SAN DIEGO—Elafibranor and seladelpar, both recently approved by the FDA for treatment of primary biliary cholangitis, showed prolonged efficacy and led to some reductions in pruritus, according to an extension study and new analyses of the ELATIVE and RESPONSE trials presented at The Liver Meeting 2024.

A three-year, open-label extension of the ELATIVE study (poster 5041), showed that responses to elafibranor “are sustained long term, and the side effect profile shows it is a very safe drug,” said Mark Swain, MD, reporting the results.

Elafibranor: Liver Stiffness And Fatigue Benefits

The study also showed that elafibranor had an effect on liver stiffness. “Normally, if you follow PBC over time, in people that have not responded to therapy, they start to climb in their liver stiffness measurement and fibrosis markers,” said Dr. Swain, a professor of medicine at the University of Calgary, in Alberta. “But what this shows is this is stabilized. It doesn’t seem to be improving, but it’s the same, and if you’re the same and not advancing, your prognosis will be better.”

The FDA granted the peroxisome proliferator–activated receptor (PPAR) agonist elafibranor accelerated approval in June 2024, following results from the ELATIVE study, which was a phase 3, double-blind, placebo-controlled trial that included 161 patients with PBC who responded inadequately to or were intolerant of ursodeoxycholic acid.

Patients in the study received 80 mg of elafibranor once daily or placebo. At week 52, 51% of patients in the elafibranor group and 4% in the placebo group demonstrated response, defined as an alkaline phosphatase (ALP) level of less than 1.67 times the upper limit of normal and at least a 15% reduction from baseline, normal total bilirubin levels, and a reduction in pruritus intensity through weeks 24 and 54. The level of ALP normalized in 15% of patients receiving elafibranor and no patients in the placebo group (P=0.002).

In the open-label extension, participants could remain on 80 mg daily of elafibranor or cross over after participating in the placebo group. The researchers reported on a three-year interim analysis that included 138 patients, 93 of whom previously received elafibranor and 45 who initially received placebo. The ALP reductions remained stable during the extension period, but biochemical responses fluctuated. Of those who had a biological response at week 52, 30% failed to record a biological response more than once between weeks 52 and 156. Of patients who did not achieve a biochemical response at week 52, 37% had at least one biochemical response between weeks 52 and 156.

In a separate analysis, researchers examined fatigue levels during the ELATIVE extension study (poster 5042). “When you ask PBC patients what one thing really impacts [quality of] life, fatigue is by far the No. 1 thing, and there is no treatment for fatigue,” said Dr. Swain, who was involved in both analyses.

The results included data from 48 patients at baseline and week 104, and 26 who had data available at baseline and week 130. From baseline to week 104, of patients with moderate to severe fatigue, 56% experienced a minimally clinically important difference (MCID) in Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue Short Form 7a (=3), 50% achieved MCID in the PBC-40 fatigue domain (=5) and 69% in the Epworth Sleepiness Scale (=2). From baseline to week 130, the percentages were 78%, 58% and 50%, respectively.

“When you look at people who started off with moderate or severe fatigue at the very beginning, and you look at two to two-and-a-half years—well past any placebo effect you might have, which [would last] maybe six months—at least half of these patients, or more, are getting better, improving by the minimum clinically significant difference,” Dr. Swain said. “It looks like [the benefit] is going to last a long time, which will probably be highly relevant to people who have fatigue with PBC.”

Ongoing Seladelpar Responses

Also at The Liver Meeting, researchers reported on an open-label extension of the phase 3 RESPONSE study, originally published in February 2024, which led to accelerated FDA approval of seladelpar for treatment of PBC in combination with ursodeoxycholic acid (poster 5044).

The original RESPONSE trial found a greater biochemical response in patients taking 10 mg of the PPAR-delta agonist seladelpar daily than those taking placebo (61.7% vs. 20.0%; P<0.001), as well as more frequent normalization of ALP (25.0% vs. 0%; P<0.001) and reduction in pruritus scores.

In the extension study, which included 30 months of follow-up, 81% of patients on seladelpar had a biochemical response by month 30, 90% had normal ALP levels, and there was no change in the rate of adverse events. The mean change from baseline in the pruritus numerical rating scale was a decrease of 3.3 at month 6 among 99 participants with moderate to severe pruritus.

Potential for Combination Therapy

These studies are encouraging and suggest that combination therapy may be effective, said Saul Karpen, MD, PhD, the chief scientific officer at the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University, in Richmond. “Since they do target different aspects of disease pathogenesis, there’s always this question about whether combination therapies are both effective and safe. I think we’re happy that there are additional agents that are building on some history with PPARs as being good anti-inflammatory and anti-fibrotic targets for these chronic cholestatic diseases,” said Dr. Karpen, who was not involved in any of the studies.

“As far as comparative efficacy, that’s certainly a question that no one can answer just yet, but these [drugs] certainly look like they’re hitting the mark with being agents to study more deeply for both safety and efficacy,” he added.

Dr. Karpen was not convinced about the improvements in pruritus with both drugs, saying that such improvements would be welcome, but the trials included too few patients to be convincing. “They really need to be expanded to many more patients to know whether or not there’s some applicability,” he said. “The seladelpar study is bigger, which is certainly much more helpful, and that was just primarily a biochemical improvement with that drug. There did not seem to be a great pruritus improvement.”

—Jim Kling

Dr. Karpen reported no relevant financial disclosures. Dr. Swain reported financial relationships with AbbVie, Allergan, Altimmune, Arbutus, Assembly, AstraZeneca, Axcella, BMS, Calliditas, Celgene, CymaBay, Eiger, Enanta, Galectin, Galmed, GENFIT, Gilead, GSK, Intercept, Inventiva, Ipsen, Janssen, Kowa, Madrigal, Merck, Novartis, Novo Nordisk, Pfizer, Roche and Sagimet.