A recent single-arm, phase 3 study (RIDGELINE VX21-121-105)1 published in The Lancet Respiratory Medicine2 has shown positive results for vanzacaftor–tezacaftor–deutivacaftor in treating paediatric cystic fibrosis (CF) patients, demonstrating improvements in lung function, sweat chloride levels and quality of life. This trial focused on children aged 6 to 11 years, a group often excluded from studies involving adults or older children, as well as key ages for CF treatment.
CF is a monogenetic disorder caused by CFTR gene mutations, leading to an impairment in salt and water regulation within the lungs.3 This results in respiratory problems, mucus buildup, and frequent infections. Vanzacaftor–tezacaftor–deutivacaftor, a CFTR modulator, aims to improve the functionality of the defective CFTR protein. This study explores the efficacy and safety of the therapy in younger patients, who may experience a faster decline in lung function compared to adults.
The trial, conducted across multiple international sites, enrolled children with CFTR mutations responsive to the treatment. Participants were required to have stable CF with baseline FEV1 values of 60% or higher. The study followed participants for 24 weeks after administration of the drug, with primary endpoints focused on safety and secondary endpoints evaluating lung function, sweat chloride levels and quality of life.
The primary endpoint of the study was to assess the safety and tolerability of vanzacaftor–tezacaftor–deutivacaftor using adverse events, vital signs, clinical laboratory values, electrocardiograms and pulse oximetry. After 24 weeks, participants displayed a clinical improvement with a 13.7% increase in lung function, indicating decreased respiratory symptoms and improved airflow.
Additionally, the treatment maintained FEV1% values (predicted from elexacaftor–tezacaftor–ivacaftor) and enhanced CFTR function, potentially offering a new opportunity to restore normal physiology early and prevent both the development and progression of CF. Improvements in CFTR function were further evidenced by sweat chloride levels: nearly all participants achieved levels below the CF diagnostic threshold (<60 mmol/L), and more than half achieved normal levels (<30 mmol/L).
Participants also reported an improved quality of life, experiencing less frequent symptoms such as coughing and breathlessness. Scores from the Cystic Fibrosis Questionnaire-Revised (CFQ-R) revealed fewer pulmonary exacerbations and better overall day-to-day functioning.
Most adverse events were mild to moderate, with gastrointestinal symptoms and events consistent with CF being the most common. These side effects were transient and manageable. Notably, elevated liver enzyme levels were observed in 83% of participants, but these were controlled with corticosteroids. For heavier patients, corticosteroids were required for longer durations. Importantly, no severe adverse effects, such as symptomatic hepatotoxicity, were reported. These findings emphasise the importance of personalised treatment approaches, particularly for paediatric patients who may have varying immune responses.
The study’s findings are limited by a small sample size and the absence of comparator groups, and further research is needed to assess long-term outcomes. However, treatment with vanzacaftor–tezacaftor–deutivacaftor demonstrated significant improvements in lung function and quality of life in paediatric CF patients. The therapy also achieved the trial’s primary endpoint with a favourable safety profile. Despite the limitations, this research represents an important step towards the potential for expanded treatment options and improved health outcomes for children with CF.
References:
- Evaluation of VX-121/Tezacaftor/Deutivacaftor in Cystic Fibrosis (CF) Participants 1 Through 11 Years of Age. Clinicaltrials.gov. Available at:https://clinicaltrials.gov/study/NCT05422222?term=VX21-121-105&rank=1
- Hoppe JE, Kasi AS, Pittman JE, et al. Vanzacaftor–tezacaftor–deutivacaftor for children aged 6–11 years with cystic fibrosis (RIDGELINE Trial VX21-121-105): an analysis from a single-arm, phase 3 trial. Lancet Respir Med. 2025; Epub. DOI:10.1016/S2213-2600(24)00407-7
- Shteinberg M, Haq IJ, Polineni D, Davies JC. Cystic fibrosis. Lancet. 2021;397:2195-2211. DOI: 10.1016/S0140-6736(20)32542-3.
Disclosures: This article was created by the touchRESPIRATORY team utilizing AI as an editorial tool (ChatGPT (GPT-4o) [Large language model]. https://chat.openai.com/chat.) The content was developed and edited by human editors. No funding was received in the publication of this article.
Acknowledgments: Editorial assistance was provided by Joey Heywood at Touch Medical Media.
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