New treatment may benefit approximately 90% of patients with cystic fibrosis, many of whom had no approved therapeutic options.
The US Food and Drug Administration (FDA) approved on October 21, 2019, a drug named Trikafta (elexacaftor/ivacaftor/tezacaftor), the first triple combination therapy available to treat patients with the most common cystic fibrosis mutation.
Trikafta is approved for patients aged 12 years or over with cystic fibrosis who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is estimated to represent roughly 90% of the population with cystic fibrosis. However, in Brazil, the drug still needs to be approved by the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária, ANVISA) so that it can be submitted to the National Committee for the Incorporation of New Technologies into the Brazilian Unified Health System (Sistema Único de Saúde, SUS) and then, if incorporated, be available via SUS. Nonetheless, FDA approval is an important first step to make it available to patients worldwide. There are no deadlines for these steps yet, but we will inform you of any updates. In addition, it is worth noting that only the physician can inform the patient of a possible indication for treatment. Only the health care team can determine whether the patient is eligible and will benefit from this or any other medication.
“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. 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,” said acting FDA Commissioner, Dr. Ned Sharpless. “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. That’s why we used all available programs, including Priority Review, Fast Track, Breakthrough Therapy, and orphan drug designation, to help advance today’s approval in the most efficient manner possible, while also adhering to our high standards. The FDA remains committed to advancing novel treatment options for areas of unmet patient need, particularly for diseases affecting children.”
Cystic fibrosis is a rare disease resulting in the formation of thick mucus that builds up in the lungs, digestive tract, and other parts of the body. This leads to severe respiratory and digestive problems as well as other complications such as infections and diabetes. Cystic fibrosis 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 most common is the F508del mutation.
Trikafta is a combination of three drugs targeting the defective CFTR protein. It helps the protein produced by the CFTR gene mutation function more effectively. Currently available therapies targeting the defective protein are treatment options for some patients with cystic fibrosis, but many patients have mutations that are ineligible for treatment. Trikafta is the first approved treatment that is effective for patients aged 12 years or over with cystic fibrosis with at least one F508del mutation, which affects 90% of the population with cystic fibrosis, or approximately 27,000 people in the US.
The efficacy of Trikafta in patients aged 12 years or over with cystic fibrosis was demonstrated in two studies. The first study was a 24-week, randomized, double-blind, placebo-controlled trial in 403 patients with one F508del mutation and one mutation in the second allele, which results in either no CFTR protein or a CFTR protein not responsive to ivacaftor or tezacaftor/ivacaftor alone. The second study was a 4-week, randomized, double-blind, active-controlled trial in 107 patients with two identical F508del mutations.
In each trial, the primary analysis examined increases in percent predicted forced expiratory volume in one second, known as ppFEV1, which is an established marker for cystic fibrosis lung disease progression. Trikafta increased ppFEV1 in both studies. In the first study, it increased mean ppFEV1 by 13.8% from baseline compared with placebo. In the second study, it increased mean ppFEV1 by 10% from baseline compared with tezacaftor/ivacaftor. In the first study, treatment with Trikafta also improved sweat chloride, number of lung exacerbations (worsening respiratory symptoms and lung function), and body mass index (weight-to-height ratio) compared with placebo.
The safety profile of Trikafta is based on data from the 510 patients with cystic fibrosis in the two trials. The safety profile was generally similar across all patient subgroups. Severe adverse drug reactions that occurred most frequently in patients receiving Trikafta compared with placebo were rash and flu events. The most common adverse drug reactions were headache, upper respiratory tract infections, abdominal pain, diarrhea, rash, increased liver enzymes (alanine aminotransferase and aspartate aminotransferase), nasal congestion, increased blood creatine phosphokinase (an enzyme that can be associated with muscle damage), rhinorrhea (mucus in the nasal cavity), rhinitis (swelling of the mucous membrane of the nose), flu, sinusitis, and increased blood bilirubin (which may be caused by problems involving the liver, gallbladder, or red blood cells).
The prescribing information for Trikafta includes warnings related to elevated liver function tests (transaminases and bilirubin), concomitant use of other products that induce or inhibit another liver enzyme named cytochrome P450 3A4 (CYP3A), and risk of cataracts. Before starting treatment, patients and caregivers should speak with a health care professional about these risks and any medications they take.
Patients with cystic fibrosis should speak with a health care professional and have tests performed to understand which gene mutations they have. The presence of at least one F508del mutation should be confirmed with an FDA-approved genotyping assay prior to treatment. The safety and effectiveness of Trikafta in patients under 12 years of age with cystic fibrosis have not been established.
The FDA granted this application Priority Review, in addition to Fast Track and Breakthrough Therapy Designation. Trikafta also received orphan drug designation, which provides incentives to assist and promote the development of drugs for rare diseases. Drugs approved under expedited programs are held to the same standards as other FDA approvals. Because of Trikafta’s benefit to the cystic fibrosis community, the FDA reviewed and approved this drug in approximately three months, ahead of the March 19, 2020 review goal date. The approval of Trikafta was granted to Vertex Pharmaceuticals Incorporated, which will receive a Rare Pediatric Disease Priority Review Voucher for developing this therapy.
About the FDA: The FDA, an agency within the US Department of Health and Human Services, protects public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency is also responsible for the safety and security of the supply of foods, cosmetics, dietary supplements, and products that emit electronic radiation, and for the regulation of tobacco products in the US.
And in Brazil?
The next step after FDA approval is for the drug to be approved and registered by ANVISA. This step has no deadline yet.
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Source: Food and Drug Administration (https://www.fda.gov/news-events/press-announcements/fda-approves-new-breakthrough-therapy-cystic-fibrosis ), complemented by Unidos pela Vida Team (www.unidospelavida.org.br).
Translated by: Vera Carvalho, volunteer translator for Instituto Unidos pela Vida. Vera is a professional translator specializing in scientific translation (carvalho.vera.carvalho@gmail.com).
Revised and complemented by: Verônica Stasiak Bednarczuk de Oliveira, psychologist – CRP registration number 08/16.156, specialist in behavior analysis, founder and general director of Unidos pela Vida – Brazilian Institute for Cystic Fibrosis Awareness, member of the Brazilian Cystic Fibrosis Study Group, was diagnosed with CF at 23 years of age.
Note: The information contained herein is strictly educational in nature. Under no circumstances do they intend to replace medical appointments, examinations, and/or treatments. If you have any questions, please contact your physician
15/02/2020