Editorial: Peroxisome Proliferator‐Activated Receptor Agonists—Shifting the Goalpost From Biochemical Response to Symptom Directed Therapy in PBC

In the post hoc analysis by Levy et al. 1 they further examine data from the pivotal RESPONSE trial (NCT04620733), which demonstrated that seladelpar, a selective peroxisome proliferator-activated receptor (PPAR) delta agonist, significantly improved biochemical response in patients with Primary Biliary Cholangitis (PBC) 2. A key secondary endpoint in RESPONSE showed significant reduction in pruritus, measured using the Worst Itch Numeric Rating Scale (NRS) at Month 6 in patients with baseline NRS scores ≥ 4 (i.e., moderate–severe pruritus). Fatigue was not a prespecified endpoint in RESPONSE. This analysis provides a more granular evaluation of pruritus and an exploratory assessment of fatigue 1. The authors also evaluated patients with severe itch (NRS ≥ 7, PBC-40 itch ≥ 7) and incorporated additional dimensions of itch burden available from the 5-D Itch scale, including pictorial representations of itch distribution and analyses of patient-level transitions in itch severity over 12 months. These analyses offer a more comprehensive view of pruritus reduction by seladelpar across multiple patient-reported outcome instruments. The improvement in PBC-related pruritus by PPAR agonist treatment appears to be a class effect. The ELATIVE study (elafibranor; PPARα/δ agonist) reported significant improvements in PBC-40 Itch and 5D Itch scores, but not WI-NRS 3. Similarly, bezafibrate (a pan-PPAR agonist) demonstrated significant antipruritic effect in the pruritus focused FITCH trial 4, with improvements in pruritus also reported in the BEZURSO 5 trial and from real world experience. The mechanisms by which PPAR agonists modulate pruritus are incompletely defined and likely multifactorial. Proposed pathways include modulation of innate and adaptive immune responses, alterations in systemic cytokine profiles, and downstream effects on signalling within the central nervous system, peripheral sensory neurons, and skin 6-9. Levy et al. 1 also performed an exploratory fatigue analysis using the PBC-40 fatigue domain in patients with severe itch (NRS ≥ 7, PBC-40 Itch ≥ 7). Although patient numbers were small, fatigue improvement was most apparent in the NRS ≥ 7 subgroup. In contrast, among patients with a PBC-40 itch score ≥ 7, fatigue improvements varied and were not sustained at 12 months. A potential interplay between pruritus, sleep disturbance and fatigue was also explored, showing improvements in sleep question scores in the 5-D Itch and PBC-40 instruments, and a weak to moderate correlation between itch and fatigue. These findings highlight the complexity of evaluating fatigue as a treatment outcome and underscore the need to distinguish tiredness from central fatigue. Central fatigue reflects physical and/or mental exhaustion, not relieved by rest, and often associated with neurocognitive and psychosocial impairment. In contrast, tiredness typically has an identifiable precipitant, such as sleep disruption, and improves with rest. Disturbed sleep commonly accompanies severe itch. In this context, and given the post hoc nature and small subgroup sizes, dedicated prospective studies are required to better define the impact of PPAR agonists on fatigue. Such studies should address key challenges in fatigue assessment, including the absence of robust biomarkers, high variability in patient-reported symptoms, distinctions between central fatigue and tiredness, a substantial placebo effect, and the natural fluctuation of fatigue over time independent of intervention, particularly in symptom-enriched populations. Henry H. Nguyen: conceptualization, writing – original draft, writing – review and editing. Mark S. Swain: conceptualization, writing -review and editing. The authors have nothing to report. Clinical trial or research funding from 89Bio, Altimmune, Ancella, Boehringer Ingelheim, Cymabay, Eli Lilly, Galectin, Gilead, GlaxoSmithKline, Inventiva, Ipsen, Kowa, Madrigal, Merck, Mirum, Novo Nordisk, Pfizer, Roche, Mirum, Kowa. Received speaker payments or honoraria from Abbott, Gilead, Ipsen, Novo Nordisk, Umecrine, Mirum. Participated on an Advisory Board for Abbott, Advanz, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Ipsen, Mirum and Novo Nordisk. This article is linked to Levy et al. paper. To view this article, https://doi.org/10.1111/apt.70630. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.