Seladelpar still eases itch, liver damage after 2 years: PBC trial

Two years of treatment with seladelpar, Gilead Sciences’ oral candidate, safely results in rapid and sustained reductions in itching and liver damage markers for most people with primary biliary cholangitis (PBC), trial data showed.

Interim findings from the open-label, long-term Phase 3 ASSURE clinical trial (NCT03301506) — which were consistent with previous one-year data — were shared in a presentation at the European Association for the Study of the Liver (EASL) Congress, held June 5-8 in Milan.

“The data presented at EASL further support the sustained efficacy and safety profile of seladelpar observed across its robust development program, including a capacity to normalize ALP values [a liver damage marker] for many of the people studied with PBC,” Timothy Watkins, MD, vice president, clinical development of inflammation therapeutics at Gilead, said in a company press release.

Because “ALP is recognized as an important surrogate marker of disease progression in PBC, providers are shifting to normalization as a treatment goal, which could potentially be enabled by seladelpar, if approved,” Watkins said.

Applications seeking approval of the seladelpar are currently under review in the U.S. as well as the European Union and the U.K. A decision in the U.S. is expected by Aug. 14.

‘Current medications fall short’ for many

PBC is a disorder marked by chronic inflammation of the bile ducts, a series of tubes that carry bile (a digestive fluid) out of the liver to the intestines. This leads to a buildup of bile in the liver, which can cause liver damage and result in bile spilling into the bloodstream, which results in symptoms such as itching.

The first-line treatment for PBC is ursodeoxycholic acid (UDCA), sold as Urso and Actigall. Ocaliva (obeticholic acid), a second-line therapy for PBC, is used in patients who don’t respond to UDCA, but it can worsen itching in some cases.

“Currently, there is no cure for PBC,” said Palak Trivedi, PhD, associate professor and consultant hepatologist at the University of Birmingham, who presented the findings at EASL. “While there are lifelong medicines that may slow liver damage and stop it from progressing, current medications fall short in about 40% of people. This is because many individuals continue to have abnormal liver tests on the current treatment options, and these treatments don’t reduce one of the main relentless symptoms, [itching], which impacts the quality of life in people living with PBC.”

Seladelpar is a daily oral therapy designed to reduce bile production and liver inflammation and scarring by selectively activating a protein called PPAR-delta.

The ASSURE study is evaluating the therapy’s long-term safety and efficacy in PBC patients who participated in prior seladelpar trials. All ASSURE participants are receiving seladelpar for up to five years.

Newly presented data concerned 158 patients who entered ASSURE after completing the Phase 3 RESPONSE trial (NCT04620733). RESPONSE results demonstrated that seladelpar outperformed a placebo at inducing a clinically meaningful biochemical response in adults with PBC who didn’t respond to or couldn’t tolerate UDCA.

Response was defined as showing normal blood levels of the liver damage marker bilirubin and having less than 1.67 times the upper limit of total ALP levels and at least a 15% decrease in these levels.

Raising the treatment bar

Of 102 patients who had been on seladelpar for 18 months — one year in RESPONSE, then another six months in ASSURE — 62% met the biochemical response and 33% achieved ALP normalization. Among 29 patients who continuously received seladelpar for two years, 72% showed a biochemical response and 17% attained ALP normalization.

After six months on seladelpar treatment in ASSURE, three-quarters (75%) of the 52 patients who’d been on placebo in RESPONSE also met the biochemical response outcome, and 27% showed ALP normalization. These rates were increased to 94% and 50%, respectively, among the 16 patients who completed one year of treatment.

Similar response rates were observed among the 179 patients who participated in studies other than RESPONSE before entering ASSURE.

Seladelpar treatment also led to long-term reductions in itch, which patients rated on a scale from 0 to 10. Among patients with available data who started with a score of 4 or higher — indicating moderate to severe pruritis — average scores decreased more than 3 points after one and two years on seladelpar.

Seladelpar continued to be well tolerated with longer treatment.

The results “demonstrate that seladelpar may meaningfully raise the bar in PBC,” Trivedi said.

Both RESPONSE data and interim ASSURE results are part of the regulatory application seeking approval of the therapy for PBC.

“Seladelpar is a potential best-in-class therapy that could transform the treatment landscape for people living with PBC by not only improving or even normalizing markers of liver function, but also improving pruritis or itch,” Watkins said. “We’re committed to transforming the management of PBC and the lives of those impacted by this rare disease as we work together to bring seladelpar to the community, if approved.”

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