Vanzacaftor/tezacaftor/deutivacaftor (Alyftrek, Vertex Pharmaceuticals), a once-daily next-in-class triple combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been approved for the treatment of cystic fibrosis (CF) in people aged ≥6 years who have at least 1 F508del mutation or another mutation in a responsive CFTR gene.1
The approval of this first, once-daily CTFR modulator is based on phase 3 trial data, which included more than 1000 patients across more than 20 countries and more than 200 sites. These data were presented at the North American Cystic Fibrosis Conference in September 2024.
The SKYLINE 102 and 103 phase 3 studies in people with CF aged ≥12 years met their primary end point (noninferiority on absolute change from baseline in ppFEV1 compared with TRIKAFTA) and all key secondary end points (including absolute change from baseline in sweat chloride [SwCl] compared with TRIKAFTA). In the phase 3 study of children with CF aged 6-11 years, the triple combination demonstrated safety, the primary end point. Secondary end points, such as absolute change from baseline in ppFEV1 and absolute change from baseline in SwCl, were presented, supporting the benefit of the study treatment in this age group.
“In phase 3 clinical trials, across a broad range of genotypes, once-daily Alyftrek demonstrated noninferiority to TRIKAFTA in ppFEV1 response and statistically significant improvement in SwCl, a welcomed advancement for the treatment of CF,” Claire L. Keating, MD, Co-Director of the Gunnar Esiason Adult Cystic Fibrosis and Lung Program at Columbia University, and investigator in the therapy’s clinical trial program, noted in a statement about the approval.1
CF is a rare, life-shortening genetic disease affecting more than 92,000 people globally. CF is a progressive, multiorgan disease that affects the lungs, liver, pancreas, GI tract, sinuses, sweat glands, and reproductive tract. CF is caused by a defective and/or missing CFTR protein resulting from certain mutations in the CFTR gene. Children must inherit 2 defective CFTR genes—1 from each parent—to have CF, and these mutations can be identified by a genetic test. While there are many different types of CFTR mutations that can cause the disease, most people with CF have at least 1 F508del mutation. CFTR mutations lead to CF by causing CFTR protein to be defective or by leading to a shortage or absence of the CFTR protein at the cell surface. The defective function and/or absence of CFTR protein results in poor flow of salt and water into and out of the cells in a number of organs. In the lungs, this leads to the buildup of abnormally thick, sticky mucus, chronic lung infections, and progressive lung damage that eventually leads to death for many patients. The median age of death is in the 30s, but with treatment, projected survival is improving.
Reference
- Vertex Pharmaceuticals. Vertex announces US FDA approval of Alyftrek, a once-daily next-in-class CFTR modulator for the treatment of cystic fibrosis [press release]. Published December 20, 2024. Accessed January 31, 2025. https://news.vrtx.com/news-releases/news-release-details/vertex-announces-us-fda-approval-alyftrektm-once-daily-next