Elafibranor achieves response, improves pruritus symptoms in primary biliary cholangitis

Key takeaways:

• More patients on elafibranor compared with placebo achieved biochemical response, with a 47% treatment benefit.
• Change in alkaline phosphatase from baseline for elafibranor vs. placebo was 40.6%.

BOSTON — After 52 weeks, elafibranor achieved biochemical response and improved symptoms of pruritus in patients with primary biliary cholangitis, according to late-breaking data presented at The Liver Meeting.

“There is a high unmet need for effective treatments in primary biliary cholangitis (PBC), a rare and chronic autoimmune cholestatic liver disease primarily affecting women over the age of 40 years,” Christopher Bowlus, MD, chief of gastroenterology and hepatology at UC Davis Health, told Healio. “PBC can lead to cirrhosis and the need for liver transplantation. In addition, patients with PBC experience a significant symptom burden irrespective of the stage of their liver disease. These symptoms include fatigue and pruritus.”

Bowlus continued: “Currently there are only two licensed therapies for PBC, including ursodeoxycholic acid (UDCA) and obeticholic acid (OCA). However, up to 40% of patients treated with UDCA do not achieve an adequate response, meaning that they remain at risk for disease progression. In addition, 3% to 5% of patients do not tolerate UDCA. Further, UDCA does not improve the symptoms of PBC. OCA is indicated as second-line therapy, but fewer than half of patients achieve an adequate response and OCA can exacerbate pruritus.”

Elafibranor, an investigational dual peroxisome activated receptor alpha/delta agonist, improves cholestasis through mediating transcriptional expression of genes with improved bile acid metabolism and flow and reduced inflammation, Bowlus said.

“In a phase 2 study of elafibranor in PBC, markers of cholestasis and pruritus improved, suggesting that elafibranor may be effective in filling the unmet need in treating PBC disease related outcomes as well as symptoms of pruritus,” he continued.

In the ELATIVE, phase 3, randomized, double-blind, placebo-controlled trial, Bowlus and colleagues randomized 161 patients with PBC 2:1 to elafibranor 80 mg or placebo once daily for 52 weeks. Those with inadequate response to UDCA continued their UDCA regimen throughout the trial.

Of note, 148 patients completed the double-blind period of the study, Bowlus said; patients remained in the double-blind treatment for up to 104 weeks or until all patients completed 52 weeks of treatment.

The study’s primary endpoint was response at week 52 (defined as alkaline phosphatase <1.67 x upper limit normal) with 15% reduction from baseline and total bilirubin levels at or below upper limit normal. Other endpoints included ALP normalization at week 52, change in pruritus in patients with moderate to severe pruritus based on the PBC Worst Itch Numeric Rating Scale (NRS) score at weeks 24 and 52, and change from baseline through week 52 in PBC-40 Itch and 5-D Itch total scores.

After 52 weeks, 51% of patients who received elafibranor compared with 4% on placebo achieved biochemical response, with a treatment benefit of 47%. ALP normalization was achieved by 15% of those on elafibranor, Bowel said during the presentation, while among patients on placebo it “remained unchanged throughout the 52 weeks.”

The ALP change from baseline between elafibranor and placebo was 40.6%, and ALP reduction was “rapid and sustained” through week 52.

“A reduction in the PBC Worst Itch NRS score was observed in patients treated with elafibranor, but the difference was not statistically significant compared to placebo,” Bowlus told Healio. “In contrast, greater reductions in pruritus measured by the itch domain of the PBC-40 questionnaire and the total score of the 5-D Itch questionnaire were observed in patients treated with elafibranor compared to placebo.”

According to Bowlus, more patients who received elafibranor compared with placebo experienced mild to moderate treatment-emergent adverse events such as abdominal pain, diarrhea, nausea and vomiting, Serious treatment emergent adverse events were reported in 10.2% of those who received treatment compared with 13.2% on placebo.

“We have not seen significant advances in new treatments for PBC for nearly a decade, so it is exciting that we now have an innovative treatment, with the potential to treat the disease progression and the often-debilitating symptom of pruritus,” Bowlus told Healio. “This is good news for treating physicians and their patients. I believe these positive data from the ELATIVE study, investigating the use of elafibranor in patients with PBC, mean we can feel confident that this investigational treatment could offer an effective treatment option for our patients who have an inadequate response or intolerance to UDCA.”