What are the recommended pharmacotherapies for patients with Cystic Fibrosis (CF) who have either the homozygous F508del mutation or the heterozygous F508del mutation?

From the Guidelines

For patients with cystic fibrosis (CF) with homozygous F508del mutation, the recommended pharmacotherapy includes a combination of elexacaftor/tezacaftor/ivacaftor (Trikafta), which has shown significant improvement in lung function and reduction in pulmonary exacerbations, as supported by the most recent evidence 1. The standard dosing is two tablets (containing elexacaftor 100mg/tezacaftor 50mg/ivacaftor 75mg) in the morning and one tablet of ivacaftor 150mg in the evening, taken with fat-containing food. For heterozygous F508del mutation patients, the same triple combination therapy is recommended if they have at least one F508del allele. If Trikafta is not available, alternatives include tezacaftor/ivacaftor (Symdeko) or lumacaftor/ivacaftor (Orkambi) for homozygous patients, though these are less effective, as noted in the european position paper on rhinosinusitis and nasal polyps 2020 1. These CFTR modulators work by improving the function of the defective CFTR protein - elexacaftor and tezacaftor help with protein folding and trafficking to the cell surface, while ivacaftor enhances the channel's opening probability. All patients should continue standard CF treatments including:

• mucolytics (like dornase alfa)
• hypertonic saline
• airway clearance techniques
• antibiotics as needed, as recommended by the cystic fibrosis pulmonary guidelines 1. Treatment should be monitored for side effects including liver function abnormalities, cataracts, and drug interactions, particularly with strong CYP3A inhibitors or inducers which may require dose adjustments. Key considerations for management include:
• Inhaled tobramycin for moderate to severe disease
• Dornase alfa for moderate to severe disease
• Inhaled hypertonic saline
• Azithromycin with P. aeruginosa, as outlined in the cystic fibrosis pulmonary guidelines 1. It is essential to prioritize the patient's quality of life, morbidity, and mortality when making treatment decisions, and to consider the most recent and highest-quality evidence available, such as the european position paper on rhinosinusitis and nasal polyps 2020 1.

From the FDA Drug Label

The safety profile of TRIKAFTA in patients with CF with at least one F508del mutation is based on data from 510 patients aged 12 years and older in two double-blind, controlled trials of 24 weeks and 4 weeks treatment duration a 24-week, open-label trial in 66 patients with CF aged 6 to less than 12 years who were either homozygous for the F508del mutation or heterozygous for the F508del mutation, and a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor and tezacaftor/ivacaftor (Trial 3)

The recommended pharmacotherapy for patients with cystic fibrosis is TRIKAFTA, which includes tezacaftor, for patients with at least one F508del mutation.

• For patients who are homozygous for the F508del mutation, TRIKAFTA is recommended.
• For patients who are heterozygous for the F508del mutation, TRIKAFTA is also recommended, provided the second allele has a mutation that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor and tezacaftor/ivacaftor 2.

From the Research

Pharmacotherapies for Cystic Fibrosis

Homozygous F508del Mutation

• Lumacaftor/ivacaftor is a recommended pharmacotherapy for patients with cystic fibrosis who are homozygous for the F508del mutation 3, 4, 5, 6, 7
• This combination therapy has been shown to improve lung function, reduce pulmonary exacerbations, and improve body mass index (BMI) in patients with cystic fibrosis who are homozygous for the F508del mutation 3, 4, 5, 6
• Lumacaftor/ivacaftor has an acceptable tolerability profile, with the most common adverse events being respiratory or gastrointestinal in nature 3, 4

Heterozygous F508del Mutation

• There is limited evidence on the effectiveness of lumacaftor/ivacaftor in patients with cystic fibrosis who are heterozygous for the F508del mutation
• However, the combination therapy of elexacaftor-tezacaftor-ivacaftor has been shown to be effective in patients with cystic fibrosis who have one or two F508del variants, including those who are heterozygous for the F508del mutation 7
• This triple therapy has been shown to improve quality of life, respiratory function, and reduce pulmonary exacerbations in patients with cystic fibrosis who have one or two F508del variants 7

Comparison of Pharmacotherapies

• Lumacaftor-ivacaftor and tezacaftor-ivacaftor are both effective in improving quality of life and respiratory function in patients with cystic fibrosis who are homozygous for the F508del mutation, but lumacaftor-ivacaftor is associated with an increase in early transient shortness of breath and longer-term increases in blood pressure 7
• Tezacaftor-ivacaftor has a better safety profile, although data are lacking in children under 12 years 7
• Elexacaftor-tezacaftor-ivacaftor has been shown to be effective in patients with cystic fibrosis who have one or two F508del variants, including those who are heterozygous for the F508del mutation, with probably little or no difference in adverse events compared to placebo or control 7