Getting insight in the exposure effect relationship of Elexacaftor/ Tezacaftor/Ivacaftor treatment in people with cystic fibrosis

On January 1st, 2022, the use of Elexacaftor/Tezacaftor/Ivacaftor (ETI) has
been reimbursed in Netherlands for adult people with cystic fibrosis (pwCF) and
at least one copy of the F508del mutation. The treatment involves taking 2
tablets of ETI in the morning and 1 tablet of ivacaftor in the evening. ETI is
a combination of two correctors, Elexacaftor and Tezacaftor, and one
potentiator, Ivacaftor.

Treatment with ETI has shown an impressive clinical effect. However, despite
its effectiveness at group level, there is a high level of variability in the
response to treatment among individuals with the same Cystic Fibrosis
Transmembrane conductance Regulator (CFTR) gene mutation, even with
standardised dosages. In daily practice, more side effects have been observed
than expected based on registration studies. Adverse effects such as elevated
transaminase, bilirubin, creatine kinase, rashes and mental problems have been
observed in pwCF treated with ETI.

There is currently limited information available on how exposure to CFTR
modulators affects the clinical effect of these drugs, and the relationship
between exposure and (side) effects is still not clear. To improve our
understanding of this relationship, we will compare the serum concentrations of
ETI in 10 people with CF who show the highest clinical effect, with those of 10
people with CF who show the lowest clinical effect.

Sweat chloride will be used as a clinical endpoint because sweat chloride can
be used as a substitute biomarker for CFTR function, since its quantity
indicates the activation of the CFTR protein. Although the reproducibility of
the sweattest is moderate, it has the advantage of being independent of the
severity of CF disease, as sweat glands do not appear to be susceptible to the
progression of CF. In this study, we hypothesize that pwCF who have a greater
reduction in absolute sweat chloride levels also have a higher concentration of
ETI in their blood compared to those with less reduction in their absolute
sweat chloride levels.

Primary objective: To compare the exposure of ETI in a group of pwCF with the
highest decrease in sweat chlorid and the lowest decrease in sweat chloride as
result of ETI therapy.

This study is a single-centre study in which 20 pwCF will be included. The 10
patients with the highest absolute sweat chloride decrease and the 10 patients
with the lowest absolute sweat chloride decrease, who are currently undergoing
treatment with ETI will be selected for the study. After that we will ask them
for participation in the study. Patients who are interested will be referred to
the principal investigator, who will inform them about the study and ask for
their consent. All participants will receive an information letter and an
informed consent form and will be given at least 2 days to decide about their
participation. If the patients agree to participate, a visit for blood sample
collection will be scheduled. If possible, we will combine their study visit
with their conventional appointment on the outpatient clinic.

The sole intervention in this study is a single venous puncture for the
collection of 5 ml of blood.

Included pwCF will visit the hospital once. One blood sample will be collected
before their daily dose of ETI by venepuncture.
We do not consider the study to be high-risk since the patients with cystic
fibrosis included in the study will continue with their existing ETI treatment,
which is approved by both the FDA and EMA, and is already being used by the
patients on a daily basis. The dose used in the study will be the same as the
standard dose. The only intervention is that during the study, one blood sample
will be taken by venepuncture and participants are asked to take their morning
ETI dose after venapunction in the hospital. Their visits will therefore be
scheduled in the morning.