PBC treatment Livdelzi shows benefits for 2.5 years in Phase 3 trial
More than 4 in 5 saw meaningful reductions in liver damage markers
After 2.5 years of Livdelzi (seladelpar) treatment, more than 4 in 5 adults with primary biliary cholangitis (PBC) saw meaningful reductions in liver damage markers in the long-term Phase 3 ASSURE clinical trial.
These and other trial findings were presented by Livdelzi’s developer Gilead Sciences at the American Association for the Study of Liver Diseases’ Liver Meeting 2024, held Nov. 15-19 in San Diego.
“With Livdelzi, we’ve introduced an effective and well tolerated option for people living with PBC, offering an important novel treatment option,” Timothy Watkins, MD, vice president of clinical development, inflammation therapeutics at Gilead, said in a company press release.
PBC is marked by inflammation in the bile ducts, a series of tubes that carry the digestive fluid bile out of the liver and to the intestines. This inflammation sets the stage for stalled bile flow, or cholestasis, that ultimately results in liver damage and increased bile in the bloodstream, which leads to symptoms such as itchy skin.
Livdelzi, taken as an oral capsule once a day, is designed to slow or prevent further liver damage and ease symptoms in PBC patients by activating PPAR-delta, a protein that helps regulate bile production, inflammation, and scarring in the liver.
Second-line PBC treatment
Livdelzi was granted accelerated approval in the U.S. earlier this year as a second-line treatment for adults with PBC who don’t respond to or cannot tolerate ursodeoxycholic acid (UDCA), a first-line PBC treatment sold as Urso and Actigall.
The decision was based on trial data showing that Livdelzi reduced blood levels of the liver damage marker alkaline phosphatase (ALP).
“ALP levels are critical markers in assessing liver health, and for people with PBC who are not adequately responding to first-line therapies, reducing, or even normalizing these levels, can make a significant difference in the management of this disease,” said Eric Lawitz, MD, ASSURE’s principal investigator and medical director of the Texas Liver Institute.
Potential full approval is conditional on further clinical data showing the therapy safely improves clinical outcomes for patients.
Similar applications seeking Livdelzi’s approval are being reviewed by regulatory agencies in the European Union and the U.K.
The Phase 3 ASSURE trial (NCT03301506) is tracking outcomes of continual Livdelzi treatment in PBC patients who completed earlier trials of the drug. To be eligible for the earlier trials, participants needed to be unresponsive or intolerant to UDCA.
Newly presented results showed that, after 2.5 years on Livdelzi, 30 out of 37 patients (81%) achieved a composite biochemical response. This response was defined as blood ALP levels decreasing by at least 15% to below 1.67 times the upper limit of normal and normalization of blood bilirubin levels (another liver damage marker). Forty-one percent of the patients achieved a normalization of ALP levels.
“ALP levels are recognized as an important surrogate marker of disease progression in PBC, and providers are shifting to view ALP normalization as a treatment goal,” said Lawitz, who is also a professor of medicine at University of Texas Health San Antonio. “The long-term data from the ASSURE study reinforce that [Livdelzi] consistently lowers ALP, offering a promising and much-needed option for patients living with this chronic liver condition.”
These findings were consistent with ASSURE’s one-year and two-year results. Safety data have also been consistent, without new safety concerns reported with longer-term treatment.
Additional data support results
In separate presentations at the meeting, Gilead also presented new data from RESPONSE (NCT04620733), one of the Phase 3 trials that, together with ASSURE, formed the basis for Livdelzi’s accelerated approval in the U.S.
One-year results from this completed, placebo-controlled study showed that ALP levels decreased by significantly more with Livdelzi than with a placebo, both in patients with compensated cirrhosis (35% vs. 6.6%) and in those without cirrhosis (43.5% vs. 5.8%).
Cirrhosis refers to irreversible liver scarring that interferes with normal liver functioning, and compensated cirrhosis is a stage in which the liver can still perform its functions.
Additional analyses, focused on changes in self-reported itching scores, showed that more than a quarter (26.5%) of those reporting moderate itch at the study’s start experienced near resolution of itch after a year on Livdelzi. Near resolution was also observed in nearly a fifth (18.8%) of those initially reporting severe to very severe itch.
This was in sharp contrast to results seen among patients given a placebo, with none experiencing such dramatic decreases in itch severity.
Livdelzi treatment leads to “statistically significant and durable improvements in both [itching] and markers of cholestasis related to the risk of disease progression,” Watkins said.
Gilead also shared results from a large safety database of PBC patients treated with Livdelzi for up to five years. Data from a total of 486 patients given the therapy’s approved dose (10 mg) and 152 patients given a placebo showed that Livdelzi was generally well tolerated.
Estimated rates of adverse events, serious adverse events, and liver-related adverse events were generally comparable between both groups. There were no reports of Livdelzi-related serious adverse events.
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