Adding obeticholic acid to slow-release bezafibrate shows promise for PBC

In a late-breaking poster at the EASL Congress 2024 in Milan, Italy, David Jones and colleagues told attendees that the results “suggest that obeticholic acid plus bezafibrate is generally well tolerated and has therapeutic potential to normalize multiple serum biomarkers associated with improved transplant-free and decompensation-free survival.”

The study participants included 75 patients with PBC who had alkaline phosphatase (ALP) levels at least 1.5 times the upper limit of normal (ULN) and total bilirubin levels above ULN but below 2 times ULN. They had either taken ursodeoxycholic acid (UDCA) for at least 12 months before the study or had not used UDCA for 3 months prior to the study.

The patients were randomly assigned to receive one of four treatment regimens for a 12-week double blind period:

• Once-daily oral bezafibrate sustained release (SR) 400 mg with obeticholic acid 5 mg titrated to 10 mg after 4 weeks or placebo;
• Once-daily oral bezafibrate immediate release (IR) 200 mg with obeticholic acid 5 mg titrated to 10 mg after 4 weeks or placebo.

The participants were aged a mean of 55.4 years, 93.3% were women, and their mean ALP and total bilirubin levels were 285.6 U/L and 0.6 mg/dL. The majority (98.7%) had used UDCA with a mean total daily dose of 15.8 mg/kg.

At 6 months, the greatest reduction in ALP was seen in the 18 patients receiving obeticholic acid plus bezafibrate SR 400 mg, at 65.3%, compared with 49.0% for the 19 patients receiving bezafibrate SR 400 mg alone, and 42.4% and 39.3% for the 19 patients each receiving bezafibrate IR 200 mg with or without obeticholic acid, respectively.

The corresponding rates of ALP normalization, defined as levels below ULN or at least a 40% reduction, were 61.1%, 57.9%, 42.1%, and 36.8%.

The findings were similar for biochemical remission, which was defined as ALP normalization plus gamma-glutamyl transferase, alanine aminotransferase, and aspartate aminotransferase levels at or below ULN, and a total bilirubin level of no more than 0.6 times ULN.

The rates for this were 66.7% for the patients in the obeticholic acid plus bezafibrate SR 400 mg group, 42.1% for those in the bezafibrate SR 400 mg only group, and 47.4% and 31.6% for those in the bezafibrate IM 200 mg with or without obeticholic acid groups, respectively.

These biochemical improvements seen with the use of obeticholic acid plus bezafibrate SR 400 mg were associated with reductions in the GLOBE and UK-PBC scores, which measure the risk for liver transplant and death, of 0.7 and 1.1, respectively.

The researchers note that treatment-emergent adverse events (TEAEs) “were generally balanced across cohorts,” occurring in 63.2–73.7% of patients.

Serious TEAEs occurred in two patients receiving obeticholic acid plus bezafibrate SR 400 mg and one patient receiving bezafibrate IR 200 mg. And TEAEs leading to discontinuation occurred in a corresponding three and one patients, none resulted in death.

Jones and associates note that rates of pruritus were “substantially lower” with obeticholic acid plus bezafibrate SR 400 mg, at 11.1%, compared with those seen with obeticholic acid in the phase 3 POISE study, at 56–68%.

They conclude: “The data support phase 3 development of the SR formulation of [bezafibrate] with low doses of [obeticholic acid].”