Kaftrio eases gastrointestinal symptoms, inflammation: Study
Maximum effect of treatment achieved after two months
The treatment’s maximum effect was achieved after two months and included a decline in gut inflammation.
The study, “Reduction in abdominal symptoms (CFAbd-Score), faecal M2-pyruvate-kinase and Calprotectin over one year of treatment with Elexacaftor-Tezacaftor-Ivacaftor in people with CF aged ≥12 years – The RECOVER study,” was published in the Journal of Cystic Fibrosis.
CF is caused by mutations in the CFTR gene that lead to abnormally thick and sticky mucus accumulating in several organs, including the lungs and the digestive tract.
A distinctive CF symptom is exocrine pancreatic insufficiency, when digestive enzymes produced in the pancreas cannot move into the digestive tract. Other gastrointestinal symptoms related to the disease result in a significant burden that affects quality of life.
Kaftrio’s effect on digestive system
Kaftrio (Trikafta in the U.S.) is a CFTR modulator therapy that combines elexacaftor, tezacaftor, and ivacaftor. It’s able to reduce sweat chloride, a measure of CFTR protein dysfunction, and improve organ function.
In earlier studies, the therapy’s effect on the digestive system was only observed indirectly in the “substantial incremental improvement in the nutritional status of [people with CF] on treatment,” leading researchers in Europe to research Kaftrio’s action on abdominal symptoms and biomarkers of intestinal inflammation. They evaluated 117 patients, ages 12 or older, who participated in the RECOVER study (NCT04602468), a Phase 4 trial in Ireland and the U.K. designed to assess the impact of Kaftrio on clinically relevant measures in a real-world setting.
The participants had at least one F508del mutation, the most common CF-causing mutation. More than half were men (54.6%) and their median age was 15. The evaluation included 71 patients younger than 18 and 34 adults.
Gastrointestinal symptoms were assessed with the CFAbd-Score, the first validated CF-specific outcome measure to focus on digestive symptoms. It comprises 28 items in five domains and ranges from 0 to 100 points, with higher scores representing more severe symptoms.
One-year treatment with Kaftrio significantly improved the total CFAbd-Score — it was 15 at baseline versus 9.8 after a year — as well as its five domains, pain, gastroesophageal reflux disease (acid reflux), disorders of bowel movement, appetite, and impaired quality of life. A major improvement was seen in the first month, with symptoms reaching the minimum two months after treatment started.
Adults reported significantly higher scores in gastroesophageal reflux disease than adolescents, both at the start of treatment, or baseline (16.2 vs. 13.1), and after a year (15.2 vs. 7) on Kaftrio. Females had significantly higher scores than males in disorders of appetite at baseline (10 vs. 4.5) and after a year (7.9 vs. 2.2).
The researchers also analyzed markers of gastrointestinal inflammation, including fecal calprotectin (FC) and M2-pyruvate kinase (M2-PK) in 93 participants, who provided at least one stool sample for analysis.
FC levels decreased significantly from baseline to one month — 70 micrograms (mcg)/g versus 27.4 mcg/g — and remained consistent after six months. M2-PK levels also decreased significantly by 76% in the first month and remained stable.
Fecal elastase (FE-1), a marker of pancreatic function, had activity levels below 5 mcg/g at baseline in 87.5% of the patients, indicative of severe pancreatic dysfunction. Although FE-1 levels were significantly higher after six months, they weren’t sufficient to result in clinical effects, according to the researchers.
FC levels correlated with both appetite disorders and impaired quality of life at baseline, but not after six months of treatment. Higher M2-PK levels correlated with a worse total CFAbd-Score and with the pain domain at baseline, and with a worse total CFAbd-Score and the gastroesophageal reflux disease domain at six months. FE-1 levels were correlated with the quality of life domain after six months on Kaftrio.
“This study adds to the growing evidence that [Kaftrio] reduces [gastrointestinal] symptoms in [people with CF], highly significant findings being likely due to the sensitivity of the CF-specific CFAbd-Score used to measure symptoms,” wrote the researchers, who said more longitudinal data and biological samples are being collected for the RECOVER study.