Vanzacaftor, tezacaftor, deutivacaftor safe in children with cystic fibrosis

Key takeaways:

• Researchers deemed 24-week vanzacaftor/tezacaftor/deutivacaftor safe in 6- to 11-year-olds with cystic fibrosis.
• The FDA approved this combination therapy in late 2024 based, in part, on data from this trial.

Patients aged 6 to 11 years with cystic fibrosis receiving 24-week once-daily vanzacaftor/tezacaftor/deutivacaftor generally tolerated it well, according to data published in The Lancet Respiratory Medicine.

“Vanzacaftor-tezacaftor-deutivacaftor was safe and well tolerated and maintained FEV₁ percent predicted from elexacaftor/tezacaftor/ivacaftor baseline with further improved CFTR function,” Jordana E. Hoppe, MD, of the University of Colorado School of Medicine and Children’s Hospital Colorado, and colleagues wrote.

“Improvements in CFTR function compared with baseline elexacaftor/tezacaftor/ivacaftor values demonstrate the potential opportunity to restore normal physiology early and prevent development or progression of cystic fibrosis,” they continued.

Hoppe and colleagues analyzed 78 6- to 11-year-olds (median age, 9.3 years; 56% male; 91% white) with cystic fibrosis in the single-arm, multicenter, phase 3 RIDGELINE Trial VX21-121-105 to uncover the impact of vanzacaftor/tezacaftor/deutivacaftor (Alyftrek, Vertex Pharmaceuticals) on patient safety, percent-predicted FEV₁ and sweat chloride at 24 weeks (median exposure, 168 days).

Children had to possess a CFTR variant that was responsive to elexacaftor/tezacaftor/ivacaftor (Trikafta; Vertex Pharmaceuticals), have a percent-predicted FEV₁ of at least 60% and have stable cystic fibrosis to be included, according to the study.

Notably, the FDA recently approved Alyftrek for patients aged 6 years and older with cystic fibrosis with certain mutations based, in part, on data from this trial and the SKYLINE VX21-121-102 and -103 trials, according to a press release.

The study reported that patients previously received elexacaftor/tezacaftor/ivacaftor prior to the 24-week treatment period for either 28 days (n = 61) or during a 4-week run-in period (n = 17).

The oral, once daily, 24-week Alyftrek dose depended on patient bodyweight. Those weighing less than 40 kg took three fixed-dose combination tablets made up of 12 mg vanzacaftor, 60 mg tezacaftor and 150 mg deutivacaftor, whereas those weighing 40 kg or more took two fixed-dose combination tablets made up of 20 mg vanzacaftor, 100 mg tezacaftor and 250 mg deutivacaftor.

Safety

When assessing safety, mild or moderate adverse events occurred in 96% of children, and six children (8%) experienced a serious adverse event.

Of the recorded adverse events, cough had the highest proportion of patient reports at 46%. Researchers also found frequent reports of pyrexia (21%), headache (18%), infective pulmonary exacerbation of cystic fibrosis (17%) and oropharyngeal pain (17%).

Among those who reported a serious adverse event, the event differed for most patients. These events included infective pulmonary exacerbation (n = 2), adenovirus infection (n = 1), constipation (n = 1), reduced pulmonary function test (n = 1) and cough (n = 1), according to the study.

As a result of adverse events “considered possibly related to study drug,” researchers noted that one patient had to discontinue treatment.

Efficacy

When evaluating percent-predicted FEV₁, the difference between baseline (mean, 99.7 percentage points) and week 24 revealed no change (least squares mean absolute change, 0.0 percentage points; 95% CI, –2 to 1.9). In contrast, the study reported that sweat chloride concentrations decreased between baseline (mean, 40.4 mmol/L) and week 24 (least squares mean absolute change, –8.6 mmol/L; 95% CI, –11 to –6.3).

At the 24-week mark, a sweat chloride concentration less than 60 mmol/L was achieved by 94.9% of patients vs. 84.4% at baseline. Researchers further noted that achievement of a concentration less than 30 mmol/L was observed in 52.6% of patients at week 24 vs. 39% at baseline.

According to the study, little change occurred between baseline and week 24 for several body-related measures: BMI, weight, height, BMI-for-age z score, weight-for-age z score and height-for-age z score.

The minimum clinically important difference for the Cystic Fibrosis Questionnaire-Revised respiratory domain score (4 points) was almost reached when researchers assessed this measure at the end of the treatment period (least squares mean absolute change, 3.9 points; 95% CI, 1.5-6.3).

Lastly, lung clearance index was slightly reduced from baseline (mean, 6.63) to week 24 (least squares mean absolute change, –0.08; 95% CI, –0.18 to 0.02), according to the study.

“Additional long-term data in children with cystic fibrosis are being collected in an open-label extension study to demonstrate clinical benefits and safety,” Hoppe and colleagues wrote. “These findings will inform health care providers and people with cystic fibrosis regarding the benefits of early initiation of CFTR modulators.”