Safety, improved outcomes with cystic fibrosis triple therapy maintained through 96 weeks

Safety and improvements in lung function, respiratory symptoms and CFTR function with elexacaftor/tezacaftor/ivacaftor were maintained through 96 weeks of treatment in patients with cystic fibrosis and at least one F508del allele.

At the North American Cystic Fibrosis Conference, Cori L. Daines, MD, professor, division chief and director at the Cystic Fibrosis Center at University of Arizona and Banner Health, presented 96-week interim results from an ongoing open-label extension study of elexacaftor/tezacaftor/ivacaftor (Trikafta, Vertex Pharmaceuticals). Improvements with triple therapy in pivotal phase 3 trials previously reported were maintained in the open-label extension. Analyses will continue through 192 weeks.

The open-label extension study included 506 participants with cystic fibrosis aged 12 years and older (mean age, 26.7 years; 49.6% female) with F508del and a minimal function mutation (n = 399) or who were homozygous for F508del (n = 107) from the phase 3 pivotal parent studies. All participants received at least one dose of elexacaftor/tezacaftor/ivacaftor and enrolled in the open-label extension study.

Nearly 500 participants (n = 498) experienced at least one adverse event. Most reported adverse events were mild (23.3%) or moderate (58.5%). Exposure-adjusted adverse event rates were similar (2.6 per year vs. 2 per year) and serious adverse events were lower (22.5 per year vs. 67 per year) were lower in the extension study compared with the placebo group in the parent study that included participants who were heterozygous for F508del and a minimal function mutation.

Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels greater than three times the upper limit of normal were reported in 9.9% of participants, ALT/AST levels greater than five times the upper limit of normal in 4.9% and ALT/AST levels greater than eight times the upper limit of normal in 1.8%. Two participants had levels at least three times the upper limit of normal and bilirubin levels at least two times the upper limit of normal. Rash events were reported in 14.6% of participants.

There were no new safety findings observed in the 96-week analysis, Daines said during the presentation.

Improvements in percent predicted FEV₁, CFTR function as assessed by decreases in sweat chloride concentrations, Cystic Fibrosis Questionnaire-Revised respiratory domain scores and BMI were maintained at 96 weeks.

The estimated pulmonary exacerbation rate per 48 weeks was 0.21 for participants with F508del/minimal function genotype compared with 0.98 in the placebo group of the F508del/minimal function genotype parent study. For participants with the F508del/F508del genotype, the estimated pulmonary exacerbation rate per 48 weeks was 0.21 for the 96-week interim analysis, according to the results.

In a post hoc analysis, the annualized rate of change in percent predicted FEV₁ was 0.28 points, Daines said.

“Elexacaftor/tezacaftor/ivacaftor is generally safe and well tolerated, with no new safety findings. Week 96 interim results of this open-label extension study are generally consistent with the previously established safety profile of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis greater than or equal to 12 years of age and at least one F508del allele,” Daines said. “Clinically meaningful improvements in lung function, respiratory symptoms and CFTR function assessed as decreases in sweat chloride concentration observed in the parent studies were maintained through an additional 96 weeks of elexacaftor/tezacaftor/ivacaftor treatment.”

Further, Daines said, “the positive annualized mean rate of change and percent predicted FEV₁ indicates no loss of pulmonary function on average across the study population through the 96-week treatment period. Prevention of lung function decline has not previously been demonstrated for any CFTR modulator.”