Elexacaftor-tezacaftor-ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) modulating therapy for cystic fibrosis (CF), is a triple-combination therapy consists of two corrector agents (elexacaftor and tezacaftor) working at distinct binding sites to assist in the proper folding and trafficking of the CFTR protein, as well as ivacaftor, a potentiator that enhances CFTR channel function. Approval for this novel medication was spearheaded by two pivotal randomized controlled trials assessing individuals with CF aged 12 years or older who either were homozygous for the F508del mutation or carried one copy of F508del and a minimal function mutation. In those homozygous for F508del, elexacaftor-tezacaftor-ivacaftor, compared to tezacaftor-ivacaftor alone, improved lung function (10 percentage point increase in percent predicted forced expiratory volume in 1 second [ppFEV1]), reduced sweat chloride, and enhanced quality of life. Data from heterozygous patients showed a ppFEV1 increase of 13.8% vs. placebo, sustained through 24 weeks, with a 41.8 mmol/L drop in sweat chloride, a 63% reduction in pulmonary exacerbations, and improvements in BMI (improved by 1.04 kg/m²) and quality-of-life scores (improved by 20.1 points). [1]
A 2023 systematic review analyzed data from nine randomized controlled trials and 16 observational studies, encompassing individuals aged six years and older with at least one Phe508del mutation. The studies demonstrated substantial improvements in lung function, as evidenced by an increase in ppFEV1 of up to 13.8 points after treatment initiation. Additional pulmonary benefits included a significant reduction in pulmonary exacerbation rates and a notable decrease in lung clearance index, indicating improved ventilation homogeneity. Sweat chloride concentration was consistently reduced across multiple studies, frequently by more than 40 mmol/L, suggesting a robust restoration of CFTR function. Improvements in quality of life were reflected in increased scores on the Cystic Fibrosis Questionnaire-Revised Respiratory Domain, with some studies reporting enhancements exceeding 20 points. A pharmacokinetic analysis highlighted extensive metabolism via CYP3A, necessitating caution with concomitant use of CYP3A modulators. [2]
Safety analysis across multiple studies confirmed elexacaftor-tezacaftor-ivacaftor was well tolerated, reporting primarily mild to moderate adverse events, including cough, headache, and transient liver enzyme elevations. Serious adverse events were infrequent, though some cases of rash and hypertension necessitated treatment modifications. With its approval, elexacaftor-tezacaftor-ivacaftor expanded CFTR modulation therapy eligibility to approximately 90% of the CF population, marking a significant advancement in disease management. [1], [2]
More recently, a 2024 systematic review and meta-analysis of six randomized controlled trials encompassing seven reports and 1,125 CF patients evaluated the efficacy and safety elexacaftor–tezacaftor–ivacaftor (ELX-TEZ-IVA) in individuals with at least one Phe508del mutation. The primary outcomes included the ppFEV1, sweat chloride concentration, and the Cystic Fibrosis Questionnaire-Revised Respiratory Domain (CFQ-R RD). The results demonstrated that ELX-TEZ-IVA significantly improved ppFEV1 by 10.29% (95% confidence interval [CI] 6.44 to 14.14, p< 0.00001) and CFQ-R RD scores by 14.59 points (95% CI 9.25 to 19.94, p< 0.00001) compared to placebo, ivacaftor, or tezacaftor–ivacaftor. Additionally, sweat chloride concentrations were markedly reduced by 40.30 mmol/L (95% CI –49.85 to –30.74, p< 0.00001), indicating a substantial improvement in CFTR function. A safety analysis of the trials revealed that adverse events (AEs) were slightly more prevalent in the ELX-TEZ-IVA group compared to control arms; however, serious adverse events were significantly less frequent (odds ratio [OR] = 0.55, 95% CI 0.38 to 0.79, p= 0.001). While mild to moderate AEs, including oropharyngeal pain, cough, nasopharyngitis, and headache, were commonly reported, their incidence was comparable between treatment and control groups. Infective pulmonary exacerbations of CF occurred less frequently among ELX-TEZ-IVA-treated patients (OR = 0.25, 95% CI: 0.18–0.35, p <0.00001). Notably, no significant differences were observed in severe AEs or treatment discontinuations between groups, and no fatalities were reported. These findings reinforce the efficacy of ELX-TEZ-IVA in improving lung function and quality of life while maintaining an overall favorable safety profile. However, the analysis underscores the necessity for continued monitoring, particularly concerning long-term adverse effects and drug tolerability. [3]