Benefits of Kaftrio, Trikafta in US, may come with lasting side effects
Some patients in real-world study note memory, sleep problems across 6 months
Kaftrio (elexacaftor/tezacaftor/ivacaftor) — known as Trikafta in the U.S. — brings broad benefits in the form of better lung function, quality of life, and cognitive processing, while also helping to ease depression and improve stool frequency for cystic fibrosis (CF) patients, a real-world study in Italy found.
For some patients, however, it also brought neuropsychological side effects ranging insomnia, headache, and memory loss to brain fog or lack of concentration. These effects did not go away over the study’s six months, and they were more common in female than male patients.
While Kaftrio “is associated with substantial benefits in health outcomes,” the researchers wrote, its side effects “should be systematically monitored, and interventions which mitigate them are needed.”
The study, “Longitudinal effects of Elexacaftor/Tezacaftor/Ivacaftor: Multi-dimensional assessment of neuropsychological [side]-effects, physical and mental health outcomes in adolescents and adults,” was published in the journal Chest.
Kaftrio, Trikafta in US, is known to effectively treat cystic fibrosis
During clinical testing, this oral CFTR modulator was seen to improve lung function and ease various disease symptoms in people with at least one copy of F508del, the most common CF-causing mutation, with minimal treatment side effects.
But its “pivotal trials did not include a broad range of outcomes reflecting the ‘whole person,'” the scientists wrote, adding that in real-world settings, some patients have reported sleep problems, mental health issues, and mood or cognitive changes while using Kaftrio/Trikafta.
Researchers, led by those at Bambino Gesù Children’s Hospital in Rome, assessed a broad range of outcomes in 92 adults and adolescents, ages 12 to 59, diagnosed with CF and followed at that hospital’s adult and pediatric CF center. Most (69.6%) were new to CFTR modulator treatment, and 25 (27.2%) previously had been using Orkambi (lumacaftor/ivacaftor).
The majority (98%) had pancreatic insufficiency, which occurs when the pancreas fails to release enough enzymes to break down food in the bowel, causing gastrointestinal (digestive) symptoms. Sixteen (17%) had CF-related diabetes or CFRD.
Patients were evaluated prior to starting the treatment, and again one, three, and six months later.
As early as one month after treatment initiation, patients’ mean predicted forced expiratory volume in one second, a measure of lung function, improved significantly, rising from 74.7% to 83.6%. These gains were maintained for up to six months.
Significant improvements in quality of life and symptoms of depression — but not anxiety — also were noted one month into treatment, as were gains in body mass index, a measure of body fat based on height and weight, after three months.
Cognitive processing was assessed using the Symbol Digit Modalities Test, which evaluates working memory and processing speed. Mean scores improved as early as one month after treatment start, indicating that the person was able to perceive, store, and respond to information faster.
An easing of some gastrointestinal symptoms, assessed using a tool called the GI Symptom Tracker, was seen as a better frequency of stools and adherence to enzyme replacement and other CF treatments. But improvements in abdominal pain or digestion (“eating challenges”), were not evident.
Side effects like insomnia and brain fog persisted over study’s six months
Side effects, namely insomnia, headache, memory loss, brain fog, and lack of concentration, occurred in 9.9% to 30.4% of these patients over six months of follow-up. The proportion experiencing such neuropsychological effects also did not decrease over that time.
Insomnia, headache, brain fog, and lack of concentration were more common among female than male patients, “possibly due to the effects of [the triple-combination therapy] on estrogen,” the sex hormone responsible for the development and regulation of the female reproductive system, the researchers noted.
“This is the first real-world study to evaluate the effects of [Kaftrio] on the whole person using multiple measures over time,” the researchers wrote. Despite significant improvements in many outcomes, some side effects persisted for at least six months.
“This study offers guidance on which [side effects] to measure over time, and as [Kaftrio/Trikafta] is prescribed for school-age children and downwardly extended to preschoolers, we recommend they also be monitored,” the team concluded.