Highlights
– Pooled analysis of two phase 3 trials (ENHANCE and RESPONSE) found seladelpar 10 mg daily produced greater reductions in pruritus scores than placebo in patients with PBC and moderate-to-severe itch at baseline.
– Numeric rating scale (NRS) itch decreased by 3.33 points with seladelpar vs 1.77 with placebo at 6 months (P < .01); 5-D itch total score and sleep-related itch measures also improved significantly.
– Safety and tolerability were similar between seladelpar and placebo groups over the 6-month period analyzed.
– Findings support seladelpar’s potential to reduce symptomatic burden in PBC patients who fail or cannot tolerate ursodeoxycholic acid (UDCA), with implications for earlier use in selected cases.
Background: disease context and unmet need
Primary biliary cholangitis (PBC) is an immune-mediated, chronic cholestatic liver disease characterized by progressive destruction of intrahepatic bile ducts, biochemical cholestasis, and risk of cirrhosis and liver failure. Pruritus (itch) is a frequent and often debilitating symptom reported in up to two-thirds of patients, ranging from intermittent nuisance to persistent, severe problems that impair sleep, concentration, mood, and overall quality of life.
Ursodeoxycholic acid (UDCA) has been the standard first-line disease-modifying therapy for PBC and improves biochemical indices and long-term outcomes for many patients; nevertheless, approximately 30–40% of patients do not achieve an adequate biochemical response or cannot tolerate UDCA. For these patients, second-line therapies that improve disease markers and, importantly, symptoms such as pruritus are needed. Historically, management of cholestatic itch has relied on agents like bile acid sequestrants, rifampicin, naltrexone, and sertraline, but efficacy is variable and adverse effects and drug interactions can limit use.
Study design and pooled-analysis methods
Marlyn J. Mayo and colleagues presented a pooled analysis of two randomized, placebo-controlled, phase 3 trials—ENHANCE and RESPONSE—at the American College of Gastroenterology (ACG) 2025 Annual Scientific Meeting. Both trials enrolled patients with PBC who had moderate-to-severe pruritus at baseline and an inadequate biochemical response to UDCA or were intolerant to UDCA. Where tolerated, seladelpar was given as add-on therapy to UDCA.
Key design features reflected in the pooled dataset:
- ENHANCE: randomized 1:1:1 to oral seladelpar 5 mg, 10 mg, or placebo daily for up to 52 weeks; the trial was terminated early and key endpoints were amended to 3 months.
- RESPONSE: randomized 2:1 to oral seladelpar 10 mg daily or placebo for up to 52 weeks.
The pooled analysis focused on the subset of patients with baseline numerical rating scale (NRS) itch scores ≥4 (indicative of moderate-to-severe itch). The analysis cohort comprised 126 patients: 76 treated with seladelpar 10 mg and 50 with placebo. Baseline characteristics were similar between groups (mean age 53 years, 96% female, mean age at PBC diagnosis 47 years), and baseline itch measures (NRS, PBC-40 itch domain, and 5-D itch scale) were comparable.
Key results
This pooled analysis examined multiple validated itch metrics and sleep disturbance measures over a 6-month period. Principal findings were:
Pruritus intensity (NRS)
Mean change from baseline in pruritus NRS at 6 months was a decrease of 3.33 points for seladelpar 10 mg versus a decrease of 1.77 points with placebo (between-group P < .01). Notably, statistically greater decreases with seladelpar were observed as early as month 1 and maintained through months 3 and 6.
PBC-40 itch domain
The PBC-40 is a disease-specific quality-of-life instrument with an itch domain. The mean reduction from baseline at 6 months was 2.41 points with seladelpar compared with 0.98 points with placebo. The presentation notes that statistical significance for this measure at month 6 was lost due to reductions in evaluable numbers (likely related to trial termination and missing data), although the direction and magnitude favored seladelpar.
5-D itch scale and domain scores
The 5-D itch scale (a multidimensional measure including duration, degree, direction, disability, and distribution) showed robust improvement. Mean reduction in 5-D total score at 6 months was 5.09 points with seladelpar versus 1.70 with placebo (P < .0001). The 5-D itch ‘degree’ domain decreased by 1.08 versus 0.47 (P = .01), favoring seladelpar.
Sleep disturbance
Sleep disturbance related to pruritus was assessed with the 5-D itch Sleep Item and the PBC-40 Sleep Disturbance item. Seladelpar-treated patients experienced greater improvement on both instruments. The 5-D Sleep Item favored seladelpar at 6 months (P < .01), and PBC-40 Sleep Disturbance was significantly improved at month 1 (P < .0001) though not significant at month 6 in the pooled analysis (likely reflecting reduced sample size and missing data).
Safety and tolerability
Overall adverse-event rates were similar between groups. Any adverse events occurred in 75% (57/76) of seladelpar-treated patients versus 80% (40/50) of placebo-treated patients. Grade 3 or higher adverse events occurred in 8% of seladelpar patients and 12% of placebo patients. Pruritus-specific adverse events were reported in 8% of seladelpar and 14% of placebo patients. No new safety signals were reported in this pooled six-month analysis.
Interpretation and clinical implications
These pooled data provide evidence that seladelpar 10 mg daily reduces both the intensity of itch and itch-related sleep disturbance in patients with PBC and moderate-to-severe baseline pruritus who have an inadequate response to UDCA. The magnitude of change in NRS (mean reduction ≈3.3 points at 6 months) is clinically meaningful for patients suffering from moderate-to-severe itch and suggests a rapid onset of symptomatic benefit (as early as month 1).
Seladelpar is a selective peroxisome proliferator-activated receptor delta (PPAR-δ) agonist. By modulating nuclear receptor–mediated pathways, seladelpar has been shown in earlier studies to improve cholestatic biochemical markers and markers of disease activity in PBC. Although the precise mechanisms by which PPAR-δ agonism reduces pruritus remain under investigation, plausible biological explanations include modulation of bile acid transport and metabolism, anti-inflammatory effects, and indirect effects on pruritogenic mediators. Further mechanistic work is required to clarify whether seladelpar substantially influences pathways implicated in cholestatic pruritus such as autotaxin–lysophosphatidic acid signaling.
From a therapeutic standpoint, seladelpar’s symptom benefit is particularly relevant given the high prevalence and impact of pruritus in PBC and the limitations of existing antipruritic options. The pooled findings support current positioning of seladelpar as an approved second-line option for patients who do not respond or cannot tolerate UDCA. The rapidity and durability of itch reduction raise a reasonable clinical question—should seladelpar be considered earlier for patients in whom pruritus is prominent at presentation or rapidly progressive? While compelling, this notion requires careful balancing of long-term safety data, cost, and disease-modifying goals.
Strengths and limitations of the analysis
Strengths:
- Use of two randomized, placebo-controlled phase 3 datasets increases patient-level evidence and external validity for the symptomatic effect of seladelpar in PBC-associated pruritus.
- Multiple validated itch instruments were employed (NRS, 5-D itch, PBC-40), providing consistent, multidimensional signal of benefit across intensity, quality-of-life impact, and sleep disturbance.
Limitations:
- The pooled cohort for pruritus analyses was modest in size (n = 126) and derived from subsets of two parent trials; ENHANCE was terminated early and key endpoints were amended to 3 months, which reduced evaluable numbers for some outcomes at 6 months and likely limited statistical power for certain measures (for example, PBC-40 at 6 months).
- Presentation of pooled data at a meeting has limited detail on handling of missing data, sensitivity analyses, and longitudinal modeling; full peer-reviewed publication of primary data would allow more complete appraisal.
- Generalizability may be limited because the cohort was predominantly female (96%) and drawn from trial populations that exclude some comorbidities encountered in routine practice.
How this fits with current symptom-management options
Patients with cholestatic pruritus are often managed with bile acid sequestrants (cholestyramine), rifampicin, opioid antagonists, and selective serotonin reuptake inhibitors among other agents, each with variable efficacy and tolerability. Newer approaches targeting bile acid reabsorption (ileal bile acid transporter inhibitors) and other pathways show promise in some cholestatic conditions. The seladelpar findings are notable for directly addressing both disease biology and symptom burden with a single oral agent, which may help reduce polypharmacy for some patients. Clinicians should individualize treatment sequencing based on symptom severity, prior therapy, comorbidities, and patient preference.
Expert commentary and practice perspectives
As reported from the ACG 2025 session, investigators and discussants emphasized the unmet need in PBC-related pruritus and the potential of seladelpar to materially improve patient quality of life. Some experts suggested consideration of earlier use of seladelpar in patients presenting with significant itch unresponsive to UDCA, to avoid escalating symptomatic polypharmacy and to address both biochemical disease activity and symptomatic burden. Others cautioned that long-term safety and real-world experience should inform changes to standard practice.
Conclusion
Pooled phase 3 data presented at ACG 2025 indicate that seladelpar 10 mg daily provides clinically meaningful reductions in pruritus intensity and related sleep disturbance in patients with PBC and moderate-to-severe baseline itch who have not responded adequately to UDCA. The results strengthen the therapeutic profile of seladelpar as an agent that can address both disease activity and a highly impactful symptom. Pending full peer-reviewed publication and longer-term follow-up data, clinicians should consider seladelpar within current guideline-based treatment pathways for PBC while weighing patient-specific factors and alternative antipruritic strategies.
Funding and clinicaltrials.gov
The pooled analysis described was presented at ACG 2025; the original ENHANCE and RESPONSE trials were industry-sponsored phase 3 programs. The ACG presentation did not provide trial registry numbers or detailed sponsor acknowledgements within the session summary; clinicians and researchers should consult trial registry entries and full study publications for registration identifiers, sponsor information, and detailed methodology when available.
References
1. Gershwin ME, Chuang C, Kaplan MM. Primary biliary cirrhosis. N Engl J Med. 2005;353(12):1261-1273.
2. European Association for the Study of the Liver (EASL). EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017;67(1):145-172.
3. Mayo MJ et al. Seladelpar reduces pruritus measures in primary biliary cholangitis: pooled analysis of the ENHANCE and RESPONSE phase 3 trials. Presented at: American College of Gastroenterology (ACG) Annual Scientific Meeting; 2025. (Abstract and presentation materials.)
Practical takeaways for clinicians
– In patients with PBC who have moderate-to-severe pruritus and an inadequate biochemical response to UDCA, seladelpar 10 mg daily produced clinically meaningful itch reductions vs placebo over 6 months in pooled phase 3 data.
– Improvements were observed early (month 1) and sustained through month 6 on multiple validated instruments, including measures of sleep disturbance.
– Safety and tolerability in the pooled 6-month dataset were comparable to placebo, though continued post-marketing and long-term surveillance data are important.
– Consider seladelpar as part of the therapeutic armamentarium for symptomatic PBC management where indicated; discussions with patients should weigh benefit, safety, cost, and alternative antipruritic approaches.
