The treatment of cystic fibrosis (CF) since the beginning of the disease has focused on symptomatic and preventive treatment. With the approval of new CFTR (cystic fibrosis transmembrane regulator) modulator drugs by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the CF paradigm has undergone a major shift.

We can say that we are in the “New Era” of modulatory treatments. We currently have several drugs on the market, including ivacaftor, the first drug approved in 2012, lumacaftor and tezacaftor in combination with ivacaftor, and the latest to join the list is elaxacaftor, which is administered together with tezacaftor and ivacaftor. All of them have shown improvement in some clinical aspects as shown in the following studies.1–3

Elexacaftor/tezacaftor/ivacaftor (ETI) was approved by the FDA in 2019 and by the EMA in August 2020. In Spain, the application was allowed through the access programme in December 2019. The indication for ETI is in patients with the F508del mutation in homozygosis or heterozygosis.4 Since September 2022 the age range has been reduced and it can be prescribed to children aged ≥6 years.

Elexacaftor is a CFTR protein corrector that binds to the protein at a different binding site than tezacaftor, having an additive effect to facilitate cellular processing and transport of F508del of CFTR and increase the amount of CFTR protein released to the cell surface. Clinical trials have shown that ETI improves ion transport, maximum exhaled volume during the first second of forced exhalation (FEV1%), body mass index (BMI) and reduces the number of exacerbations. It is a safe drug to administer with only mild to moderate adverse effects reported.

In this manuscript we present the experience of 16 Spanish centres with ETI in CF patients with advanced lung disease (FEV1 <40%) after 30 months of treatment upon entry into the early access programme.

We conducted an ambispective, multi-centre, observational, real-life study with 114 patients in 16 CF hospitals of Spain. The patients entered a compassionate use programme because the drug was authorised by the FDA, but its authorisation was not approved in Spain. All patients received elexacaftor 200mg once daily (qd)/tezacaftor 100mg (qd)/ivacaftor 150mg every 12h (q12h). Inclusion criteria: patients 12 years of age and older with confirmed diagnosis of CF. Patients who have homozygous or heterozygous F508del mutation and meet at least one of the following criteria: FEV1 <40% for a minimum of 2 months before the date of completion, documentation of being active on a lung transplant waiting list or being evaluated for lung transplantation. Exclusion criteria: patients currently receiving invasive mechanical ventilation, patients with severe hepatic impairment (Child-Pugh Class C), history of advanced liver disease with or without hepatic impairment that in the opinion of the treating physician might pose undue risk in administering ETI to the patient or have any of the following abnormal laboratory values during the eligibility assessment (>5×upper limit of normal (ULN) alanine transaminase (ALT) or aspartate transaminase (AST), >3×ULN ALT or AST with >2×ULN total bilirubin). In addition, the history of solid organ or haematological transplantation, known history of alcohol or drug abuse in the past year. For sexually active patients of reproductive potential who are not willing to use appropriate contraception methods approved by the treating physician.

Eligibility assessments should occur before administration of ETI. Patients signed the informed consent form and underwent the following examinations prior to inclusion: baseline ophthalmologic examination for patients less than 18 years of age, spirometry (assessed pre- or post-bronchodilator), pregnancy test for females, liver function tests (ALT, AST, and total bilirubin) and review of prior and concomitant medications.

We collected the following general clinical variables: age, age at treatment initiation, sex, mutation type, exocrine pancreatic insufficiency, endocrine pancreatic CF-related diabetes (CFRD) and glucose intolerance, hepatopathy, chronic bronchial infection. Moreover, the treatment use collected were previous modulator use, oxygen therapy and non-invasive ventilation (NIV) or pending or on an active list for lung transplantation. We recorded tolerability and overall drug safety data with the adverse effects observed and whether this had an impact on the decision to discontinue the drug. We compared these results between homozygous and heterozygous patients.

In addition, we monitored clinical visits: values of forced vital capacity (FVC), FEV1 and BMI and quality of life questionnaires (CFQ-R), chronic bronchial infection by bacteria, mycobacteria and fungi: baseline, 3, 6, 9, 12, 18, 24, 30 months after treatment.

In addition, we recorded the number of respiratory exacerbations oral (vo.) and intravenous (iv.) in the year before and after the start of ETI, differentiating between oral and intravenous antibiotic cycles.

The document followed STROBE (http://www.strobe-statement.org/) recommendations for observational studies.

The study conducted descriptive analyses on quantitative variables, including mean and standard deviation calculations. The normality and homoscedasticity of continuous variables were checked using the Shapiro-W Kolmogorov-Smirnov and Levene's tests, respectively. Parametric tests were used when distributions were normal and homoscedastic. Non-parametric tests were used when either assumption was not met. For qualitative variables, proportions were compared using chi-square. Additionally, a Random Forest analysis was performed to assess explanatory variable importance in FEV1 improvement. All analyses were conducted using R,5 and statistical significance was set at p<0.05.

This paper presents data from a Spanish multicentre study in patients with advanced disease who received ETI as part of an early access programme showing follow-up beyond 48 weeks. We showed that the improvement in lung function, BMI and the reduction of potentially pathogenic microorganisms, especially MSSA, P. aeruginosa, and Aspergillus sp. were maintained up to 30 months. We also note that recovery was superior in the heterozygous group in all parameters analysed. However, in quality of life, although at the beginning all CFQ-R scores, in all domains, improved, this improvement was attenuated over time after 12 months, being more striking in the homozygous patients.

The number of cycles of vo. and iv. were reduced during the year before and after the onset of ETI, with no significant differences between the homozygous and heterozygous groups when assessed globally, although it showed a higher reduction in the homozygous group.

In this profile of patients with severe CF, several experiences have been published, such as that of an Irish centre (St Vincent's University Hospital)6 with 14 patients analysing a follow-up period of 4.9±1.94 months, where a functional and BMI improvement was observed, as well as a reduction of sweat chloride concentration and exacerbations compared to the previous year. The largest patient series is from the French Network, which included all 47 centres in the country with 245 adult patients with FEV1% of 29%. The mean absolute increase in FEV1% was +15.1 (CI95%: +13.8 to +16.4; p<0.0001), and in weight was +4.2kg (CI95%: +3.9 to +4.6; p<0.0001).7 A relevant aspect evaluated was how the number of patients requiring long-term oxygen, NIV and/or enteral tube feeding decreased by 50%, 30% and 50%, respectively (p<0.01). Of the total, 16 patients were on the active transplant list and 37 were undergoing transplant evaluation at baseline, two received a transplant, one died and five patients remained on the transplant list after starting treatment.

Compared to the previous 2 years in France, they observed a halving in the number of lung transplants performed in CF patients in 2020. In our series, we observed a 40% reduction in the use of oxygen therapy and that only 20% of the 65 patients referred for lung transplantation remained on the active transplant list. Of the 114 patients, three patients died.

The same authors analysed the patients’ perspective in different areas, using a 13-item questionnaire. Of the 245 patients who started ETI, 101 (41%) responded to the questionnaire, with a mean treatment duration of 4.3 [3.0–5.6] months. Patients generally reported a rapid impact on respiratory symptoms, sleep quality, general well-being and physical self-esteem, and a reduction in overall treatment burden. Most patients contrasted treatment burden, symptom severity, depression and a closed future marked by death or transplantation prior to ETI with significant and rapid physical strength, leading to increased self-confidence, autonomy and long-term planning after treatment initiation. A small number of patients expressed concerns, mainly regarding changes in body representation and/or fear of becoming dependent on treatment.8

The series from three Italian centres, albeit with a small number of patients (26 in total) showed a follow-up of 48 weeks.9 An improvement in FEV1% was described in 1206 (CI95%: 8.54, 1557) after 4 weeks of treatment, of 1532 (CI95%: 11.3, 1934) after 24 weeks and 1448 (CI95%: 1064, 1832) after 48 weeks. The increase in FEV1% was accompanied by a decrease in sweat chloride concentration, an improvement in BMI and a marked reduction in exacerbations. In our case, we observed that the improvement in functional and anthropometric parameters was still observed up to 30 months. However, quality of life scores in all domains started to decline after 12 months.

A very relevant aspect of our work is the exhaustive analysis of the microbiological follow-up in this severe patient profile. The three main bacteria with the highest presence at the beginning of the study (12 months before treatment) were P. aeruginosa (60.5%), MSSA (47.4%) and A. xylosoxidans (17.5%), maintaining this range at 6 months prior to treatment. The analysis of the percentage of microbiological isolates, between 12 months before the onset of ETI and 30 months after, showed a decrease in all microorganisms isolated, with the reduction being significant for MSSA (−63.9%), P. aeruginosa (−100.0%) and Aspergillus sp. (−79.3%). This is probably explained by the improvement of mucociliary clearance with CFTR functioning with ETI. Likewise, P. aeruginosa reduction has been described in a study of patients with severe functional impairment treated with ivacaftor treatment and mutations gating (non-functional surface CFTR protein).10 In a small study of 20 patients homozygous for F508del on lumacaftor-ivacaftor treatment, showed a non-significant decrease of P. aeruginosa.11 We observed in 144 patients treated with tezacaftor–ivacaftor a reduction of different microorganisms, among them the greatest reductions were for non-tuberculous mycobacteria (−66.7%), Haemophilus influenzae (−66.7%), Stenotrophomonas maltophilia (−53.8%), Aspergillus sp. (−35.7%) and MSSA (−25.0%).12

Clinical results in patients homozygous and heterozygous for F508 who started ETI already showed a better response in the heterozygous group at 24 weeks, as in the respective pivotal studies.4,13,14 We consider the present work to be novel as it shows the difference between the two groups that had not been analysed in real life.

Another notable aspect highlighted in this work was the evaluation of the factors that have the greatest impact on FEV1% improvement. The most relevant variables were lung function (FVC%, FEV1%), BMI, previous antibiotic treatment courses and age at treatment initiation, as well as oxygen therapy prescription, among others. The French article compares the populations of patients who improved a FEV1% greater than or equal to 13% after ETI vs. those who did not. This study concluded that patients with lower improvement (of FEV1% <13) were significantly older (p<0.001) and more likely to be treated with long-term oxygen therapy (p<0.001) and/or NIV (p=0.006).7,15

Regarding the adverse effects of ETI, our study showed that it is generally safe and has an acceptable side-effect profile. The majority of patients had mild to moderate adverse events (15%), of which 50% of patients showed liver and skin rash problems (29.4%). Adverse events leading to discontinuation of ETI occurred in only 4 patients for hypertransaminemia similar to the data observed in the clinical trial.14

The strengths of our study include a large number of patients, multicenter, a long follow-up period of 30 months and an analysis of previously unevaluated aspects such as microbiology, differences between homo- and heterozygous F508del groups and the assessment of factors related to FEV1% improvement in this patient profile with advanced disease.

Limitations of the study include a small number of subjects <12 years of age for group comparison, only one third of the patients had completed 30 months of follow-up and chloride concentrations were not analysed.

Another limitation to take into account is that given the timing of the study (COVID-19 pandemic), it could have an influence on the results obtained. However, our findings are consistent with those published in pivotal clinical trials.4,14 Consequently, we believe that the effect that the COVID-19 pandemic may have had on the findings is of little relevance, as preventive measures are a common measure routinely used by these patients.

To our knowledge, the current data provide the first long-term evidence of ETI in CF patients with advanced lung disease. Clinical and nutritional improvement as well as reduction of micro-organisms was sustained up to 30 months and was superior in heterozygous patients. Quality of life scores became lower after 12 months and were more striking in F508del homozygous. Previous lung function, BMI, previous exacerbations, age at treatment initiation as well as oxygen therapy were factors influencing the observed improvement in FEV1%. Longer studies with larger numbers of patients and from different countries provided by CF registry data would be recommended.

The authors state that they have no conflict of interests.