The United States Food And Drug
Administration (FDA) has approved a new cystic fibrosis (CF) drug combination
(tezacaftor/ivacaftor) that can be used in patients who have two
copies of F508del mutation (the most common CF mutation), and in patients who
have at least a single copy of one of 26 specified mutations.
- Dual drug combination
of tezacaftor/ivacaftor has been approved by the FDA
for cystic fibrosis (CF)
- Cystic fibrosis is a
genetic disorder where the cystic fibrosis transmembrane conductance
regulator (CFTR) protein function is abnormal due to mutations in the gene
that codes for it
- Combination drug that
can correct the function of the CFTR protein has been approved to treat
people with CF who are above 12 years of age with certain gene mutations
Using this combination can treat more number of CF patients than compared
to an earlier combination.
treatment consists of targeting the underlying cause of the disease, namely the
functioning of the CFTR protein. Drugs that are used to correct or modulate
the function of the CFTR protein are called "modulators."
When the primary
function of the CFTR protein is corrected to a certain extent, a proper
chloride flow is reestablished, and the mucus gets rehydrated inside the lungs
and other organs. Improving chloride flow even to a certain extent can relieve
symptoms for people with CF.
‘The FDA approval of a new drug combination for cystic fibrosis paves the way for new, and more effective triple combination therapies scheduled to begin late-stage clinical trials in the next several months.’
FDA Approved Drug
(Symdeko™) is the new drug combination that has been approved by the FDA for
people with CF ages 12 and older who have two copies of the most common CF
mutation, F508del. Symdeko has also been approved for people with CF ages 12
and older who have a single copy of one of 26 specified mutations, regardless
of their other mutation.
Ivacaftor is a
type of CFTR modulator called a "potentiator."
It keeps the
gates of the CFTR protein channel open to allow chloride flow through the cell
Two copies of the
F508del mutation is found in almost half of people with CF. Having this
mutation prevents the CFTR protein to form the right three-dimensional shape,
in turn, preventing the transport of the protein to the cell surface in order
to function. Another kind of modulator known as a "corrector" can accomplish
the task but not a hundred percent. Hence using a drug combination of a
corrector along with a potentiator, (to keep the protein gates open long enough
for enough chloride to pass through) can double the benefits of a modulator.
combination tezacaftor/ivacaftor was developed by Vertex
Pharmaceuticals Inc., a global biotechnology company based in Boston,
Massachusetts, along with significant clinical, scientific, and funding support
from the Cystic Fibrosis
3 Clinical Trials
The first phase 3
trial was a 24-week randomized, placebo-controlled study known as EVOLVE that
tested the efficacy and safety of the tezacaftor/ivacaftor combination treatment in people with CF ages 12 and older with two
copies of the F508del mutation. There was a mean absolute improvement in
lung function by four percentage points in people with CF compared to those
taking a placebo.
Other significant improvements were a 35 percent
reduction in the sudden worsening of symptoms requiring treatment
(exacerbations) and an increase in quality of life.
The second phase 3 trial was a 8-week randomized,
placebo-controlled, crossover study known as EXPAND that evaluated the efficacy
and safety of tezacaftor/ivacaftor combination treatment as well as ivacaftor
monotherapy in people with CF 12 and
older who have at least one copy of the 26 specified mutations that results in
residual CFTR function and one F508del mutation. There was a mean absolute
improvement in lung function of 6.8 percentage points in people with CF
compared to placebo
and a 4.7 percentage point improvement in the ivacaftor
monotherapy group compared to placebo.
is exciting news for the cystic fibrosis community and a big step forward in
our ongoing efforts to find new and better treatments to address the underlying
cause of the disease," said Preston W. Campbell, III, M.D., president and CEO
of the CF Foundation. "We are optimistic that next-generation CFTR modulators
that build on this advance could bring transformative treatments to nearly 90
percent of people with CF, and we remain committed to finding effective new treatments
for every individual living with the disease."
Late stage clinical trials have been
planned in the next several months for triple combination
therapies (treatments consisting of three different modulators, including
tezacaftor, ivacaftor and a next-generation modulator that
can also benefit individuals
with a single F508del mutation).
Cystic fibrosis is
a progressive, genetic
disease that is caused by mutations in a gene called the cystic
fibrosis transmembrane conductance regulator (CFTR) gene.
are more than 1,700 different mutations in the CFTR gene that can cause
The CFTR gene is
responsible for creating the CFTR protein whose primary function is to
regulate the transport of chloride (a component of salt) and fluids inside and
outside of the cell.
When there is a mutation or a defect in the CFTR gene
the resulting CFTR protein is not made correctly or not made at all, which
affects the salt and fluid conduction across the cell membrane. This results
in thick, sticky mucus build-up in the lungs, pancreas, and
In the lungs,
mucus buildup can clog the airways and trap bacteria leading to infections,
extensive lung damage, and respiratory failure. Similarly, in the pancreas, the
mucus prevents the release of digestive enzymes that in turn affects digestion.
Overall, CF patients experience symptoms like wheezing or shortness of breath,
persistent coughing (with or without phlegm), pneumonia
or bronchitis, weight gain and poor
- FDA Approves New CFTR Modulator Treatment for Cystic Fibrosis - (https://www.cff.org/News/News-Archive/2018/FDA-Approves-New-CFTR-Modulator-Treatment-for-Cystic-Fibrosis/)