The US Food and Drug Administration (FDA) has approved the first triple combination therapy to treat patients with the most common cystic fibrosis (CF) mutation.
Vertex Pharmaceuticals' Trikafta combines elexacaftor, ivacaftor, and tezacaftor and is approved for patients age 12 years or older with CF and at least one F508del mutation in the CF transmembrane conductance regulator (CFTR) gene. This mutation is estimated to affect 90% of the population with CF, or roughly 27,000 people, in the United States.
The ivacaftor/tezacaftor combination (Symdeko, Vertex) is already approved in the US to treat children as young as 6 years with CF and two copies of the F508del mutation in the CFTR gene, as reported by Medscape Medical News.
The "landmark" approval of the elexacaftor/ivacaftor/tezacaftor combination makes a novel treatment available to most CF patients, "including adolescents, who previously had no options, and giving others in the cystic fibrosis community access to an additional effective therapy," Ned Sharpless, MD, acting FDA commissioner, said in a statement.
“The incredible speed of this approval underscores our shared sense of urgency with the CF community for bringing this medicine to eligible people with CF, particularly those without a medicine targeting the underlying cause of their disease,” Reshma Kewalramani, MD, chief medical officer at Vertex, said in a company news release.
The efficacy of elexacaftor/ivacaftor/tezacaftor in patients with CF aged 12 years or older was demonstrated in two trials. The first was a 24-week, randomized, double-blind, placebo-controlled trial in 403 patients who had a 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.
The second trial was a 4-week, randomized, double-blind, active-controlled trial in 107 patients who had two identical F508del mutations.
In both trials, the triple combination led to an increase in percent predicted forced expiratory volume in one second (ppFEV1), an established marker of CF lung disease progression.
In the first trial, it increased mean ppFEV1 13.8 percentage points from baseline compared with placebo. In the second trial, it increased mean ppFEV1 10 percentage points from baseline compared with the tezacaftor/ivacaftor combination.
In the first trial, the combined treatment of elexacaftor/ivacaftor/tezacaftor also led to improvements in sweat chloride, number of pulmonary exacerbations, and body mass index compared with placebo.
The most common adverse reactions in patients taking the triple combination included headache, upper respiratory tract infection, abdominal pains, diarrhea, rashes, increased liver enzymes, nasal congestion, increased blood creatine phosphokinase, rhinorrhea, rhinitis, influenza, sinusitis, and increased blood bilirubin.
The prescribing information includes warnings related to elevated liver function tests, concurrent use with other products that are inducers or inhibitors of cytochrome P450 3A4 (CYP3A), and the risk of cataracts.
The elexacaftor/ivacaftor/tezacaftor combination had fast track, breakthrough therapy and orphan drug designation and received priority review, a regulatory process reserved for medicines that represent potentially significant improvements in safety or efficacy in treating serious conditions.
Cite this: FDA OKs First Triple Combo Therapy for Cystic Fibrosis (Trikafta) - Medscape - Oct 21, 2019.