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FDA Approves Trikafta for Cystic Fibrosis

Drug combo treats genetic mutation found in 90% of patients

The FDA has approved elexacaftor/ivacaftor/tezacaftor (Trikafta, Vertex Pharmaceuticals Inc.), the first triple combination therapy for patients with the most common cystic fibrosis (CF) mutation. Trikafta is indicated for patients 12 years of age and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which represents an estimated 90% of the CF population.

CF results in the formation of thick mucus that builds up in the lungs, digestive tract, and other parts of the body, leading to severe respiratory and digestive problems as well as other complications. CF is caused by a defective protein that results from mutations in the CFTR gene. While there are approximately 2,000 known mutations of the CFTR gene, the F508del mutation is the most common.

By combining three drugs that target the defective CFTR protein, Trikafta helps the protein function more effectively. Other therapies target the defective protein, but many CF patients have mutations that are ineligible for treatment.

The efficacy of elexacaftor/ivacaftor/tezacaftor in CF patients 12 and older was demonstrated in two trials. The first trial was a 24-week, randomized, double-blind, placebo-controlled trial in 403 patients who had an 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 (Kalydeco, Vertex) or tezacaftor/ivacaftor (Symdeko, Vertex) alone. The second trial was a four-week, randomized, double-blind, active-controlled trial in 107 patients who had two identical F508del mutations.

In each trial, the primary analysis looked at increases in the percent predicted forced expiratory volume in one second (ppFEV1). In the first trial, elexacaftor/ivacaftor/tezacaftor increased mean ppFEV1 13.8% from baseline compared to placebo. In the second trial, it increased mean ppFEV1 10% from baseline compared to tezacaftor/ivacaftor. In the first trial, treatment with elexacaftor/ivacaftor/tezacaftor also improved sweat chloride, pulmonary exacerbations, and body mass index compared to placebo.

Serious adverse drug reactions that occurred more frequently in patients receiving elexacaftor/ivacaftor/tezacaftor compared to placebo were rash and influenza events. The most common adverse drug reactions included headaches, upper respiratory tract infections, abdominal pains, diarrhea, rashes, increased alanine aminotransferase and aspartate aminotransferase, nasal congestion, increased blood creatine phosphokinase, rhinorrhea, rhinitis, influenza, sinusitis, and increased blood bilirubin.

The presence of at least one F508del mutation should be confirmed using an FDA-cleared genotyping assay prior to treatment.

The FDA granted this application priority review, fast track, breakthrough therapy, and orphan drug designations. The agency reviewed and approved the drug in about three months.

Source: FDA, October 21, 2019

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