Vanzacaftor, tezacaftor, deutivacaftor similar to current cystic fibrosis standard of care

Key takeaways:

• Percent-predicted FEV₁, sweat chloride and safety were analyzed in two phase 3 trials of vanzacaftor/tezacaftor/deutivacaftor.
• This triple combination therapy received FDA approval on Dec. 20.

Among individuals aged at least 12 years with cystic fibrosis, receipt of vanzacaftor/tezacaftor/deutivacaftor was similar or better than Trikafta depending on the endpoint, according to results published in The Lancet Respiratory Medicine.

“These results demonstrate the potential for vanzacaftor-tezacaftor-deutivacaftor to further improve the lives of people with cystic fibrosis by limiting disease manifestation in those who are younger and preventing progression of disease in adults,” Claire Keating, MD, associate director of the Gunnar Esiason Adult Cystic Fibrosis and Lung Program at Columbia University Irving Medical Center, and colleagues wrote.

Keating and colleagues analyzed 398 patients (median age, 31 years; 59% male; 97% white) with cystic fibrosis aged at least 12 years who possessed the F508del-minimal function mutation in the randomized, active-controlled, double-blind phase 3 SKYLINE Trial VX21-121-102 to uncover how vanzacaftor/tezacaftor/deutivacaftor (Alyftrek, Vertex Pharmaceuticals) impacts percent-predicted FEV₁ vs. Trikafta (elexacaftor/tezacaftor/ivacaftor, Vertex Pharmaceuticals) across 52 weeks.

Researchers assessed the same outcome in 573 patients (median age, 33.1 years; 51% male; 93% white) with cystic fibrosis aged at least 12 years in the randomized, active-controlled, double-blind phase 3 SKYLINE Trial VX21-121-103, but these patients possessed one of the following genotypes: F508del-F508del, F508del-residual function, F508del-gating or elexacaftor-tezacaftor-ivacaftor-responsive-non-F508del.

As Healio previously reported, the FDA recently approved Alyftrek for patients aged 6 years and older with cystic fibrosis with certain mutations based, in part, on data from these trials, according to a press release.

Notably, before the 52-week period, the study reported that patients received two fixed-dose combination tablets in the morning (200 mg elexacaftor once daily, 100 mg tezacaftor once daily and 150 mg ivacaftor once every 12 hours) and an ivacaftor tablet in the evening for 4 weeks.

After this timeframe, 202 patients in the -102 trial continued to receive the above regimen, whereas the remaining 196 patients shifted to two once-daily fixed-dose combination tablets in the morning made up of 20 mg vanzacaftor, 100 mg tezacaftor and 250 mg deutivacaftor.

For patients in the -103 trial, 289 received Trikafta and 284 received Alyftrek over 52 weeks, according to the study.

In both trials, researchers observed “non-inferiority” in percent-predicted FEV₁ with Alyftrek vs. Trikafta at week 24 (least squares mean treatment difference, Trial -102, 0.2 percentage points; 95% CI, –0.7 to 1.1; Trial -103, 0.2 percentage points: 95% CI, –0.5 to 0.9; both P < .0001).

Patients in the Alyftrek groups of both trials also experienced more improved sweat chloride concentrations vs. patients in the Trikafta groups at the 24-week mark (least squares mean treatment difference, Trial -102, –8.4 mmol/L; 95% CI, –10.5 to –6.3; P < .0001; Trial -103, –2.8 mmol/L: 95% CI, –4.7 to –0.9; P = .0034), according to the study.

At this time point, a sweat chloride concentration less than 60 mmol/L was achieved by 86% of all patients receiving Alyftrek and 77% of all patients receiving Trikafta. The study further reported that achievement of a concentration less than 30 mmol/L was observed in 31% of patients receiving Alyftrek and 23% of patients receiving Trikafta.

When assessing safety, a comparable proportion of those receiving Alyftrek and those receiving Trikafta experienced an adverse event (96% in each of the pooled groups), with mild or moderate as common severity classifications and serious adverse events occurring less often (Alyftrek , 14% vs. Trikafta, 16%).

Researchers found frequent reports of infective pulmonary exacerbation among those receiving Alyftrek and those receiving Trikafta (28% vs. 32%).

Other adverse events occurring in around 20% of both the Alyftrek group and the Trikafta group included cough (23% vs. 21%), COVID-19 (22% vs. 26%) and nasopharyngitis (21% vs. 19%), according to the study.

As a result of adverse events, researchers noted that both groups had 18 patients who had to discontinue their assigned treatment.

“Vanzacaftor-tezacaftor-deutivacaftor may have the potential to further restore CFTR function in a broader population compared with elexacaftor-tezacaftor-ivacaftor; however, these in-vitro findings will need to be confirmed in real-world studies to establish benefits in people with cystic fibrosis with these variants,” Keating and colleagues wrote.