What pharmacologic therapy is recommended for patients with cystic fibrosis (CF) having a homozygous F508del mutation, a heterozygous F508del mutation, and those without an F508del mutation?

From the Guidelines

For patients with cystic fibrosis who have a homozygous F508del mutation, the recommended pharmacologic therapy is a combination of elexacaftor/tezacaftor/ivacaftor (Trikafta), as it has shown significant improvements in lung function, reduced pulmonary exacerbations, and improved quality of life, as supported by recent studies 1. The standard adult 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 patients with a heterozygous F508del mutation (one F508del allele plus another mutation), Trikafta is also the preferred therapy, with the same dosing regimen. Some key points to consider in the management of cystic fibrosis include:

• The use of CFTR modulators, such as elexacaftor, tezacaftor, and ivacaftor, which have been shown to improve lung function and quality of life in patients with specific mutations 1.
• The importance of genetic testing to guide drug choice, as certain mutations may respond better to specific treatments 1.
• The need for symptom management, including mucolytics, hypertonic saline, airway clearance techniques, bronchodilators, antibiotics, pancreatic enzyme replacement, and nutritional support, in patients who do not respond to CFTR modulators or have no F508del mutation. For patients with no F508del mutation, treatment depends on their specific mutations, and some may benefit from ivacaftor (Kalydeco) monotherapy if they have gating mutations like G551D, while others might require alternative CFTR modulators based on their specific genetic profile, as supported by studies 1. If no CFTR modulator is appropriate, therapy focuses on symptom management, including mucolytics like dornase alfa (Pulmozyme), hypertonic saline, airway clearance techniques, bronchodilators, antibiotics for infections, pancreatic enzyme replacement, and nutritional support, as recommended by guidelines 1. These therapies work by addressing the underlying defect in the CFTR protein, either by improving its processing to the cell surface (correctors like elexacaftor and tezacaftor) or enhancing its function once there (potentiators like ivacaftor), as described in studies 1.

From the FDA Drug Label

The combined effect of elexacaftor, tezacaftor and ivacaftor is increased quantity and function of CFTR at the cell surface, resulting in increased CFTR activity as measured both by CFTR mediated chloride transport in vitro and by sweat chloride in patients with CF Patient Selection Select patients 2 years of age and older for treatment of CF with TRIKAFTA based on the presence of at least one F508del mutation or another responsive mutation in the CFTR gene Table 6 lists CFTR mutations responsive to TRIKAFTA based on clinical response and/or in vitro data in FRT or HBE cells or based on extrapolation of efficacy

• Homozygous F508del mutation: The pharmacologic therapy that should be used is tezacaftor/ivacaftor/elexacaftor.
• Heterozygous F508del mutation: The pharmacologic therapy that should be used is tezacaftor/ivacaftor/elexacaftor, if the other mutation is responsive to this therapy.
• No F508del mutation: The pharmacologic therapy that should be used is tezacaftor/ivacaftor/elexacaftor, if the patient has at least one qualifying non-F508del mutation that is responsive to this therapy 2, 2.

From the Research

Pharmacologic Therapy for Cystic Fibrosis Patients with F508del Mutation

• For patients with cystic fibrosis who have a homozygous F508del mutation, lumacaftor/ivacaftor is a recommended pharmacologic therapy 3, 4, 5. This combination of a corrector (lumacaftor) and potentiator (ivacaftor) of the cystic fibrosis transmembrane conductance regulator (CFTR) has been shown to improve lung function and reduce pulmonary exacerbations in these patients.
• For patients with a heterozygous F508del mutation, lumacaftor/ivacaftor may not provide a significant improvement in lung function, but it can improve sweat chloride levels and respiratory symptom scores 6.
• For patients with no F508del mutation, there is no specific pharmacologic therapy recommended based on the provided evidence. However, other CFTR modulators such as tezacaftor/ivacaftor may be considered for patients with other CFTR mutations 7.

Considerations for Treatment

• The effectiveness of lumacaftor/ivacaftor in patients with homozygous F508del mutation has been demonstrated in several studies, with improvements in lung function and reductions in pulmonary exacerbations 3, 4, 5.
• The use of lumacaftor/ivacaftor in patients with heterozygous F508del mutation is less clear, with some studies suggesting potential benefits in terms of sweat chloride levels and respiratory symptom scores, but not lung function 6.
• The impact of CFTR modulator therapy on treatment response in pulmonary exacerbations of F508del/F508del cystic fibrosis patients has been evaluated, and it was found that lumacaftor/ivacaftor and tezacaftor/ivacaftor do not convey additional clinical or biochemical advantage above standardized treatment in the acute setting 7.