated, were included in the safety analysis. This study was registered with ClinicalTrials.gov, number NCT02514473. FINDINGS: Between July 23, 2015, and Sept 20, 2016, a total of 206 patients were enrolled and randomly assigned to receive lumacaftor and ivacaftor (n=104) or placebo (n=102). Two randomly assigned patients were never dosed with study drug (one in the placebo arm due to ineligibility arising from a streptococcal throat infection and one in the lumacaftor and ivacaftor arm due to withdrawal based on refusal to provide blood tests) and were not included in the analyses. 103 patients received at least one dose of lumacaftor and ivacaftor and 101 patients received at least one dose of placebo. For the primary endpoint, the average absolute change in LCI2·5 from baseline over all study visits up to and including the week 24 visit, least squares mean difference was -1·09 units (95% CI -1·43 to -0·75, p<0·0001) for lumacaftor and ivacaftor versus placebo. For the key secondary endpoint of sweat chloride concentration, the least squares mean difference versus placebo was -20·8 mmol/L (95% CI -23·4 to -18·2, average absolute change at day 15/week 4; p<0·0001). The least squares mean difference compared with placebo in absolute change in ppFEV1 from all on-treatment study visits until week 24 was 2·4 (95% CI 0·4-4·4, p=0·0182). 196 (96%) of 204 patients reported adverse events, most of which were mild (87 [43%]) or moderate (98 [48%]). Treatment was discontinued due to adverse events in three (3%) of 103 patients in the lumacaftor and ivacaftor group and two (2%) of 101 patients in the placebo group. Serious adverse events were reported in 13 (13%) of 103 patients in the lumacaftor and ivacaftor group and 11 (11%) of 101 patients in the placebo group. INTERPRETATION: Treatment with lumacaftor and ivacaftor was associated with statistically significant improvements in lung function, as measured by LCI2·5 and ppFEV1, versus placebo in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR. The overall safety profile was consistent with previous phase 3 studies of lumacaftor and ivacaftor. FUNDING: Vertex Pharmaceuticals.

Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study.

BACKGROUND: The 24-week safety and efficacy of lumacaftor/ivacaftor combination therapy was shown in two randomised controlled trials (RCTs)-TRAFFIC and TRANSPORT-in patients with cystic fibrosis who were aged 12 years or older and homozygous for the F508del-CFTR mutation. We aimed to assess the long-term safety and efficacy of extended lumacaftor/ivacaftor therapy in this group of patients in PROGRESS, the long-term extension of TRAFFIC and TRANSPORT. METHODS: PROGRESS was a phase 3, parallel-group, multicentre, 96-week study of patients who completed TRAFFIC or TRANSPORT in 191 sites in 15 countries. Patients were eligible if they were at least 12 years old with cystic fibrosis and homozygous for the F508del-CFTR mutation. Exclusion criteria included any comorbidity or laboratory abnormality that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering the study drug to the participant, history of drug intolerance, and history of poor compliance with the study drug. Patients who previously received active treatment in TRANSPORT or TRAFFIC remained on the same dose in PROGRESS. Patients who had received placebo in TRANSPORT or TRAFFIC were randomly assigned (1:1) to receive lumacaftor (400 mg every 12 h)/ivacaftor (250 mg every 12 h) or lumacaftor (600 mg once daily)/ivacaftor (250 mg every 12 h). The primary outcome was to assess the long-term safety of combined therapy. The estimated annual rate of decline in percent predicted FEV1 (ppFEV1) in treated patients was compared with that of a matched registry cohort. Efficacy analyses were based on modified intention-to-treat, such that data were included for all patients who were randomly assigned and received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01931839. FINDINGS: Between Oct 24, 2013, and April 7, 2016, 1030 patients from the TRANSPORT and TRAFFIC studies enrolled in PROGRESS, and 1029 received at least one dose of study drug. 340 patients continued treatment with lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h; 176 patients who had received placebo in the TRANSPORT or TRAFFIC studies initiated treatment with lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h, the commercially available dose, for which data are presented. The most common adverse events were infective pulmonary exacerbations, cough, increased sputum, and haemoptysis. Modest blood pressure increases seen in TRAFFIC and TRANSPORT were also observed in PROGRESS. For patients continuing treatment, the mean change from baseline in ppFEV1 was 0·5 (95% CI -0·4 to 1·5) at extension week 72 and 0·5 (-0·7 to 1·6) at extension week 96; change in BMI was 0·69 (0·56 to 0·81) at extension week 72 and 0·96 (0·81 to 1·11) at extension week 96. The annualised pulmonary exacerbation rate in patients continuing treatment through extension week 96 (0·65, 0·56 to 0·75) remained lower than the placebo rate in TRAFFIC and TRANSPORT. The annualised rate of ppFEV1 decline was reduced in lumacaftor/ivacaftor-treated patients compared with matched controls (-1·33, -1·80 to -0·85 vs -2·29, -2·56 to -2·03). The efficacy and safety profile of the lumacaftor 600 mg once daily/ivacaftor 250 mg every 12 h groups was generally similar to that of the lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h groups. INTERPRETATION: The long-term safety profile of lumacaftor/ivacaftor combination therapy was consistent with previous RCTs. Benefits continued to be observed with longer-term treatment, and lumacaftor/ivacaftor was associated with a 42% slower rate of ppFEV1 decline than in matched registry controls. FUNDING: Vertex Pharmaceuticals Incorporated.

Efficacy and safety of lumacaftor/ivacaftor combination therapy in patients with cystic fibrosis homozygous for Phe508del CFTR by pulmonary function subgroup: a pooled analysis.

BACKGROUND: Lumacaftor/ivacaftor combination therapy has shown clinical benefits in patients with cystic fibrosis homozygous for the Phe508del CFTR mutation; however, pretreatment lung function is a confounding factor that potentially affects the efficacy and safety of this therapy. We aimed to assess the efficacy and safety of lumacaftor/ivacaftor therapy in these patients, defined by specific categories of lung function. METHODS: Both trials (TRAFFIC and TRANSPORT) included in this pooled analysis were multinational, randomised, double-blind, placebo-controlled, parallel-group, phase 3 studies. Eligible patients from 187 participating centres in North America, Australia, and the European Union (both trials) were aged 12 years or older with a confirmed diagnosis of cystic fibrosis, homozygous for the Phe508del CFTR mutation, and with a percent predicted FEV1 (ppFEV1) of 40-90 at the time of screening. Patients were randomly assigned with an interactive web response system (1:1:1) to receive placebo, lumacaftor (600 mg once daily) plus ivacaftor (250 mg every 12 h), or lumacaftor (400 mg every 12 h) plus ivacaftor (250 mg every 12 h) for 24 weeks. Prespecified subgroup analyses of pooled efficacy and safety data by lung function, as measured by ppFEV1, were done for patients with baseline ppFEV1 (<40 and ≥40) and screening ppFEV1 (<70 and ≥70). The primary endpoint was the absolute change from baseline in ppFEV1 at week 24 analysed in all randomised patients who received at least one dose of study drug. Both trials are registered with ClinicalTrials.gov (TRAFFIC: NCT01807923; TRANSPORT: NCT01807949). FINDINGS: Both trials were done between April, 2013, and April, 2014. Of the 1108 patients included in the efficacy analysis, 81 patients had a ppFEV1 that decreased to lower than 40 between screening and baseline and 1016 had a ppFEV1 of 40 or higher at baseline. At screening, 730 had a ppFEV1 of less than 70, and 342 had a ppFEV1 of 70 or higher. Improvements in the absolute change from baseline at week 24 in ppFEV1 were observed with both lumacaftor/ivacaftor doses in the subgroup with baseline ppFEV1 levels lower than 40 (least-squares mean difference vs placebo was 3·7 percentage points [95% CI 0·5-6·9; p=0·024] in the lumacaftor [600 mg/day]-ivacaftor group and 3·3 percentage points [0·2-6·4; p=0·036] in the lumacaftor [400 mg/12 h]-ivacaftor group). Improvements in ppFEV1 compared with placebo were also reported in the subgroup with baseline ppFEV1 levels of 40 or higher (3·3 percentage points [2·3-4·4; p<0·0001] in the lumacaftor [600 mg per day]-ivacaftor group and 2·8 percentage points [1·7-3·8; p<0·0001] in the lumacaftor [400 mg/12 h]-ivacaftor group). Similar absolute improvements in ppFEV1 compared with placebo were observed in subgroups with screening ppFEV1 levels lower than 70 and ppFEV1 levels of 70 or higher. Increases in body-mass index and reduction in number of pulmonary exacerbation events were observed in both lumacaftor/ivacaftor dose groups compared with placebo across all lung function subgroups. Treatment was generally well tolerated, although the incidence of some respiratory adverse events was higher with lumacaftor/ivacaftor than with placebo in all subgroups. In patients with baseline ppFEV1 levels lower than 40, these adverse events included cough, dyspnoea, and abnormal respiration. INTERPRETATION: These analyses confirm that lumacaftor/ivacaftor combination therapy benefits patients with cystic fibrosis homozygous for Phe508del CFTR who have varying degrees of lung function impairment. FUNDING: Vertex Pharmaceuticals.