Alyftrek improved CFTR function in young children with CF

Alyftrek, a next-generation triple-combination CFTR modulator, further improved the function of the defective CFTR protein in children ages 2 to 5 with cystic fibrosis (CF) who switched from Trikafta, new clinical trial data suggest.

Vertex Pharmaceuticals, the company that markets both Alyftrek and Trikafta, presented the findings at the European Cystic Fibrosis Conference.

“The data we’re presenting today bring us to the cusp of our 25-year mission to advance medicines that restore CFTR function to people living with CF,” Carmen Bozic, MD, executive vice president of global medicines development and medical affairs, and chief medical officer at Vertex, said in a company press release.

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CF is caused by mutations in the gene that encodes CFTR, a protein that helps control the movement of water and chloride ions, a type of salt particle, in and out of cells. This is key for allowing the body to produce watery, slippery mucus; in people with CF, a lack of functional CFTR leads to the production of unusually thick and sticky mucus that builds up in organs to drive most disease symptoms.

CFTR modulators are medications that can increase the defective protein’s functionality in people with CF caused by certain mutations. Trikafta contains a combination of three modulators — elexacaftor, tezacaftor, and ivacaftor. Alyftrek (vanzacaftor/tezacaftor/deutivacaftor) contains one of the same modulators used in Trikafta and also two new modulators; it was developed with the aim of providing similar or better efficacy and more convenient dosing — once per day — than Trikafta, which is taken twice daily.

In the U.S., Trikafta is indicated for CF patients ages 2 and older with eligible mutations, while Alyftrek is approved for patients with eligible mutations ages 6 and older.

The new data come from an open-label Phase 3 clinical trial testing Alyftrek in children with CF. The data specifically center on 67 children with CF, ages 2 to 5, who carried at least one copy of F508del, the most common CF-causing mutation, and had previously been on Trikafta. In the study, all these children switched to treatment with Alyftrek for about six months. The main goal was to evaluate Alyftrek’s safety in young children, and safety data were overall consistent with the therapy’s known profile in older patients.

To evaluate CFTR protein function, the researchers measured sweat chloride levels. These levels are usually less than 30 millimoles per liter (mmol/L), but they become abnormally high when CFTR isn’t working correctly. Data showed average sweat chloride levels decreased by 9.6 mmol/L after children switched from Trikafta to Alyftrek, indicating further improvement in CFTR function from a Trikafta baseline in this study.

Most children reached lower sweat chloride levels

In fact, almost all (92%) of the children achieved sweat chloride levels lower than 60 mmol/L, the diagnostic threshold for CF, and nearly two-thirds (65%) achieved levels lower than 30 mmol/L.

“ALYFTREK is the first medicine to bring the majority of children ages 2 to 11 to [sweat chloride levels] below 30 mmol/L, which is incredibly exciting because [sweat chloride less than] 30mmol/L is the median value seen in carriers who are known to have normal health and is a key marker of restoration of CFTR function,” Bozic said.

“As someone who has been treating people with CF for more than 20 years and whose center is involved in the ALYFTREK 2 to 5 years clinical program, I have seen firsthand how the medicine can help patients achieve better CFTR function through reduction in sweat chloride and improve other important markers of disease,” said Marcus A. Mall, MD, of the Cystic Fibrosis Center at Charité Universitätsmedizin Berlin. “The findings add to the evidence base exploring CFTR modulation in very young children with cystic fibrosis. Taken together with existing data, these results underscore the rationale for studying treatments that aim to restore CFTR function as early as possible in the disease course.”

At the same conference, Vertex also presented data from a Phase 3 study (NCT05882357) that tested Trikafta in children with CF who were at least 1 year old but younger than 2. In these young children, Trikafta’s safety profile was consistent with its established profile in older patients, and the treatment reduced mean sweat chloride levels by 71.8 mmol/L after six months. By the end of the study, 98% of children had sweat chloride levels lower than 60 mmol/L, and 68.6% had levels lower than 30 mmol/L.

Vertex also noted that it is working toward global regulatory approvals for Alyftrek in children ages 2 to 5 and has begun global regulatory submissions to expand Trikafta treatment to children ages 1 to under 2.