Biochemical response benefits with elafibranor are ‘consistent’ for PBC

In the primary analysis of the phase 3 trial, biochemical response was reported based on the POISE criteria, comprising an alkaline phosphatase (ALP) level below 1.67 times the upper limit of normal (ULN), an ALP reduction of at least 15% from baseline, and a total bilirubin level at or below ULN.

At 52 weeks, this was achieved by 51% of the 108 patients who were randomly assigned to receive the dual PPAR delta and alpha agonist elafibranor 80 mg/day, with 15% showing ALP normalization. This was significantly more than the corresponding 4% and 0% of the 53 patients who instead received placebo, giving a significant treatment difference in biochemical response of 47.2 percentage points.

At the EASL Congress 2024 in Milan, Italy, Mark Sonderup (University of Cape Town, South Africa) expanded on this finding to show that biochemical response was “consistently” achieved by more patients in the elafibranor treatment group than the placebo group according to several other criteria, namely Paris I, Paris II, Barcelona, Momah/Lindor, and complete biochemical response, which he said “have nuanced differences.”

The treatment benefit with elafibranor versus placebo for achieving a biochemical response according to Paris I criteria was 22 percentage points (69 vs 47%). This is defined as an ALP level of less than three times ULN, aspartate aminotransferase (AST) less than two times ULN, and a total bilirubin level of 1 mg/dL or below.

Similarly, 43% of elafibranor-treated patients achieved a biochemical response according to Paris II criteria (ALP ≤1.5 times ULN; AST ≤1.5 times ULN; and normal total bilirubin), which was significantly more than the 6% who were treated with placebo, with a treatment benefit of 37 percentage points.

According to Barcelona criteria – ALP normalization or more than a 40% reduction from baseline – the treatment benefit with elafibranor versus placebo was 55 percentage points (55 vs 0%), and for Momah/Lindor criteria (ALP ≤1.67 times ULN and total bilirubin ≤1 mg/dL) it was 43 percentage points (52 vs 9%).

Complete biochemical response was seen in 10 (9.3%) patients treated with elafibranor, compared with none of those given placebo, giving a 9 percentage point treatment difference that Sonderup commented was “really quite remarkable over such a short space of time.”

Presenting the odds ratios for these biochemical response criteria, he said that in each case there is a “clear benefit in favor of elafibranor.” They ranged from 2.85 for Paris I to 16.65 for Paris II and even infinity for Barcelona and complete biochemical response.

Sonderup concluded: “Elafibranor demonstrated a significant benefit regardless of the biochemical response criteria used.”

In a late-breaking poster at the conference, by Christopher Bowlus (UC Davis School of Medicine, Sacramento, California, USA) and colleagues, analysis of ELATIVE data also suggested that the superior biochemical response with elafibranor compared with placebo at 52 weeks is “sustained or improved” through 78 weeks.

Their findings in 27 elafibranor- and 13 placebo-treated patients showed that 70% versus 0% had a biochemical response according to POISE criteria at week 78 – 21% of patients achieved this after week 52, while for 79% the response was sustained from week 52. The corresponding rates for ALP normalization were 19% versus 0%, with 40% achieving this response after week 52 and 60% sustaining the response from week 52.

However, the researchers acknowledge that their analysis is “limited by low patient numbers, which was impacted by the study design as all patients stopped their assigned regimen once the final patient had completed the Week 52 visit.”