FDA Approves Novel Triple Combination Therapy for Cystic Fibrosis

The triple combination therapy of elexacaftor, ivacaftor, and tezacaftor, to be sold as Trikafta and developed by Vertex Pharmaceuticals, was approved today by the FDA as a novel treatment among patients with the most common cystic fibrosis mutation (F508del).

The novel therapy will be available for patients 12 years and older with cystic fibrosis who have at least 1 F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which represents approximately 90% of the cystic fibrosis population. Acting FDA Commissioner Ned Sharpless, MD, noted that this “landmark approval” will serve to provide this novel treatment to “most cystic fibrosis patients, including adolescents, who previously had no options and [give] others in the cystic fibrosis community access to an additional effective therapy.”

Cystic fibrosis is a progressive, life-threatening rare disease resulting in the formation of thick mucus that builds up in the lungs, digestive tract, and other parts of the body. These complications lead to severe respiratory and digestive problems, in addition to infections and diabetes. The triple combination therapy targets the cause of the disease, a defective protein that results from mutations in the CFTR protein and helps the protein function more effectively.

The approval comes after the FDA granted Priority Review, as well as Fast Track and Breakthrough Therapy Designation to the triple combination therapy. The therapy was additionally given orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

Efficacy of the novel therapy on patients with cystic fibrosis aged 12 years and older was shown through 2 trials:

• The first trial was a 24-week, randomized, double-blind, placebo-controlled trial in 403 patients who had F508del mutation and a mutation on the second allele resulting in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor or the combination of tezacaftor and ivacaftor alone.
• The second trial was a 4-week, randomized, double-blind, active controlled trial on 107 patients who had 2 identical F508del mutations.
• The primary analysis in both trials looked at increases in the percent predicted forced expiratory volume in 1 second, known as ppFEV₁, an established marker of cystic fibrosis lung disease progression.

Both trials exhibited the stark impact of the triple combination therapy in increasing the mean ppFEV₁ from baseline, compared to placebo for the first trial and compared to tezacaftor/ivacaftor for the second trial (first trial: 13.8% increase; second trial: 10% increase). The first trial further showcased potential through improvement in sweat chloride, number of pulmonary exacerbations, and body mass index, compared to placebo.

Prescribing information for the therapy includes warnings associated with elevated liver function tests, complications from simultaneous use of other products that are inducers or inhibitors of another liver enzyme called Cytochrome P450 3A4, and the risk of cataracts.

“In the past few years, we have seen remarkable breakthroughs in therapies to treat cystic fibrosis and improve patients’ quality of life, yet many subgroups of cystic fibrosis patients did not have approved treatment options,” said Sharpless.