Large US registry study supports lifesaving power of CFTR modulators
Medications shown to reduce cystic fibrosis death risk by 66% over 8 years
Written by |
People with cystic fibrosis (CF) treated with CFTR modulators have a significantly lower risk of death than untreated patients, with an overall 66% lesser risk over eight years, according to a large U.S. registry study.
The survival benefit was similar in magnitude in males and females.
“Our study is the largest registry-based cohort with the longest longitudinal follow-up examining the real-world effectiveness of CFTR modulator therapies on death to date,” the scientists at Johns Hopkins University said. “A better understanding of the effect of CFTR modulator therapies on death will allow individuals living with CF, their families, and clinical providers to have reasonable expectations about their survival and appropriately plan and allocate care and resources as needs change with increased life expectancy.”
The study, “Effectiveness of CFTR modulator therapy on risk of death for individuals with cystic fibrosis,” was published in CHEST.
CFTR modulators target specific disease-causing mutations
CF is caused by genetic mutations that result in the loss or dysfunction of the CFTR protein, leading to the accumulation of thick, sticky mucus in various organs. The symptoms of CF particularly affect the respiratory, digestive, and reproductive systems.
CFTR modulators are a class of medications used to treat CF in people with specific disease-causing mutations. They work to increase CFTR functionality, helping to ease CF symptoms and slow disease progression.
“Clinical trials of [CFTR-modulator] therapies have focused on outcomes that can be captured under relatively short follow-up periods,” the investigators wrote. In contrast, the “effectiveness of CFTR modulator therapies on survival has not been fully described.”
Risk of death varied based on patients’ age when initiating treatment
To learn more, the team used U.S. Cystic Fibrosis Foundation Patient Registry data from 2012 to 2022. Participants met the age and genetic profile eligibility criteria as of 2020.
A total of 25,103 patients who attended 178,835 clinical or telehealth visits were included. A total of 18,056 participants began taking CFTR modulator therapies. Almost all (98%) had a severe genetic variant. The vast majority had at least one copy of the F508del mutation (92%), the most common CF-causing mutation.
Overall, 3,797 patients (15%) died during follow-up. Compared with patients who were not treated, those who received CFTR modulators had a lower risk of death at one year (0.4% vs. 1%), five years (2.5% vs. 8.1%), and eight years (4.1% vs. 11.4%) of treatment. This corresponded to a 66% overall lower risk of death over eight years after starting CFTR modulator therapy.
According to the researchers, “risk estimates are influenced by the timing of regulatory approvals for each CFTR modulator therapy.” Eight-year estimates were driven by Kalydeco (ivacaftor), five-year data also incorporated the effects of Orkambi (ivacaftor/lumacaftor) and Symdeko (ivacaftor/tezacaftor), and one-year results also included Trikafta (ivacaftor/tezacaftor/elexacaftor). Of note, a next-generation modulator therapy called Alyftrek (vanzacaftor/tezacaftor/deutivacaftor), marketed by Vertex Pharmaceuticals, was approved more recently, in December 2024.
Hopefully, demonstration of broader effectiveness of CFTR modulator therapies will motivate expanded access through reduced costs and wider insurance coverage, and further reduce CF mortality through increased uptake.
The risk of death varied according to patients’ age when starting the treatment, from 49% lower for those starting between 12 and 17 years to 72% lower for those initiating between 18 and 29 years to 70% lower for patients starting at age 30 or older.
After treatment initiation, the risk of death was 69% lower in males and 65% lower in females, a difference that is not statistically significant.
Among patients treated with a CFTR modulator, 6.7% discontinued treatment after a median of 1.9 years. Those who remained on treatment were followed up for a median of 4.2 years.
“Although about 90% of individuals with CF are now eligible for CFTR modulator therapies, they remain inaccessible to some due to unresponsive genetic variants, lack of tolerance, and high costs, but new treatments are under development that will hopefully benefit them,” the researchers wrote. “Hopefully, demonstration of broader effectiveness of CFTR modulator therapies will motivate expanded access through reduced costs and wider insurance coverage, and further reduce CF mortality through increased uptake.”
