Ryleigh Messmer is a 15-year-old from Colorado Springs who has cystic fibrosis (CF), a rare, life-shortening genetic disease that affects the lungs, pancreas, and other organs. When she was born, the only treatments to maintain lung health for people with CF were mucus clearance treatments to try to alleviate symptoms such as the buildup of thick, sticky mucus that would eventually damage the lungs.
However, just two years later everything changed when the FDA approved ivacaftor, the first drug designed to target the defective protein that causes CF. This protein is called the cystic fibrosis transmembrane conductance regulator or CFTR. Much of the clinical research that ultimately led to the approval of ivacaftor, the first CFTR modulator, in 2012 took place at Children’s Hospital Colorado in collaboration with the Colorado Clinical and Translational Sciences Institute (CCTSI), which provides specialized research nursing, expert laboratory services and clinical space for the hundreds of children who participated in the research studies over the years.
Today, 15-year-old Ryleigh has benefited enormously from these groundbreaking research advances. She has been receiving treatment with a CFTR modulator for nearly a decade, and has participated in several clinical studies. She is a vibrant, healthy high schooler.
“I find a lot of rest and comfort knowing her experience in middle or high school is very much like any girl,” said Tricia Messmer, Ryleigh’s mom.
Despite CF research successfully leading to effective treatment, the story is not over. Doctors at CU Anschutz are currently leading clinical studies to learn more about the disease and advance treatment for people with CF. In the early days of the CFTR modulators, only a small percentage of individuals were eligible due to their specific genetic profile. Today, the therapy has evolved so that approximately 90 percent of all people with CF in the U.S. are eligible for a CFTR modulator. The ultimate goal of ongoing clinical research is to improve the lifespan and quality of life for all people with CF.
To that end, Scott Sagel, MD, PhD, recently published results from the PROMISE study in the Annals of the American Thoracic Society, showing the impact of Elexacaftor/Tezacaftor/Ivacaftor (ETI) on inflammation, a feature and cause of CF lung disease. ETI is the most commonly prescribed CFTR modulator therapy.
For the past three years, Ryleigh has been participating in PROMISE, a large, multisite, real-world clinical effectiveness observational study. Sagel leads the PROMISE study at Children’s Colorado, where he is a pediatric pulmonary physician. Researchers want to see if patients experience similar benefits in a real-world setting as opposed to a more tightly controlled clinical trial. Through this ongoing study, physicians will try to understand more about the biology of CFTR modulation. Parts of PROMISE will look at liver and pancreatic function. Sagel focused his particular research on inflammation because it is associated with, and predictive of, worse clinical outcomes.
“While we knew ETI improves a lot of things, we did not know for sure how it changes inflammation both in both the lungs and in circulation,” said Sagel. He and his colleagues found that ETI is associated with sustained reductions in airway and circulating (blood) markers of inflammation through 2.5 years of therapy. They found that reductions in the markers of inflammation in both mucus and serum were associated with improved lung function and fewer hospitalizations.
“For many years, we thought that people with CF would need effective, anti-inflammatory therapy that would target and block inflammation. This study shows that many may not need additional anti-inflammatory therapy, at least through two and a half years of ETI treatment,” Sagel said.
Ryleigh explained that, as part of the PROMISE study, the research nurses performed a full battery of tests, including blood, serum, sputum, lung function, and sweat chloride. Sweat chloride is a marker of how the CFTR protein is functioning in the sweat gland, and it is our best, least invasive way to assess CFTR function in the body.
Ryleigh’s sweat chloride numbers had been elevated from the time she was diagnosed with CF as a baby, a clear indicator that she had the disease. “But with Ryleigh being on Trikafta [trade name for ETI], there was a significant change in the sweat chloride test,” Tricia said.
In fact, Ryleigh’s sweat chloride test numbers dropped so dramatically that once the study coordinator saw the results, she rushed to the waiting room and said, “Trish, you will not believe this!”
Ryleigh’s sweat chlorides, as measured through the PROMISE study, were considered ‘normal’ sweat chlorides.
“These results indicate an extraordinary response to ETI therapy. And assuming the CFTR protein is functioning as well throughout her body as it is in the sweat gland, it means that it is far less likely she will develop the disease and end-organ manifestations so common in people with CF,” Sagel said. “This level of improvement in CFTR function will ensure she continues to thrive despite having CF.”
Tricia summed it up, “To have her cells functioning as normal was pretty significant and amazing.”