A new drug that can treat approximately 9 out of 10 people living with the life-threatening chronic genetic disorder cystic fibrosis (CF) has been approved by the U.S. Food and Drug Administration (FDA).
Trikafta (elexacaftor/tezacaftor/ivacaftor), the first triple combination therapy to treat cystic fibrosis, gained FDA approval on Monday (October 21).
Manufactured by Vertex Pharmaceuticals, the medication is approved for CF patients 12 years of age and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. F508del is the most common cystic fibrosis mutation, accounting for an estimated 90 percent of people with the disease.
“Trikafta is a landmark therapy for individuals living with cystic fibrosis,” says Elliot Dasenbrook, MD, the director of the adult cystic fibrosis program and the bronchiectasis center in the Respiratory Institute at the Cleveland Clinic in Ohio. “For the 90 percent of the population of individuals living with cystic fibrosis that Trikafta can treat, it’s going to change their lives forever,” says Dr. Dasenbrook.
“Not only is this drug going to improve the way those people feel on a day-to-day basis, but it will also hopefully significantly prolong their lives,” he says.
About 30,000 people in the United States have cystic fibrosis, an inherited disease that’s caused by a defective protein that results from mutations in the CFTR gene. CF gets progressively worse and results in a buildup of thick, sticky mucus that can damage many organs in the body. The mucus can clog the airways and lead to breathing problems and bacterial infections, and eventually result in permanent scarring and damage to the lungs, according to the National Health Institute.
Digestive problems typically come with CF because the mucus can interfere with the body’s ability to produce insulin and digestive enzymes. Diarrhea and malnutrition can impair normal growth and also lead to weight loss.
Currently, the average life span for people with CF who live to adulthood is 37 years, although people with the disease can live into their fifties or sixties, according to the Golisano Children’s Hospital at the University of Rochester in New York.
Fast-Tracked Drug Approved Months Earlier Than Perceived
After the FDA granted the medication the status of Priority Review, Fast Track, and gave it the Breakthrough Therapy designation, three programs designed to expedite the approval process for drugs that are considered “game changers,” Trikafta was reviewed and approved in three months’ time, well ahead of the March 19, 2020, goal date.
These designations and accelerated approvals were due to the perceived benefit to the patient population, many of whom had no approved treatment options, according to Nathan Arnold, an FDA press officer.
The FDA also granted an orphan drug designation to Trikafta, a status given to drugs and biologics for relatively rare diseases or disorders that affect fewer than 200,000 people in the United States, or that affect more than 200,000 persons but for which there is no reasonable expectation of recovering the costs of developing and marketing a treatment drug.
“For a drug to receive all four designations is definitely rare,” Arnold says.
Successful Results in Two Different Trials
The approval of Trikafta was based on two trials. The primary indicator of the drug’s success was based on increases in predicted forced expiratory volume in one second, known as ppFEV1, which is a key measure of lung disease progression in CF.
A 24-week randomized double-blind placebo-controlled trial published in the New England Journal of Medicine in October 2018 included 403 patients who had an F508del mutation and a mutation on the second allele (a variant form of a gene) that results in either no CFTR protein or a CFTR that is not responsive to ivacaftor or the combination of tezacaftor and ivacaftor alone, medications currently used to treat CF.
Trikafta increased the mean ppFEV1 13.8 percent from baseline compared with placebo. It also lowered the number of pulmonary exacerbations (worsening respiratory symptoms and lung function) and improved body mass index (BMI) compared with placebo.
A separate, four-week randomized double-blind active-controlled trial was conducted with 107 patients who had two identical F508del mutations. Trikafta increased the mean ppFEV1 by 10 percent from baseline compared with Symdeko (tezacaftor/ivacaftor).
The results show improvements that will translate into longer lives for people with CF-extending life for several years or even decades in some cases, according to Dasenbrook.
“Part of that depends on where the person is in the disease progression,” he says. “For example, for a 12-year-old without much lung function, this medication may potentially normalize the length of their life span. That’s certainly the hope.”
Even for adults with a more advanced stage of lung disease, this is going to add years to their lives, says Dasenbrook.
As with any drug or treatment plan, deciding if Trikafta is appropriate for a patient will be a question of weighing the risks and the benefits.
“With this particular medication, we’ll monitor liver function closely and look at interactions with other medications to make sure that it’s safe for our patients,” he says. “Reassuringly, in the clinical trials that have been done, there were no significant safety signals.”
According to a statement released by Vertex, the drug is currently being evaluated in children ages 6 through 11 in an ongoing phase 3 study, and the company is committed to evaluating Trikafta in children younger than 6 years as part of planned future studies.
How Trikafta Works
According to Dasenbrook, Trikafta gets at the “root cause” of what’s wrong in cystic fibrosis, which is a chloride channel that doesn’t function. The chloride channel is essential in maintaining the balance of salt and water on many surfaces of the body, including the lung.
“The three drugs that make up Trikafta work in concert to help the chloride channel to function as effectively as possible,” he says. “It doesn’t normalize it, but it improves it to the point where we’re seeing patients whose lungs are functioning much better and so is their GI system as well.”
The most common mutation (and the one that Trikafta targets) actually causes the chloride channel to have a hard time even being formed, says Dasenbrook.
“These medications allow the chloride channel to stay intact and actually get to the position in the cell where it needs to be in order to function,” he says. “It’s been a very difficult problem previously because we didn’t have medicines to allow the chloride channel to be formed.”
As a result, this medication will help maintain lung health over a period of time, says Dasenbrook.
“This means less exacerbations where patients get acutely sick and have to be hospitalized, as well as an improvement in lung function that we measure with breathing tests,” he says.
“We know that if someone improves their lung function by 13 percent — when without the medication they usually lose one or one and a half percent of function per year — it’s going to add years to that person’s life,” says Dasenbrook.
Will Cost Be a Blockage to Patient Access?
Vertex set Trikafta’s list price at $23,896 for a 28-day pack, which translates to about $850 a day, or an annual cost of $311,503. Most people don’t pay the list price of prescription drugs because of various discounts and rebates that are offered through insurance and government agencies.
It remains to be seen if there will be any issues with access, says Dasenbrook. “In the US, almost 100 percent of individuals living with cystic fibrosis have some insurance coverage. With other drugs that have had a high price tag, we’ve not had significant issues getting access to these medications for our patients,” he says.
“This new drug is really the culmination of years of research; to find a treatment that’s going to be broadly available to help over 90 percent of our cystic fibrosis patients. It’s really going to be transformative,” he says.