Orkambi Shows Long-term Safety, Efficacy in Children Ages 2-5

Vanda Pinto avatar

by Vanda Pinto |

Share this article:

Share article via email
Orkambi long-term safety study

Long-term use of Orkambi (lumacaftor/ivacaftor), an approved cystic fibrosis (CF) treatment, is safe and effective for children between ages 2 and 5 with two copies of the disease-causing F508del mutation in the CFTR gene, a study reported.

It draws on results from a Phase 3 open-label extension trial (NCT03125395) showing that Orkambi’s safety and efficacy could be maintained for up to 120 weeks (about 2.3 years), well beyond the 24 weeks of treatment that supported the therapy’s 2018 U.S. approval for this patient age group.

Findings also suggested that young children could benefit from early use of Orkambi.

“Starting CFTR modulator treatments at a younger age may help to slow and hopefully prevent some of the devastating consequences of CF, such as lung damage, lung function decline and frequent illnesses or hospitalizations,” Jordana Hoppe, MD, the study’s lead author and a pediatric pulmonologist at Children’s Hospital Colorado, said in a press release.

The study, “Long-term safety of lumacaftor–ivacaftor in children aged 2–5 years with cystic fibrosis homozygous for the F508del-CFTR mutation: a multicentre, phase 3, open-label, extension study,” was published in The Lancet Respiratory Medicine.

CF is caused by mutations in the CFTR (CF transmembrane conductance regulator) gene that encodes for the CFTR protein responsible for controlling the flow of chloride ions in and out of cells. These mutations affect the protein’s production and how it works.

Orkambi, developed and marketed by Vertex Pharmaceuticals, was the first combination CFTR modulator to be approved for CF patients with two copies of the F508del mutation, the most common disease-causing mutation.

“Lumacaftor–ivacaftor treatment in children aged 2–5 years homozygous for the F508del-CFTR mutation currently accounts for most modulator use in this age group, thus highlighting the importance of ascertaining its long-term safety in this population,” the researchers wrote.

The main Phase 3 study (NCT02797132) — also open-label (no placebo group) — found that Orkambi was safe and effective for 24 weeks of treatment in 2- to 5-year-olds whose CF was due to two F508del mutations. Children who completed this trial were then invited to continue treatment in a long-term safety and effectiveness extension.

Of the 60 enrolled in the main trial, 57 children moved into the extension study, continuing to receive Orkambi at an age and weight relevant dose every 12 hours. Forty-seven children (82%) completed its 96 weeks, for a total of up to 120 weeks of treatment.

Orkambi’s safety and tolerability was this extension’s primary goal. Most children (98%) had at least one adverse event during the study period, with most being mild or moderate and not thought related to treatment by study investigators.

The most common adverse events reported were coughing (82%), a blocked nose (44%), fever (40%), a runny nose (32%), and vomiting (30%). Nine percent of children experienced non-serious respiratory adverse events.

At least one serious adverse events was seen in 26% of the participants, including six cases of an infective pulmonary exacerbation and two cases of pneumonia.

A total of 10 (18%) patients showed increased levels of aminotransferase, a marker of liver damage. Three children (5%) stopped treatment because of adverse events, including two with higher aminotransferase concentrations. No significant changes were reported regarding heart or lung function, oxygen saturation, or vision.

“Overall, the exposure-adjusted rates of adverse events in study 116 [extension trial] was similar to that observed” in the main trial, the researchers reported.

Treatment efficacy signs were secondary goals, and researchers reported “sustained improvements” in sweat chloride concentration, a marker of CFTR protein function, and in growth. Better pancreatic function, as well as stable lung function were also observed.

A two-week interruption in treatment, called a washout period, separated the main and extension trial. Improvements noted with 24 weeks of treatment in sweat chloride, lung function (indicated by the lung clearance index, or LCI) and biomarkers of pancreatic health (namely, fecal elastase-1, and immunoreactive trypsinogen or IRT) declined during the washout, but returned with Orkambi’s use in the extension study.

“The rapid reversal of improvements in sweat chloride, faecal elastase-1, and IRT concentrations … followed by improvements in those endpoints when lumacaftor–ivacaftor was re-initiated … strongly suggest that the improvements noted in this open-label study were associated with lumacaftor–ivacaftor treatment,” the team wrote.

A low incidence of pulmonary exacerbations and CF-associated hospitalizations continued to be observed in the extension trial, the researches noted.

Orkambi “was generally safe and well tolerated, and treatment effects were generally maintained for the duration of the extension study. These findings support the use of lumacaftor–ivacaftor for up to 120 weeks in young children with cystic fibrosis aged 2 years and older [with two copies of the] F508del-CFTR mutation,” the researchers concluded.

“There were no new safety concerns, and treatment effects were maintained for up to 120 weeks,” they added.

Orkambi’s approval was extended to children ages 2 to 5 with two F508del mutations who reside in Canada in December 2018, and for those in countries of the European Union in January 2019.


Featured Column

How I Discovered That PTSD Was Causing My Post-transplant Struggles

PTSD, mental health, communities, stress, grateful, work, trauma, rare disease day, transplant, CF community, National Blood Donor Month, birthdays, holidays
Columnist Lara Govendo addresses an issue that several readers may relate to: post-transplant PTSD, which can wreak havoc.

Read the Column


Your CF Community


Visit the Cystic Fibrosis News Today forums to connect with others in the CF community.