Kaftrio may ease fibrosis in adults with severe CF-related liver disease
No change in liver stiffness seen in most patients on therapy known as Trikafta in US
Almost two years of treatment with Kaftrio (elexacaftor, tezacaftor, and ivacaftor) did not affect liver stiffness — an indicator of liver fibrosis — in adults with cystic fibrosis (CF), according to a recent study in the U.K.
However, patients with elevated markers of liver stiffness before starting on Kaftrio saw those fibrosis markers drop.
While similar effects were not observed in liver fibrosis markers according to CF-related liver disease (CFLD) status, these findings suggest that the therapy — sold as Trikafta in the U.S. — might ease liver fibrosis in adults with severe CFLD.
The study, “Effects of elexacaftor/tezacaftor/ivacaftor on liver fibrosis markers in adults with cystic fibrosis,” was published in the Journal of Cystic Fibrosis.
Few studies into CF modulator effects on CF-related liver disease
CF is caused by mutations in the CFTR gene, leading to no, low, or faulty production of the CFTR protein. This results in the accumulation of abnormally thick and sticky mucus, particularly in the lungs and organs of the digestive system, including the liver.
In the U.K., most people with CF are eligible for Kaftrio, a CFTR modulator therapy shown to be highly effective at restoring CFTR function and improving the patients’ lung function.
However, the treatment in clinical trials was shown to increase the levels of liver enzymes and to associate with liver problems in some patients.
Additionally, “there remains a relative lack of data on the impact of highly effective CFTR modulation on the clinical course of established liver disease in CF,” the researchers wrote, an important consideration given the lack of effective therapies for CF-related liver disease.
Among other features, CFLD is characterized by liver scarring, or fibrosis. Measures of liver stiffness, such as transient elastography, a noninvasive and validated measure, can be used to diagnose the condition. Findings of elevated stiffness also are associated with biomarkers and imaging evidence of CFLD.
Researchers evaluated changes in markers of liver fibrosis among 74 adults with CF, before and after starting on Kaftrio, with treatment given for a median of 21 months. Patients, whose median ages ranged from 24 to 32, were being seen at the Manchester Adult CF Centre and followed from February 2022 to February 2023.
During follow-up, liver fibrosis was assessed by measures that included liver stiffness and two fibrosis indices: aminotransferase to platelet ratio index (APRI) and gamma-GT to platelet ratio (GPR). Findings were compared to similar measures taken for these patients in 2018, before Kaftrio was available in the U.K.
A minority of patients (16.9%) in 2018 were using Orkambi (lumacaftor/ivacaftor), another CFTR modulator also marketed by Vertex Pharmaceuticals, whose U.K. availability then was restricted to a managed access program.
Liver stiffness measure declines in 14 adults with initial liver disease
During follow-up, there was a significant increase in the median APRI compared to pre-Kaftrio treatment levels (0.33 vs. 0.28), but no changes were observed in liver stiffness measures or GPR.
Overall, no differences were seen in fibrosis markers according to the severity of CFLD.
However, in 14 patients with preexisting liver fibrosis (with or without liver nodularity) — meaning a 2018 liver stiffness measure higher than 6.8 kPa — treatment with Kaftrio significantly reduced that measure, a decrease of 3.3 kPa, relative to patients with no previous liver fibrosis and a kPa change at follow-up indicating an increase of 0.25.
Ten adults (71.4%) with preexisting liver fibrosis had a liver stiffness measure at follow-up equal to or lower than 6.8 kPa — considered a normal measure — indicating a reduction in liver fibrosis with treatment.
Moreover, those with CFLD and liver nodularity before treatment showed a trend toward a greater a reduction in liver stiffness measures. According to the researchers, this suggests a “potential positive treatment effect of [Kaftrio] in this category of those with severe CFLD.”
No significant differences were observed regarding APRI or GPR in this patient subgroup, before or after starting on Kaftrio.
Five patients (8.3%) with normal liver stiffness measure values before starting on Kaftrio had a value indicative of fibrosis during follow-up.
Study limitations included the small number of patients with severe CFLD, and the lack of a control group with CFLD who were not eligible for Kaftrio.
“Further study of markers of liver disease following [Kaftrio] would be warranted and more refined definitions of CFLD would be helpful in research settings,” the scientists wrote.
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