Cystic fibrosis (CF) was once considered a fatal pediatric disease, but treatments have improved outcomes, enabling many patients with this condition to live well into adulthood. Patients with CF have mutations in the cystic fibrosis transmembrane conductance regulator (CFTR
) gene, which encodes for CFTR protein, an epithelial cell-surface expressed protein that regulates transport of chloride and water across the cell membrane. CFTR
gene mutations disrupt the function of the chloride channels, thereby inhibiting the flow of chloride ions and water across the cell membranes, leading the epithelial cells that line the lungs, pancreas, and other organs to produce thick and sticky mucus that clogs these organs and prevents them from functioning normally.
One common mutation among patients with CF is the gating mutation G551D, which substitutes the amino acid glycine with aspartate at position 551 in the nucleotide binding domain-1 of the CFTR
gene. In January 2012, the FDA approved ivacaftor (Kalydeco), the first agent targeting this mutation, for patients aged 6 years and older with at least one allele having the G551D mutation. In February 2014, ivacaftor’s approval was expanded to include 8 additional mutations: G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, and G1349D.
Currently, the FDA is reviewing a new drug application for ivacaftor for children aged 2 to 5 years who have some of these mutations. A target review date of March 17, 2015 was set under the Prescription Drug User Fee Act for the FDA’s approval decision. Vertex Pharmaceuticals is also conducting several studies combining ivacaftor with other agents.
“Our goal is to develop combinations of medicines to treat many more people with CF and to improve the benefit that these combinations of medicines may provide," said Jeffrey Chodakewitz, MD, senior vice president and chief medical officer at Vertex, in a Vertex press release.
One such combination that is showing considerable promise is the addition of VX-661 to invacaftor, and several studies are ongoing or planned for the second quarter of 2015. VX-661 is Vertex Pharmaceutical’s second CFTR corrector. It is being developed to enhance combinations of CFTR modulators aimed at treating patients with CF who have one or two copies of the F508del mutation.
In May 2014, Vertex Pharmaceuticals announced
the results of a 28-day, phase 2 proof-of-concept study that showed that the addition of VX-661 to ivacaftor improved lung function in people with CF who were heterozygous for the F508del and G551D mutations and already on an ivacaftor regimen.
In the study, VX-661 was added to patients’ ongoing treatment for 4 weeks to evaluate the safety of the combination regimen and its effect on lung function, sweat chloride levels, and other measures. Treatment with the combination for 28 days resulted in a mean within-group absolute improvement in lung function of 4.6% (P
=.012), a mean within-group relative improvement in lung function of 7.3% (P
=.012), and a mean reduction in sweat chloride of -7.02 mmol/L (P
=0.053) through the end of treatment. Once VX-661 was discontinued at the end of the 28-day treatment period, lung function and sweat chloride levels returned to baseline levels. VX-661 was generally well tolerated, with all 18 patients completing the 28-day treatment period.
The positive findings with the addition of VX-661 paved the way for an ongoing 12-week, phase 2 study of ivacaftor/VX-661 in patients with CF and two copies of the F508del mutation. The study completed enrollment in October 2014 and includes approximately 40 patient, with half receiving placebo and the other half receiving one of two doses of VX-661 (50 mg every 12 hours or 100 mg once daily) in combination with ivacaftor (150 mg every 12 hours). The primary endpoint is safety and the secondary endpoints concern pharmacokinetics and efficacy of VX-661. Vertex Pharmaceuticals plans to announce data from the study in the first quarter of 2015; however, it is already enrolling patients into its first phase 3 study of ivacaftor/VX-661, which is expected to start in February. Like the earlier studies, this trial will enroll patients with two copies of the 508del mutation.
In addition to this study, 3 other phase 3 studies of ivacaftor/VX-661 are expected to start in the second quarter of 2015 and will enroll patients (aged ≥12 years) with a single copy of the 508del mutation plus one other mutation. The anticipated trials are as follows:
One copy of the F508del mutation and a second mutation that results in a gating defect in the CFTR protein. The study will enroll approximately 200 patients in North America and Europe. The primary endpoint will be absolute change in percent-predicted forced expiratory volume in 1 second (ppFEV1) through 8 weeks of treatment with ivacaftor/VX-661 versus ivacaftor alone.
One copy of the F508del mutation and a second mutation that results in residual CFTR function. The study will enroll approximately 300 patients in North America and Europe. It will evaluate ivacaftor/VX-661 versus ivacaftor alone. The primary endpoint of the study will be absolute change in ppFEV1 through 8 weeks of treatment as part of a crossover design.
One copy of the F508del mutation and a second mutation that results in minimal CFTR function. This trial will evaluate ivacaftor/VX-661 in approximately 120 patients. The primary endpoint will be absolute change in ppFEV1 through 12 weeks of treatment versus placebo. Expansion of the study to an additional 150 patients will depend on an interim futility analysis of efficacy data from the initial 120 patients.
Rare Disease Quick Facts: Cystic Fibrosis
CF most commonly affects white patients, occurring in 1 in 2500 to 3500 white newborns, compared with 1 in 17,000 African-Americans newborns and 1 in 31,000 Asian-American newborns.
In the United States, approximately 1,000 new cases of CF are diagnosed annually.
An estimated 30,000 children and adults in the United States (70,000 worldwide) have CF.
More than 75% of CF cases are diagnosed by age 2 years.
Approximately 50% of the CF population is aged 18 years or older.
In the 1950s, few children with CF lived long enough to attend elementary school.
"CFTR Protein Panels" by Lbudd14 - Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:CFTR_Protein_Panels.svg#mediaviewer/File:CFTR_Protein_Panels.svg