Updated ELATIVE analysis reflects elafibranor advantage for fatigue in PBC patients

Findings from the phase III ELATIVE^® trial demonstrate that the peroxisome proliferator-activated receptor (PPAR) agonist elafibranor improves fatigue in individuals with primary biliary cholangitis (PBC), with limited correlation with pruritus.

Treatment with elafibranor up to week 52 led to clinically meaningful improvements in fatigue, with greater improvements than placebo. These were reflected in the greater improvements in PROMIS* Fatigue Short Form 7a (PFSF 7a) and PBC-40 Fatigue domain scores from baseline with the experimental agent, with more pronounced improvements observed among individuals with moderate-to-severe fatigue at baseline, the investigators reported.

In patients with moderate-to-severe fatigue at baseline (defined as PFSF 7a score ≥60 or PBC-40 Fatigue domain score ≥29), there were more elafibranor than placebo recipients who improved to mild/normal fatigue, be it in the PFSF 7a (42.9 percent vs 31.3 percent) or PBC-40 Fatigue domain (22.6 percent vs 15.4 percent) subset. [EASL 2025, abstract LBP-027]

Compared with the placebo arm, the elafibranor arm had greater mean percentage changes from baseline to week 52 in both PFSF 7a (-9.5 percent vs -4.2 percent) and PBC-40 Fatigue domain score (-9.8 percent vs -5.8 percent) subgroups.

There were also more patients achieving ≥MCID** by week 52 with elafibranor than placebo (66.7 percent vs 31.3 percent [PFSF 7a] and 39.6 percent vs 26.9 percent [PBC-40 Fatigue domain]) in the subgroup of participants with moderate-to-severe fatigue at baseline.

Weak correlations between fatigue, pruritus

Baseline fatigue and pruritus patient-reported outcome (PRO) scores had weak correlations in participants with moderate-to-severe fatigue at baseline (r=0.05–0.35). According to the investigators, this suggests that, although both debilitating symptoms could co-exist, pruritus was not a main driver of fatigue.

Changes in fatigue and pruritus PRO scores from baseline to week 52 did not show a strong correlation in the overall population (r=0.08–0.26), as well as in the subset of participants with moderate-to-severe fatigue at baseline (r=0.21–0.33) who were on either the experimental agent or placebo. Correlations <0.3 were defined as weak, the investigators noted.

Similar results were seen in patients receiving elafibranor (r=<0.01–0.26 [all] and r=0.19–0.26 [those with moderate-to-severe fatigue at baseline]), implying that pruritus and fatigue improve independently of one another.

Common PBC symptoms

“Fatigue and pruritus are common symptoms in PBC. While their underlying mechanisms are unclear, it has been hypothesized that fatigue may be exacerbated by pruritus in some patients,” the investigators said.

A total of 141 participants (mean age 56 years) were randomized 2:1 to receive once-daily elafibranor 80 mg or placebo up to week 52. About 95 percent of participants were women.

The mean PFSF 7a scores at baseline were 56.5 and 54.3 in the respective elafibranor and placebo arms, while the mean PBC-40 Fatigue domain scores at baseline were 29 and 28.5, respectively. Improvements of ≥3 points in PFSF 7a and ≥5 points in PBC-40 Fatigue domain scores were deemed MCIDs.

The current findings augment previous results showing the significant favourable impact of elafibranor – which exerts effects on PPARα and PPARδ – on prognostic biomarkers of cholestasis in PBC. [N Engl J Med 2024;390:795-805]

“The key learning in this analysis is that the improvements in fatigue and pruritus with elafibranor treatment can occur independently of each other in patients with PBC,” the investigators concluded.