A new cystic fibrosis therapy dramatically improved patients' lung function and showed clear signs of targeting the genetic root of the disease, instead of just alleviating symptoms - a breakthrough so long-sought that many doctors and patients are moved to tears when talking about it.
The data, to be unveiled Thursday at a national conference in Tennessee and simultaneously published in two leading medical journals, was so persuasive that the Food and Drug Administration last week approved the three drug combination, called Trikafta - five months ahead of the agency's deadline. The drug could benefit 90% of patients with the disease, a major advance over previous drugs that worked in a tiny fraction of the people with the disease or had more modest effects.
"I'm overjoyed," said Francis Collins, the director of the National Institutes of Health, who was part of one of the teams that discovered the gene defect that causes cystic fibrosis in 1989. "Thirty years along, with many bumps along the road and so many people waiting and hoping that something like this would happen - and here we are."
The drug is the product of decades of steady, incremental scientific work that began with research in academic laboratories and was pushed forward and funded by patient advocates through an unusual "venture philanthropy" model now being emulated by other patient groups. The leap forward was preceded by many steps - Trikafta is the fourth therapy developed by Vertex Pharmaceuticals, a Boston-based company that has built a lucrative franchise around the disease.
Cystic fibrosis affects an estimated 30,000 people in the United States. Thick mucus builds up in the body's organs, damaging people's lungs and digestive systems. Patients wear vibrating vests to break up the mucus and spend hours each day coughing to keep their lungs clear. They assiduously protect themselves from respiratory illnesses that can send them to the hospital. They often take antibiotics, enzymes and vitamins, to stay healthy. The life expectancy of patients has been increasing, and patients born today live on average 44 years.
Doctors who began their careers at a time when there were few adults with cystic fibrosis because patients died in their teens are now cautiously anticipating that the disease will be transformed into a chronic condition, akin to diabetes, that can be managed with a drug regimen - particularly if Trikafta is eventually approved for use in younger children and babies, before any lung damage has occurred. (It is initially approved for patients 12 and older.) Patients who were unsure about whether they should bother attending college because they had always known they would die young are now being told they should think about planning for retirement.
Brian O'Sullivan, a pediatric pulmonologist at the Geisel School of Medicine at Dartmouth, who was not involved in either trial and has no financial ties to Vertex, said, "I'm in my 60s now, and I never thought I would see this day. It's pretty amazing."
Sarah Carollo, 28, a special needs teacher in Lee's Summitt, Missouri, started Trikafta through a clinical trial in late 2018. Carollo feared she was heading into yet another hospitalization and might have to step away from the classroom where she teaches children with nonverbal autism. She couldn't walk down a hallway without stopping to rest and catch her breath.
"As a person living with CF, my parents had been passing it on to me this fear - we always had this constant fear of when the decline was going to happen, because we knew it was going to happen," Carollo said.
A few days after she began taking the pill, her doctors tested her lung function and were so stunned at the improvement that they had to check whether they were really looking at the results from the right patient. Two weeks ago, Carollo ran a 5K race with another patient, Laurana Blackburn, who was also taking the drug through the clinical trial.
"We felt like we had to honor what we had been given and show the capacity of what we had now," Carollo said.
Cystic fibrosis has become a model for how to study, advocate for and develop drugs for other genetic diseases. The discovery of the gene in 1989 was a major scientific feat that helped persuade scientists and politicians to move forward with the $3 billion human genome project, Collins recalled. But that wasn't just important to scientists.
On August 25, 1989, an 8-year-old girl named Jenny wrote in her diary, "To Day is the most Best day ever in my Life They found a Jean for Cistik fibrosis." Jenny McGlincy, now 38, was on vacation with her husband and daughter in Mexico when word began to circulate that the drug had been approved. She read the news on her phone and began crying.
McGlincy feels fortunate that she hasn't been as sick as other people with cystic fibrosis, but is eagerly awaiting the doctor's appointment in a week and a half where she will find out the next steps to get access to the medication.
"We've finally reached the time an improvement is possible," McGlincy said. "To think of my lung function improving or my digestion increasing, or even adding a few years to my life that I could spend with my daughter. . . . Now that it's available, I'm [feeling] a little like, 'is this really happening?'"
The therapy is a combination of three drugs that wouldn't have been possible if scientists working in academic laboratories hadn't unraveled the basic biology of the disease. Finding the gene was a "needle in a haystack" type problem, Collins said, and led scientists to a malfunctioning protein that normally keeps the right balance of salt and water in the lungs. There are more than 1,700 gene mutations that can cause the protein to malfunction, but in the most common mutation, the protein is misfolded and can't reach the right spot in the cell - and even if it does reach the cell, it doesn't work properly. The new combination therapy includes one drug that corrects the misfolded protein and two that activate the correctly folded protein when it reaches the right spot in the cell.
In the largest trial, reported in the New England Journal of Medicine, 403 patients who had at least one copy of the most common gene mutation underlying cystic fibrosis received either Trikafta or a placebo. There were improvements in objective tests of lung function, decreases in lung problems and hospitalizations and an increase in people's quality of life.
Many physicians see the most transformative potential impact of the drug in the hope that it will be eventually approved for younger children, as Vertex's other drugs have been over time. The drug can help older patients, but can't erase years of lung damage; if it works and is safe in younger children, it could prevent damage in the first place.
"With treatments like this we can actually anticipate that if a young child were started on this therapy they could actually expect to have a normal life expectancy," said Deepika Polineni, a pulmonologist at the University of Kansas Medical Center involved in the trial who has received consulting fees from Vertex. "This is a breakthrough therapy for people with cystic fibrosis."
Patients continued their maintenance therapy, such as coughing and using a vibrating vest, during the therapy - and future trials will test whether patients can reduce their dependence on the intervention. Future research will also be needed to help the remaining 10% of patients, who have disease driven by different mutations.
Meghan McGarry, a pulmonologist at the University of California, San Francisco, recently completed a study that examined Puerto Rican and Dominican patients and found that their diseases were driven by rare mutations. Her concern is that the new drugs, as exciting as they are, will deepen health inequities, since minority patients already have greater mortality than white patients with cystic fibrosis.
"It's really heartbreaking for the patients who don't qualify. I think it's really hard to celebrate with a portion of your patients and have other patients where you know they don't have that. We had a mom who said, 'Those drugs aren't for our people,'" McGarry said. She noted that when some of Vertex's early drugs came out and helped a small population of patients, it gave others in the community hope because it foreshadowed the development of better drugs that would work for more people.
"Now, when the majority of patients already have it," she said, they ask, "When it's my child's turn? And is that going to come?"
It also remains to be seen if patients have an easy time gaining access to the drug, which will cost $311,000 a year. While that is a tremendous amount, orphan drugs for small patient populations typically carry very large price tags and physicians are optimistic that insurers will cover the drug.
For now, the cystic fibrosis community will be celebrating. Collins said that after he discovered the gene behind the illness in 1989, he wrote a song called "Dare to Dream" about the hope for a treatment. He plans to sing it at the meeting.