FDA Approves New Breakthrough Therapy for Cystic Fibrosis
Treatment approved for approximately 90 percent of patients with cystic fibrosis, many of whom had no approved therapeutic options
The U.S. Food and Drug Administration today approved 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 12 years and older with cystic fibrosis who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is estimated to represent 90 percent of the cystic fibrosis population.
Ann & Robert H. Lurie Children’s Hospital of Chicago participated in one of the clinical trials that established efficacy of Trikafta for children 12-18 years old. The trial results showed a significant improvement in lung function, body weight, and quality of life in patients taking the drug combination compared to placebo.
“The approval of this drug combination is a huge step forward in cystic fibrosis care,” says Susanna McColley, MD, Principal Investigator at Lurie Children’s and Professor of Pediatrics at Northwestern University Feinberg School of Medicine. “Until now, patients with only one copy of F508del mutation had no treatment that targets the underlying genetic defect in cystic fibrosis. This represents about 40 percent of patients with cystic fibrosis in the United States. While nearly 50 percent of U.S. patients with cystic fibrosis have two copies of the F508del mutation, previously available treatments have less benefit than this new drug combination.”
The newly approved drug combination is currently under study in children 6-11 years old. Dr. McColley is the Global Lead Co-Principal Investigator on this clinical trial, as well as the Site Principal Investigator at Lurie Children’s.
“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 Ned Sharpless, M.D. “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, a rare, progressive, life-threatening disease, results in the formation of thick mucus that builds up in the lungs, digestive tract, and other parts of the body. It 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 mutation is the F508del mutation.
Trikafta is a combination of three drugs that target the defective CFTR protein. It helps the protein made by the CFTR gene mutation function more effectively. Currently available therapies that target 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 cystic fibrosis patients 12 years and older with at least one F508del mutation, which affects 90 percent of the population with cystic fibrosis or roughly 27,000 people in the United States.
The efficacy of Trikafta in patients with cystic fibrosis aged 12 years 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 or tezacaftor/ivacaftor 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, known as ppFEV1, which is an established marker of cystic fibrosis lung disease progression. Trikafta increased the ppFEV1 in both trials. In the first trial, it increased mean ppFEV1 13.8 percent from baseline compared to placebo. In the second trial, it increased mean ppFEV1 10 percent from baseline compared to tezacaftor/ivacaftor. In the first trial, treatment with Trikafta also resulted in improvements in sweat chloride, number of pulmonary exacerbations (worsening respiratory symptoms and lung function), and body mass index (weight-to-height ratio) compared to placebo.
The safety profile of Trikafta is based on data from the 510 cystic fibrosis patients in the two trials. The safety profile was generally similar across all subgroups of patients. Serious adverse drug reactions that occurred more frequently in patients receiving Trikafta compared to placebo were rash and influenza (flu) events. The most common adverse drug reactions included headaches, upper respiratory tract infections, abdominal pains, diarrhea, rashes, 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), influenza, sinusitis and increased blood bilirubin (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), 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. Patients and their caregivers should speak with a health care professional about these risks and any medicines they take before starting treatment.
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 using an FDA-cleared genotyping assay prior to treatment. The safety and effectiveness of Trikafta in patients with cystic fibrosis younger than 12 years of age 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 encourage the development of drugs for rare diseases. Drugs approved under expedited programs are held to the same approval standards as other FDA approvals. Because of Trikafta’s benefit to the cystic fibrosis community, the FDA reviewed and approved Trikafta 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.
The FDA, an agency within the U.S. Department of Health and Human Services, protects the 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 also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.
Research at Ann & Robert H. Lurie Children’s Hospital of Chicago is conducted through the Stanley Manne Children’s Research Institute. The Manne Research Institute is focused on improving child health, transforming pediatric medicine and ensuring healthier futures through the relentless pursuit of knowledge. Lurie Children’s is ranked as one of the nation’s top children’s hospitals by U.S. News & World Report. It is the pediatric training ground for Northwestern University Feinberg School of Medicine. Last year, the hospital served more than 220,000 children from 48 states and 49 countries.