Kalydeco effective for patients with certain mutations: Real-world study
Study included variants for which therapy's approval was based on lab data
The real-world use of Kalydeco (ivacaftor) effectively eased disease severity in people with cystic fibrosis (CF) who had certain disease-causing mutations, according to a study that included patients with mutations for which Kalydeco was approved in the U.S. in 2017 based largely on laboratory data.
“This study adds to the growing real-world evidence of the long-term effectiveness of [Kalydeco], particularly in a population with limited clinical trial data,” the researchers wrote.
The study, “Real-world impact of ivacaftor in people with cystic fibrosis and select ivacaftor-responsive mutations,” was published in BMJ Open Respiratory Research. All its authors work for Vertex Pharmaceuticals, which markets Kalydeco and other CFTR modulator therapies.
Kalydeco was the first therapy approved for CF that addresses its underlying cause, that is, a dysfunctional or missing CFTR protein resulting from mutations in the CFTR gene. CFTR acts as a gate that regulates the flow of salt and water into and out of cells.
The therapy is what’s known as a CFTR potentiator and is intended largely for those with CFTR gating mutations by helping to keep the CFTR gate open longer at the cell’s surface. It was first approved in the U.S. in 2012 for patients ages 6 and older with at least one G551D mutation, one of the most common CF-causing gating mutations. The label has been expanded a few times and is currently cleared for patients as young as 1 month old with any of nearly 100 eligible mutations.
In the 2017 expansion, 28 mutations were added to Kalydeco’s label. Most were approved based on laboratory experiments that suggested they’d be responsive to treatment, not on clinical trial data, meaning clinical data that indicates how well the CFTR modulator works with those mutations is still needed.
Improved lung function with Kalydeco
Here, researchers looked at real-world responses to Kalydeco using data from the U.S. CF Foundation Patient Registry (CFFPR). The analysis involved 1,004 patients, ages 2 or older, with at least one copy of any of the 28 mutations approved in 2017 who’d started Kalydeco in 2017 or 2018. Clinical data for up to a year before starting treatment and up to two years after was reviewed. The overall mean duration on Kalydeco was 16.5 months, or about 1.3 years.
Lung function improved by 1.9% in the first year of treatment compared to before treatment in those who started taking Kalydeco in 2o17, the primary analysis group, and by 1.8% in the second year, with similar gains across age groups. Lung function assessments were conducted only on patients who were at least 6 years old for technical reasons.
Body mass index, or BMI, an indicator of body fat based on height and weight, also increased in the first and second years of treatment. BMI adjusted for sex and age remained stable with treatment.
Across all the patients, pulmonary exacerbations, or bouts of acutely worsening lung function, decreased from 0.41 per patient-year in the pre-Kalydeco period to 0.24 during treatment. This metric is calculated by dividing the total number of events in the study by the total number of follow-up years across all patients. Likewise, the annual hospitalization rate decreased from 0.45 to 0.28 events per patient-year. The changes in the rate of exacerbations and hospitalizations were more pronounced in adults than in pediatric patients.
The prevalence of infection with Pseudomonas aeruginosa, the most common infection-causing bacteria in CF, was similar before and after treatment (35.8% versus 37.4%).
The data looked generally similar in a subset of patients who also had at least one Kalydeco-responsive splicing mutation. Mutations that affect CFTR splicing, a natural process that lets a single gene give rise to many different proteins, occur in about 10%-15% of all CF cases.
Overall, “the study findings are consistent with previous real-world observational data demonstrating the significant benefits of [Kalydeco] therapy … in terms of improvements in lung function and reduced incidences of [pulmonary exacerbations] and hospitalizations,” the researchers wrote.
Still, the magnitude of the observed benefits were not as great as those seen in earlier studies. That could be due because the mutations studied here are associated with a less severe disease course than others like G55D. The patients in this study had higher lung function at the start of treatment than in other studies.
Missing data from the registry such as specific dates related to hospitalizations or infections were among the study’s limitations, the researchers said.
“Despite these limitations, we are confident the overall findings of this study are likely to be generalizable to other populations of people with CF with ivacaftor-responsive CFTR mutations, especially given the fact that the U.S. CFFPR is one of the largest and most comprehensive national CF registries in the world,” they wrote.
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