Kalydeco safe in CF babies as young as 1 month: Phase 3 trial

FDA expanded therapy's use for children of this age last year

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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The CFTR modulator therapy Kalydeco (ivacaftor) can safely be given to babies with cystic fibrosis (CF) as young as 4 weeks old, according to data from a Phase 3 clinical trial.

The findings were the basis of the U.S. Food and Drug Administration (FDA)’s decision to expand approval of Kalydeco for children in this age range last year. The therapy was recently recommended for a similar expansion in Europe, where it’s approved for babies 4 months and older.

“This is a huge moment in cystic fibrosis,” Paul McNally, MD, co-author of the study at the Royal College of Surgeons in Ireland, said in a press release“Over the years Ivacaftor, or [Kalydeco], has been put through clinical trials in younger and younger children. Now, through this study, it has been shown to be safe and effective all the way down to four weeks of age.”

The full results were detailed in “Safety and efficacy of ivacaftor in infants aged 1 to less than 4 months with cystic fibrosis,” which was published in the Journal of Cystic Fibrosis. The work was funded by Vertex Pharmaceuticals, which sells Kalydeco.

CF is caused by mutations in the gene that provides instructions to make the CFTR protein, which normally functions like a gate on the surface of cells, helping regulate the flow of chloride into and out of them. Certain CF-causing mutations cause the gate to become stuck closed so the protein can’t function. Kalydeco works to prop open the gate, restoring CFTR function in patients with eligible mutations.

The Phase 3 clinical trial ARRIVAL (NCT02725567) tested Kalydeco in multiple groups of children younger than 2 years who had CF caused by eligible mutations. This study reported detailed outcomes for the final group of seven babies who were 1 to 3 months old when they started treatment. In countries where newborn screening for CF is routine, most babies are diagnosed very early in life, McNally said.

The initial Kalydeco dose was determined based on weight. Three children were started at 5.7 mg every 12 hours, while the other four started at 11.4 mg every 12 hours. The active agent in Kalydeco is broken down by an enzyme called CYP3A, but its maturation is uncertain in infants. To account for this, about two weeks after starting Kalydeco, drug levels were individually adjusted. Six babies underwent dose adjustments to get blood levels equivalent to those known to be safe and effective in adults.

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Results of ARRIVAL study

The study’s main goal was to evaluate safety and the results were positive; no serious side effects were reported. One safety issue, a runny nose, is often seen in young babies with CF.

“Ivacaftor [Kalydeco] was generally safe and well tolerated during the 24-week treatment period in this small cohort, with all adverse events being mild in severity and nonserious and generally consistent with common manifestations of CF,” the researchers wrote.

One child interrupted Kalydeco treatment after about two months after having a viral infection and gastrointestinal illness, and blood tests showed high levels of a marker of liver damage over several months.

It’s unlikely the patient’s liver damage was a side effect of Kalydeco, the researchers said. There were some signs of mild liver damage, which is a known side effect of Kalydeco, in the other children, but these were “consistent with older age cohorts from the ARRIVAL study,” said the researchers, who noted the levels didn’t rise high enough to stop treatment.

Kalydeco also showed signs of efficacy in the young babies. Levels of sweat chloride, which are elevated in people with CF, decreased by about 50 millimoles per liter after a few weeks and remained low through several months of follow-up.

“These results suggest that treatment with ivacaftor in infants leads to rapid and clinically meaningful improvement in CFTR function, similar to other cohorts in this study and other studies of ivacaftor in older children, adolescents, and adults,” the researchers wrote.

Children with CF often have difficulty gaining weight due to digestive symptoms. Before starting Kalydeco, growth parameters in the seven babies were toward the lower end of what’s considered normal. Over the trial, patients’ growth improved and remained in the normal range.

The finding supports Kalydeco’s use in young infants, though there can be much variability in babies’ growth rates, said researchers, who said long-term studies are needed to see how Kalydeco affects growth.

The study included the first baby in the world with CF who was diagnosed from birth and enrolled directly into such a trial. The baby, Isaac Moss, took part in the study with his sister, Kara.

“Both Kara and Isaac are doing really well and remarkably are not experiencing any of the typical symptoms of Cystic Fibrosis at the moment,” said Debbie. their mother.