Safety, tolerability of pediatric cystic fibrosis dual therapy sustained for 4 years
Click Here to Manage Email Alerts
Key takeaways:
- Children aged 12 years and older with cystic fibrosis taking tezacaftor/ivacaftor showed sustained, improved lung function.
- Only four patients discontinued treatment due to adverse events.
Combination therapy with tezacaftor/ivacaftor was safe and well tolerated for up to 216 weeks in children aged 12 years or older, according to results of an extension study published in Journal of Cystic Fibrosis.
“Since we are talking about medications that would be taken forever, it is important to know that safety and benefits persist,” Patrick A. Flume, MD, director of the Medical University of South Carolina Adult Cystic Fibrosis Center, told Healio. “Clinical trials are typically conducted over shorter periods prior to approval, so these open-label extension studies offer additional information over the longer term. Although we have now moved on to the triple modulator combination with even greater clinical benefits, the dual combination used in this study is part of that triple combo, so it adds to our confidence that safety will be the same.”
In an open-label extension study of the phase 3 EXTEND trial, Flume and colleagues analyzed 464 children with cystic fibrosis aged 12 years and older homozygous with the F508del mutation (F/F genotype) or heterozygous for F508del and a residual function mutation (F/RF genotype) treated with tezacaftor/ivacaftor (TEZ/IVA; Symdeko, Vertex Pharmaceuticals) to assess the safety and efficacy of the combination therapy over 4 years.
The EXTEND trial evaluated these patients taking TEZ/IVA over 120 weeks (Part A), and this study covers 96 more weeks. To be included, patients had to either come from Part A (n = 377) or other eligible studies (n = 87).
As Healio previously reported, another dual therapy made up of lumacaftor/ivacaftor (Orkambi, Vertex Pharmaceuticals) was safe and well tolerated in children with cystic fibrosis aged 6 to 11 years for up to 120 weeks.
Over the study period, patients took one dose of 100 mg of TEZ/150 mg of IVA in the morning and one dose of 150 mg of IVA in the evening.
Researchers followed up with patients at weeks 12, 24, 36, 60, 72, 84 and 96 to collect spirometry, BMI, number of pulmonary exacerbations, adverse events and serum liver function tests. Further, within 28 days following the end of the study, researcher checked in with patients to evaluate safety.
Treatment discontinuation occurred in 248 patients, with the main reason being commercial drug availability (79.8%), followed by rollover into another study (10.1%) and adverse events (n = 4; 1.6%).
Of the total cohort, 427 (92.2%) patients had one or more adverse event, including 236 (51%) patients with moderate severity events, 129 (27.9%) with mild severity events and 62 (13.4%) patients with severe events.
In their patient population, researchers observed several frequent adverse events: infective pulmonary exacerbation of CF (51.6%), cough (24.2%), nasopharyngitis (19%), hemoptysis (14.7%) and headache (10.2%).
Additionally, 136 (29.4%) patients experienced serious adverse events, according to researchers.
When evaluating long-term safety of the combination therapy through serum liver function tests, researchers found no clinically meaningful changes.
In terms of efficacy, 347 patients made up the F/F group and 106 patients made up the F/RF group. For both sets of patients, lung function stayed close to measurements taken at part B’s baseline (F/F mean absolute change in FEV1 percent predicted, 1.7; F/RF mean absolute change in FEV1 percent predicted, 8.3), which had already shown improvements after 120 weeks of the treatment in Part A.
Additionally, comparable annual pulmonary exacerbation rates from part A of the trial were found in this extension trial in the F/F group (0.77 pulmonary exacerbations/year) and the F/RF group (0.51 pulmonary exacerbations/year).
Lastly, researchers found that absolute change from baseline in BMI slowly went up over 96 weeks in the F/F group (0.7) and the F/RF group (1.84).
“There will always be interest in knowledge about safety and benefits over even longer durations, and this may rely on patient registries to monitor such questions,” Flume told Healio. “We are pleased with what has been accomplished so far for those with CF, but we remain focused on developing therapies of similar benefit for the rest; we are not done yet. There are active trials looking at novel approaches to increasing CFTR activity.”
For more information:
Patrick A. Flume, MD, can be reached at flumepa@musc.edu.
Reference:
- Breakthrough drug combination remains safe and effective in patients with cystic fibrosis after four years. https://muschealth.org/patients-visitors/news/2023/03/15/cystic-fibrosis-trial. Published March 15, 2023. Accessed March 15, 2023.