Research continues for cystic fibrosis patients not helped by breakthrough drugs

In 2019, when the U.S. Food and Drug Administration approved Trikafta, a breakthrough drug for cystic fibrosis, newspaper articles and television segments were full of dramatic anecdotes about what happened when people started taking the drug. These included patients who hadn’t been expected to live until adulthood, patients who, despite advancements in antibiotics and other ways to manage the disease, had been in and out of hospitals with infections throughout their lives, patients who were awaiting lung transplants. And now, they were climbing mountains. They were taking up skiing. They were scuba-diving. Two young women who participated in the clinical trial for Trikafta at the University of Kansas Medical Center, a primary site for that trial, ran a 5K — because they could.

“To have seen this transition happen … I think it's one of the greatest experiences in my life as a physician, and obviously, in the lives of cystic fibrosis patients,” said Steve Stites, M.D., a pulmonologist and executive vice chancellor of KU Medical Center.

But as effective as it is, Trikafta, a combination of three drugs that kickstarts a malfunctioning protein, doesn’t work for everyone. It was designed for people who have the most common genetic defect that causes the disease. “It works well for almost 90% of people right now,” said Matthias Salathe, M.D., chief research officer for the University of Kansas. “But the other 10% don’t have a treatment like this. In addition, there are some people who do not tolerate the drug well and have side effects. So that’s about 20% who still have no good alternative treatment.”

Salathe and Joel Mermis, M.D., a professor of pulmonary, critical care and sleep medicine at KU Medical Center, appeared on the May 6 episode of “Open Mics with Dr. Stites,” produced by the health system, to talk about research happening at KU to help the 20% of patients who have been left behind. Stites is also chief medical officer for the health system.

Cystic fibrosis is caused by mutations to a gene known as CFTR. This gene produces a protein that functions like a door in cell membranes, opening and closing to regulate the flow of salt and water through cells in different parts of the body, including the lungs and digestive system. When that gene is damaged, the protein is absent or malfunctions and there is no working door. Thick mucus then builds up in the lungs, digestive tract and other parts of the body and can lead to infections, respiratory problems and damage to the lungs and other organs.

Mermis is overseeing clinical trials for gene therapy for cystic fibrosis. Gene therapies aim to deliver a corrected copy of the CFTR gene to cells, fixing the problem at the root. One trial is for patients whose disease causes them not to produce the CFTR protein at all. “Trikafta works for people who have mutations where the protein is still in the body. But some patients with cystic fibrosis have a mutation where it doesn't make the door …. It's not in the proteins, not in their body, to modify,” said Mermis, also a pulmonologist and critical care specialist at the health system. “For those people, or people who have had really rare side effects to Trikafta, we have to have a different approach. So instead of modifying the protein like Trikafta does, with gene therapy, (study participants) are actually nebulizing or inhaling the actual DNA that has the code that then makes the door.”

Scientists at KU Medical Center also are studying which patients with rarer gene mutations still might benefit from Trikafta, as well as Alyftrek, a similar drug the FDA approved in December 2024. As Salathe pointed out, conducting clinical trials for a rare gene mutation is difficult because it’s hard to find enough people with that mutation to participate.

Researchers at KU are getting around that problem through a process known as theratyping. Cells are collected from a person’s nose with a swab, just as if they were being tested for COVID-19. In the laboratory, these cells are grown in a culture, and different drugs are added to them to see how they react. How well the drug restores the function of the CFTR protein can be measured by the micro-currents of electricity that indicate its level of activity. In this way, scientists can identify if that patient, with their particular set of mutations, will respond well to different drugs.

“If you have cells that respond (to a drug), it is highly predictable that clinically, the patients will improve as well,” said Salathe, who is also chief science officer for the health system. “The amazing thing is that the FDA has decided that for them, this (in vitro test) is sufficient proof. This has led to almost 300 (rare) mutations now being approved by the FDA (for Trikafta).”

Additionally, researchers at KU are looking beyond the CFTR protein. “There are lots of other doors in these cells,” said Salathe. “And there are also developments of medications to look at whether stimulation or opening of the other doors helps cystic fibrosis patients as well. So that is a part that we're doing in the lab every day, to see whether we can introduce new Trikafta equivalents that are not targeting the CFTR protein, but other proteins that may be as beneficial to people.”

Salathe noted that the tremendous progress made in the treatment of cystic fibrosis is a classic example of how research can make a real difference in medicine and in people’s lives.

“This research that starts in a basic science lab and then goes into translation and clinical research is absolutely needed to make progress in clinical medicine, and it is the bright light at the end of the tunnel,” said Salathe. “We should all be aware of that and push for it really hard.”