FDA Approves Triple Therapy to Treat Cystic Fibrosis

The US Food and Drug Administration (FDA) has approved Trikafta (elexacaftor/ivacaftor/tezacaftor), the first ever triple combination therapy to treat patients with the most common cystic fibrosis mutation.

The approval gives a new treatment option for patients 12 years and older with at least 1 f508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is estimated to include approximately 90% of the cystic fibrosis population.

“At the FDA, we’re consistently looking for ways to help speed the development of new therapies for complex diseases, 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.”

The drug is a combination of 3 drugs that target the defective CFTR protein by helping the protein made by the CFTR gene mutation function more effectively.

Cystic fibrosis is a rare, progressive, life-threatening disease that results in the formation of thick mucus build up in the lung, digestive tract, and other parts of the body that lead to severe respiratory and digestive problems, as well as other complications including infections and diabetes.

The disease is caused by a defective protein that results from mutations in the CFTR gene.

While there are medications currently available to target the defective protein, many patients with cystic fibrosis have mutations that are ineligible for treatment.

Investigators tested the efficacy of Trikafta in a pair of trials. The first trial was a 24-week, randomized, double-blind, placebo-controlled trial involving 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 or tezacaftor/ivacaftor alone.

The second trial was a 4-week randomized, double-blind, active-controlled trial involving 107 patients who had 2 identical F508del mutations.

The primary analysis in each trial looked at increases in the percent predicted forced expiratory volume in 1 second, known as ppFEV₁, which is an established marker of cystic fibrosis lung disease progression. The combination therapy increased ppFEV₁ in both trials.

In the first trial, it increased mean ppFEV1 13.8% from baseline compared to placebo and in the second trial, it increased mean ppFEV1 10% from baseline compared to tezacaftor/ivacaftor.

In the first trial, treatment with Trikafta also resulted in improvements in sweat chloride, number of pulmonary exacerbations, and body mass index compared to placebo.

The safety profile of the drug was generally similar across all subgroups of patients. Serious adverse drug reactions that occurred more frequently in patients receiving Trikafta were rash and influenza events.

The most common adverse drug reactions included headaches, upper respiratory tract infections, abdominal pains, diarrhea, rashes, and increased liver enzymes.

Some of the other common adverse drug reactions were nasal congestion, increased blood creatine phosphokinase, rhinorrhea, rhinitis, influenza, sinusitis and increased blood bilirubin.

The prescribing information for Trikafta includes warnings related to elevated liver function tests (transaminases and bilirubin), use at the same time with other products that are inducers or inhibitors of another liver enzyme called Cytochrome P450 3A4 (CYP3A), and the risk of cataracts.