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Study published in NEJM shows breakthrough drug can benefit more people with cystic fibrosis

Trikafta can provide additional benefit for CF patients who have genetic mutations that made them eligible for previously approved CFTR modulators.

Deepika Polineni, M.D., MPH portrait
Deepika Polineni, M.D., MPH, co-led a study showing that Trikafta can provide additional benefit for CF patients who have genetic mutations that made them eligible for previously approved CFTR modulators.

Since the U.S. Food and Drug Administration approved a breakthrough drug for cystic fibrosis (CF) in 2019, the media has been full of joyful, moving stories about its wondrous effect on the lives of individual patients.

A man who had been trying to raise money for a lung transplant experienced a massive clearing of his lungs within just one day of his first dose. A young teacher who hadn't been able to walk down a hallway without stopping to catch her breath completed a 5K race. Patients who had never expected to grow old suddenly were told they should start saving money for retirement.

And now, there's even more good news. According to a study published in the August 26, 2021, issue of the New England Journal of Medicine and co-led by Deepika Polineni, M.D., MPH, an associate professor in the Division of Pulmonary, Critical Care and Sleep Medicine at the University of Kansas Medical Center, the drug, known by its brand name, Trikafta, can provide additional benefit for CF patients who have genetic mutations that made them eligible for previously approved CFTR modulators. These modulators are drugs that work to improve the functionality of the CFTR protein, which is damaged in people with CF.

CF is a progressive genetic disease that causes thick mucus to build up in the lungs and digestive track, damaging organs and making it hard for people to breathe before eventually killing them. Some die before reaching adulthood. For the nearly 90% of CF patients in the United States who have specific genetic mutations that make them eligible for CFTR modulators, Trikafta, which is actually a combination of three modulators, has often led to improvement in their health so dramatic that it just might turn this debilitating, deadly disease into a chronic condition they can manage into old age.

These patients were already taking one, or two, of the drugs included in Trikafta depending on their genetic mutations that caused CF. Trikafta further improved their ability to breathe easily, and for half the study participants, it also dropped the levels of chloride in their sweat-a key measurement used to diagnose CF.

"Particularly in the subgroup analyses of this study, the drug not only appeared to incrementally improve lung function and produce added gains in quality of life, but it reduced sweat chloride to ranges that could be expected in people without a clinical diagnosis of CF," said Polineni. "That's truly remarkable."

Pass the salt

When Trikafta, a treatment in pill form produced by Vertex Pharmaceuticals, was approved in 2019, it had been 30 years since scientists first identified the gene that causes CF. That gene, known as CFTR, produces the protein that conducts chloride ions across cell membranes and helps maintain the balance of water and salt (chloride is a component of salt) on many surfaces of the body, including the surface of the lungs.

When the CFTR gene is mutated, or damaged, it either fails to produce enough protein or produces a defective protein that can't do its job. Chloride then gets stuck in cells, and cell surfaces cannot be properly hydrated. The result is the hallmark of CF: thick mucus that clogs the lungs, pancreas and intestines.

For a person to have CF, there must be a mutation in both copies of their CFTR gene. Scientists have identified more than 1,000 different mutations in the CFTR gene that can lead to the disease. The most common, accounting for 70% of known CF mutations in the United States, is known as F508del. This mutation stops the CFTR protein from folding into the three-dimensional shape that enables it to move to the cell surface to channel the chloride.

Polineni was the principal investigator for KU Medical Center on the multi-site clinical trial that led to Trikafta's approval in 2019. The first triple combination therapy for CF, Trikafta includes these CFTR modulators:

  1. Ivacaftor, which in 2012 became the first drug on the market designed to correct the damaged CTFR protein and addresses "gating" mutations. It holds open the gate to the chloride channel so that chloride can move through it. Less than 10% of CF patients in the United States have this type of mutation and qualify for ivacaftor alone.

  2. Tezacaftor, which corrects for the F508del mutation by helping the CTFR protein fold into the right shape and position itself on the cell surface to channel chloride. In 2018, FDA approved a tezacaftor/ivacaftor combination for people who have either two copies of the F508del mutation, or one F508del mutation plus one of a specific list of mutations found to respond to tezacaftor/ivacaftor in vitro.

  3. Elexacaftor, the new compound in Trikafta (elexacaftor/tezacaftor/ivacaftor), further helps the CFTR protein fold into the right shape by correcting an additional flaw in the formation of the protein.

When it was first released two years ago, Trifakta made headlines because it improved predicted lung function by a record-setting absolute change of 14 percentage points. Prior CF treatments had been approved that improved predicted lung function by just 3 percentage points.

Soon after Trikafta was first approved, Steven Stites, M.D., the director of the KU Medical Center's Cystic Fibrosis Center, talked about how amazing it was to talk to a patient taking it who didn't have to cough any more-a remarkable change for someone with CF. "I've seen a lot of patients die of this disease, I've been doing this for a long time, and I've never seen anything like this," he said.

Closer to fine

All the more reason to bring the drug to even more patients. Around the time of Trikafta's initial release, Polineni was asked by Vertex to co-lead an international study looking at the effect of the drug on people who had the F508del mutation, plus either a gating mutation or what is known as a residual function mutation, which results in very little protein being produced.

The trial participants took Trikafta for eight weeks. At the end, they experienced an increase in their FEV1 that was 3.7 percentage points higher than it was when they started the trial, or 3.5 percentage points compared with the active control group (who took existing CFTR modulators). This increase is on top of the gain they were already getting from the active control ivacaftor or the tezacaftor-ivacaftor combination.

"They were all taking a standard of care drug that treated their CFTR mutation(s)," said Polineni. "What this study shows is that the triple combination drug [Trikafta] further rescued their F508del mutation, in addition to what CFTR rescue they already had, and yielded further improvement in lung function."

Moreover, the participants' sweat chloride levels dropped significantly, by 22.3 millimoles per liter compared with baseline or 23.1 millimoles per liter compared with the active-control group. A sweat chloride level of at least 60 millimoles per liter is considered a diagnostic criterion for CF. Normal is below 30. (Between 30 and 60 is a grey zone.) For half of the participants, their sweat chloride concentrations fell to levels within normal range or levels similar to people who are asymptomatic carriers with just one mutant CFTR gene.

And that, points out Polineni, is astonishing.

More to do

Meanwhile, in January, Vertex submitted its application to the FDA to change the age of eligibility for the drug from 12 years of age to as young as 6; the FDA announced approval of this application on June 9. And a case report was published about a pregnant woman with CF who was taking Trikafta throughout her pregnancy. Even though both copies of the baby's CFTR gene have F508del mutations, the baby still passed the screening tests for CF-the effect of the drug passing to the baby from the mother.

But there is still much more to do. Some people with CF have mutations that do not meet the criteria for any of the CF modulators. In the United States, these patients are disproportionately from non-white racial and ethnic minority groups, in part because the most common mutation, F508del, originated in northern Europe. Though far fewer, there are also people who cannot tolerate these drugs well because of problems with their liver or other side effects.

There are already studies begun on next modulator therapies for CF, as well as prospects for editing the damaged CFTR gene.

"The goal is to reach all people with CF. Treatment is aimed at human CFTR functioning correctly no matter what the disease-causing mutation," said Polineni. "When we as a research community can do that, that will truly be a great day."

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