Cystic fibrosis (CF) is the most common inherited life-shortening disease among Caucasians. As indicated by a latest U.S. registry report (Cystic Fibrosis Foundation, 2022), life expectancy for people with CF (pwCF) is more than 50 years and the most frequent cause of death is progressive lung disease (Elborn, 2016).

For many decades, the cornerstone of CF care was only symptomatic approach. Mucoactive drugs along with chest physiotherapy, antibiotics, anti-inflammatory drugs, bronchodilators, oxygen therapy, noninvasive ventilation and ultimately lung transplantation have been used to treat impaired mucus clearance, airway infection and inflammation, and respiratory disorders (Girón Moreno et al., 2021).

The discovery of the cystic fibrosis transmembrane regulator (CFTR) gene in 1989 raised hopes for a curative therapy. Unfortunately, after more than 30 years the gene therapy is yet unavailable. However, since 2012 variant-specific therapy (VTS) has become a clinical reality. The first-in-class drug was ivacaftor (IVA), potentiating the CFTR protein function in pwCF carrying G551D or other gating mutations of the CFTR gene (Ramsey et al., 2011). IVA alone was followed by lumacaftor (in therapeutic combination with ivacaftor; LUM/IVA) for patients homozygous for F508del and tezacaftor (in combination with ivacaftor; TEZ/IVA) for patients homozygous for F508del or compound heterozygotes with residual function mutation (Wainwright et al., 2015; Rowe et al., 2017; Taylor-Cousar et al., 2017).

Finally, elexacaftor in combination with tezacaftor and ivacaftor (ETI) was approved for clinical use in 2019 for pwCF aged 12 years and older who carry at least one F508del mutation (Heijerman et al., 2019; Middleton et al., 2019). Subsequently, the ETI combination was shown to be superior to IVA for pwCF with the F508del along with the gating mutation, as well as to the TEZ/IVA combination for pwCF with the F508del along with the residual function mutation (Barry et al., 2021).

The above-mentioned studies demonstrated an improvement in lung function, nutritional status and quality of life together with a reduction in the pulmonary exacerbation rate and, in case of IVA and the ETI, the studies also proved a considerable decrease of sweat chloride concentration.

In general, inclusion and exclusion criteria of the respective clinical trials allowed only a clinically stable patient population to be enrolled. Thus, pwCF with severe airway obstruction (a percent predicted forced expiratory volume in one second (ppFEV1) below 40) or those harboring bacteria with a high risk of a rapid decline in lung function (Burkholderia cenocepacia, Burkholderia dolosa, Mycobacterium abscessus) were excluded from the trials. Also, pwCF with a well-preserved lung function (ppFEV1 above 90) were outside the range of 40–90, a key inclusion criterion that best sets the baseline for the change to observe statistically meaningful changes of ppFEV1 during the trial.

The aim of our study was to evaluate the real-world results of ETI treatment in pwCF who do not fulfill the classical criteria for participation in the trials. We also analyzed the clinical effect of the switch to ETI from LUM/IVA, which in contrast to TEZ/IVA switch (Heijerman et al., 2019) has not been studied before.

Demographic and clinical data of the patients on ETI are summarized in Table 1. In addition to Pseudomonas aeruginosa, B. cenocepacia and M. abscessus, several subjects had airway infections caused with methicillin-resistant Staphylococcus aureus (n = 6), Achromobacter xylosoxidans (n = 1), Burkholderia stabilis (n = 1) or Burkholderia contaminans (n = 1).

TABLE 1. Demographic and clinical characteristics of the patients.

Changes in lung function, nutritional status and sweat chloride concentration in the study and control groups after initiation of ETI treatment are shown in Table 2. The study population reached such changes in nutritional status and sweat chloride concentration that were comparable to the control group (i.e., there were found no significant differences in changes of both parameters between the groups). The improvement of lung function in the control group was higher than in the study group. Further stratification by sex showed no statistically significant difference between males and females within each of the two groups for FEV1 or BMI (Table 2).

TABLE 2. The changes in lung function, nutritional status and sweat chlorides on ETI treatment.

Further analysis of the lung function change was based on subgrouping of the study group participants according to following parameters: prior treatment with LUM/IVA, baseline ppFEV1 values and airway infection with pathogens at risk of more rapid decline in ppFEV1. Results are summarized in Table 3.

TABLE 3. Analysis of change in lung function in subgroups of the study population.

This analysis showed that patients with severe airway obstruction or with well-preserved lung function had a lower potential for improvement with ETI treatment compared to the control group. Changes in lung function in individual subjects of studied subgroups are depicted in Figure 1.

FIGURE 1. Changes in lung function in subgroups of the study population. FEV1 = forced expiratory volume in 1 s. LUM/IVA, lumacaftor/ivacaftor. White bars = subjects with FEV1 >90% pred. Light gray bars = subjects with FEV1 40%–90% pred. Dark gray bars = subjects with FEV1 <40% pred. Asterisks = subjects with pathogens at risk of more rapid FEV1 decline.

PwCF ineligible for participation in clinical trials represent a substantial part of the CF population. This is well documented in this study, where approximately a half of all patients treated with ETI (i.e., 49 of 96 patients) met one classical exclusion criterion or more. The aim of our study was to check the ETI effect on patients whose clinical conditions fall outside the inclusion criteria of clinical trials that were represented with registration studies for ETI. We believe that such postmarketing data are of paramount importance as it ensures not only a CF community, but also regulatory agencies and healthcare payers that the ETI therapy is effective in pwCF who were ineligible for classical clinical trials. For instance, the efficacy of the ETI treatment on pwCF with B. cenocepacia is found to be highly relevant to the Czech CF care where the prevalence of the infection is much higher (13%) compared to other European countries (4%) (Orenti et al., 2022).

Clinical data on lung function and nutritional status were collected from routine outpatient visits. We reported the best values of ppFEV1 and BMI during the 6 months before and after the initiation of ETI treatment for evaluation of clinical efficacy. This approach to analyze the best ppFEV1 and BMI values was chosen to minimalize the effect of intra-individual visit-to-visit variability, and for ppFEV1 it was similar to the common strategy of four-week screening/run-in period in clinical trials to ensure a patient is clinically stable. This is a similar approach to the assessment of pulmonary exacerbation in pwCF, where the current ppFEV1 value is compared to the best value in last 6 months (Goss, 2019).

The control group consisted of pwCF on ETI treatment who did not meet the common exclusion criteria for clinical trials participation. Their improvement in lung function was similar to the results published in phase 3 clinical trials with the ETI treatment: ppFEV1 +15.8 points in our study (over one to 6 months period) vs. +14.3 points in Week 24 (pwCF heterozygous for F508del, ETI vs. placebo) (Middleton et al., 2019) or +10.0 points in Week 4 (pwCF homozygous for F508del, ETI vs. TEZ/IVA combination) (Heijerman et al., 2019). The even better results in our cohort can be explained by the inclusion also of pwCF heterozygous for F508del with a mutation on the other allele which is regarded mild, as opposed to minimal function mutations, included as the only qualifying CFTR mutations in the registration study. The improvement in BMI was very comparable: +1.02 kg/m2 (control group in our study) vs. +1.04 kg/m2 (Middleton et al., 2019).

It is of note that our study group consisted of a heterogeneous population: subjects with severe airway obstruction as well as well-preserved lung function, subjects with pathogens at risk of more rapid FEV1 decline and subjects with prior LUM/IVA therapy. Compared to the control group, this group as a whole showed less of improvement in lung function (i.e., +10.3 points), in contrast to a very comparable improvement in nutritional status and in a decrease in sweat chloride concentration. In the subgroup analysis, subjects with severe airway obstruction and those with well-preserved lung function showed lower potential for improvement in their lung function. Our results indicated the lung function improvement to a lesser extent than published for pwCF with advanced lung disease by Burgel et al. (Burgel et al., 2021) or O'Shea et al. (O'Shea et al., 2021). While the former publication reported an improvement in mean ppFEV1 in patients without prior CFTR modulator therapy by + 12 points after 3 months (along with a reduction in the need for long-term oxygen therapy and non-invasive ventilation), and the latter showed ppFEV1 +9 points after 26 days on ETI, we observed the change of median ppFEV1 to be +4.9 points only. However, our observed change is similar to the work of Djavid and coworkers (ppFEV1 +5.5 points after 1 month) (Djavid et al., 2021).

Data on pwCF with prior therapy with LUM/IVA combination and their switch to ETI have not been previously published. Our small group showed an improvement in lung function (ppFEV1 +8.6 points) which indicates that the switch from LUM/IVA to ETI results in a very comparable outcome like the switch from TEZ/IVA to ETI (Heijerman et al., 2019).

Improvement in nutritional status in the whole study group (BMI +1.04 kg/m2) as well as the reduction in sweat chloride concentration was similar to our control group as well as to the clinical trial study by Middleton et al. (Middleton et al., 2019).

In conclusion, pwCF not eligible for inclusion in clinical trials demonstrated improvement in lung function and in nutritional status after initiation of the treatment with the ETI combination, comparable to the population studied by respective clinical trials. Likewise, they manifested the decrease in sweat chloride concentration. Less improvement in FEV1 was observed in a subcategory of pwCF who presented with severe airway obstruction or well-preserved lung function.

Barry, P. J., Mall, M. A., Álvarez, A., Colombo, C., de Winter-de Groot, K. M., Fajac, I., et al. (2021). Triple therapy for cystic fibrosis phe508del-gating and -residual function genotypes. N. Engl. J. Med. 385 (9), 815–825. doi:10.1056/NEJMoa2100665

PubMed Abstract | CrossRef Full Text | Google Scholar

Burgel, P. R., Durieu, I., Chiron, R., Ramel, S., Danner-Boucher, I., Prevotat, A., et al. (2021). Rapid improvement after starting elexacaftor-tezacaftor-ivacaftor in patients with cystic fibrosis and advanced pulmonary disease. Am. J. Respir. Crit. Care Med. 204 (1), 64–73. doi:10.1164/rccm.202011-4153OC

PubMed Abstract | CrossRef Full Text | Google Scholar

Djavid, A. R., Thompson, A. E., Irace, A. L., Gusman, E., Altman, K., DiMango, E. A., et al. (2021). Efficacy of elexacaftor/tezacaftor/ivacaftor in advanced cystic fibrosis lung disease. Ann. Am. Thorac. Soc. 18 (11), 1924–1927. doi:10.1513/AnnalsATS.202102-220RL

PubMed Abstract | CrossRef Full Text | Google Scholar

Girón Moreno, R. M., García-Clemente, M., Diab-Cáceres, L., Martínez-Vergara, A., Martínez-García, M. Á., and Gómez-Punter, R. M. (2021). Treatment of pulmonary disease of cystic fibrosis: A comprehensive review. Antibiot. (Basel) 10 (5), 486. doi:10.3390/antibiotics10050486

CrossRef Full Text | Google Scholar

Heijerman, H. G. M., McKone, E. F., Downey, D. G., Van Braeckel, E., Rowe, S. M., Tullis, E., et al. (2019). Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: A double-blind, randomised, phase 3 trial. Lancet 394 (1023/8), 1940–1948. doi:10.1016/S0140-6736(19)32597-8

PubMed Abstract | CrossRef Full Text | Google Scholar

Middleton, P. G., Mall, M. A., Dřevínek, P., Lands, L. C., McKone, E. F., Polineni, D., et al. (2019). Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N. Engl. J. Med. 381 (19), 1809–1819. doi:10.1056/NEJMoa1908639

PubMed Abstract | CrossRef Full Text | Google Scholar

O'Shea, K. M., O'Carroll, O. M., Carroll, C., Grogan, B., Connolly, A., O'Shaughnessy, L., et al. (2021). Efficacy of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis and advanced lung disease. Eur. Respir. J. 57 (2), 2003079. doi:10.1183/13993003.03079-2020

PubMed Abstract | CrossRef Full Text | Google Scholar

Ramsey, B. W., Davies, J., McElvaney, N. G., Tullis, E., Bell, S. C., Dřevínek, P., et al. (2011). A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N. Engl. J. Med. 365 (18), 1663–1672. doi:10.1056/NEJMoa1105185

PubMed Abstract | CrossRef Full Text | Google Scholar

Rowe, S. M., Daines, C., Ringshausen, F. C., Kerem, E., Wilson, J., Tullis, E., et al. (2017). Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N. Engl. J. Med. 377 (21), 2024–2035. doi:10.1056/NEJMoa1709847

PubMed Abstract | CrossRef Full Text | Google Scholar

Taylor-Cousar, J. L., Munck, A., McKone, E. F., van der Ent, C. K., Moeller, A., Simard, C., et al. (2017). Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. N. Engl. J. Med. 377 (21), 2013–2023. doi:10.1056/NEJMoa1709846

PubMed Abstract | CrossRef Full Text | Google Scholar

Wainwright, C. E., Elborn, J. S., Ramsey, B. W., Marigowda, G., Huang, X., Cipolli, M., et al. (2015). Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N. Engl. J. Med. 373 (3), 220–231. doi:10.1056/NEJMoa1409547

PubMed Abstract | CrossRef Full Text | Google Scholar