CF-AIR and CF@LANTA primary investigators Rachel Linnemann, MD and Ajay Kasi, MD, along with collaborators, recently published impactful journal articles outlining the results of phase 3 clinical trials in people with cystic fibrosis (CF) that led to the U.S. Food and Drug Administration (FDA) approval on December 20, 2024 of the new triple-combination modulator Alyftrek (vanzacaftor/tezacaftor/deutivacaftor). Alyftrek is a once-daily cystic fibrosis transmembrane conductance regulator (CFTR) modulator for people with cystic fibrosis ages 6 and older who have a mutation that is eligible for Trikafta or one of 31 rare mutations that had not been approved previously for a modulator.
Dr. Kasi was a national principal investigator for the trial for children ages 6-11 years, and second author on the journal article titled, “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,” published in The Lancet Respiratory Medicine on January 1, 2025.
Dr. Linnemann was a national principal investigator for the trial for children ages 12 and above, and co-author on the journal article titled, “Vanzacaftor–tezacaftor–deutivacaftor versus elexacaftor–tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years and older (SKYLINE Trials VX20-121-102 and VX20-121-103): results from two randomized, active-controlled, phase 3 trials,” also published in The Lancet Respiratory Medicine on January 1, 2025.
The FDA approved Alyftrek based on results from these clinical trials, which compared the drug to Trikafta, along with lab test data that showed additional rare mutations were responsive to Alyftrek. With administration once a day, Alyftrek provides a simpler dosing regimen for people with cystic fibrosis, as compared to twice daily for other modulators. The studies were funded by Vertex Pharmaceuticals.
Overall, nine patients with cystic fibrosis enrolled and participated in these studies from the Emory + Children’s CF Care Centers.
“The approval of vanzacaftor-tezacaftor-deutivacaftor is a significant milestone for people with cystic fibrosis,” said Dr. Kasi. “The multicenter international study showed that vanzacaftor-tezacaftor-deutivacaftor was safe, well-tolerated, and improved lung function comparably to Trikafta, while reducing sweat chloride levels further than Trikafta. In the pediatric study, nearly all participants achieved sweat chloride levels below the diagnostic threshold for CF and more than half had normal levels highlighting the efficacy of this drug. Improvement in CFTR function could prevent progression of cystic fibrosis.”
“It is exciting that Alyftrek will be an alternative treatment option for people with CF, including those who cannot tolerate Trikafta, and it will be available for additional individuals who weren’t previously eligible for any modulator. We expect Alyftrek’s once daily dosing will also facilitate adherence, since modulators need to be taken with fat-containing food,” Dr. Linnemann said.
Drs. Linnemann and Kasi would like to thank the Cystic Fibrosis research team, particularly the Clinical Research Coordinators, who played a significant role in conducting the study at Emory + Children’s CF Care Centers.
These new modulators are life changing therapeutics for many individuals with cystic fibrosis, although there are many unanswered scientific questions remaining, particularly the longer-term effects of increasing CFTR activity in the growing child. In addition, 2025 will bring testing at our Emory + Children’s CF clinical trials site of more exciting and potentially life changing treatments for our patients with cystic fibrosis, including the bionic pancreas for those with CF-related diabetes and an mRNA CFTR genetic therapy, which is agnostic to CFTR genotype.
Concurrent with this announcement, the FDA also approved the expansion of Trikafta (elexacaftor/tezacaftor/ivacaftor) to people with cystic fibrosis ages 2 and older who have at least one of 94 rare mutations in the CFTR gene, including the N1303K variant. Emory + Children’s researchers Dr. Linnemann and Dr. Eric Sorscher, along with collaborators, recently published an impactful journal article in The Lancet Respiratory Medicine, which outlined the results of a clinical trial in people with cystic fibrosis encoding the N1303K variant that demonstrates significant positive outcomes for Trikafta. The article, titled “Evaluation of elexacaftor–tezacaftor–ivacaftor treatment in individuals with cystic fibrosis and CFTR-N1303K in the USA: a prospective, multicentre, open-label, single-arm trial,” can be found here.
The Lancet Respiratory Medicine is a world-leading respiratory medicine and critical care journal with an Impact Factor of 38·7, ranking first among 54 critical care and 100 respiratory system journals globally.
Dr. Linnemann serves as the Director of the Cystic Fibrosis Care Center at Children’s Healthcare of Atlanta and Emory University, and she is also an Associate Professor, Department of Pediatrics at the Emory University School of Medicine.
Dr. Kasi is a pediatric pulmonologist at Children's Healthcare of Atlanta and an Associate Professor of Pediatrics at Emory University School of Medicine. He is the Medical Director of the Technology-Dependent Pulmonary Program at Children's Healthcare of Atlanta.
Dr. Sorscher is a Georgia Research Alliance Eminent Scholar, the Hertz Endowed Professor in Cystic Fibrosis Research, and Professor, Department of Pediatrics at Emory University.