The effect of Ivacaftor in CF patients with a class III mutation

The cystic fibrosis trans membrane conductance regulator (CFTR), a chloride and
bicarbonate channel encoded by the CFTR gene, is essential for fluid and
electrolyte homeostasis at the epithelial surfaces of many organs, including
the lung, intestine, and sweat gland. Over 1900 CFTR mutations have been
identified causing impaired protein production (class I), folding (class II),
channel gating (class III), conductance (class IV), or reduced synthesis (class
V). The CFTR potentiator-drug Ivacaftor will be approved for the treatment of
CF patients with a mutation associated with residual CFTR function, probably by
the beginning of 2015. Introduction of this drug in clinical treatment of these
patients is to be expected shortly after approval. The estimated costs of this
treatment are ¤ 200.000 per patient per year.
Currently, several CF patients with gating mutations are using curcumin and
genistein because of anecdotally reported beneficial effects of these
self-administered food supplements. Using various primary cell models from CF
patients (organoids), we also found the combination of natural food components
curcumin and genistein to synergize in potentiating CFTR mutants with a channel
gating defect, (e.g. F508del; S1251N), thereby enhancing function of these
mutants significantly. Based on these findings we currently perform the
TICTAC-I study. In this study we evaluate the therapeutic potential of these
food supplements. In the TICTAC-II study we will objectively evaluate the
therapeutic effect of Ivacaftor in patients with a class III mutation. The
introduction of Ivacaftor is the ideal moment to measure this therapeutic
effect because we can perform a before and after measurement without changing
the treatment of a patient.

Primary objective is to objectively investigate the therapeutic potential of
Ivacaftor in Dutch CF patients carrying a mutation associated with residual
CFTR function. A secondary objective is to evaluate the correlations between
individual Ivacaftor induced CFTR function in vitro (organoid-based
measurements) and the in vivo treatment effect. Other secondary objectives are:
to assess the colonization status and microbiome of the airways before and
after introduction of Ivacaftor treatment, to evaluate the concentration of
Ivacaftor in the patient*s blood samples and CFTR stimulating ability of this
concentration. We will examine this by measuring serum concentrations and by in
vitro testing (in the organoid model). The last secondary objective is to
compare the therapeutic potential of Ivacaftor with the therapeutic potential
of the natural food components curcumine and genistein.

A multicenter observational study

Patients participating in this study will visit the hospital for two study
visits.The following tests will be done during each study visit: Quality of
Life Questionnaire, a brief anamnesis, physical examination, sweat test (SCC),
lung function (FEV1%), NO fraction of exhaled air and airway resistance (Rint
and bodybox). We will also ask patients to bring a feces sample at both visits,
collect a blood and sputum sample at both visits and perform oro-and
nasopharyngeal swabs. In addition, patients are asked to perform a FEV1
measurement at home with a small FEV1 meter once a week and to fill out a diary
about using their Ivacaftor.
By the start of the study Ivacaftor will be an approved treatment in the
Netherlands. In this project we propose to measure the therapeutic effect of
the regular treatment with Ivacaftor in CF patients with a mutation associated
with residual CFTR function. The introduction of Ivacaftor is the ideal moment
to measure this therapeutic effect because we can perform a before and after
measurement without changing a patients treatment. A number of CF patients with
a class III gating mutation already use Ivacaftor as part of a compassionate
use program and they report a clear diminution of their CF symptoms.

When our hypothesis that curcumin and genistein turn out to improve the CFTR
function in patients with a class III gating mutation similar to Ivacaftor and
therefor diminish CF symptoms is confirmed, this is a major benefit not only
for the patient but also for society because of the much lower costs of
curcumin and genistein in comparison with Ivacaftor (¤ 500 per year per patient
versus ¤200.000 per year per patient). When this study also confirms our
hypothesis that organoids can predict clinical responders, this is a major
benefit not only for the individual patient but for the entire CF-population.
With the use of organoids we will then be able to generate optimal treatment
strategies for individuals based on (combinations of) current and future drugs
with only limited patient discomfort.