Clinical Trials

Date: 2017-06-09

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the 40th European Cystic Fibrosis Society (ECFS) Conference

Company: Vertex Pharmaceuticals (USA - MA)

Product: Orkambi® (lumacaftor in combination with ivacaftor )

Action mechanism: CFTR potentiator/cystic fibrosis transmembrane regulator (CFTR) protein modulator. Ivacaftor (Kalydeco®) is a CFTR (CF transmembrane conductance regulator protein) potentiator. Lumacaftor is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. This gene encodes for the CFTR protein which is a chloride channel normally present at the surface of epithelial cells in multiple organs. Lumacaftor improves the cellular processing and trafficking of the F508del-CFTR protein to the cell membrane, while ivacaftor facilitates the function of the CFTR protein by increasing the CFTR channel gating. The combined effect of lumacaftor and ivacaftor results in increased quantity and function of F508del-CFTR protein at the cell surface, resulting in increased chloride ion transport.

Disease: children with cystic fibrosis (CF) ages 6 through 11 who have two copies of the F508del mutation

Therapeutic area: Rare diseases - Genetic diseases

Country: Australia, Belgium, Canada, Denmark, France, Germany, Sweden, UK, USA

Trial details: The study is evaluating the efficacy and safety of lumacaftor in combination with ivacaftor in subjects aged 6 Through 11 years with cystic fibrosis (CF), homozygous for the F508del CF transmembrane conductance regulator (CFTR) mutation. (NCT02514473)

Latest news:

• • On June 9, 2017, Vertex Pharmaceuticals announced presentations of data on Orkambi® (lumacaftor/ivacaftor) at the 40th European Cystic Fibrosis Society (ECFS) Conference . Data from a Phase 3 placebo-controlled study of Orkambi® in children with cystic fibrosis (CF) ages 6 through 11 who have two copies of the F508del mutation were presented at the meeting and published online in The Lancet Respiratory Medicine. Orkambi® in children ages 6 to 11 ("Efficacy and safety of lumacaftor/ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomized placebo-controlled Phase 3 trial." WS13.4.): Data were presented for the first time from a Phase 3 randomized, double-blind, placebo-controlled study that evaluated Orkambi® in 204 children with CF ages 6 through 11 who have two copies of the F508del mutation. At the start of the study, the average baseline predicted forced expiratory volume in one second (ppFEV1) was approximately 90. In the study, all children received a twice-daily fixed-dose combination of lumacaftor (200mg) and ivacaftor (250mg) for 24 weeks. As announced in November 2016 , the study met its primary endpoint of absolute change in lung clearance index (LCI2.5) through 24 weeks of treatment, demonstrating a statistically significant improvement in LCI2.5 among those treated with Orkambi® compared to placebo. The study also demonstrated significant improvements in ppFEV1 and sweat chloride in children receiving Orkambi® compared with those receiving placebo. • On November 7, 2016, Vertex Pharmaceuticals announced the results of a Phase 3 study of Orkambi® in children with cystic fibrosis ages 6 through 11 who have two copies of the F508del mutation. The study met its primary endpoint of absolute change in lung clearance index (LCI2.5) through 24 weeks of treatment, demonstrating a statistically significant improvement in LCI2.5 among patients treated with Orkambi® compared to placebo. LCI is a sensitive measure of lung function in early CF disease and the European Medicines Agency (EMA) agreed to the primary endpoint for this study.
• The study compared children who received treatment with lumacaftor (200 mg q12h) in combination with ivacaftor (250 mg q12h) (n=103) with those who received placebo (n=101) for 24 weeks. Baseline lung function as measured by percent predicted forced expiratory volume in one second (ppFEV1) was 89.8.
• The primary endpoint of the study was absolute change in lung clearance index (LCI2.5) from baseline through Week 24. LCI2.5 measures the efficiency of ventilation in the lungs by quantifying how long it takes to reduce an inhaled tracer gas to 2.5 percent of its starting value. LCI is considered a more sensitive measure to detect early lung disease than forced expiratory volume in one second (FEV1). Higher LCI scores indicate poorer lung function. To participate in the study, children had to have an LCI2.5 ?7.5 at the initial screening visit, considered the cutoff for abnormal gas exchange. At baseline, mean LCI2.5 was 10.28. In the study, children treated with Orkambi® experienced an improvement in lung function (LCI2.5) of -1.09 compared to placebo through 24 weeks (p < 0.0001).
• Improvements in secondary endpoints were also observed in this study, including a statistically significant reduction in sweat chloride assessed by the average absolute change from baseline at Day 15 and Week 4 (-20.8 mmol/L compared to placebo; p < 0.0001). Improvements in body mass index (BMI) and the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score were also observed, although not statistically significant. The improvement in absolute change from baseline in body mass index (BMI) at Week 24 was 0.11 kg/m2 compared to placebo (p=0.2522) and the improvement in absolute change from baseline in CFQ-R respiratory domain score through Week 24 was 2.5 points compared to placebo (p=0.0628). Lung function as assessed by an absolute change from baseline in ppFEV1 through Week 24 was an additional endpoint of the study for which a statistically significant improvement of 2.4 percentage points compared to placebo (p=0.0182) was observed.
• Overall, safety data were similar to those observed in a previous Phase 3 open-label safety study in children ages 6 through 11. In this study, the most common adverse events that occurred more frequently among those receiving Orkambi® compared to placebo were infective pulmonary exacerbation, productive cough, nasal congestion, oropharyngeal pain, abdominal pain upper, headache, upper respiratory tract infection and sputum increased. The incidence of liver enzyme elevations and respiratory events were slightly higher in the Orkambi® group compared to placebo. Treatment discontinuations due to adverse events were low across those receiving placebo (n=2) and those receiving Orkambi® (n=3) through 24 weeks. In the first half of 2017, Vertex plans to submit a Marketing Authorization Application (MAA) line extension to the EMA for the use of Orkambi® in this patient population. Data from a previous Phase 3 open-label safety study in children ages 6 through 11 supported the FDA approval of Orkambi® in September 2016. In this second study, Orkambi® was well tolerated with safety data that were similar to data from the previous Phase 3 study.

Is general: Yes