Elafibranor for primary biliary cholangitis scores high in phase III trial

The oral, dual peroxisome proliferator-activated receptor-α/δ agonist elafibranor improves biomarkers of cholestasis and quells itching in patients with primary biliary cholangitis, while having an acceptable safety profile, as shown in the phase III ELATIVE study.

In a cohort of 161 patients with inadequate response to ursodeoxycholic acid, significantly more patients treated with elafibranor than with placebo achieved biochemical response (defined as alkaline phosphatase <1.67 x the upper limit of normal, with ≥15-percent reduction from baseline, and total bilirubin at or below the upper limit of normal) at week 52 (51 percent vs 4 percent; p<0.0001). [AASLD 2023, abstract 5007]

“Reductions in alkaline phosphatase were observed as early as week 4 and sustained through week 52,” with a treatment difference of –41 percent (95 percent confidence interval [CI], –48 to –33; p<0.0001), reported lead researcher Dr Christopher Bowlus of University of California Davis in Sacramento, California, US.

Alkaline phosphatase returned to normal levels in 15 percent of patients on elafibranor and in none of those on placebo (p=0.0019).

Elafibranor also yielded benefits for patients with moderate-to-severe pruritus. Bowlus pointed out that compared with placebo, the active drug significantly reduced the pruritus based on the Primary Biliary Cholangitis-40 Itch score (–2.5 vs –0.1; p=0.007) and the 5-Dimensional Itch total score (–4.2 vs –1.2; p=0.0199). Meanwhile, the PBC Worst Itch numerical rating score only trended lower with elafibranor (–1.9 vs –1.1; p=0.1970).

“Elafibranor was generally well tolerated with an acceptable safety profile,” Bowlus said.

The most common treatment-emergent adverse events (TEAEs) occurring in proportionally more patients receiving elafibranor versus placebo (>1-percent difference) included mild or moderate abdominal pain, diarrhoea, nausea, and vomiting, he added.

The frequency of serious TEAEs was comparable between the two treatment groups, occurring in 10.2 percent and 13.2 percent of patients receiving elafibranor and placebo, respectively.

New treatment option

Of the patients included in ELATIVE, 108 received elafibranor 80 mg and 53 received placebo. Treatment was given orally every day. Baseline characteristics were comparable between the elafibranor and placebo groups (mean age 57.5 vs 56.4 years, 94 percent vs 98 percent women, mean alkaline phosphatase levels 321.3 vs 323.1 U/L, liver stiffness >10 kPa and/or bridging fibrosis or cirrhosis 34 percent vs 38 percent).

The positive results of the phase III trial are especially favourable, given that between 40 percent and 50 percent of patients have an inadequate response to ursodeoxycholic acid and obeticholic acid—the only currently licensed first-line and second-line treatments for primary biliary cholangitis, according to Bowlus. [Hepatology 2008;48:871-877; N Engl J Med 2016;375:631-643]

Elafibranor binds to both PPAR-α and PPAR-δ receptors and activates them. It works by increasing bile acid metabolism and elimination and, in turn, lowering bile acid production and inflammation, Bowlus explained.

The drug “may provide an effective new treatment for patients with primary biliary cholangitis,” he said.