Cystic Fibrosis (CF) is related to structural and/or functional defects of chloride channel
CFTR (Cystic Fibrosis Transport Regulator). These anomalies are associated with different
classes of genetic mutations (class I to VI). The most common mutation is p.Phe508del class
II (40% of homozygous and 70% heterozygous patients), it is responsible for the phenylalanine
deletion at position 508 with improper intracellular processing of CFTR with less than normal
amounts of CFTR protein at the apical cell membrane.
Over the last 20 years the CF patient outcome has been mainly improved using symptomatic
treatments. More recently, new therapeutic strategies targeting directly CFTR defects have
been developed. Initially potentiators which correct functional defects of CFTR (class
Mutations 3 and 4) were studied. Then, correctors that target CFTR production were also
developed. These molecules demonstrated substantial effect.
In 2015, the American company VERTEX - producing already KALYDECO (IVACAFTOR, VX-770)
potentiator molecule that is recommended for the treatment of CF patients aged ≥ 6 y, with
mutation altering the channel regulation (class III mutations) as G551D, G1244E, G1349D,
G178R, G551S, S1251N, S1255P, S549Nou S549R) - was allowed by the Federal Drug Administration
(FDA) and European Medicines Agency (EMA) for producing and using LUMACAFTOR-IVACAFTOR in
clinical trials to manage CF patients over 12 years and having two p.Phe508del mutations.
ORKAMBI represents the combination of two molecules (LUMACAFTOR + IVACAFTOR) respectively
correctors and potentiator of CFTR.
This EMA authorization follows the results of two international studies (TRAFFIC and
TRANSPORT) based on more than 1,000 CF patients showing that patients under
LUMACAFTOR-IVACAFTOR compared to the group taking placebo have:
A moderate improvement in lung function (FEV1) at 24 weeks of 4.3 to 6.7%,
A significant reduction in lung exacerbations (bronchitis) up - 39%,
An increase in body mass index (BMI). These results confirm that LUMACAFTOR-IVACAFTOR
may represent the first medicine to treat the whole underlying cause of CF in people
ages 12 and older who have two copies of the p.Phe508del mutation. They complete the
decrease or disappearance of pulmonary colonization with Pseudomonas aeruginosa
(including mucoid phenotype isolates) observed under IVACAFTOR alone (KALYDECO
treatment), even if the impact on fungal flora (or mycobiota) has not been described up
to date.
In 2016, the French patients homozygous for the p.Phe508del mutation and older than 12 years
were treated with this molecule association. Since January 2018, the European Commission has
granted an extension of the Marketing Authorization for lumacaftor/ivacaftor to include 6 to
11 years old children with cystic fibrosis, and this authorization's extension is in process
in France.
Since 2018 in France, VERTEX company has been allowed for producing and using new generations
of ivacaftor combinations (tezacaftor/ivacaftor, tezacaftor/ivacaftor/VX-659,
tezacaftor/ivacaftor/VX-445 and tezacaftor/ivacaftor/VX-152) in clinical trials for patient
with cystic fibrosis, according to age (from 6 years old) and mutation eligibility criteria.
Patients treated by lumacaftor/ivacaftor or other ivacaftor combinations are closely
monitored according to criteria established by the working group "New Therapeutic Approaches"
of the French Society Cystic fibrosis. This study was a phase IV observational trial for a
period of 1 year. In this context, the team aims at initiating a comprehensive monitoring of
the lung and gut mycobiota and microbiota evolution under ivacaftor combinations
(lumacaftor/ivacaftor or other ivacaftor combination).
This project is directly linked to the monitoring of homozygous p.Phe508del patients who
begin treatment with ivacaftor combination in France (in agreement with the working group
"New Therapeutic Approaches" of the French Society Cystic Fibrosis for lumacaftor/ivacaftor
therapy, and the working group "Fungal Risks in CF").
As LUMACAFTOR-IVACAFTOR (or other ivacaftor combinations) impacts chloride secretion through
CFTR at the apical site epithelial cells, with an expected improvement in secretion hydration
and mucociliary clearance, it should modify the whole pulmonary microbial flora, including
fungal microbiota (mycobiota) of CF lungs; this newly modified flora being expected achieving
the characteristics of the "healthy type" in terms of flora composition, richness and
diversity. We can expect same processes at the gut levels.
