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.