DISCUSSION
In this case-series we have observed, for the first time globally,
improvements in exercise capacity following 6 weeks treatment with
Kaftrio®, especially in those with more severe CF lung
disease and deconditioning at baseline. In a previous study, 2 years of
treatment with Lumacaftor-Ivacaftor (Orkambi®)
improved \(\dot{V}\)O2peak and the AT to a similar
magnitude to that observed in the present
case-series12. The
authors speculated that these improvements were due to better health
enabling increased PA
levels12. Importantly,
our findings were achieved over a much shorter time period and
improvements appeared to occur independently of changes in daily PA
undertaken. Although the observed improvements in\(\dot{V}\)O2peak may be due to improvements in
FEV1%pred, parameters of ventilatory function from CPET
were mostly unchanged. Furthermore, the 2 participants who experienced
the greatest improvements in \(\dot{V}\)O2peak also
experienced a reduced\(\dot{V}\)E/\(\dot{V}\)O2peak,
suggesting that O2 uptake, transport and/or utilisation
improved independently of ventilation.
Body mass index increased in all of our participants, but this is
unlikely to reflect significant increases in muscle mass given the short
duration and unchanged PA. This assumption is supported by only modest
improvements in Wpeak compared to the larger
improvements in AT and \(\dot{V}\)O2peak. Our findings
of increased \(\dot{V}\)O2 per unit of power output in
two participants who were deconditioned are consistent with Saviet al. 12 and a
prior study in two patients treated with Ivacaftor for G551D gating
mutations13. The latter
study showed, using near-infrared spectroscopy, that the improvement in\(\dot{V}\)O2max in one adolescent was due to improved
muscle O2 extraction and/or
utilisation13.
Although not directly measured, the fitness improvements we have
observed might be due to CFTR modulator treatment directly improving a
CFTR-related defect of skeletal muscle. CFTR is expressed within
skeletal muscle
tissue14 and CFTR
activity may regulate mitochondrial
function15.
Consequently, it is possible that this treatment may improve
abnormalities at a cellular level, by altering skeletal muscle oxidative
metabolism during exercise, resulting in improved muscle oxidative
capacity.
Our results differ from those of a 28 day cross-over trial of Ivacaftor
in 20 adults with CFTR gating
mutations16. Although
FEV1%pred was significantly improved, only time to
exhaustion was improved during
CPET16. Notably,
treatment effects over placebo might have been blunted by a carry-over
effect in this cross-over design study, despite a 28 day wash out period
between treatments. Alternatively, validity concerns when conducting
CPET without supramaximal verification may have meant submaximal tests
were
included8,9.
Limitations of our case series were a small sample size, and that
supramaximal verification was only obtained in Case 3, due to time
constraints in the clinics attended by Cases 1 and 2. However,
supramaximal verification had previously confirmed that both patients
achieved maximal effort at annual CPET. Our participants might also have
been motivated to work harder knowing they were on active medication,
however, this would not have affected effort-independent parameters,
such as the AT.