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Data from the First Part of a Phase 2 Study Support the Approach of Treating the Most Common Form of Cystic Fibrosis (F508del) by Targeting the Underlying Cause of the Disease With a Combination of KALYDECO™ (ivacaftor) and VX-809
- New data at
- Part 2 of study now enrolling patients -
There were three treatment arms in Part 1 of this 21-day study that
evaluated VX-809 (200 mg once daily) or placebo alone for 14 days,
followed by VX-809 (200 mg) in combination with KALYDECO (150 mg or 250
mg every 12 hours) or placebo for seven days. The study enrolled people
18 and older with two copies of the F508del mutation. Data from the
first part of this study showed that there was a nearly two-fold greater
reduction in sweat chloride between Day 14 and Day 21 when KALYDECO (250
mg) was added to VX-809 compared to those who continued to receive
"The first part of this study has given us important information about
how the combination of a CFTR potentiator and corrector may help people
with the most common form of cystic fibrosis, which is also one of the
most severe forms of the disease," said
No significant differences were seen between study groups in the frequency or type of adverse events, and no serious adverse events occurred. Respiratory-related adverse events were the most commonly reported, with an overall incidence of 50 percent across treatment arms.
The CFTR protein functions as a chloride channel, enabling the movement of chloride, with secondary effects on sodium ions into and out of these cells. When the protein is defective or absent, as in CF, the salt balance in certain tissues in the body is disturbed. This causes people with CF to have more chloride, or salt, in their sweat. Elevated sweat chloride levels are a diagnostic hallmark that occur in people with CF and result directly from defective CFTR function in the sweat ducts. Measurement of the chloride in sweat has been the standard method for diagnosing CF for more than 40 years.
"In people with the most common form of CF, the CFTR protein is
defective — it doesn't usually reach the cell surface and is relatively
inactive if it does," said
About the Phase 2 Study
These data are from the first part of an ongoing, multiple-part, randomized, double-blind, placebo-controlled Phase 2 trial that will inform future clinical studies of a CFTR corrector, VX-809, in combination with CFTR potentiator, KALYDECO. The first part of the study enrolled 62 people with CF aged 18 years or older who had two copies of the F508del mutation in the CFTR gene. The primary goals of the trial were to evaluate the safety and tolerability and the effect on CFTR function of the combination of VX-809 and KALYDECO as measured by sweat chloride.
Part 2 of this trial will evaluate dosing of VX-809 alone for four weeks
followed by dosing of KALYDECO and VX-809 in combination for four weeks.
The study is expected to evaluate multiple dose levels of VX-809,
including doses higher than those studied in the first part of the
trial, and longer dosing periods. The study is expected to enroll
approximately 100 people with CF who have one or two copies of the
F508del mutation. Similar to Part 1, the primary goals of the second
part of the trial are to evaluate safety and tolerability and the effect
of the combination of KALYDECO and VX-809 on CFTR function as measured
by sweat chloride. Lung function will be measured as a secondary
endpoint. Patient screening for Part 2 of this study began in
Final Results from Part 1 of the Phase 2 Study
Safety: In Part 1 of this study, no serious adverse events were reported, and the adverse event profile observed during the 7-day portion in which VX-809 and KALYDECO were dosed in combination was similar to the profile observed during the prior 14-day dosing period in which VX-809 was dosed as monotherapy. The most commonly reported adverse events were respiratory in nature and occurred in approximately half of people across all arms of the study. One person receiving VX-809 in the monotherapy portion of the study discontinued treatment due to an increase in respiratory symptoms during the first 7 days of the study.
Sweat Chloride: A co-primary endpoint of the study was the effect on CFTR function as measured by sweat chloride during the combination-dosing portion of the study (Day 14 to Day 21). Elevated sweat chloride levels are a diagnostic hallmark in CF and are the result of CFTR protein dysfunction. Although not a clinically validated endpoint, a reduction in sweat chloride is considered to be a marker of improved CFTR function. The amount of chloride in the sweat is measured using a standard test. People with CF typically have elevated sweat chloride levels in excess of 60 mmol/L, while normal values are less than 40 mmol/L.
In Part 1 of this study, the baseline sweat chloride levels across the three study arms were approximately 100 mmol/L. The within-group mean change in sweat chloride from baseline for each of the treatment groups was as follows:
Within-Group Mean Change in Sweat Chloride From Baselines
(Day 0 and Day 14)
Day 0 — 14:
Day 14 — 21: VX-809 in
Combination with KALYDECO
Arm 1 (n=20): VX-809 (200mg);
VX-809 (200 mg) in combination
with KALYDECO (150 mg)
|-4.21 mmol/L (p=0.008)||-2.24 mmol/L (p=0.163)|
Arm 2 (n=21): VX-809 (200mg);
VX-809 (200 mg) in combination
with KALYDECO (250 mg)
|-9.10 mmol/L (p<0.001)|
Arm 3 (n=21): VX-809 placebo;
VX-809 placebo in combination
with KALYDECO placebo
|-2.86 mmol/L (p=0.179)||+1.25 mmol/L (p=0.446)|
A statistically significant reduction in sweat chloride of 9.10 mmol/L (p<0.001) was observed after KALYDECO (250 mg) was added to VX-809 (200 mg) from Day 14 to Day 21. As compared to baseline (Day 0), people who received the combination regimen in this arm had a 13.17 mmol/L reduction in sweat chloride.
Eight of the 17 patients with evaluable data in Arm 2 had a reduction of sweat chloride that exceeded 15.0 mmol/L, while four of these 17 patients had a reduction of sweat chloride that exceeded 20.0 mmol/L. Four of the 21 patients in this arm were not part of the responder analysis (n=17) because they did not have evaluable data at the relevant time points. Across the treatment arms, sweat chloride levels returned to baseline following the completion of dosing with VX-809 and KALYDECO.
About CFTR and CFTR Modulators
CF is caused by defective or missing CF transmembrane conductance regulator (CFTR) proteins, which result in poor ion flow across cell membranes, including in the lungs, causing the accumulation of abnormally thick, sticky mucus that leads to chronic lung infections and progressive lung damage. Approximately 90 percent of people with CF have at least one copy of the F508del mutation. In these people CFTR proteins do not reach the cell surface in normal amounts and don't function properly at the cell surface. As a CFTR corrector, VX-809 aims to increase CFTR function by increasing the movement of CFTR to the cell surface. Once these CFTR proteins are at the cell surface, KALYDECO, a CFTR potentiator, aims to keep them open longer to improve the transport of chloride ions across the cell membrane.
Vertex submitted requests to the
About Cystic Fibrosis
CF is a life-threatening genetic disease affecting approximately 30,000
Collaborative History with
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 creates new possibilities in medicine. Our team discovers, develops and commercializes innovative therapies so people with serious diseases can lead better lives.
Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, rheumatoid arthritis, epilepsy and other life-threatening diseases.
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Special Note Regarding Forward-Looking Statements
This press release contains forward-looking statements including
statements regarding (i) the data from the first part of the Phase 2
study supporting the approach of treating the most common form of CF by
targeting the underlying cause of the disease with a combination of
KALYDECO and VX-809; (ii) the belief that Vertex is on the right track
for potentially helping more people with this combination approach and
(iii) the design and goals of the second part of the Phase 2 study.
While the Company believes the forward-looking statements contained in
this press release are accurate, those statements are subject to risks
and uncertainties that could cause actual outcomes to vary materially
from the outcomes referenced in the forward-looking statements. These
risks and uncertainties include, among other things, the risk that
efforts to develop VX-809 in combination with KALYDECO may not proceed
due to technical, scientific, commercial, financial or other reasons,
that an adverse event profile for VX-809 or KALYDECO could be revealed
in the future that could put further development of VX-809 or KALYDECO
in jeopardy, and other risks listed under Risk Factors in Vertex's
annual report and quarterly reports filed with the
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