Next-generation CF treatment found safe for kids as young as 2

The next-generation triple-combination CFTR modulator Alyftrek can be safely given to children with cystic fibrosis (CF) as young as 2, according to results from a Phase 3 clinical trial.

Findings from the trial also suggest that Alyftrek can improve CFTR activity in kids who switch from the first-generation triple-modulator therapy, Trikafta. The trial’s sponsor — Vertex Pharmaceuticals, which markets both Alyftrek and Trikafta — presented the study results earlier this year. Now, the findings have undergone peer review, the process in which independent scientists look through the data.

Final results from the trial were published in The Lancet Respiratory Medicine, in a paper titled, “Safety and efficacy of vanzacaftor–tezacaftor–deutivacaftor in children with cystic fibrosis aged 2–5 years (TIMBERLINE Trial VX21-121-105): a phase 3, open-label study.”

CF is a genetic disorder in which CFTR, a protein that helps control mucus production, is defective or entirely absent. Lacking functional CFTR protein, people with CF produce abnormally thick, sticky mucus that builds up in the lungs and other organs to drive CF symptoms. Low CFTR activity also leads to high levels of chloride (a type of salt molecule) in sweat. This is why sweat chloride levels are often measured to assess CFTR activity.

CFTR modulators are a recently developed class of medications that can improve the activity of defective CFTR protein in people who carry certain mutations. By improving the defective protein’s function, these therapies can help normalize mucus production and ease symptoms.

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Evaluating Alyftrek

Trikafta (elexacaftor/tezacaftor/ivacaftor) is the first triple-combination modulator therapy to be widely available. In the U.S., it’s approved to treat people with CF as young as 2 who carry a responsive mutation, including the most common CF-causing mutation called F508del.

Alyftrek (vanzacaftor/tezacaftor/deutivacaftor) contains two novel modulators, alongside one of the same therapies used in Trikafta. It aims to offer similar or better CFTR activity as well as more convenient dosing; it’s given  once daily instead of twice daily, as with Trikafta. Alyftrek is approved in the U.S. to treat CF patients with eligible mutations ages 6 and older. It’s similarly approved in other countries, including Canada, the U.K., and the European Union.

To evaluate the safety and efficacy of Alyftrek in younger children with CF, Vertex funded a Phase 3 study called TIMBERLINE (NCT05422222). In the first part, 20 children ages 2 to 5 were given Alyftrek for about three weeks, with the main goal of evaluating safety and confirming the optimal dose for further testing.

The second, main part of the study involved 67 kids with CF ages 2 to 5 who were taking Trikafta. These patients all switched from Trikafta to Alyftrek, which they continued to take for at least six months at a dose determined based on body weight.

The primary goal was to evaluate safety, and results were positive: No treatment-related serious side effects were reported, and safety data were in line with the therapy’s known profile in older children and adults. Common side effects of Alyftrek include respiratory infections, cough, headache, rash, congestion, and fever.

Analyses of sweat chloride showed that mean levels decreased by 9.6 millimole per liter (mmol/L) in six months after switching from Trikafta to Alyftrek.

A sweat chloride level of 60 mmol/L or higher is considered to definitively indicate CF, while levels between 30 mmol/L and 60 mmol/L are considered possible CF. With Trikafta, most patients (86%) had achieved levels below 60 mmol/L, but only about a third (38%) achieved levels below 30 mmol/L. After six months on Alyftrek, however, nearly all (92%) evaluable children had sweat chloride levels below 60 mmol/L, and about two-thirds (65%) had levels below 30 mmol/L.

“These results show that [Alyftrek] treatment can lead to sweat chloride concentrations typically seen in [people who don’t have CF]  in more children with cystic fibrosis than [Trikafta],” the researchers wrote. They noted that long-term studies are needed to assess the clinical impact of this difference in CFTR protein function.

Average scores on tests of lung function and pancreas health were generally within normal ranges while patients were on Trikafta, and remained within normal ranges after switching to Alyftrek. Growth trends were also generally within normal ranges.

“There were no new safety signals identified from the profile established in older trial participants, establishing [Alyftrek] as a safe and generally well tolerated once-daily CFTR modulator that offers a more substantial correction of the underlying cause of cystic fibrosis,” the scientists wrote.