Kaftrio Treated Severe CF Without Confirmed Secondary CFTR Mutation

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by Steve Bryson PhD |

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Kaftrio successfully improved lung function and quality of life in three Italian cystic fibrosis (CF) patients who have severe lung disease with an unknown mutation in the CFTR gene in addition to the common F508del mutation, a case series reported.

Kaftrio (elexacaftor, tezacaftor, and ivacaftor), sold as Trikafta in the U.S. and marketed by Vertex Pharmaceuticals, is available only for CF patients with at least one CFTR F508del mutation or another known secondary mutation. Patients whose DNA analysis is inconclusive typically are excluded from Kaftrio clinical trials and treatment.

These findings support expanding Kaftrio treatment in CF patients without a confirmed secondary CFTR mutation, especially in those with advanced lung disease, the scientist said.

The case series was published in the journal Genes, in the study, “Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor Therapy in Three Subjects with the Cystic Fibrosis Genotype Phe508del/Unknown and Advanced Lung Disease.”

In CF, mutations (variants) in the CFTR gene lead to a faulty CFTR protein, which normally acts as a channel to transport water and chloride ions across cell membranes.

With some mutations, such as the most common CF-related genetic defect known as F508del, the CFTR protein is improperly processed and unable to reach the cell membrane, while in others the CFTR channel is blocked and is unable to transport ions. These impairments in the CFTR protein result in the buildup of mucus in various organs, including the lungs and digestive system.

Kaftrio combines three CF medicines: elexacaftor and tezacaftor, designed to help faulty CFTR get to the cell membrane, and ivacaftor, a so-called CFTR potentiator that aims to open blocked channels allowing water and ion transport.

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In the European Union (EU), Kaftrio is approved for CF patients ages 12 and older whose disease is caused by either two F508del mutations or one F508del mutation and another that leads to a partially active CFTR protein. The list of these Kaftrio-treatable secondary mutations has been expanded recently in the EU and also in the U.S.

However, there are people with CF, some with severe lung disease, for which the second CFTR mutation is unknown ━ even after extensive DNA analysis. As such, these patients have been excluded from Kaftrio clinical trials and treatment.

study recently demonstrated Kaftrio significantly improved CFTR function in epithelial cells that line the nasal airways isolated from CF patients with these unknown secondary mutations.

Now, a team of investigators in Italy reported the outcome of Kaftrio treatment in three unrelated women with CF who carried one F508del mutation and one unknown mutation, all with advanced lung disease.

The first patient was a 48-year-old woman diagnosed with CF at the age of 8 years based on a persistent cough, diarrhea, and elevated chloride in her sweat ━ a hallmark of CF. When she was started on Kaftrio treatment (baseline) she had chronic lung failure, which required long-term oxygen therapy. She also had chronic lung infections, CF-related diabetes, and liver disease.

The second patient was a 59-year-old woman, diagnosed with CF at age 20, her diagnosis based on chronic productive cough, evidence of lung disease on a CT scan, infection, and high sweat chloride. Lung disease progressed to chronic lung failure with antibiotic-resistant infections. She required long-term oxygen therapy at age 57.

The third patient, a 43-year-old woman diagnosed at age 18, based on a diagnosed sibling and with a chronic productive cough, lung disease, infection, and high sweat chloride levels. She also had lung failure associated with infections, requiring oxygen supplementation.

Results showed that over 24 weeks of Kaftrio treatment (almost six months), the sweat chloride levels in all participants progressively lowered, eventually reaching the normal range.

The treatment also led to clinically relevant improvements in lung function in all patients. The third patient, in particular, showed a 20% improvement in lung function at two months and 24.5% by months three and six. No pulmonary exacerbations were reported during the treatment.

The distances walked in six minutes (a test of physical performance) increased from 360 meters (393 yards) at baseline to 558 meters (610 yards) for the first patient after eight weeks of Kaftrio and was sustained throughout the six months. Similarly, the second patient improved by 80 meters (87 yards) the distance walked, and the third by 72 meters (78 yards).

A patient-reported assessment completed by the patients included the CF Questionnaire‐Revised (CFQ‐R) respiratory domain scores (0 to 100), with higher scores reflecting an improved quality of life regarding lung symptoms. CFQ‐R respiratory domain scores significantly increased for all participants by eight weeks and were sustained for the six months of treatment. Other CFQ‐R domains showed an enhanced quality of life.

The daily insulin dose of the first patient with CF-related diabetes was cut in half after one month of Kaftrio treatment, and she stopped oral steroid therapy after three months of treatment. Also, her mean blood oxygen saturation levels increased from 88 to 93% during sleep, and she discontinued daytime oxygen therapy after two months.

The second patient stopped daytime oxygen after one month of treatment, while the third individual showed increased oxygen saturation during sleep and discontinued oxygen therapy after three months.

In the three months before Kaftrio treatment, all participants had lung infections that needed antibiotic therapy. Notably, during the six months of treatment, no antibiotics were required for all three.

Finally, no abnormal adverse events were reported in terms of vital signs, clinical laboratory tests, or physical examinations. No patient withdrew from the treatment.

Overall, “this study demonstrates the benefit from [Kaftrio] treatment in patients with CF with the [F508del] and one unidentified CFTR variant,” the researchers wrote.

Furthermore, it “confirms that the response predicted on nasal epithelial cells correlates with in vivo therapeutic endpoints … confirming the efficacy of such model as a predictor of clinical effectiveness of novel drugs,” they added. “Moreover, it also opens a new possibility of treatment for patients with CF with a [F508del] and one unidentified CFTR variant.”


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