How does elexacaftor (ELEX)/ivacaftor (IVA)/tezacaftor (TEZ) compare to dual cystic fibrosis transmembrane conductance regulator (CFTR) modulators like ivacaftor (IVA)/tezacaftor (TEZ), ivacaftor (IVA)/lumacaftor (LUM), and ivacaftor (IVA) in terms of efficacy and safety in patients with cystic fibrosis (CF)?

From the Guidelines

Elexacaftor/ivacaftor/tezacaftor (Trikafta) is significantly more effective than dual CFTR modulators for most cystic fibrosis patients, particularly those with at least one F508del mutation. This triple combination therapy demonstrates superior improvements in lung function, with average FEV1 increases of 10-14% compared to 2-4% with dual modulators like Ivacaftor/tezacaftor (Symdeko) or Ivacaftor/lumacaftor (Orkambi) 1. Some key points to consider when comparing Elexacaftor/ivacaftor/tezacaftor to dual CFTR modulators include:

• Superior improvements in lung function, as measured by FEV1
• Greater reductions in pulmonary exacerbations, with a 63-70% reduction versus 30-40% with dual therapy
• More substantial improvements in sweat chloride levels, a key biomarker of CFTR function
• A safety profile that is generally comparable to dual modulators, with common side effects including headache, upper respiratory tract infections, abdominal pain, diarrhea, and rash
• The potential for liver enzyme elevations, which can occur with all CFTR modulators and require monitoring 1 The mechanism of Elexacaftor/ivacaftor/tezacaftor - elexacaftor improves F508del CFTR protein processing and trafficking while tezacaftor enhances cellular processing and ivacaftor increases channel opening time - addresses multiple defects in the CFTR protein, making it effective for approximately 90% of CF patients compared to the more limited populations that benefit from dual modulators or ivacaftor monotherapy 1. For patients with eligible mutations, Trikafta represents the current standard of care due to its superior efficacy across multiple clinical outcomes.

From the FDA Drug Label

CFTR Chloride Transport Assay in Human Bronchial Epithelial Cells Expressing Mutant CFTR Protein Homozygous and heterozygous N1303K-Human Bronchial Epithelial (HBE) cells showed greater chloride transport in the presence of elexacaftor/tezacaftor/ivacaftor than F508del/F508del-HBE cells treated with tezacaftor/ivacaftor

• Efficacy: Elexacaftor/ivacaftor/tezacaftor has shown greater chloride transport in HBE cells compared to tezacaftor/ivacaftor.
• Safety: The label does not provide a direct comparison of the safety of elexacaftor/ivacaftor/tezacaftor to dual CFTR modulators like ivacaftor/tezacaftor, ivacaftor/lumacaftor, and ivacaftor. 2

From the Research

Efficacy Comparison

• Elexacaftor/ivacaftor/tezacaftor has demonstrated superior efficacy compared to dual CFTR modulators like ivacaftor/tezacaftor, ivacaftor/lumacaftor, and ivacaftor in terms of lung function, quality of life, sweat chloride reduction, and reducing exacerbations 3, 4, 5.
• The triple-combination therapy has shown a significant improvement in percent predicted forced expiratory volume in 1 second (ppFEV1) and Cystic Fibrosis Questionnaire-Revised respiratory domain score compared to placebo or dual CFTR modulators 4, 6, 7.
• Elexacaftor/ivacaftor/tezacaftor has also been shown to halt lung function decline over an extended time period, with a mean annualized rate of change in ppFEV1 of +0.39 percentage points compared to a 1.92 percentage point annual decline in untreated controls 6.

Safety Comparison

• The safety profile of elexacaftor/ivacaftor/tezacaftor is generally acceptable, with most common adverse events being mild or moderate, including rash and headache 3, 4.
• Laboratory monitoring is recommended to evaluate liver function, and adverse events leading to discontinuation of the trial regimen occurred in 1% of patients in the elexacaftor/ivacaftor/tezacaftor group 4.
• Real-world evidence from an Italian single-center study showed that elexacaftor/ivacaftor/tezacaftor was well tolerated, with no patients interrupting treatment due to toxicity 7.

Patient Population

• Elexacaftor/ivacaftor/tezacaftor is approved for patients with cystic fibrosis who have at least one F508del mutation in the CFTR gene, providing potential therapy to many patients who had previously been excluded from CFTR modulation therapy due to the nature of their genetic mutations 3, 5.
• The triple-combination therapy has been shown to be efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective 4.
• Real-world evidence suggests that elexacaftor/ivacaftor/tezacaftor is effective in patients with advanced lung disease, with significant improvements in lung function, quality of life, and reduction in pulmonary exacerbations 7.