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: cystic fibrosis

Therapeutic area: Rare diseases - Genetic diseases

Country:

Trial details: The TRAFFIC and TRANSPORT studies evaluate the efficacy of lumacaftor in combination with ivacaftor at Week 24 in participants aged 12 years and older with cystic fibrosis (CF) who are homozygous for the F508del mutation on the CF transmembrane conductance regulator (CFTR) gene. (NCT01807923 and NCT01807949.)

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, being held June 7-10, 2017. Progressive loss of lung function is the leading cause of death in people with cystic fibrosis; therefore, slowing the decline of lung function is a key goal of cystic fibrosis treatment. As previously reported, up to 120 weeks of Orkambi® treatment in the Phase 3 TRAFFIC, TRANSPORT and PROGRESS studies resulted in a reduced annual rate of ppFEV1 decline and mean ppFEV1 that remained above baseline. A post-hoc analysis of these studies evaluated whether there is any correlation between acute improvement in lung function and the long-term rate of lung function decline. Results presented at the meeting showed that treatment with Orkambi® produces two effects on lung function - an acute improvement in ppFEV1 and a reduced rate of decline over the long term. The magnitude of the acute improvement was not correlated with the reduction in the rate of lung function decline. These data, together with similar results previously reported for Kalydeco® in patients with the G551D mutation, suggest that baseline ppFEV1 or the magnitude of acute ppFEV1 change are not predictors of the potential for disease modification, measured in this case by a reduced rate of decline in ppFEV1, with CFTR modulation.
• • On June 10, 2016, Vertex Pharmaceuticals announced presentations of Orkambi® (lumacaftor/ivacaftor) data at the 39th European Cystic Fibrosis Society (ECFS) Conference , being held June 8 to 11, 2016 in Basel, Switzerland . The presentations include results from the Phase 3 safety study of lumacaftor/ivacaftor in children ages 6 through 11 with CF. Final data were presented from an open-label Phase 3 safety study that evaluated lumacaftor/ivacaftor in 58 children with cystic fibrosis ages 6 through 11 who have two copies of the F508del mutation. In the study, all children received a twice-daily fixed-dose combination of lumacaftor (200mg) and ivacaftor (250mg) for 24 weeks. As announced in January 2016 , the study met its primary safety endpoint. Safety data showed that the combination was well tolerated, and the most common adverse events were cough, headache, infective pulmonary exacerbation, nasal congestion, abdominal pain, increased sputum and elevated liver enzymes. Two patients (3.4%) discontinued treatment because of adverse events (rash and abnormal liver function tests). Respiratory events, including dyspnea, respiration abnormal and wheezing, were observed in four patients (6.9%) and were not associated with treatment discontinuation. Serious adverse events were reported in four patients (6.9%), with one patient (1.7%) having elevated abnormal liver function tests. Additional details from the study are being presented at ECFS, including results for the study's secondary and exploratory efficacy endpoints. At 24 weeks, there were improvements in multiple secondary endpoints, including a reduction in sweat chloride of -24.8 mmol/L (p < 0.0001), a weight gain of 2.6 kg (p < 0.0001), an improvement in the CFQ-R respiratory domain score of 5.4 points (p=0.0085), an absolute improvement in FEV1 of 2.5 percentage points (p=0.067), and a -0.88 (p=0.0018) improvement in the exploratory endpoint of lung clearance index (LCI2.5). The FDA recently granted Vertex's request for Priority Review of a supplemental New Drug Application (sNDA) for approval of Orkambi® for children ages 6 through 11 who have two copies of the F508del mutation and set a target review date of September 30, 2016 for a decision on the sNDA. There are approximately 2,400 children ages 6 to 11 who have two copies of the F508del mutation in the U.S. Enrollment is complete in a six-month Phase 3 efficacy study required to support potential approval of lumacaftor/ivacaftor in the European Union in children ages 6 through 11 who have two copies of the F508del mutation. The study is evaluating lumacaftor/ivacaftor in approximately 200 children and the primary endpoint is the absolute change in lung clearance index. Pending data from the study, Vertex plans to submit a Marketing Authorization Application (MAA) variation in the European Union in the first half of 2017. In Europe , there are approximately 3,400 children ages 6 through 11 who have two copies of the F508del mutation. Efficacy and safety of lumacaftor/ivacaftor across sub-groups in TRAFFIC and TRANSPORT studies: A pre-specified pooled analysis of the TRAFFIC and TRANSPORT studies evaluated whether baseline lung function was predictive of the efficacy and safety of lumacaftor/ivacaftor treatment by stratifying patients based on their screening and study baseline lung function values. These data were previously presented at the North American CF Conference in October 2015 and will be presented as part of an invited talk during Symposium 29, Best of Journal of Cystic Fibrosis / The Lancet Respiratory Medicine Symposium, at ECFS.
• * On October 8, 2015, Vertex Pharmaceuticals announced significant progress in its development efforts to treat the underlying cause of cystic fibrosis (CF) for the vast majority of people with the disease. These updates were made in conjunction with the 29th Annual North American Cystic Fibrosis Conference (NACFC) in Phoenix . Vertex is currently conducting two Phase 3 clinical studies of lumacaftor/ivacaftor in children 6 to 11 years of age. The first study is evaluating lumacaftor/ivacaftor in approximately 50 children to support the potential FDA approval in children ages 6 to 11. The primary endpoint of this six-month study is safety. Vertex plans to submit an sNDA to the FDA in the first half of 2016, pending data from this study. To support approval in the European Union , a six-month Phase 3 efficacy study is ongoing to evaluate lumacaftor/ivacaftor in approximately 200 children. The primary endpoint of the second study is the absolute change in lung clearance index. Efficacy and Safety of Lumacaftor/Ivacaftor Across Sub-Groups in TRAFFIC and TRANSPORT Studies: A pre-specified pooled analysis that evaluated whether baseline lung function was predictive of the efficacy and safety of lumacaftor/ivacaftor treatment will be presented at NACFC for the first time. In this analysis, patients were stratified based on their screening and study baseline lung function values. The results showed that the efficacy and safety of lumacaftor/ivacaftor were generally similar across lung function subgroups. These data will be presented as part of a poster titled "Efficacy and Safety of Lumacaftor/Ivacaftor Combination Therapy in Patients With CF Homozygous for F508del-CFTR by FEV1 Subgroups."
• * On May 17, 2015, Vertex Pharmaceuticals announced that the New England Journal of Medicine (NEJM) published data from the two Phase 3 studies of Orkambi® (lumacaftor/ivacaftor), an investigational medicine designed to treat the underlying cause of cystic fibrosis (CF) in people ages 12 and older with two copies of the F508del mutation, the most common form of the disease. The data were published online in conjunction with the American Thoracic Society International Conference ( May 15-20 , Denver) where the data were presented in a session titled, "Discussion on the Edge: Recent Pulmonary Research Published in NEJM or JAMA." In November 2014, Vertex submitted a New Drug Application (NDA) to the FDA for the combination of lumacaftor and ivacaftor in people with CF ages 12 and older who have two copies of the F508del mutation. On May 12th, 2015 , the FDA's Pulmonary Allergy Drugs Advisory Committee (PADAC) voted 12-1 to recommend that the FDA approve ORKAMBI for this group of people with CF. The FDA is expected to make a decision on the NDA by July 5, 2015 .
• • On October 9, 2014, Vertex Pharmaceuticals reviewed recent progress and announced upcoming milestones in its efforts to develop multiple combinations of medicines that treat the underlying cause of cystic fibrosis (CF) for the majority of people with the disease. These updates were made in conjunction with the 28th Annual North American Cystic Fibrosis Conference (NACFC), in Atlanta. Kalydeco® (ivacaftor) is currently approved to treat more than 2,600 people ages 6 and older in North America, Europe and Australia who have specific mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In the United States, these mutations include G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P and G1349D. Multiple clinical studies are complete, underway or planned that are designed to evaluate whether ivacaftor, used alone or in combination with other potential CF medicines known as CFTR correctors, may help more people with CF, including people with one or two copies of the most common mutation, F508del. Data from several of these studies will be presented at NACFC, including the results of the Phase 3 TRAFFIC and TRANSPORT studies of the CFTR corrector lumacaftor in combination with ivacaftor, as well as the first interim data from a rollover study of patients who completed treatment in TRAFFIC and TRANSPORT.
• NDA and MAA Planned in the Fourth Quarter: In June 2014, Vertex announced results from the Phase 3 TRAFFIC and TRANSPORT studies of lumacaftor in combination with ivacaftor in people with CF who have two copies of the F508del mutation. Based on the results of these studies, Vertex plans to submit a New Drug Application (NDA) in the United States and Marketing Authorization Application (MAA) in Europe in the fourth quarter of 2014. The global regulatory submissions will seek approval for the use of lumacaftor (400 mg q12h) in combination with ivacaftor (250 mg q12h) in people ages 12 and older with two copies of the F508del mutation. The combination of lumacaftor and ivacaftor will be fully co-formulated and dosed as two individual tablets every 12 hours (four tablets daily).
• Sustained Improvements in Lung Function Through 48 Weeks of Treatment: Patients who completed 24 weeks of treatment in either TRAFFIC or TRANSPORT were able to enter a Phase 3 rollover study to receive a combination regimen. One thousand thirty-one people started treatment in the rollover study, and at the time of the interim analysis, approximately 25 percent of patients within each arm of the rollover study had received an additional 24 weeks of treatment for a total of 48 weeks of treatment (48 weeks of treatment with a combination regimen for patients who received a combination regimen in TRAFFIC and TRANSPORT; 24 weeks of treatment with a combination regimen for patients who received placebo in TRAFFIC and TRANSPORT). The first interim data from this rollover study will be presented at NACFC and showed that the initial improvements in lung function (percent predicted forced expiratory volume in one second, or ppFEV1) observed in the 24-week TRAFFIC and TRANSPORT studies were sustained through 48 weeks of treatment with lumacaftor in combination with ivacaftor. The pattern of response observed after the initiation of combination dosing across all patients who received placebo in TRAFFIC and TRANSPORT and subsequently received a combination regimen in the rollover study was similar to that seen in patients who received a combination regimen in TRAFFIC and TRANSPORT.
• At the time of the interim analysis, the safety and tolerability results, including the rate of serious adverse events, were consistent with those observed in the Phase 3 TRAFFIC and TRANSPORT studies. Among patients new to treatment in the rollover study, infective pulmonary exacerbation, cough, increased sputum, haemoptysis, respiration abnormal and dyspnea were the most common adverse events at the time of the interim analysis.

Is general: Yes