The FDA today approved elexacaftor/ivacaftor/tezacaftor (Trikafta, Vertex Pharmaceuticals), a new treatment for patients 12 years of age and older with cystic fibrosis (CF) who have at least 1 F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, according to a press release.

Elexacaftor/ivacaftor/tezacaftor is the first triple combination therapy approved for this indication. Approximately 90% of patients with CF have this mutation, according to the FDA.

The 3-drug combination targets the defective CFTR protein to help the protein made by the CFTR gene mutation function more effectively.

This approval is based on efficacy and safety data from 2 clinical trials. In the first trial, the elexacaftor/ivacaftor/tezacaftor combination was evaluated in 403 patients with CF aged 12 years and older with the F508del mutation and a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor or tezacaftor/ivacaftor alone over 24 weeks. The second study evaluated 107 patients who had 2 identical F508del mutations over a 4-week period.

For both analyses, the researchers looked at increases in the percent predicted force expiratory volume in 1 second (ppFEV1), an established marker of CF lung disease progression. In both the first and second trial, elexacaftor/ivacaftor/tezacaftor demonstrated increased ppFEV1 of a mean 13.8% from baseline and 10% from baseline, respectively, compared with a placebo. The first study also showed that treatment with the combination resulted in improvements in sweat chloride, number of pulmonary exacerbations (worsening respiratory symptoms and lung function), and body mass index (weight-to-height ratio) compared with placebo.

The safety profile of elexacaftor/ivacaftor/tezacaftor, which is based on data from the 510 patients with CF in both trials, was generally similar across all subgroups of patients. The most common adverse effects observed in the studies included headaches, upper respiratory tract infections, abdominal pains, diarrhea, rashes, increased liver enzymes (alanine aminotransferase and aspartate aminotransferase), nasal congestion, increased blood creatine phosphokinase, rhinorrhea, rhinitis, influenza, sinusitis, and increased blood bilirubin.

Serious adverse effects that occurred more frequently in patients who received elexacaftor/ivacaftor/tezacaftor than those with placebo were rash and flu events.

Additionally, the prescribing information for elexacaftor/ivacaftor/tezacaftor includes warnings related to elevated liver function tests (transaminases and bilirubin), concurrent use with other products that are inducers or inhibitors of another live enzyme called Cytochrome P450 3A4, and the risk of cataracts. 

The FDA granted this application priority review, in addition to fast track and breakthrough therapy designation.

“At the FDA, we’re consistently looking for ways to help speed the development of new therapies for complex disease, while maintaining our high standards of review,” acting FDA Commissioner Ned Sharpless, MD, said in a statement. “Today’s landmark approval is a testament to these efforts, making a novel treatment available to most cystic fibrosis patients, including adolescents, who previously had no options and giving others in the cystic fibrosis community access to an additional effective therapy.”

Reference

FDA approves new breakthrough therapy for cystic fibrosis [news release]. FDA’s website. https://www.fda.gov/news-events/press-announcements/fda-approves-new-breakthrough-therapy-cystic-fibrosis. Accessed October 21, 2019.