Woman breathing into spirometer

Modulators of the cystic fibrosis transmembrane conductance regulator (CFTR) protein have emerged as a promising therapeutic strategy for cystic fibrosis (CF).

“Modulators offer the hope of fewer treatments and potentially the withdrawal of some chronic therapies,” specialists of the Respiratory Medicine and Specialized Cystic Fibrosis Unit of the Children’s Hospital for Wales in the United Kingdom wrote in Archives of Disease in Childhood.

CFTR modulators are generally safe and well-tolerated, with low discontinuation rates compared to placebo. Overall, the most evident safety concerns are elevations in liver enzymes and drug-drug interactions. However, Gavioli et al wrote, “As CF patients continue to live longer, they will be at risk for developing adverse drug reactions associated with older age, comorbidities, and pharmacokinetic and pharmacodynamic changes.”

Generally, CFTR modulators can be subdivided into correctors, which facilitate CFTR processing and trafficking to the cell surface, and potentiators, which promote the ability of the ion channel to open once at the apical membrane. To select which class is most appropriate for a given CF case, it is important to know the underlying CFTR variant.

For instance, a potentiator should be enough to improve ion channel function in patients with class III or IV variants. In class III variants, the CFTR at the apical membrane fails to open due to impaired regulation, whereas there is a reduction in ion conduction in class IV variants.

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On the other hand, class II variants lead to abnormal protein folding and premature degradation of CFTR, thereby decreasing its expression. Therefore, patients with class II variants, which include the most common variant, F508del, would require cotreatment with a corrector and a potentiator.

There are 4 CFTR modulators available worldwide: ivacaftor (Kalydeco®), lumacaftor/ivacaftor (Orkambi®), tezacaftor/ivacaftor (Symdeko®), and Trikafta® (elexacaftor/tezacaftor/ivacaftor). Ivacaftor is a CFTR potentiator, whereas lumacaftor, tezacaftor, and elexacator are CFTR correctors. All are disease-modifying agents with proven clinical efficacy.

Ivacaftor, the Starting Point

Ivacaftor was the first CFTR modulator to become available. Initial studies pointed to an improvement of 8.7% in the forced expiratory volume in 1 second (FEV1) measured as a percentage predicted (% predicted) adjusted for age, sex, and height, in patients heterozygous for the most common class III variant, G551D.

Research showed that ivacaftor was also able to decrease the sweat chloride concentration significantly, an effect observed for the first time in a CF treatment. “The decrease in sweat chloride to 59.5 mmol/L was such that many of the participants would not fit the diagnostic criteria for CF on sweat test,” Edmondson et al, the specialists from Children’s Hospital for Wales, explained.

The benefits of ivacaftor monotherapy were further confirmed in subsequent studies. It was shown to reduce pulmonary exacerbations, lower hospital admission rates, and decrease the rates of respiratory Pseudomonas and Aspergillus infection, as well as the need for intravenous antibiotics.

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Ivacaftor monotherapy can be initiated in patients as young as 4 months old. The initiation of ivacaftor in children aged 12 months or less seems to improve pancreatic exocrine function and allowed for the discontinuation of insulin therapy for CF-related diabetes in some older patients.

Despite the substantial improvements, ivacaftor monotherapy is not sufficient to reverse all late complications of CF and it is not effective in most patients with CF who have the F508del mutation.

Expanding the Options With Combination Therapies

Due to the limitations of ivacaftor, additional CFTR modulators have been approved to be used in combination regimens.

Lumacaftor/ivacaftor and tezacaftor/ivacaftor combinations have shown similar improvements in FEV1 % predicted (2.8% and 4.0%, respectively) and sweat chloride concentration (10 mmol/L for both). These improvements were less pronounced than those observed for ivacaftor monotherapy. Moreover, tezacaftor/ivacaftor showed some benefit for patients heterozygous for F508del and a milder CFTR variant, but lumacaftor/ivacaftor did not.

The elexacaftor/tezacaftor/ivacaftor combination seems promising in changing the treatment paradigm for most patients with CF. “The magnitude of improvement in FEV1 % predicted, the decrease in pulmonary exacerbations, the nutritional improvement and improved quality of life are unparalleled,” Edmondson et al wrote.

One study reported a sustained improvement of 14% in FEV1 % predicted, a 63% reduction in annual pulmonary exacerbation rate, and a decrease in sweat chloride concentration to levels under the diagnostic threshold for CF. The study also revealed improvements in body mass index and quality of life scores.

Another study showed better performance of the elexacaftor/tezacaftor/ivacaftor combination in patients homozygous for Phe508del, when compared to tezacaftor/ivacaftor combination.

In terms of safety concerns, evidence suggests that lumacaftor/ivacaftor may result in more respiratory-related adverse events and drug-drug interactions than elexacaftor/tezacaftor/ivacaftor and tezacaftor/ivacaftor.

According to Gavioli et al, “Longer studies are required to determine whether dual or triple combination therapy will have long-term safety concerns, as well as the large financial burden these medications may have for patients.”


Edmondson C, Course CW, Doull I. Cystic fibrosis transmembrane conductance regulator modulators for cystic fibrosis: a new dawn? Arch Dis Child. 2021;106(10):941-945. doi:10.1136/archdischild-2020-320680

Gavioli EM, Guardado N, Haniff F, Deiab N, Vider E. A current review of the safety of cystic fibrosis transmembrane conductance regulator modulators. J Clin Pharm Ther. 2021;46(2):286-294. doi:10.1111/jcpt.13329