Kaftrio restores pancreatic function in 2 women with milder mutation
Treatment allowed women to stop pancreatic enzyme replacement therapy
Treatment with Kaftrio (elexacaftor/tezacaftor/ivacaftor) improved the pancreatic function of two women with cystic fibrosis (CF), allowing them to stop their pancreatic enzyme replacement therapy (PERT).
The women each had a combination of an F508del mutation, which leads to the abnormal folding of the CFTR protein, and a milder mutation known as 3849+10kbC>T, which causes insufficient production of CFTR.
“Carriers of this mutation combination are likely pancreatic sufficient, however, these patients may develop chronic pancreas inflammation and EPI [exocrine pancreatic insufficiency] in adulthood,” according to researchers.
The study, “Case report of two adults with F508del/3849+10 kb C > T genotype regaining exocrine pancreatic function following treatment with elexacaftor/tezacaftor/ivacaftor,” was published in the Journal of Cystic Fibrosis.
CF is caused by mutations in the CFTR gene that provide instructions to produce CFTR, a protein that controls the flow of chloride across the cell membrane. A faulty or absent CFTR protein leads to the accumulation of thick mucus in organs such as the lungs and pancreas, impairing their function.
Exocrine pancreatic insufficiency is common CF symptom
EPI, a common CF symptom, is characterized by the insufficient release of enzymes from the pancreas to break down nutrients. PERT provides missing enzymes to help with nutrient absorption and maintaining a healthy weight.
CFTR modulators, such as Kaftrio (sold in the U.S. as Trikafta), are designed to increase CFTR protein functionality, thereby easing symptoms and slowing disease progression.
“The modest improvement of frequency and severity of gastrointestinal symptoms in CF was reported after CFTR modulator use, but to date, [CFTR modulators] have not been demonstrated to affect exocrine pancreatic function in adults,” the researchers, based in the Czech Republic, wrote.
In the report, they describe the cases of two adult women with CF and a combination of F508del/3849+10kbC>T mutations, who improved their pancreatic function after starting treatment with Kaftrio.
The first patient was a 38-year-old woman referred to a CF center at age 16, when she was diagnosed with CF through genetic testing. Her levels of fecal elastase (FE-1) were indicative of EPI, so she was started on PERT.
Woman also diagnosed with CF-related diabetes at age 26
However, she had no symptoms of digestive problems, including no failure to thrive and no severe vitamin deficiencies. At 26, she was diagnosed with CF-related diabetes.
She was started on Symkevi (tezacaftor/ivacaftor; sold in the U.S. as Symdeko) at 35 years old, and one year later, she switched to Kaftrio. No side effects were reported. After 24 weeks of treatment (about six months), her sweat chloride levels notably decreased, “suggesting a positive response to the treatment,” the team wrote.
At the same time, her FE-1 levels increased to levels indicative of normal pancreatic function. She was able to discontinue PERT with no side effects. She kept having stable bowel movements and no abdominal discomfort. Her body weight was 2 kg (4.4 lbs) higher than when she started on Kaftrio.
Therefore, the scientists decided to retest a second woman with the same mutations. That woman was 40 years old and had been diagnosed with CF at age 11. Her diagnosis was also confirmed by high sweat chloride levels. Her first signs of EPI appeared when she was 31, and was associated with intermittent bloating and flatulence.
She started on PERT, but after several years, she decided to stop the treatment without consulting her CF specialist, and used alternative therapies. Although her FE-1 value was indicative of EPI, her symptoms didn’t worsen after she stopped PERT, nor did her body weight change.
Improvements seen after Kaftrio treatment
The woman started on Symkevi at age 38, and switched to Kaftrio about one year later. Sweat chloride levels dropped after six months and even more at one year. “This drop to a physiological [normal] level indicated a particularly good response to the medication as well,” the scientists added.
Nearly two years after the woman started on Kaftrio, her FE-1 increased to levels indicative of normal pancreatic function, and she has had no digestive problems. During this period, her nutritional status, as assessed by body weight and body mass index (a measure of body fat), did not change significantly.
“Rescue and restoration of EPI in adult patients with CF appears possible, especially among those who carry at least 1 functionally milder CFTR mutation,” the researchers concluded.
However, “further research needs to determine the effect of [Kaftrio] treatment on exocrine pancreatic function in this patient population,” they added.