2nd-line PBC treatment options call for personalized care: Analysis
Iqirvo seen better for reducing liver damage, Livdelzi for itching
Among second-line treatments for primary biliary cholangitis (PBC), Iqirvo (elafibranor) may work better than Livdelzi (seladelpar) at reducing markers of liver damage, while Livdelzi may be the most effective at reducing itching.
Ocaliva (obeticholic acid), which was pulled from the European Union (EU) market and turned down for full approval in the U.S., also reduced markers of liver damage but was linked to new-onset itching and serious side effects.
These are the findings of a meta-analysis of data from three Phase 3 clinical trials. While not a direct comparison of the three treatment options, “these findings can be used in clinical practice to personalise second‐line treatment and inform decisions,” the researchers wrote. For patients, this could mean better clinical outcomes.
The findings were described in the study, “Second‐Line Treatment for Patients With Primary Biliary Cholangitis: A Systematic Review With Network Meta‐Analysis,” published in Liver International by researchers in the U.S. and Italy. Three of them have links to Ipsen, which markets Iqirvo, and two to Gilead, which markets Livdelzi.
“The therapeutic landscape for PBC is expanding,” four other researchers in Italy wrote in an accompanying editorial. “However, “high-quality head-to-head studies are needed to directly compare short-term efficacy and safety profiles, and real-world data will provide insights into long-term outcomes,” they wrote.
Many need 2nd-line PBC treatment
PBC is a chronic form of cholangitis, an inflammation in the tubes that transport bile from the liver to the intestines to help digest food. As a result of this damaging inflammation, bile accumulates in the liver and leaks into the bloodstream, leading to itching and a range of other cholangitis symptoms.
The first-line PBC treatment is ursodeoxycholic acid (UDCA), marketed in the U.S. as Actigall and Urso or as generics, but many patients fail to respond to it and need second-line treatment to prevent the disease from progressing and causing complications.
Three therapies —Ocaliva, Livdelzi, and Iqirvo — have been cleared for use as second-line PBC treatments in the U.S. and other regions. However, Ocaliva is no longer available in the EU, and its continued use in the U.S. may be at risk due to reportedly insufficient evidence of its clinical benefits.
There has been no direct comparison among medications used for second-line treatment, making it challenging for doctors to choose the best option for each patient.
With this in mind, the researchers conducted a network meta-analysis, which compares three or more medications simultaneously in a single analysis by combining data across a network of studies.
When searching for published studies up to July 2024 reporting on data from placebo-controlled Phase 3 trials of second-line PBC therapies that were available at the time, the team found three such studies: POISE (NCT01473524) for Ocaliva, RESPONSE (NCT04620733) for Livdelzi, and ELATIVE (NCT04526665) for Iqirvo.
The studies involved a total of 570 PBC patients who either did not respond to or did not tolerate UDCA: 379 patients received treatment, and 191 were given a placebo.
As a main outcome, the researchers looked at the proportion of patients achieving a biochemical response after one year, defined as specific blood levels or level reductions of alkaline phosphatase and bilirubin, two markers of liver damage. Secondary outcomes included the occurrence of new-onset itching as an adverse event and of serious adverse events.
All PBC treatments outperform placebo
The network meta-analysis showed that all three medications led to a significantly greater proportion of patients attaining biochemical response compared with those on the placebo.
However, indirect comparisons indicated that Iqirvo was significantly superior to Livdelzi, but not significantly different from Ocaliva. There were no significant differences between Livdelzi and Ocaliva in terms of rates of biochemical response.
Regarding secondary outcomes, Ocaliva was associated with a significantly higher risk of new-onset itching and serious side effects compared with a placebo. In turn, Livdelzi was linked to a significantly lower risk of new-onset itching relative to a placebo.
When comparing the three therapies indirectly, the team found that Livdelzi and Iqirvo were associated with a significantly lower risk of new-onset itching when compared with Ocaliva.
There were no significant differences between Livdelzi and Iqirvo regarding new-onset itching or among all three therapies on the risk of serious adverse events.
“All treatment regimens, with variable results, showed efficacy as compared to placebo although both new drugs — [Livdelzi] and [Iqirvo] — showed a higher margin of efficacy as compared to [Ocaliva],” the researchers wrote. “Considering the potential, future limitations to the use of [Ocaliva], at least in the EU, one has to balance the increased efficacy [Iqirvo] with the lower incidence of [itching] with [Livdelzi], a finding that could be related to an intrinsic mechanism of action of the drug, and that might indicate its preferential use in patients at higher risk of developing this troublesome symptom,” the team wrote.
In the absence of a direct comparison, “selection of optimal treatment for second‐line therapy of patients with PBC may be quite nuanced, and the decision should be tailored on the single patient rather than being universal,” they wrote.
Further studies are needed to confirm these findings and refine treatment strategies, the researchers said. Until then, they wrote, the results “may inform decisions regarding second‐line treatment of patients with PBC and help better tailor treatment to patients’ needs.”
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