FDA OKs New Option for Primary Biliary Cholangitis

The FDA granted accelerated approval to seladelpar (Livdelzi) for adults with primary biliary cholangitis (PBC), a rare and chronic autoimmune disease of the bile ducts, drugmaker Gilead Sciences announced on Wednesday.

An oral peroxisome proliferator-activated receptor (PPAR)-delta agonist, seladelpar is indicated for use in combination with ursodeoxycholic acid (UDCA) for patients with an inadequate response to that standard therapy, or as monotherapy for those who cannot tolerate UDCA. Seladelpar is not recommended for patients with decompensated cirrhosis.

Approval of seladelpar was supported by the RESPONSE trial, which included 193 patients with PBC at risk of disease progression. In the phase III study, seladelpar improved markers of disease activity and pruritus.

At 1 year, 62% of patients treated with the PPAR-delta agonist achieved a biochemical response compared with 20% of those assigned to placebo (P<0.0001), with that composite endpoint defined as an alkaline phosphatase (ALP) <1.67 times the upper limit of normal (ULN), an ALP decrease ≥15%, and total bilirubin <1 times the ULN.

Normalization of ALP — a cholestatic marker that predicts the risk of needing a liver transplant or mortality — reached 25% in the seladelpar group versus none in the placebo group at that time point (P<0.0001). Pruritus, a key secondary endpoint, was also significantly improved with the PPAR-delta agonist.

Managing pruritus is “a significant priority for our patients who want, and deserve, a better quality of life,” said investigator Gideon Hirschfield, PhD, MB BChir, of the Toronto Centre for Liver Disease at the University of Toronto, when the findings were presented last year at the annual meeting of the American Association for the Study of Liver Diseases. “These are very exciting results for people living with PBC.”

Among the patients with a baseline pruritus score ≥4 (with 0 representing no itch and 10 the “worst imaginable itch”), those in the seladelpar group had a change of -3.2 at 6 months compared with a change of -1.7 in the placebo group (P=0.0051).

An estimated 130,000 Americans — predominantly women — have PBC, a disease with no cure that can lead to liver damage and, if left untreated, progress to liver failure.

“More people are being diagnosed with PBC, impacting people of varied ages, gender, race and ethnicity. Those living with PBC share common symptoms, including incessant itching or skin-crawling sensations, as well as debilitating fatigue that is made worse by the itching at night,” said Carol Roberts, president of the PBCers Organization, a patient advocacy and support group. “The availability of a new treatment option that can help reduce this intense itching while also improving biomarkers of active liver disease is a milestone for our community.”

Continued approval of seladelpar may be contingent on verification of clinical benefit in confirmatory trials. An ongoing placebo-controlled phase III study — AFFIRM — aims to evaluate seladelpar’s effect on clinical outcomes in patients with compensated cirrhosis due to PBC.

The recommended dosage of seladelpar is 10 mg, once daily with or without food.

According to the labeling, common adverse events with the drug in RESPONSE included headache (8% vs 3% with placebo), abdominal pain (7% vs 2%), nausea (6% vs 5%), abdominal distension (6% vs 3%), and dizziness (5% vs 2%).

Warnings and precautions include risks for fractures, liver test abnormalities, and biliary obstructions. Patients with cirrhosis should be monitored for decompensation and discontinuation should be considered if progression to moderate or severe hepatic impairment (Child-Pugh B or C) occurs.

Due to drug interactions, concomitant use of seladelpar and OAT3 inhibitors or strong CYP2C9 inhibitors should be avoided. The prescribing information also includes considerations for patients on CYP2C9, CYP3A4, and BCRP inhibitors; rifampin; and bile acid sequestrants due to drug interactions.

Mike Bassett contributed to this report.

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