Inside Pediatrics, Pulmonology

Study Shows Long-Term Effectiveness of Ivacaftor in Children and Adults with Cystic Fibrosis

The world of cystic fibrosis was radically changed in 2012 with the approval of the first cystic fibrosis transmembrane conductance regulator (CFTR) modulator, ivacaftor, which targets certain genetic mutations responsible for the disease. Now, a recently published study by the Cystic Fibrosis Foundation’s multi-center Observational Study in People with CF with the G551D Mutation (GOAL) trial (conducted through the Therapeutics Development Network and funded through the Cystic Fibrosis Foundation) finds that ivacaftor remains effective for at least 5.5 years. Study investigators included Children’s of Alabama pediatric pulmonologist Jennifer S. Guimbellot, M.D., Ph.D, Scott Sagel, M.D., Ph.D., at the University of Colorado, and Steven M. Rowe M.D., who directs the Gregory Fleming James Cystic Fibrosis Research Center at the University of Alabama Birmingham (UAB), as well as other GOAL investigators,

The study followed patients who participated in the drug’s original six-month study. Although a small study with 96 participants, 81% continued as throughout the study duration. “To follow them over five years is a big feat,” said Guimbellot. But it allowed the team to understand whether ivacaftor is helpful with long-term use.

While the study found the drug remained effective overall, with clinically important improvements in lung function, pulmonary exacerbations, quality of life, weight gain, and P. aeruginosa infection, there were some differences based on age and baseline lung function. Adults and those with lower baseline lung function experienced greater improvements in lung function at 5.5 years than children and those with higher baseline lung function. As might be expected, quality-of-life improvement was greater in and more sustained in adults who had lower baseline quality of life scores. Importantly, this was the first study to show quality-of-life improvement beyond 2 years.

Another important finding is that while the overall cohort maintained an average lung function above the pre-ivacaftor level, some continued to experience lung function decline, particularly children. Some also continued to experience infections and remained underweight.

This suggests that “there’s something going on that we need to understand better,” Guimbellot said. “It doesn’t mean that ivacaftor doesn’t work for children; it definitely does work for children. It’s just something we don’t understand and there’s still room for improving care.”

One interesting observation is that while most participants gained weight (in part because they didn’t spend as much metabolic energy fighting the lung disease and attendant infections), some gained an unhealthy amount of weight. “This is something we have to pay attention to,” Guimbellot said. This may include revising the typical high-calorie, high-protein, high-fat diet recommended for certain people with CF to a more balanced diet.

The study is important not only because it shows the long-term effects of ivacaftor, she said, but because it can, hopefully, be extrapolated to the newest approved CTFR, a combination of elexacaftor, ivacaftor, and tezacaftor. Unlike ivacaftor, which is effective for just 4% or 5% of the CF population, this combination, approved in 2019, works in up to 90% of people with the disease.

“As a physician who helps diagnose newborns with cystic fibrosis, I am often asked what parents can expect the child’s lifespan to be,” Guimbellot said. Today the median age of survival is 47, but that doesn’t take into account the effect of the CTFR modulators. “With the new drugs,” she said, “we may see a population of children who don’t have the typical findings of cystic fibrosis as long as they adhere to their therapies.”

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