US approval of CF treatments may have cut need for liver transplants
Study suggests CFTR modulators have benefited patients with liver disease
The U.S. approval of CFTR modulators for cystic fibrosis (CF) may have reduced or delayed the need for liver transplants among people in the country with CF-related liver disease, or CFrLD, a new study suggests.
Since the U.S. Food and Drug Administration (FDA) approved Trikafta (elexacaftor/tezacaftor/ivacaftor) — the first triple therapy CFTR modulator cleared for use in the nation — a smaller proportion of the people on the U.S. liver transplant waiting list were individuals with CFrLD, the researchers found. According to the team, which sought to quantify the impact of such treatments on people with CF, the “rates of waitlisting for CFrLD decreased over time and were lower after FDA approval of triple therapy CFTR modulators.”
Waitlist candidates with CFrLD did tend to have signs of more advanced liver disease after the approval, the data showed.
“These findings suggest that CFTR modulators may mitigate CFrLD complications and delay the need for waitlisting as physicians await the patient’s response to therapy and reassess the need for [liver transplant],” the researchers wrote.
The study, “Impact of Cystic Fibrosis Transmembrane Conductance Regulator Modulating Therapies on Liver Transplant Outcomes,” was published in the journal Gastro Hep Advances.
Mutations in the CFTR gene cause CF, which can manifest with a wide range of symptoms. CFTR contains information to produce a protein of the same name that normally helps regulate the flow of salts and water in and out of cells. Defects in the CFTR protein can lead to severe liver disease, which may ultimately warrant a liver transplant.
Trikafta in 2019 became first approved triple CFTR modulator in US
CFTR modulators are a class of treatments that aim to increase the protein’s function in people with certain mutations.
In 2019, Trikafta became the first approved triple CFTR modulator therapy in the U.S. when it received an FDA green light for use among certain CF patients. It contains ivacaftor, which helps keep the CFTR gate open for longer, along with elexacaftor and tezacaftor, which help the protein fold properly and reach the cell surface.
While the impact of CFTR modulators on lung function and referrals for lung transplants is well documented, changes in liver disease and related clinical outcomes remain to be better explored, according to the researchers.
“We sought to investigate the practice patterns of LT [liver transplant] waitlist, characteristics, and post-LT outcomes for patients with CFrLD pre- and post-FDA approval of CFTR modulators from a large, national transplant registry in the U.S., with a particular focus on the period following the introduction of triple therapy CFTR modulators,” the scientists wrote.
Among the more than 250,000 individuals put on the waitlist between 2000 and 2023, 551 (0.2%) had CFrLD. Slightly more than half (58%) were male, and the vast majority (96%) were white individuals. At the time of listing, the participants had a mean age of nearly 19.
In the era after Trikafta’s approval, people with CFrLD made up 0.14% of the liver transplant waiting list — a significantly lower proportion than the 0.23% before approval.
After the approval of Trikafta and earlier (double) CFTR modulators, the mean MELD-Na score — Model for End-Stage Liver Disease score, which helps decide how high to place a patient on the liver transplant waiting list — of people with CFrLD was significantly higher, indicating more advanced disease. According to the researchers, this “may reflect an increased capacity for recovery among younger individuals with less severe liver disease.”
Correspondingly, waitlist candidates after the approval of dual combinations of CFTR modulators (currently Orkambi and Symdeko) were significantly older, with a mean age of 20.6 versus 17.4 before approval. A similar trend was seen after Trikafta approval, although this did not reach statistical significance.
CFTR modulators may be linked to ‘stabilizing effect’ on progression
Among people who received transplants, survival rates and cause of death did not vary significantly pre- and post-CFTR modulator approval.
“Collectively, these findings highlight the potential of CFTR modulators to improve the trajectory of CFrLD,” the team wrote, noting that the results “suggest that CFTR modulators may be associated with a stabilizing effect on the progression of severe CFrLD.”
Among the study’s limitations, the investigators noted that using FDA approval dates to define different treatment eras may not fully capture clinical practice variations, as some patients may remain on older modulators.
“It is also important to note that advancements in the management of CF and CFrLD have occurred in parallel with the introduction of CFTR modulators which include improved nutritional support, antibiotic use, pulmonary care, recognition and management of liver disease, and developments in immunosuppressant protocols,” the team added.
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