FDA approves Alyftrek, once-daily triple-combination therapy for CF
Alyftrek designed for better efficacy, more convenient dosing than Trikafta
A new triple-combination CFTR modulator therapy — vanzacaftor, tezacaftor, and deutivacaftor — has been approved by the U.S. Food and Drug Administration (FDA).
The therapy, which developer Vertex Pharmaceuticals will market under the name Alyftrek, is indicated for cystic fibrosis (CF) in patients 6 and older who carry at least one copy of a mutation that’s responsive to the therapy, including the most common CF-causing mutation called F508del.
“Alyftrek is our fifth CFTR modulator to secure FDA approval and represents another significant milestone in our journey to serially innovate and to improve the lives of people living with cystic fibrosis,” Reshma Kewalramani, MD, president and CEO of Vertex, said in a company press release.
CF is caused by mutations in the CFTR gene, which provides instructions to make a protein, also called CFTR, that is essential for regulating the production of mucus. Mutations in the gene lead to dysfunction or absence of this protein and, as a result, the body makes unusually thick and sticky mucus that builds up in organs, driving most CF symptoms. Dysfunction of the CFTR protein also leads to excessively high levels of chloride (a salt molecule, half of sodium chloride or table salt) in sweat.
CFTR modulators are a type of therapy that can improve the functionality of the mutated CFTR protein in people with CF whose disease is caused by specific mutations in the CFTR gene.
Alyftrek is a next-generation successor to Trikafta
The new triple-combination therapy was developed as a next-generation successor to Trikafta (elexacaftor/tezacaftor/ivacaftor), a modulator therapy made by Vertex that’s widely approved for patients with F508del and other responsive mutations. The new therapy includes tezacaftor, one of the modulators that’s contained in Trikafta, in combination with two new modulators called vanzacaftor (VX-121) and deutivacaftor (VX-561).
Alyftrek was designed for better efficacy and more convenient dosing — once per day — than Trikafta, which is taken twice daily.
“Our north star for more than 20 years has been to address the underlying cause of cystic fibrosis, treat more people with this disease, and bring more people to normal levels of CFTR function — Alyftrek, with once-daily dosing, efficacy in 31 additional mutations, and lower sweat chloride levels than Trikafta, is another step in achieving this goal,” Kewalramani said.
Common side effects of Alyftrek include cough, sinus congestion, respiratory infections, headache, throat pain, fatigue, rash, and increases in markers of liver damage. The therapy includes a boxed warning noting that it can cause severe or life-threatening liver damage, so monitoring of liver health is required for patients taking it, and the medication is not recommended for patients with moderate or severe liver impairment.
Vertex’s application seeking FDA approval of the new treatment was based on data from three Phase 3 clinical trials: the SKYLINE 103 (NCT05076149) and SKYLINE 102 (NCT05033080) studies, which enrolled CF patients 12 and older, and an ongoing study (NCT05422222) in children ages 1 to 11. The ongoing study is still enrolling children at a few sites in the U.S.
All three trials tested the new treatment against Trikafta, and results showed the next-generation treatment was better at reducing sweat chloride levels, which implies greater ability to boost CFTR protein function. Patients given either treatment generally had stable lung function measures, and safety findings were comparable as well.
“In Phase 3 clinical trials, across a broad range of genotypes, once-daily Alyftrek demonstrated non-inferiority to Trikafta in ppFEV1 [a lung function measurement] response and statistically significant improvement in [sweat chloride], a welcomed advancement for the treatment of CF,” said Claire L. Keating, MD, an investigator in the Alyftrek clinical trial program at Columbia University. “Alyftrek has the potential to improve the care of patients with CF.”
Alyftrek is under regulatory review in the European Union, the U.K., Canada, Switzerland, Australia, and New Zealand.
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