Next-in-Class Once-Daily Pill Approved for Cystic Fibrosis

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CFTR modulator carries boxed warning over risk of drug-induced liver injury and liver failure

by
Ian Ingram, Managing Editor, MedPage Today
December 20, 2024

The FDA approved a once-daily oral combination of vanzacaftor/tezacaftor/deutivacaftor (Alyftrek) for cystic fibrosis (CF) in adults and children 6 years and up, drugmaker Vertex Pharmaceuticals announced on Friday.

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Eligible patients must have at least one mutation in F508del or another responsive mutation in the CFTR gene. Of note, the CFTR modulator carries a boxed warning over the risk of drug-induced liver injury and liver failure.

According to Vertex, the next-in-class drug is active against an additional 31 mutations in the CFTR gene, meaning that for the first time, an estimated 150 CF patients in the U.S. will be eligible for a CFTR modulator.

Approval was based on a large phase III trial program that included more than 1,000 patients across 20 nations. Studies in CF patients ages 12 years and up — SKYLINE 102 and SKYLINE 103 — showed that vanzacaftor/tezacaftor/deutivacaftor proved non-inferior to elexacaftor/tezacaftor/ivacaftor (Trikafta) when it came to the absolute change at week 24 in percent predicted forced expiratory volume in 1 second (ppFEV1), the primary endpoint. The trials also met their key secondary endpoints, including greater changes in sweat chloride (SwCl) with vanzacaftor/tezacaftor/deutivacaftor.

In RIDGELINE 105, a phase III trial for CF patients ages 6 to 11 years, the new triplet combination proved safe, the study’s main endpoint, with changes in ppFEV1 and SwCl supportive of clinical benefit.

“In phase III clinical trials, across a broad range of genotypes, once-daily Alyftrek demonstrated non-inferiority to Trikafta in ppFEV1 response and statistically significant improvement in SwCl, a welcomed advancement for the treatment of CF,” said investigator Claire Keating, MD, of Columbia University in New York City, in a statement. “Alyftrek has the potential to improve the care of patients with CF.”

As CFTR modulators need to be taken with fat-containing food, the new once-daily option is expected to be more convenient for patients as well.

Common adverse events (AEs) noted in the labeling for vanzacaftor/tezacaftor/deutivacaftor (occurring in at least 5% of patients and at a more frequent rate than the comparator drug) included cough, nasopharyngitis, upper respiratory tract infection, headache, oropharyngeal pain, influenza, fatigue, increased liver enzymes, rash, and sinus congestion.

The drug should not be used in patients with severe liver impairment. Baseline liver testing and ophthalmological examinations are recommended.

Beyond the liver risks, the warnings and precautions section of the prescribing information includes notes about hypersensitivity reactions, reduced effectiveness in patients on CYP3A inducers, AEs associated with concomitant use of a CYP3A inhibitor, and cataracts.