Efficacy of Elexacaftor-Tezacaftor-Ivacaftor in Cystic Fibrosis Treatment: Comparison
Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Konstantinos Douros.

Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA) is a new CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) modulator treatment, which has shown an improvement in different clinical outcomes in patients with cystic fibrosis (CF). ELX/TEZ/IVA has a significant positive effect on the lung function of patients with CF, by ameliorating parameters such as FEV1, LCI, pulmonary exacerbations or sweat chloride concentration, increasing BMI and improving quality of their life. Its role in cystic fibrosis-related diabetes (CFRD) is not yet clear. It was found that this new CFTR modulator has an overall favorable safety profile, with mild to moderate adverse events. 

  • cystic fibrosis
  • cystic fibrosis transmembrane conductance regulator (CFTR)
  • CFTR modulators

1. Introduction

Cystic fibrosis (CF) is an autosomal recessive genetic disease, which affects approximately 70,000 people worldwide [1]. It is caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, which encodes for the CFTR protein, located on the apical surface of epithelial cells of multiple tissues (respiratory system, gastrointestinal tract, male reproductive organs, pancreas, sweat glands, etc.) and is responsible for chloride and bicarbonate transport across the epithelial surfaces. Defective CFTR protein leads to a decrease in chloride secretion and an increase in sodium absorption, followed by an osmotic uptake of water, provoking thick fluid secretions. In addition, diminished bicarbonate secretion is responsible for inadequate alkalization of pH and, though impairment of antimicrobial factors, of the surface liquid. As a result, chronic pulmonary inflammation and infection develop and bronchiectasis and progressive lung function decline, in association with impaired gastrointestinal function (bowel obstruction, hepatobiliary disease and pancreatic insufficiency), malnutrition and infertility [2,3,4][2][3][4].
There are more than 2000 CFTR sequence variants and approximately 350 of them are known to cause CF. Phe508del mutation is the most common mutation and 88% of patients have at least one copy [2,3][2][3]. CFTR mutations are classified into six categories according to the molecular mechanism of decreased functional expression: in class I mutations, the production of CFTR protein is diminished; class II mutations lead to misfolding of CFTR protein, which is unable to reach the cell surface (including the Phe508del mutation); in class III mutations, the CFTR protein is not functional (“gating mutations”–for example G551D mutation); in class IV mutations. ions transport is diminished; class V mutations produce inadequate quantities of the CFTR protein and class VI mutations produce a less stable CFTR protein. Class I-III mutations cause a more severe form of the disease, whereas class IV-VI mutations lead to a milder CF phenotype [2,3][2][3].
Until recently the target of CF treatment was the management of symptoms (including airway clearance, antibiotics, and nutritional support). During the last decade, new drugs were developed that target the underlying defective CFTR protein. These drugs, named CFTR modulators, are split into two categories: correctors, which are small molecules improving the structure and trafficking of the defective CFTR protein, and potentiators, which prolong the period the CFTR protein channel remains open, and so increase chloride transport [5,6][5][6]. Ivacaftor (IVA), the first CFTR modulator approved by the FDA in 2012, is a potentiator used originally for the treatment of patients with CF and at least one G551D; since then, it has been approved for more mutations. However, it is not effective for patients carrying the most common mutation, Phe508del, since very little protein is expressed and ivacaftor does not impact expression. The CFTR corrector Lumacaftor (LUM) is used to improve the transport of the CFTR protein on the cell surface. The combination Lumacaftor-Ivacaftor is used for Phe508del homozygous patients. The next corrector Tezacaftor, paired with Ivacaftor, has sufficient effect on patients who are Phe508del homozygous or those with one Phe508del copy and one residual mutation (a CFTR mutation that causes less important damage to CFTR protein function).
The triple combination Elexacaftor (a new corrector)-Tezacaftor-Ivacaftor (Trikafta or Kaftrio) leads to clinical improvements in those with one or two copies of the Phe508del variant; it works even for those who are Phe508del heterozygous, with a minimal function mutation, defined as the complete absence of CFTR production, or lack of in-vitro responsiveness to Ivacaftor/Tezacaftor [6]. This triple combination was first approved in the USA in October 2019 for patients ≥ 12 years old [7], but has become available for children ≥ 6 years old since June 2021. In the European Union, it was approved in 2021 for patients aged ≥ 12 years and has become available for children ≥ 6 years old since January 2022. It is of interest also to notice that, according to the recent prescribing information for the medication, it is indicated for responsive CFTR mutations based on in vitro data.

2. Efficacy of Elexacaftor-Tezacaftor-Ivacaftor in Cystic Fibrosis Treatment

2.1. Efficacy of Elexacaftor-Tezacaftor-Ivacaftor

Pulmonary Efficacy and effect on sweat chloride concentration
The most commonly used indicators of lung function in CF patients are the ppFEV1 and the occurrence of pulmonary exacerbations (PEx). Another important tool is the Cystic Fibrosis Questionnaire-Revised Respiratory Domain (CFQ-R RD), which is a measure of subjective amelioration of pulmonary symptoms and quality of life. An alternative research measure of lung health is the Lung Clearance Index (LCI), usually reported as LCI2.5, which is a measure of ventilation inhomogeneity [7].
Keating et al., in a phase 2 clinical trial with adult patients with at least one Phe508del copy, treated with Elexacaftor/Tezacaftor/Ivacaftor for 4 weeks, revealed in patients with Phe508del/Minimal function (MF) genotype (n = 95) an increase of ppFEV1 up to 13.8 points (95% CI 10.9–6.6. p < 0.001), an absolute change in sweat chloride concentration (SCC) of −39.1 mmol/lt (95% CI −4.9 to −33.3), and amelioration of CFQ-R RD score by 25.7 points (95% CI 18.3–33.1). Patients with Phe508del/Phe508del genotype (n = 24) showed an 11% (95% CI 7.9–14.0, p < 0.001) improvement in ppFEV1, SCC was diminished by 39.6 mmol/lt (95% CI −45.3 to −33.8), and CFQ-R RD score increased by 20.7 points (95% CI 12.5–29), relative to control group [9][8].
The phase 3 trial, conducted by Heijerman et al., involving 113 patients aged ≥12 years, Phe508del homozygous, with ppFEV1 between 40–90% treated with ELX/TEZ/IVA after a 4-week period with TEZ/IVA, showed an increase in ppFEV1 of 10 points (95% CI 7.4–12.6, p < 0.001), a decrease in SCC with a mean treatment difference of −45.1 mmol/lt (95% CI −50.1 to −40.1, p < 0.001), and an improvement in CFQ-R RD score by 17.4 points at week 4 compared with patients receiving TEZ/IVA treatment [11][9]
Growth and Nutrition CFTR modulators have been effective in weight gain and BMI increase. Change in BMI was one of the secondary endpoints of the study conducted by Middleton et al., which noticed that patients ≥12 years receiving ELX/TEZ/IVA for 4 weeks experienced a BMI increase, with a mean treatment difference of 1.04 relative to the placebo group (95% CI 0.85–1.23, p < 0.001) [10]. The phase 3 study by Heijerman et al. revealed that Phe508del homozygous patients ≥12 years treated with ELX/TEZ/IVA had an improvement of BMI at week 4 of 0.60 kg/m2 (95% CI 0.41–0.79, p < 0.0001) and a mean body increase of 1.6 kg (95% CI 1–2.1, p < 0.0001) compared with TEZ/IVA group [11][9]. In addition, Migliorisi et al. found out that patients ≥ 12 years old, with at least one Phe508del mutation treated with ELX/TEZ/IVA for one year, significantly increased their BMI, compared to the control group [13][11]. Other clinical parameters CF patients cope with multiple infections of the respiratory tract, which require frequent antibiotic use or even hospital admission. Miller et al. performed a case-crossover analysis which included 389 CF patients who began treatment with ELX/TEZ/IVA for a 15-week period and compared them with patients without treatment for the same period. The triple combination therapy revealed a decrease in the number of healthcare visits, −2.5 (95% CI −3.31 to −1.7), a change in patients’ admissions, −0.16 (95% CI −0.22 to −0.1), a diminished number of visits related with infections, −0.62 (95% CI −0.93 to −0.31) and a change in distinct antibiotics prescribed, −0.78 (95% CI −1.03 to 0.54). Because of the small sample of rare infections, the type of infections decreased was not mentioned, but P. aeruginosa and non-tuberculous mycobacterial infections were diminished. In addition, the secondary endpoints of the study showed a decrease in healthcare visits in different places by 3.51 (95% CI −4.55 to −2.47), a change in the number of days with an outpatient antibiotic supply, −0.78 (95% CI −0.81 to −0.43) and a change in days of antibiotic use, −16.08 (95% CI −22.5 to −9.66) [17].

2.2. Safety of Elexacaftor-Tezacaftor-Ivacaftor

The safety of the triple combination treatment was assessed by Keating et al. In their study, 92% of patients in the ELX/TEZ/IVA group, 100% of people in the placebo group and 71% of patients in TEZ/IVA group reported at least one adverse event (AE). Patients who received ELX/TEZ/IVA had mild events (53%), moderate events (43%) and serious events (4%). The most frequent side effects observed in patients who received the triple therapy were cough, increased sputum production, pulmonary exacerbations, hemoptysis and pyrexia. Elevated levels of aminotransferase greater than three times the upper limit occurred in 8%, and elevated bilirubin levels greater than two times the upper limit occurred in 3% of patients in this group. Concerning the serious side effects, cases of infective pulmonary exacerbation, distal intestinal obstruction syndrome and jugular venous thrombosis were noticed. No deaths occurred, but side effects such as rash, elevated bilirubin levels and chest pain, that occurred in three patients in ELX/TEZ/IVA group, led to the discontinuation of the trial. 

Middleton et al. described the AE that occurred during their study, in which 93.1% of patients in the ELX/TEZ/IV group showed at least one, compared to 96% in the placebo group. The majority of patients in the ELX/TEZ/IVA group had mild (33.2%) and moderate (50.5%) AE and only 13.9% had a serious AE (ex. infective pulmonary exacerbation) compared to the control group (20.9% with a serious AE). In previous studies for other CFTR modulator therapy, rash and elevated levels of aminotransferase were observed, so these specific side effects were also assessed in this trial. A total of 10.9% of patients in ELX/TEZ/IVA group had elevated aminotransferase levels, mostly greater than three times the upper normal range (7.9%), compared to 4% in the placebo group. As for rash, it occurred in 10.9% of patients in the ELX/TEZ/IVA group and 6.5% in the control group. 

Zemanick et al. assessed the safety of ELX/TEZ/IVA treatment in children 6–11 years old, in whom 98.5% of the participants had at least one AE, 54.5% of which were mild and 42.4% moderate in severity. The most common AEs experienced by the candidates were cough (42.4%), headache (24.2%), and pyrexia (21.2%), 10.6% of the children presented elevated levels of aminotransferases greater than three times the upper normal range, and in 1.5% the levels were greater than five times the upper normal limit. As far as rashes are concerned, 24.2% of the patients had mild or moderate rash events (e.g., rash erythematous, rash maculopapular, rash papular, skin exfoliation, or urticaria). Due to the development of a rash after the first dose of the triple treatment, the drug was discontinued in one child. CPK levels were not greater than five times the upper normal limit. No AE of hypertension were noticed, the systolic blood pressure changed from −1.4 mmHg to 0.4 mmHg, and diastolic blood pressure from −0.3 mmHg to 1 mmHg, through the 24 weeks of treatment [22][13].

3. Summary

Impaired lung function with a gradual deterioration, starting early in life, is a key feature of CF and ELX/TEZ/IVA improves pulmonary function significantly. Both clinical trials and observational studies highlight a substantial increase in FEV1, both in adults and children, after the initiation of treatment. LCI2.5, which is used to determine the ventilation inhomogeneity, also showed noteworthy improvements, when it was used as a surrogate of pulmonary function in studies. As for SCC, which is a clinical marker of CFTR function and is related to disease severity, the triple combination therapy showed that it can reduce its values even <30 mmol/lt. The CFQ-R is a disease-specific health-related quality of life measure for children, adolescents, and adults with CF. It consists of 12 different domains, one of which concerns respiratory symptoms, which can be used in studies in order to assess the effect of the new therapies on the quality of life of CF patients. An increase in the CFQ-R RD score was observed with the new treatment. The use of ELX/TEZ/IVA also decreased the number of pulmonary exacerbations [34,35][14][15]. As far as metabolic parameters are concerned, ELX/TEZ/IVA promotes weight gain with an uncertain, but probably multi-factorial, mechanism. The new CFTR modulator ameliorates the appetite and augments food intake and weight gain. ELX/TEZ/IVA may rehabilitate part of the exocrine pancreatic function, leading to better intestinal absorption and weight gain. The increase in life expectancy in CF patients under the triple treatment results in a rising risk of hyperlipidemia and hypertension and is likely to increase the incidence of cardiovascular and cerebrovascular events [23][16]. The exact mechanism of CFRD and the role of CFTR modulators therapy in the pathophysiology of CFRD are not yet well defined. It is known that the dysfunction of insulin secretion causes CFRD. Even though CFTR protein is detected in pancreatic α and β-cells, implying a role in insulin secretion, this finding has not been confirmed by all studies. Indeed, minimal CFTR mRNA expression and CFTR protein were found in human islet cells. The impact of CFTR modulators on CFRD seems to be indirect; CFTR restoration could reduce the systemic and localized islet inflammation and, as a consequence, improve islet function and insulin sensitivity. In addition, a second possibility is the increased excretion of incretins from the gastrointestinal neuroendocrine cells, which enhance insulin secretion. On the other hand, improved calorie intake and intestinal absorption, due to CFTR modulator therapy, leads to weight gain and, as a result, increased insulin resistance. No clinical trials have evaluated the effect of ELX/TEZ/IVA on CFRD and glucose metabolism [36][17]. An observational study conducted by Scully et al. noticed an improvement in measures of hyperglycemia and glycemic variability with CGM after ELX/TEZ/IVA initiation [25][18]. Moreover, Korten et al. observed an improvement in endocrine pancreatic function with the triple modulator treatment as glucose tolerance for OGTT was improved [24][19]. In general, as has been demonstrated by clinical trials and observational studies, ELX/TEZ/IVA is a well-tolerated medication in all the CF subgroups. Patients included in the aforementioned studies mostly suffered from mild to moderate adverse events. The most frequent were cough, increased sputum production, pulmonary exacerbations, hemoptysis, and pyrexia. It was found that the increased fluidity of respiratory mucus after the ELX/TEZ/IVA initiation is responsible for cough and sputum production aggravation. Rashes (erythematous, maculopapular, papular, skin exfoliation, or urticaria) were a common side effect that occurred approximately in 4–10% of patients treated with ELX/TEZ/IVA. The exact mechanism of this event is unclear. Most likely, skin eruptions are mild to moderate in severity, but some important rashes may demand discontinuation of the triple CFTR modulator treatment. Elevations in blood pressure were noticed [10,23][10][16]. The role of CFTR modulator in vascular homeostasis is not known, as the direct effect of ELX/TEZ/IVA on non-epithelial cells is not yet understood. It has been hypothesized that CF patients have lower blood pressure because of the salt losses in their sweat, and consequently the improvement of CFTR function with the treatment leads to less salt wasting and higher levels of blood pressure [37,38,39][20][21][22]. Elevated levels of aminotransferases were noted in adults and children with CF and this was a common AE, which did not lead to treatment discontinuation. CPK levels were also found to increase, mostly in association with exercise. As far as gastrointestinal side effects of ELX/TEZ/IVA are concerned, one serious adverse event is distal intestinal obstruction syndrome (DIOS), which is mentioned in the clinical trial conducted by Middleton et al. [10]. It is already known that CF patients suffer from constipation, due to the thick intestinal mucus, intestinal mobility disorders, and indigested food being attached to the intestinal walls. After treatment initiation, the amelioration of the mucus hydration leads to fecal detachment of the bowel wall and its movement through the intestine, increasing the possibility of DIOS. In addition, the viscous bile with abnormal pH causes bile salts accumulation and bile gallstones formation, though the CFTR function restoration in the biliary epithelium, with the new treatment, leads to increased bile fluidity that could trigger the movement of pre-existing gallstones and subsequently the appearance of biliary colic and/or acute or chronic cholecystitis [37,40,41,42,43][20][23][24][25][26]. Testicular pain is another side effect described by Rotolo et al., as the thinner mucus blockage moves from either testes, vas deferens, or both when electrolytes balance is achieved with CFTR restoration [44][27]. The new CFTR modulator has many positive effects on CF patients with at least one Phe508del allele, on their lung function, nutrition, quality of life, glycemic status, and other parameters. Even patients with ALD can benefit from the ELX/TEZ/IVA treatment and many have been suspended from the waiting list for lung transplantation. It is also proven that this new triple CFTR treatment is well tolerated with a favorable safety profile in all the subgroups of patients. Further studies are needed to establish the effect of this treatment on the rest of the CF manifestations (for example glycemic status, pancreatic insufficiency, fertility). As this new CFTR modulator is highly effective for patients with Phe508del mutations, a question has been raised as to whether it could be used in patients with rare CFTR mutations who have no indication for CFTR modulator treatment [54][28]. In this direction, studies with nasal cells and intestinal organoids from patients with rare mutations are in progress.

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