A B2-agonist as a CFTR activator in CF - Part 2

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. 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. Importantly, we also found large
differences in B2-agonist-induced swelling between CFTR genotype-identical
organoids, suggesting that CFTR-genotype is not sufficient to identify clinical
responders.
Based on these in vitro findings we performed the ABBA I study in which we
investigated if we also could measure a CFTR stimulating effect of salbutamol
in vivo and, if we could measure an effect in vivo, which of the two treatments
that were used in the study (oral or aerosol) was the most potent to stimulate
CFTR. In this study we found a CFTR-stimulating effect in vivo of oral
salbutamol but not of inhaled salbutamol. Also treatment with oral salbutamol
turned out to have a better outcome on in vitro and in vivo CFTR-function-tests
than treatment with salbutamol aerosol.

Primary objective of this study is to evaluate the clinical effect of a long
term treatment (8 weeks) with oral B2-agonists in CF patients with residual
CFTR function, especially on lung function (spirometry and airway resistance).

Secondary objectives are to:
1. Evaluate the correlations between individual B2-agonist-induced CFTR
function in vitro (organoid-based measurements) and the long term clinical
treatment effect (eg. lung function and airway resistance).
2. Assess the effect of the salbutamol concentration in the blood on CFTR
function in the background of patient specific parameters. We will do this by
examining the CFTR-stimulating potential of the patients* blood in vitro (in
the organoid model).

A multicentre, open label intervention study.

After baseline measurements all patients will be assigned to receive oral
Salbutamol, during 8 weeks up untill 24 hours prior to the second study visit.

Patients participating in this study will be treated at home and will visit the
hospital for two study visits. Salbutamol has been used in clinical practice
for over decades in patients with asthma and no serious side effects have been
reported. Therefor we do not expect serious problems or side effects during
this study. Based on the results of the ABBA I study and a clear diminutions of
CF symptoms in a number of patients with a compound/A455E or compound/R117H
mutation who have been treated with an oral B2-agonist as part of their regular
care we expect to see a clear clinical effect of long term treatment with oral
salbutamol. When our hypothesis is confirmed, this is a major benefit for the
patient. Not only during the study period but also for their further treatment.
When this study confirms our hypothesis that organoids can predict clinical
responders, this is a major benefit not only for the CF population but also for
the individual patient. 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.