Ivacaftor appears safe for young children with cystic fibrosis

By Will Boggs MD

NEW YORK (Reuters Health) - Ivacaftor appears to be safe for young children with cystic fibrosis (CF), although elevated liver function tests may call for increased monitoring, according to research from the KIWI study group.

"Based on the compelling clinical efficacy in older children and adults, this drug could provide significant long-term benefit," Dr. Jane C. Davies from Imperial College London in the UK told Reuters Health by email.

Ivacaftor (Kalydeco, Vertex) is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that has been shown to benefit patients aged 6 years and older with CF and the Gly551Asp or other CFTR gating mutations.

Dr. Davies and colleagues in the two-part KIWI study assessed the safety, pharmacokinetics, and pharmacodynamics (based on sweat chloride concentrations) and explored the efficacy of ivacaftor (50 mg and 75 mg every 12 hours) in children with CF aged 2 to 5 years with a CFTR gating mutation on at least one allele.

Pharmacokinetics results were similar in these patients to those reported in adults in previously published phase 2 and 3 studies, according to the January 20 online report in the Lancet Respiratory Medicine.

Five of 34 children (15%) had rises in alanine transaminase or aspartate transaminase concentrations to greater than eight times the upper limit of normal, though all also had a history of elevated liver function tests (two-three times the upper limit of normal) at baseline.

None of the children developed new cataracts or lens opacities or other clinically relevant findings.

Sweat chloride concentrations in 19 children tested decreased by a mean of 44.0 mmol/L from a mean of 97.9 mmol/L at baseline. Fecal elastase, a marker of pancreatic exocrine function, in 27 children tested increased by a mean of 99.8 mcg/g after 24 weeks of treatment.

The fecal elastase results were surprising. Dr. Davies said, "We have long assumed that the exocrine pancreas is completely damaged by the time a baby with CF is born. This sheds significant doubt on that 'fact' and raises the possibility that there is a window of opportunity to reverse disease in other organs if we begin treatments early enough."

The concentration of immunoreactive trypsinogen, a marker of pancreatic stress, improved significantly from baseline to week 24.

There were insufficient spirometry data to assess lung function.

"The cohort is undergoing long-term follow-up in an extension study," the researchers noted, "during which the durability of these effects and longer-term safety will be assessed."

"Ivacaftor is safe in this age, but attention may need to be paid to liver function tests," Dr. Davies concluded.

Dr. Claire Wainwright, lead physician for CF at Lady Cilento Children's Hospital, South Brisbane, Queensland, Australia, told Reuters Health by email, "I found the frequency of liver function abnormality somewhat concerning. There was a hint from the data that there may be a window of opportunity, however, to influence pancreatic function, and this should be explored further as it would be of huge clinical interest."

"If ivacaftor is available and funded/reimbursed for pre-school children with appropriate genetic mutations, cautious use should be considered with careful monitoring," Dr. Wainwright said.

Vertex Pharmaceuticals funded the study, employed three of the 11 authors, and had various relationships with five other authors, including Dr. Davies.

SOURCE: http://bit.ly/202lHkx

Lancet Respir Med 2016.

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