Experts are hailing the FDA’s recent accelerated approval of seladelpar for the treatment of primary biliary cholangitis as a critical advancement for patients with PBC, particularly those who have an inadequate response or are intolerant to the standard first-line treatment, ursodeoxycholic acid (UDCA).

The approval was based on results from a series of clinical trials that demonstrated the safety and efficacy of seladelpar (Livdelzi, Gilead), a selective peroxisome proliferator–activated receptor-delta agonist, in improving liver function and alleviating symptoms in PBC patients.

“We see far too many patients with insufficient response to the current therapies and symptoms such as itch that go unresolved and impair quality of life,” Gideon Hirschfield, MB BChir, FRCP, PhD, the principal investigator in the phase 3 and open-label seladelpar extension trials, told GEN Priority Report.

“These patients have an unmet need, but when you give seladelpar, you see a durable response. You see symptoms get better. You see improvement in blood levels,” said Dr. Hirschfield, the Lily and Terry Horner Chair in Autoimmune Liver Disease Research at Toronto General Hospital.

RESPONSE Trial Shows Enzyme Normalizations

Dr. Hirschfield and his co-investigators demonstrated the safety and efficacy of seladelpar in the RESPONSE trial, a pivotal phase 3, 12-month, double-blind, placebo-controlled study in 193 patients who had an inadequate response to or could not tolerate UDCA (N Engl J Med 2024;390[9]:783-794). Participants were randomized to receive seladelpar (10 mg daily) or placebo.

The results were highly promising, with 62% of patients in the seladelpar group achieving a biochemical response at 12 months compared with 20% in the placebo group (P<0.001). Additionally, 25% of seladelpar-treated patients achieved complete normalization of alkaline phosphatase (ALP), compared with none of the placebo controls (P<0.001).

“These findings are particularly important because elevated ALP is associated with worse clinical outcomes in PBC, and its normalization is a crucial therapeutic goal,” said Anurag Maheshwari, MD, a liver disease specialist at the Center for Liver and Hepatobiliary Diseases at Mercy Medical Center, in Baltimore, who was not involved in the study. “It’s rare to find a treatment that normalizes levels, so this makes seladelpar a very attractive addition to our armament of PBC therapies.”

In the RESPONSE trial, pruritus, a common and debilitating symptom of PBC, was significantly reduced in patients treated with seladelpar. Among those with moderate to severe pruritus at baseline, seladelpar reduced the pruritus numerical rating scale score by an average of 3.2 points, versus a reduction of 1.7 points in the placebo group. This improvement in pruritus, a key secondary end point of the trial, distinguishes seladelpar from obeticholic acid, which has been associated with worsening pruritus.

“It seems that seladelpar is unique in PBC treatments because it uniquely targets [interleukin]-31, which is the mechanism of itching,” Dr. Maheshwari said. “This a very big advancement, particularly for patients whose quality of life suffers due to itching.”

Sustained Results Seen In Open-Label Studies

A two-year, open-label extension of another seladelpar trial confirmed the sustained efficacy of seladelpar with continued reductions in ALP levels and stable bilirubin levels (Aliment Pharmacol Ther 2023;59[2]:186-200). The safety profile of seladelpar remained favorable over the extended treatment period, and the treatment was well tolerated, with a similar incidence of adverse events in the seladelpar and placebo groups.

This extension study demonstrated that the improvements in liver biochemistry observed during the initial 12 months were maintained, and in some cases further enhanced, with prolonged treatment. The reduction in ALP was particularly notable, and the pruritus relief provided by seladelpar was sustained over the long term.

The ASSURE study, another ongoing open-label trial that includes patients who participated in earlier seladelpar trials (179 from legacy trials and 158 from the RESPONSE trial), is allowing for extended observation of the drug’s effects. The interim data, shown at DDW 2024 and the EASL Congress 2024, revealed that roughly 70% of legacy and RESPONSE trial participants achieved a composite biochemical response (ALP <1.67 × upper limit of normal [ULN], ALP decrease =15%, and total bilirubin =1 × ULN). In addition, more than 30% of patients achieved full normalization of ALP, reinforcing seladelpar’s efficacy in controlling cholestasis.

Given that approximately 40% of PBC patients have a suboptimal response to UDCA, the availability of a well-tolerated and effective treatment that normalizes ALP levels, reduces pruritus and maintains a favorable safety profile over the long term makes it a valuable tool in treating PBC, according to Dr. Maheshwari.

“There’s understandable excitement about the potency, efficacy and durability of seladelpar to produce a rapid response to normalize blood levels and address the symptoms that plague patients,” Dr. Hirschfield said. “And this is achieved with a well-tolerated daily oral [medication], so patients won’t feel burdened by treatment either.”

—Jordan Davidson

Dr. Hirschfield reported financial relationships with CymaBay, Escient, Falk, Gilead, GSK, Intercept, Ipsen, Mirum and Pliant. Dr. Maheshwari reported no relevant financial disclosures.