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Ivacaftor use in cystic fibrosis ‘safe and effective’ from one month old, study finds

The cystic fibrosis (CF) medication ivacaftor (brand name Kalydeco) is safe and effective in infants aged four weeks and over, paving the way for earlier initiation of therapy for newborns diagnosed with the condition, a phase 3 open-label study has found.

Ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy, was originally approved for use in adults but has since been shown to be safe and efficacious in children as young as four months.

The therapy increases channel gating activity at the cell surface in patients with CTFR gating mutations. These mutations, which prevent chloride from moving in and out of cells, are thought to cause approximately 4% of CF cases worldwide.

The latest study involved the youngest cohort treated with any CTFR modulator to date, researchers reported in the Journal of Cystic Fibrosis, with infants aged from one month to less than four months old.

Seven infants with mean age at baseline of 1.9 months with CF and an ivacaftor-responsive CTFR variant were enrolled in the phase 3 open-label trial, receiving an initial low dose of ivacaftor based on age and weight.

‘Because ivacaftor is a sensitive CYP3A substrate and CYP3A maturation is uncertain in this age group, an innovative study design was developed wherein each infant initially received a low dose of ivacaftor that was subsequently adjusted based on individual pharmacokinetic results to ensure safe dosing,’ researchers wrote.

They observed a mean decrease in sweat chloride concentration of -40.3 mmol/L from baseline through Week 24, which was generally comparable to the decreases previously reported in children aged four months to less than six months (-50 mmol/L) and in children aged six months to less than 12 months (-58.6 mmol/L).

Infants also had improvements in pancreatic function, intestinal inflammation and growth parameters, according to the study, which was sponsored by the ivacaftor manufacturer Vertex Pharmaceuticals and conducted at four medical centres in the US and Ireland.

The researchers reported ivacaftor was generally safe and well tolerated, with all adverse events being mild in severity and non-serious and generally consistent with common manifestations of CF.

‘One infant discontinued ivacaftor due to an adverse event of elevated alanine aminotransferase/aspartate aminotransferase concentration more than eight times the upper limit of normal that was not considered by the site investigator to be related to be related to ivacaftor and occurred in the context of recurrent viral illnesses in the infant,’ they added.

‘Since pharmacokinetics were predictable, an ivacaftor dosing regimen in infants one to under four months of age based on weight and age is proposed.’

Lead author Professor Paul McNally, associate professor at the Royal College of Surgeons in Ireland and consultant in respiratory medicine at Children’s Health Ireland, said the study findings were a ‘huge moment’ in CF.

‘Over the years ivacaftor… 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,’ Professor McNally said.

Almost all children were diagnosed through newborn screening at around this time, he noted.

‘The availability of a treatment that targets the underlying cause of the disease in newborns and can be started immediately at diagnosis will provide a huge sense of reassurance and hope for families,’ Professor McNally added.

Vertex Pharmaceuticals is applying to the European Medicines Agency for an extension to the marketing authorisation for ivacaftor to infants aged one month.

Last year the UK’s Medicines and Healthcare Products Regulatory Agency extended the licence of another CF medication ivacaftor-tezacaftor-elexacaftor (brand name Kaftrio) in combination with ivacaftor to include children aged two to five years old.