Comparative Efficacy of CFTR Modulators: A Network Meta-analysis.

Area of Science:

• Pharmacology and Therapeutics
• Pulmonology
• Genetics

Background:

• Cystic fibrosis (CF) is a genetic disorder affecting multiple organs, primarily the lungs.
• Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators are a class of drugs designed to treat the underlying cause of CF.
• The F508del mutation is the most common CFTR mutation, affecting a large proportion of people with CF (pwCF).

Purpose of the Study:

• To conduct a comparative efficacy analysis of novel CFTR modulators: vanzacaftor-tezacaftor-deutivacaftor (VTD) and elexacaftor-tezacaftor-ivacaftor (ETI).
• To compare VTD and ETI against older modulators, tezacaftor-ivacaftor (Tez-Iva) and lumacaftor-ivacaftor (Lum-Iva).
• To evaluate these modulators in pwCF aged 12 years and older with at least one F508del-CFTR allele.

Main Methods:

• A network meta-analysis was performed using data from randomized controlled trials and randomized active comparator trials.
• Frequentist methods were employed to compare drug efficacies and rank them using P-scores.
• Key outcomes included changes in ppFEV1, CFQ-R scores, SwCl levels, and odds of serious adverse events (SAEs).

Main Results:

• VTD and ETI showed significantly greater improvements in ppFEV1 and CFQ-R scores compared to Tez-Iva and Lum-Iva.
• A statistically significant difference in sweat chloride reduction was observed between VTD and ETI, favoring VTD.
• No significant increase in SAEs was found for any modulator; VTD, ETI, and Tez-Iva showed the lowest association with SAEs.

Conclusions:

• VTD and ETI are more efficacious than Tez-Iva and Lum-Iva in pwCF carrying at least one F508del-CFTR allele.
• The findings support the use of VTD and ETI as advanced treatment options for this patient population.
• VTD and ETI represent a significant advancement in CFTR modulator therapy.