A B2-agonist as a CFTR activator in CF

The cystic fibrosis trans membrane regulator (CFTR) protein is essential for
ion and fluid homeostasis of epithelial surfaces, and mutated in cystic
fibrosis (CF). CF disease severity is highly variable between subjects and
associated with CFTR mutations that confer CFTR residual function. We
hypothesized that CF subjects with significant CFTR residual function benefit
from therapeutic interventions that activate signal transduction pathways that
increase CFTR function. Using various primary cell models from CF patients
(organoids), we found beta-2 adrenergic receptor agonists (B2-agonists) as
potent activators of CFTR in patients with residual CTFR function. Restoration
of the CF phenotype in vitro by a B2-agonist is variable between patients.

Primary objective of this pilot study is to evaluate the in vivo effect of a
B2-agonists in CF patients with residual CFTR function, using dosages which are
clinically used in patients with asthma. Secondary objective is to evaluate the
difference between B2-agonist treatment per inhalation and oral B2-agonist
treatment. Another secondary objective is to evaluate the correlations between
individual B2-agonist-induced CFTR function in vitro (organoid-based
measurements) and the in vivo treatment effect (nasal potential difference
(NPD) and sweat chloride concentration (SCC)). Last secondary objective is to
assess whether the dosage of Salbutamol used in the clinical study is
sufficient to stimulate CFTR function, by testing the CFTR stimulating effect
of patients* blood samples in vitro.

A pilot open label cross-over dose finding study

All patients will be randomly assigned to receive four times daily 200 mcg
Salbutamol per inhalation (treatment 1) or four times daily 4 mg Salbutamol per
os (treatment 2), during four days. After a wash-out period of at least seven
days of no Salbutamol use, patients who had treatment 1 will receive treatment
2 during four days and patients who had treatment 2 will receive treatment 1
during four days.

Patients participating in this study already had a rectal biopsy to produce an
organoid as part of their regular care or another study. They will be treated
at home and will visit the hospital for four study visits. During each visit
several tests will be performed, including NPD, SCC, spirometry and taking
blood samples. Besides that, patients are asked to use Salbutamol during two
periods of four days (4 days of oral treatment and 4 days of treatment per
inhalation). Salbutamol has been used in clinical practice for over ten years
in patients with asthma and no serious side effects have been reported. We
therefore do not expect serious problems or side effects during this study.
When the hypothesis is confirmed and Salbutamol turns out to not only activate
the residual CFTR function in vitro but also in vivo, this can be a major
benefit for the patient. When this study confirms our hypothesis that organoids
can predict clinical respons to medication, this is a major benefit not only
for the individual patient but also for the 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.