Reported Adverse Events in Patients with CF Receiving Treatment with Elexacaftor/Tezacaftor/Ivacaftor: 5 Years Observational Study

1. Introduction

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, encoding a chloride and bicarbonate channel essential for the maintenance of the correct salt and water balance at the surface of epithelial cells [1,2].

Although more than 2000 mutations in CFTR have been reported so far, F508del is the most frequent pathogenic variant. This mutation causes misfolding of CFTR protein, leading to a defect in trafficking from the endoplasmic reticulum (ER). Over the past decade, the introduction of CFTR modulator therapies has transformed the CF clinical landscape. The first of these to be developed was the CFTR potentiator ivacaftor, improving CFTR protein function in the apical membrane of epithelial cells [3]. Other CFTR correctors improving the trafficking of unfolded F508del CFTR protein to the cell surface were subsequently developed. Currently, triple-combination elexacaftor-tezacaftor-ivacaftor (ETI) treatment has proved to be highly effective and safe when administered in clinical trials to patients with CF (pwCF), aged 2 years and older, harboring at least one F508del CFTR allele [3,4,5,6,7,8]. Recently, the Food and Drug Administration (FDA) expanded its ETI approval to a total of 272 CFTR mutations, allowing more pwCF to access this treatment.

ETI significantly improved lung function in pwCF, reducing the pulmonary exacerbation rate and decreasing hospitalizations [4]. It also increased body mass index, improved quality of life, decreased the sweat chloride concentration, and reduced infections. In addition, ETI was generally well tolerated in trials [5,7,9,10]: real-world data corroborate these findings, affording a valuable source of evidence on ETI’s tolerability and safety profile [10]. However, some adverse events (AEs) have been described both in controlled studies and in clinical practice. The most commonly reported AEs were increased liver marker levels and headache [3,5,9]. Post-marketing observations have highlighted additional AEs that were previously either not documented or under-reported [11,12,13,14,15], including neuropsychiatric symptoms and dermatologic reactions that required dosage modification or discontinuation of the treatment.

The aim of this study is to report potentially drug-related AEs in a large cohort of pwCF receiving long-term ETI treatment, and to assess their consequences in terms of temporary or permanent drug regimen modification.

2. Materials and Methods

2.1. Study Design and Study Participants

Between October 2019 and December 2024, 414 pwCF regularly attending the Verona Cystic Fibrosis Center initiated ETI treatment. The study was approved by the Ethics Committee of the Azienda Ospedaliera Universitaria Integrata, Verona (approval number 433CET), and informed consent was obtained from all subjects.

Dosage regimens were prescribed in compliance with the package leaflet and Italian Medicines Agency (AIFA) requirements (patients older than 6 years, weighing <30 kg, to receive elexacaftor 100 mg once daily, tezacaftor 50 mg once daily, ivacaftor 75 mg every 12 hours; patients weighing >30 kg to receive elexacaftor 200 mg once daily, tezacaftor 100 mg once daily, ivacaftor 150 mg every 12 hours).

AEs and pulmonary function were assessed quarterly, while a sweat chloride test was recorded annually; blood tests were done in accordance with AIFA guidelines (quarterly during the first year of treatment, then annually).

Percent predicted forced expiratory volume in 1 second (ppFEV1) was obtained by forced spirometry [15]. The parameter is expressed as the mean of measurements collected during consecutive 12-month periods (the year before ETI initiation, and every year of ETI treatment). Prevalence and type of AE were considered, regardless of the need for discontinuation of treatment. Serious AEs (SAEs) were defined in line with FDA and European Medicines Agency (EMA) criteria [16,17]. Identification of severe lung disease was based on ppFEV1 <40 and/or ongoing evaluation for lung transplantation.

2.2. Statistical Analysis

Descriptive statistics were used to summarize patient characteristics: continuous variables were described by median and min-max values, whilst categorical variables were reported by absolute and percentage frequencies. Baseline characteristics were compared between patients presenting AEs events and those with none. Chi-square and Mann-Whitney tests were used for categorical and continuous variables, respectively. The rate of AE occurrence during treatment was calculated, both for the overall period of ETI administration and for the first 30 days alone. Rates are reported as the number of AEs per 1000 days of treatment and were compared in relation to the main patient characteristics, using the Poisson exact test. A p-value <0.05 was considered statistically significant. All analyses were done with the R software (R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org)

3. Results

The evaluation comprised 414 patients older than 6 years (M 46%). One patient underwent lung transplantation after 3 months of treatment with ETI and was lost to follow-up. Patient characteristics are listed in Table 1.

Median duration of ETI treatment was 35.60 months [IQR 26.46 – 39.26]. During the period of observation, 142 AEs were reported, with 85 (20.53%) patients presenting at least one AE. Only one SAE was reported, consisting in epigastric pain which led to hospitalization and discontinuation of the drug. Characteristics of patients presenting AEs are shown in Table 2.

We observed no differences in age, sex, severe respiratory impairment, or genotype between patients with and without AEs (Table 1). AEs mostly occurred either early, within 2 weeks from the initiation of treatment (33%), or later, after 4 weeks of treatment (50.7%). They occurred earlier in PwCF with baseline severe respiratory impairment (35.5 % in patients with baseline ppFEV1 < 40, vs 28.8% in patients with ppFEV1 > 40); in relation to age, 47.6% and 29.46% of AEs occurred within the first 2 weeks in pediatric and adult patients, respectively (Table 2). The most frequent AEs were liver biomarker elevation (16.2%) and skin rash (11.27%), followed by epigastric pain (7.75%), headache (4.2%) and depression (4.2%). We harmonized AEs on the basis of System Organ Class (SOC) [19,20], categorizing anatomical or physiological systems involved: this ensured uniformity in reporting and analyzing data. The most frequent SOCs were psychiatric and investigations, followed by skin and subcutaneous tissue disorders and gastrointestinal disorders (Table 3).

Among the 24 psychiatric AEs as classified by SOC, 70.81% were first occurrences in the patients concerned. Pediatric subjects (n = 20) presented AEs mostly related to psychiatric disorders (7 patients), followed by gastrointestinal (4 patients), skin (4 patients), nervous system (2 patients), investigations (2 patients) and general (1 patient) disorders. Different decisions regarding ETI treatment were made for the 142 AEs reported.

Permanent discontinuation was rare (11% of all AEs), while temporary interruption, temporary dosage modification and permanent dosage modification were chosen in 17%, 25% and 32%, respectively (Figure 1).

Psychiatric disorders, investigation-related alterations, gastrointestinal, nervous system and musculoskeletal disorders most frequently resulted in permanent ETI dosage modification, whereas respiratory disorders, skin and subcutaneous tissue events mostly entailed only temporary dosage modification (Table 4).

4. Discussion

In this study we investigated potentially drug-related AEs in pwCF, treated with ETI in a real-life setting. Key strengths of this observational prospective study are that it encompasses a substantial patient cohort (414 subjects) and an extended follow-up period (median 35.6 months). A major limitation of the study is that it has been carried out in a single center; nevertheless, this also ensured consistency and reliability of the measurements.

Our findings show that 20.53% of the treated cohort experienced at least one AE, whereas a SAE occurred in only one patient (0.25%). Only a few (11%) AEs led to permanent discontinuation of the study treatment (8 pwCF, i.e. 1.9% of the treated cohort). These figures indicate that ETI was quite well tolerated. We observed that 33% and 47% of AEs occurred within 2 and 4 weeks from ETI initiation, respectively; FDA data indicate that the median time of AE onset is 70 days, with the majority occurring within 4 weeks. [21]

Earlier AEs in the pediatric population (2- to 5-year-old and 6- to 11-year-old subgroups) were described using the FDA reporting system, and speculatively attributed to the higher metabolic rate in these age groups [22]. Here, we found that the most frequent AEs were liver function marker elevation, skin rash, epigastric pain, headache and depression; the most frequently involved SOCs were investigations (mostly hepatic enzyme elevation), psychiatric, skin, gastrointestinal and musculoskeletal disorders.

The prevalence of AEs did not differ in pediatric and adult pwCF, regardless of sex, severity of respiratory function impairment, or genotype, this trend being consistent with previously described pediatric data [14]. When considering pediatric pwCF, psychiatric disorders were the most prevalent (35% in our cohort), with the majority of cases involving attention deficit. Conversely, in adult subjects, psychiatric disorders were primarily depression, anxiety and sleep disorders. A recent analysis of the UK adverse drug reaction reporting system for psychiatric events found that the proportion of reported AEs categorised as psychiatric increased in the post-ETI period [23].

Taken together, our data and previous reports suggest that systematic screening of psychiatric conditions needs to be taken into account. The high background prevalence of psychiatric disorders in pwCF has already been described. Although data from the US and German registries showed that patterns of depression prevalence did not change upon ETI treatment in adults [24], accurate evaluation of psychiatric symptoms through standardized questionnaires should be carried out for the pediatric population. Concerns may extend beyond psychiatric conditions, to encompass neurodevelopmental issues [24]. It should be borne in mind that screening for changes in mental health during the first 3 months of ETI is recommended in the European Cystic Fibrosis Society (ECFS) Standards of Care guidelines [26].

We found that AEs led to permanent dosage adjustments in 32% of cases; this raises the issue of safety in relation to dosage reduction, efficacy and minimum ETI levels. A recent case series [27] correlated AEs with ETI dosage, showing that dose reduction mitigated AEs while maintaining efficacy in terms of sweat chloride concentration. Nevertheless, the optimal dose adjustment strategy has not yet been identified and the long-term efficacy of different dosing strategies needs to be demonstrated.

In relation to permanent ETI treatment modification, whether by dosage adjustment or discontinuation, the causative AEs in most cases comprised liver marker elevation. This is not unexpected: one clinical trial found a higher incidence of liver involvement in comparison to placebo [5], albeit not resulting in the study treatment's discontinuation. Longitudinal real-world data showed a non-significant increase in median ALT, AST, and total bilirubin values after 3 months of treatment [27].

5. Conclusions

Our study shows good tolerability for ETI, with almost 80% of patients experiencing no AEs during observation. Potentially treatment-related AEs were recorded, leading to permanent discontinuation of treatment in only 11% of cases (1.9% of the entire treated population). Psychiatric disorders, liver function marker elevation, gastrointestinal and skin disorders are the most prevalent AEs in our cohort, in line with the current literature. Special attention to long-term assessment in pediatric patients is a crucial point. Since a significant number of AEs occur after one year of treatment [21], longitudinal monitoring appears to be essential. National registries might provide a useful complement with a view to AE data collection, including occurrences related to mental health issues.