INTRODUCTION
The clinical care of cystic fibrosis (CF) has now been revolutionised
with CF transmembrane conductance regulators (CFTR) for use in people
with a number of specific CFTR gene mutations.
CFTR modulators are a new class of small molecules that aim to improve
the production, intracellular processing and function of the CFTR
protein1.
Elexacaftor-Tezacaftor-Ivacaftor (Kaftrio®) is the
newest CFTR modulator that was approved in August 2020 for people with
CF aged ≥ 12 and January 2022 for people with CF aged ≥ 6 years with at
least one copy of the F508del mutation. In vitro studies have
shown that this triple-therapy combination drug increases the level of
mature CFTR proteins and chloride
transport2, and
Kaftrio® can significantly improve pulmonary function,
respiratory-related quality of life (QoL) and pulmonary exacerbation
frequency3.
Phase II studies of Kaftrio® have demonstrated that
mean absolute increases in forced expiratory volume percent predicted
(FEV1%pred) in adults and children aged >
12 years, homozygous for p.Phe508del mutations, was 10% greater in
those receiving four weeks treatment with triple therapy versus
Tezacaftor and Ivacaftor alone3. However, it is
currently unknown whether Kaftrio® improves other
functional parameters of disease severity, such as exercise capacity,
since clinical trials have focused heavily on more traditional outcome
measures (e.g. pulmonary function, sweat [chloride], body mass index
(BMI)).
Importantly, higher levels of aerobic fitness (peak oxygen uptake
[\(\dot{V}\)O2peak]) are associated with an improved
quality of life4,
reduced risk of being hospitalised with a pulmonary
exacerbation5 and better
prognosis6 and a number
of changes following the initiation of modulator therapy have been
hypothesised7. Therefore, in the present study, we
report a case-series of three CFTR modulator naïve adolescents who
participated in the phase III trial (VX-17-445-103). These individuals
underwent cardiopulmonary exercise testing (CPET) and device-based
physical activity (PA) assessments at baseline and after receiving
triple therapy for 6 weeks to explore, for the first time, the
short-term effects of this medication on prognostically important CPET
outcomes.