What class of medications are available treatment options for Cystic Fibrosis (CF)?

From the Guidelines

Cystic fibrosis treatments are available for all six classes of CFTR mutations, with options varying based on the specific genetic defect, and Ivacaftor is a key treatment option for Class III and some Class IV mutations. For Class I (protein production) mutations, read-through agents like Ataluren are being investigated. Class II (protein processing) mutations respond to CFTR modulators including Lumacaftor/Ivacaftor (Orkambi), Tezacaftor/Ivacaftor (Symdeko), and Elexacaftor/Tezacaftor/Ivacaftor (Trikafta), with Trikafta being particularly effective for F508del mutations.

Key Treatment Options

• Class III (gating) mutations are treated with potentiators like Ivacaftor (Kalydeco), which improves chloride channel opening, as shown in a study published in 2020 1.
• Class IV (conductance) mutations may partially respond to Ivacaftor or combination therapies.
• Class V (reduced protein) and Class VI (stability) mutations might benefit from combination therapies including Trikafta. All patients, regardless of mutation class, should receive supportive treatments including:
• Airway clearance techniques
• Mucolytics like hypertonic saline and DNase (Pulmozyme)
• Antibiotics for infections
• Pancreatic enzyme replacement
• Nutritional support These treatments target the underlying genetic defect by either improving CFTR protein production, processing, function, or stability, ultimately aiming to normalize chloride transport and reduce the thick mucus that causes lung and digestive complications.

Additional Recommendations

• For patients with CF, 6 years of age and older, with moderate to severe lung disease, the Cystic Fibrosis Foundation strongly recommends the chronic use of dornase alfa to improve lung, as stated in a guideline published in 2007 1.
• For patients with CF, 6 years of age and older, and with FEV1 greater than 60% predicted, the Cystic Fibrosis Foundation recommends the chronic use of oral ibuprofen to slow the loss of lung function, with a level of evidence rated as fair and a net benefit rated as moderate 1.

From the FDA Drug Label

Ivacaftor and fixed dose ivacaftor combinations (e.g., tezacaftor/ivacaftor and ivacaftor/tezacaftor/elexacaftor) Coadministration with ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, increased ivacaftor exposure by 3-fold If used concomitantly with a moderate inhibitor of CYP3A4, such as fluconazole, a reduction in the dose of ivacaftor (or ivacaftor combination) is recommended as instructed in the ivacaftor (or ivacaftor combination) prescribing information.

The available treatment options for cystic fibrosis that are affected are CFTR potentiators, such as ivacaftor.

• The class of drugs affected is CFTR potentiators.
• Ivacaftor exposure is increased by 3-fold when coadministered with fluconazole.
• A reduction in the dose of ivacaftor is recommended when used concomitantly with a moderate inhibitor of CYP3A4, such as fluconazole 2.

From the Research

Cystic Fibrosis Treatment Options

The available treatment options for cystic fibrosis affect the CFTR modulator class, which targets the defective CF transmembrane conductance regulator (CFTR) protein.

• CFTR modulators, such as ivacaftor (IVA), lumacaftor (LUM), and tezacaftor (TEZ), have been developed to restore the function of the CFTR protein 3, 4, 5, 6.
• These modulators can be classified into two main categories: correctors, which increase the trafficking of CFTR proteins to the outer cell membrane, and potentiators, which enable the opening of the dysfunctional chloride channel 4, 5.
• The combination of lumacaftor and ivacaftor (LUM/IVA) was the first CFTR modulator licensed for the homozygous p.Phe508del genotype, and it has been shown to improve lung function and reduce the rate of pulmonary exacerbations 4, 6.
• More recently, the combination of elexacaftor, tezacaftor, and ivacaftor (ELX/TEZ/IVA) has been developed and approved for patients with at least one F508del variant, corresponding to approximately 85% of patients with cystic fibrosis 3.
• These highly effective modulator therapies (HEMTs) have been shown to improve respiratory manifestations, including symptoms and lung function, and reduce the rate of pulmonary exacerbations 3.

Impact on Extrapulmonary Manifestations

The impact of CFTR modulators on extrapulmonary manifestations of cystic fibrosis is less well established, but significant weight gain and improvement in quality of life have been demonstrated 3.

• CFTR modulators have also been shown to improve nutritional outcomes and reduce the risk of complications such as diabetes and liver disease 3, 7.
• However, more research is needed to fully understand the effects of CFTR modulators on extrapulmonary manifestations and to develop more effective treatments for patients with rare mutations 7.

Future Directions

Future directions for the treatment of cystic fibrosis include the development of more potent and targeted therapies, such as gene therapy and gene editing, which have the potential to directly target genetic defects 7.

• The use of nano-compounds and drug delivery systems to enhance CFTR expression and the activity of antimicrobials against chronic pulmonary infections is also being explored 7.
• Overall, the development of CFTR modulators has revolutionized the treatment of cystic fibrosis, and ongoing research aims to further improve outcomes for patients with this disease 3, 4, 5, 6, 7.