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Vertex Announces Presentation of New KALYDECO™ (ivacaftor) Data at European Cystic Fibrosis Society Conference
-New data showed that KALYDECO reduced the loss of lung function by half over 3 years in people with CF who have the G551D mutation compared to similar untreated patients-
-New data from rollover study of ivacaftor in people with the R117H mutation support earlier results from Phase 3 study that demonstrated lung function improvements in patients ages 18 and older-
-New data showed that previously reported lung function improvements in Phase 3 ivacaftor study in people with certain non-G551D gating mutations were maintained through 24 weeks-
"People with cystic fibrosis experience significant and progressive loss
of lung function during their lives. This decline in lung function is
the primary cause of death in people with CF, and more rapid loss of
lung function is associated with earlier death," said
The effect of ivacaftor on the rate of lung function decline in CF patients with a G551D-CFTR mutation (ECFS Abstract WS3.1, Thursday at 15.00 CEST)
Progressive loss of lung function, due to chronic lung disease, is the primary cause of death for people with cystic fibrosis.
New data from an analysis of the Phase 3 STRIVE and ENVISION studies, and from patients who rolled over into the long-term extension study PERSIST, were presented at the conference and showed that treatment with KALYDECO in people with CF ages 6 and older with the G551D mutation appeared to modify the rate of lung function decline, reducing the annual loss of lung function by half over three years. The annual rate of decline among those receiving KALYDECO was 0.81 FEV1 percentage points compared to an untreated group of people matched on clinical criteria with two copies of the F508del mutation, whose annual rate of decline was 1.73 percentage points (p=0.02).
This analysis was conducted by comparing the change in lung function in people who received KALYDECO in the Phase 3 STRIVE, ENVISION and PERSIST trials (n=189) with lung function changes in a matched control group derived from the U.S. Cystic Fibrosis Foundation Patient Registry who had two copies of the F508del mutation and similar disease severity (n=886). Historical data have previously shown a similar rate of lung function decline among people with two copies of the F508del mutation and those with the G551D mutation.
Ivacaftor treatment in patients with cystic fibrosis who have an R117H-CFTR mutation, the KONDUCT Study (ECFS Abstract WS23.6, Friday at 18.15 CEST)
Vertex today announced interim results from the open-label rollover study of ivacaftor in people with CF ages 6 and older who have the R117H mutation. Sixty-five of the 67 eligible people who completed the KONDUCT study continued into this rollover study. As previously announced, the KONDUCT study did not meet its primary endpoint of absolute change from baseline in FEV1 (forced expiratory volume in one second) through 24 weeks in the overall study population. However, a pre-specified subset analysis showed that the mean absolute improvement in lung function compared to placebo (treatment difference) for patients ages 18 and older was 5.0 (p=0.01) percentage points, which corresponded to a mean relative improvement of 9.1 (p=0.008) percent. Statistically significant improvements in key secondary endpoints, including sweat chloride and patient-reported respiratory symptoms as measured by the respiratory domain of the Cystic Fibrosis Questionnaire Revised (CFQ-R), were also observed regardless of age.
In the rollover study, all patients received ivacaftor after a washout period of at least three weeks following the KONDUCT study. The interim data announced today were obtained following a pre-planned analysis conducted after all patients reached the 12-week timepoint in the rollover study. After the first 12 weeks of the rollover study, the mean absolute improvement from baseline in lung function (percent predicted FEV1) was 5.5 percentage points (p < 0.0001) among all patients (n=62; intent-to-treat analysis). For patients ages 18 and older (n=46), the mean absolute improvement in lung function was 5.1 percentage points (p < 0.0001). For patients ages 6 to 11 (n=15), the mean absolute improvement in lung function was 6.5 percentage points; the decline in FEV1 observed in the KONDUCT study for patients ages 6 to 11 who received ivacaftor was not observed in the rollover study. Similar to the KONDUCT study, treatment with ivacaftor, regardless of age, resulted in decreases in sweat chloride and improvements in CFQ-R.
In the 24-week KONDUCT study and through 12 weeks in the rollover study, the safety and tolerability results were consistent with those observed in prior Phase 3 studies of ivacaftor monotherapy in people with CF who have the G551D and other gating mutations. In KONDUCT, the most commonly observed adverse events in those who received ivacaftor were infective pulmonary exacerbation, cough and headache, which occurred with similar frequency compared to those who received placebo. Serious adverse events occurred in 17 percent of patients who received placebo versus 12 percent of patients who received ivacaftor. In the rollover study, the most common serious adverse events were infective pulmonary exacerbations.
Based on these data, Vertex plans to submit a supplemental New Drug
Application (sNDA) in the U.S. and a marketing authorization application
(MAA) variation in
The effect of ivacaftor, a CFTR potentiator, in patients with cystic fibrosis and a non-G551D-CFTR gating mutation, the KONNECTION Study (ECFS Abstract WS1.1, Thursday at 15.00 CEST)
Results from the second part of the Phase 3 KONNECTION study of
ivacaftor in people with CF ages 6 and older who have at least one copy
of certain non-G551D gating mutations (G178R, S549N, S549R, G551S,
G1244E, S1251N, S1255P, G1349D and G970R) were presented for the first
time at the conference. These data showed that the previously reported
improvements in lung function, sweat chloride, BMI and CFQ-R scores
after eight weeks of treatment (Part 1) were maintained through 24
weeks. The mean absolute improvement, from baseline, in lung function,
as measured by FEV1, through 24 weeks of treatment was 13.5
percentage points (n=18). The safety and tolerability results observed
through 24 weeks of treatment were consistent with those observed during
the eight-week first part of the study, reported in
The primary endpoint in the second part of the study was absolute change from baseline in lung function, as measured by FEV1, through 24 consecutive weeks of treatment for those who received ivacaftor in the second sequence of Part 1 of the study (n=18), which included eight weeks of ivacaftor treatment in Part 1 of the study plus 16 additional weeks in Part 2 of the study.
Hyperpolarized Helium-3 MRI Study
The effect of ivacaftor treatment on lung ventilation defects, as measured by hyperpolarized helium-3 MRI, on patients with cystic fibrosis and a G551D-CFTR mutation (ECFS Abstract WS3.2, Thursday at 15.15 CEST)
CF-related lung disease is known to start before it is detectable by deterioration in FEV1. Once FEV1 has fallen below normal (90 percent predicted), structural damage may have already occurred, much of which can be irreversible. Using a new imaging technology, hyperpolarized helium-3 MRI (3He-MRI) that is more sensitive to early- and mild-stage lung disease and gradual disease progression, this study showed that treatment with KALYDECO alleviated airway obstructions in the lung and benefited people with normal FEV1.
About KALYDECOTM (ivacaftor)
KALYDECO (ivacaftor) is the first medicine to treat the underlying cause
of CF in people with specific mutations in the CFTR gene. Known
as a CFTR potentiator, KALYDECO is an oral medicine that aims to help
the CFTR protein function more normally once it reaches the cell
surface, to help hydrate and clear mucus from the airways. KALYDECO
(150mg, q12h) was first approved by the
KALYDECO was approved by the
Vertex retains worldwide rights to develop and commercialize KALYDECO.
INDICATION AND IMPORTANT SAFETY INFORMATION FOR KALYDECO™ (ivacaftor)
Ivacaftor (150 mg tablets) is indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who have a G551D mutation in the CFTR gene.
Ivacaftor is not effective in patients with CF with 2 copies of the F508del mutation (F508del/F508del) in the CFTR gene. The safety and efficacy of ivacaftor in children with CF younger than 6 years of age have not been established.
Elevated liver enzymes (transaminases; ALT and AST) have been reported in patients receiving ivacaftor. It is recommended that ALT and AST be assessed prior to initiating ivacaftor, every 3 months during the first year of treatment, and annually thereafter. Patients who develop increased transaminase levels should be closely monitored until the abnormalities resolve. Dosing should be interrupted in patients with ALT or AST of greater than 5 times the upper limit of normal. Following resolution of transaminase elevations, consider the benefits and risks of resuming ivacaftor dosing.
Use of ivacaftor with medicines that are strong CYP3A inducers, such as the antibiotics rifampin and rifabutin; seizure medications (phenobarbital, carbamazepine, or phenytoin); and the herbal supplement St. John's Wort, substantially decreases exposure of ivacaftor and may diminish effectiveness. Therefore, co-administration is not recommended.
The dose of ivacaftor must be adjusted when used concomitantly with strong and moderate CYP3A inhibitors or when used in patients with moderate or severe hepatic disease.
Ivacaftor can cause serious adverse reactions including abdominal pain and high liver enzymes in the blood. The most common side effects associated with ivacaftor include headache; upper respiratory tract infection (the common cold), including sore throat, nasal or sinus congestion, and runny nose; stomach (abdominal) pain; diarrhea; rash; and dizziness. These are not all the possible side effects of ivacaftor. A list of the adverse reactions can be found in the product labeling for each country where ivacaftor is approved. Patients should tell their healthcare providers about any side effect that bothers them or does not go away.
Please see KALYDECO U.S. Prescribing Information, EU Summary of Product Characteristics, Canadian Product Monograph, Australian Consumer Medicine Information and Product Information, Swiss Prescribing Information and Patient Information, and the New Zealand Datasheet and Consumer Medicine Information.
About Cystic Fibrosis
Cystic fibrosis is a rare, life-shortening genetic disease affecting approximately 75,000 people in North America, Europe and Australia. Today, the median predicted age of survival for a person with CF is between 34 and 47 years, but the median age of death remains in the mid-20s.
CF is caused by a defective or missing CFTR protein resulting from mutations in the CFTR gene. Children must inherit two defective CFTR genes — one from each parent — to have CF. There are more than 1,900 known mutations in the CFTR gene. Some of these mutations, which can be determined by a genetic, or genotyping test, lead to CF by creating non-working or too few CFTR protein at the cell surface. The defective function or absence of CFTR proteins in people with CF results in poor flow of salt and water into and out of the cell in a number of organs, including the lungs. This leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage.
Collaborative History with Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT)
Vertex initiated its CF research program in 1998 as part of a
collaboration with CFFT, the nonprofit drug discovery and development
affiliate of the
Vertex is a global biotechnology company that aims to discover, develop and commercialize innovative medicines so people with serious diseases can lead better lives. In addition to our clinical development programs focused on cystic fibrosis, Vertex has more than a dozen ongoing research programs aimed at other serious and life-threatening diseases.
Founded in 1989 in
Special Note Regarding Forward-looking Statements
This press release contains forward-looking statements as defined in the
Private Securities Litigation Reform Act of 1995, including, without
limitation, Dr. Chodakewitz's statements in the second paragraph of the
press release, and the information provided regarding (i) Vertex's plans
to submit an sNDA in the U.S. and an MAA variation in
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