Cystic fibrosis triple therapy safe, tolerable for 144 weeks in older children

Key takeaways:

• Adolescents aged 12 years and older receiving cystic fibrosis triple therapy tolerated the treatment well.
• Improvements seen early on continued to be seen at week 144 of treatment.

Elexacaftor/tezacaftor/ivacaftor appeared safe and well tolerated among kids aged 12 years and older with cystic fibrosis and either F508del/minimal function or F508del/F508del genotypes for up to 144 weeks, according to study results.

Further, improvements seen in earlier studies after 4 weeks or 24 weeks of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA; Trikafta, Vertex Pharmaceuticals) treatment were sustained when assessed again at the 144-week mark of therapy, researchers wrote in the study, published in European Respiratory Journal.

“Because people with [cystic fibrosis] are likely to require long-term treatment with ELX/TEZ/IVA or similar cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimens, safety and efficacy data spanning several years, as demonstrated in this study, are crucial for making informed patient care decisions,” Cori L. Daines, MD, professor of pediatric pulmonary medicine at University of Arizona, and colleagues wrote.

In a phase 3, open-label, single-arm extension study of 24-week and 4-week phase 3 parent studies, Daines and colleagues assessed 506 children aged 12 years or older with cystic fibrosis heterozygous for F508del and a minimal function mutation (F/MF genotype; n = 399) or homozygous for F508del (F/F genotype; n = 107) treated with ELX/TEZ/IVA to determine the safety, tolerability and efficacy of the triple therapy at 144 weeks.

Researchers evaluated absolute changes in lung function, sweat chloride concentration, the Cystic Fibrosis Questionnaire-Revised respiratory domain score and BMI between parent study baseline to the end of the extension period.

These are interim results from a 192-week study, with earlier data presented at 96 weeks showing the triple therapy was safe and improved lung function, respiratory symptoms and CFTR function.

All patients received a triple therapy dose made up of 200 mg ELX once a day, 100 mg TEZ once a day and 150 mg IVA every 12 hours, according to researchers.

Primary endpoint

Over a mean treatment period of 151.1 weeks, adverse events occurred among 98.8% of children, with more than half of these events classified as moderate (60.3%) and 16.4% classified as mild. About thirty percent of children (n = 154) experienced a serious adverse event.

Infective pulmonary exacerbation (44.5%) was the most frequent adverse event, followed by cough (41.9%), headache (32.8%), oropharyngeal pain (28.9%) and nasopharyngitis (26.7%).

Researchers reported that 14 patients stopped ELX/TEZ/IVA therapy due to an adverse event. One child died, but the adverse event attributable to this outcome (accidental oxycodone toxicity) was not related to the therapy, researchers wrote.

Overall, 73 adolescents stopped receiving the triple therapy. Two main reasons for discontinuation included a switch to commercially available triple therapy (n = 24) and refusal by the child (n = 18).

Compared with data from the 24-week parent study, this extension study showed reduced exposure-adjusted rates of adverse events (586.55 vs. 1,096.01 events per 100 patient-years) and serious adverse events (22.42 vs. 36.93 events per 100 patient-years) among patients with the F/MF genotype.

Secondary endpoints

Researchers assessed children with the F/MF genotype separately from children with the F/F genotype because they came from different parent studies.

The 24-week parent study included children with the F/MF genotype, and improvements seen at this point were sustained at week 144.

When evaluating the absolute change in percent-predicted FEV₁ at week 144 vs. baseline of the parent study, researchers found a mean rise of 14.1 percentage points (95% CI, 12.6-15.6). Further, the annualized rate change in this measure of lung function was 0.08 (95% CI, –0.14 to 0.3) percentage points per year.

The pulmonary exacerbation rate per year was 0.2, according to researchers.

Patients also showed a positive change in the Cystic Fibrosis Questionnaire-Revised respiratory domain score, with an increase of 19.1 points (95% CI, 16.4-21.8), and reductions in sweat chloride concentration (mean absolute change, –47.2 mmol/L; 95% CI, –49.9 to –44.4) from baseline to week 144.

At week 144, BMI went up compared with baseline (mean absolute change, 1.61 kg/m²; 95% CI, 1.32-1.9).

For children with the F/F genotype, researchers again found that improvements seen at week 4 persisted at week 144 of treatment.

Researchers found a mean rise of 11.6 percentage points (95% CI, 9.1-14) in these adolescents when comparing the absolute change in percent-predicted FEV₁ at week 144 vs. baseline. The annualized rate change in this measure of lung function was lower than that observed among those with the F/MF genotype (0.03 percentage points; 95% CI, –0.33 to 0.39).

The pulmonary exacerbation rate in adolescents with the F/F genotype reached 0.18 per year.

Similar to those with the F/MF genotype, patients with the F/F genotype showed a positive change in in the Cystic Fibrosis Questionnaire-Revised respiratory domain score, with an increase of 18.2 points (95% CI, 13.6-22.7), and reductions in sweat chloride concentration (mean absolute change, –49.9 mmol/L; 95% CI, –54.1 to –45.7) from baseline to week 144.

This set of patients also had a higher BMI at week 144 vs. baseline (mean absolute change, 1.74 kg/m²; 95% CI, 1.36-2.12).

“The clinically meaningful improvements in measures of lung function, respiratory symptoms, CFTR function, pulmonary exacerbation rates and nutritional status reported for patients treated with ELX/TEZ/IVA in the two pivotal phase 3 studies were maintained through this longer-term analysis period,” Daines and colleagues wrote. “These results, along with the finding of no mean loss in pulmonary function over 144 weeks of treatment, further support the durable and disease-modifying benefits of ELX/TEZ/IVA.”