Novel Drug Simplifies Cystic Fibrosis Treatment Regimen

TOPLINE:

Vanzacaftor-tezacaftor-deutivacaftor, a novel therapeutic, once-daily drug, demonstrates noninferiority to elexacaftor-tezacaftor-ivacaftor (the twice-daily, standard-of-care drug) in lung function improvement with an acceptable safety profile in patients with cystic fibrosis.

METHODOLOGY:

• Researchers conducted two randomized, double-blind phase 3 trials (SKYLINE VX20-121-102 and VX20-121-103) to compare the efficacy and safety of vanzacaftor-tezacaftor-deutivacaftor with those of standard-of-care elexacaftor-tezacaftor-ivacaftor in patients with cystic fibrosis aged 12 years or older.
• Overall, 398 (elexacaftor-tezacaftor-ivacaftor, n = 202; vanzacaftor-tezacaftor-deutivacaftor, n = 196; median age, 31 years; 41% women) and 573 patients (elexacaftor-tezacaftor-ivacaftor, n = 289; vanzacaftor-tezacaftor-deutivacaftor, n = 284; median age, 33.1 years; 49% women) were enrolled in the SKYLINE VX20-121-102 and VX20-121-103 trials, respectively.
• Patients entered into a 4-week run-in period to receive elexacaftor-tezacaftor-ivacaftor once in the morning, along with only ivacaftor once in the evening, followed by which they were randomly assigned either to continue this regimen or switch to vanzacaftor-tezacaftor-deutivacaftor once in the morning for 52 weeks.
• The primary endpoint for both trials was the absolute change in forced expiratory volume in 1 second (FEV1) from baseline through week 24, with a noninferiority margin of −3 percentage points.
• Other important endpoints included changes from baseline through week 24 in sweat chloride concentration, the proportion of participants achieving sweat chloride levels below 60 mmol/L and 30 mmol/L, and adverse events.

TAKEAWAY:

• Vanzacaftor-tezacaftor-deutivacaftor demonstrated noninferiority to elexacaftor-tezacaftor-ivacaftor in both trials, with the least squares mean treatment difference in FEV1% being 0.2 percentage points in both VX20-121-102 (Pnoninferiority Pnoninferiority
• Treatment with vanzacaftor-tezacaftor-deutivacaftor resulted in superior improvements in sweat chloride concentrations across both VX20-121-102 (mean treatment difference, −8.4 mmol/L) and VX20-121-103 (mean treatment difference, −2.8 mmol/L) trials.
• Across both trials, a slightly higher proportion of patients receiving vanzacaftor-tezacaftor-deutivacaftor achieved sweat chloride concentrations below 60 mmol/L and below 30 mmol/L than those receiving elexacaftor-tezacaftor-ivacaftor.
• The safety profile was comparable between treatments, with most adverse events being mild or moderate and no deaths reported during the treatment period.

IN PRACTICE:

“Vanzacaftor-tezacaftor-deutivacaftor is noninferior to elexacaftor-tezacaftor-ivacaftor in terms of FEV1% predicted and is safe and well tolerated. Once-daily dosing with vanzacaftor-tezacaftor-deutivacaftor reduces treatment burden, potentially improving adherence, compared with the twice-daily regimen of the current standard of care,” the authors wrote.

SOURCE:

The study was led by Claire Keating, MD, Columbia University Irving Medical Center, New York City. It was published online on January 01, 2025, in The Lancet Respiratory Medicine.

LIMITATIONS:

The efficacy and safety of the new drug combination were compared with those of elexacaftor-tezacaftor-ivacaftor, and not a placebo, after a 4-week treatment period, thus limiting the assessment in patients either unable to tolerate or naive to elexacaftor-tezacaftor-ivacaftor. The study population also lacked ethnic and racial diversity, potentially limiting the generalizability of the findings. Some experiments related to lung function could not be performed due to technical challenges in detecting modest changes in older patients with more severe airway obstruction.

DISCLOSURES:

This study was funded by Vertex Pharmaceuticals. Some authors reported being employees of Vertex Pharmaceuticals and owning stock or stock options in that company. Some other authors reported receiving grants, consulting fees, speaker fees, and travel support from various organizations, including Vertex Pharmaceuticals.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.