Seladelpar Expands Toward Normalization but Payer Proof Still Hinges on Hard Outcomes

Gilead's Livdelzi Demonstrates ALP Normalization in Phase 3 PBC Study

Gilead Sciences announced positive detailed results from its Phase 3 IDEAL study, demonstrating that Livdelzi (seladelpar) significantly improved alkaline phosphatase (ALP) normalization in adults with primary biliary cholangitis (PBC). The study, which included patients with ALP levels between 1-1.67× ULN (a population often excluded from previous trials), showed that 75.4% of Livdelzi-treated participants achieved the ALP normalization composite endpoint at Week 52, compared to 16.1% on placebo. These findings support ALP normalization as an achievable treatment goal and will be discussed with global regulatory authorities. The data will be presented at The Liver Meeting® 2026 and published in the Journal of Hepatology.

• At Week 52, Livdelzi demonstrated a substantial improvement in ALP normalization, with 75.4% of participants achieving the composite endpoint (ALP ≤ 1.0× ULN and ≥ 15% decrease from baseline) compared to only 16.1% in the placebo group. This rapid and sustained response was evident after just one month of treatment, highlighting its potential for significant biochemical improvement.
• The IDEAL study uniquely evaluated Livdelzi in PBC patients with ALP levels between 1-1.67× ULN, a group typically excluded from pivotal trials. These results provide crucial evidence that seladelpar can improve biochemical response in this previously underserved population, informing individualized treatment discussions and expanding the understanding of treatment effects for a broader range of patients.
• Based on these positive Phase 3 results, Gilead Sciences plans to engage with global regulatory authorities to discuss Livdelzi's potential for approval. The detailed data will be presented at The Liver Meeting® 2026, hosted by the American Association for the Study of Liver Diseases (AASLD), from November 5-9 in Denver, Colorado, and has been accepted for upcoming publication in the Journal of Hepatology.
• The safety profile of Livdelzi observed in the IDEAL study was consistent with previously reported studies, with no new safety concerns identified. The incidence of adverse events was generally similar between Livdelzi and placebo groups, and serious adverse events occurred in 3.1% of Livdelzi-treated individuals versus 12.9% in the placebo group, with none deemed related to the trial drug.

Why Patients with Sub-Optimal ALP Levels Need New Options

Recent literature in primary biliary cholangitis (PBC) has shifted beyond a dichotomous definition of biochemical response toward a risk-based and holistic approach integrating biochemical response, fibrosis stage, liver stiffness, and patient-reported outcomes. Therapeutic targets are increasingly individualized according to age, disease stage, symptom burden, and risk of progression, with emphasis on earlier treatment escalation in high-risk and symptomatic patients.

• Patients with inadequate response to ursodeoxycholic acid (UDCA) needing early second-line therapy: UDCA remains the cornerstone of first-line therapy and improves transplant-free survival, but an important proportion show inadequate biochemical response, with suboptimal response reported in 54.2% after 1 year of UDCA and response rates of 44.44%, 41.88%, and 52.14% according to Paris II, POISE, and Barcelona criteria. Research targets earlier identification at 6 months using Toronto, Rotterdam, Paris 1 and 2, Barcelona and POISE trial criteria, and GLOBE and UK-PBC scores, with early initiation deemed appropriate in cases of UDCA intolerance or partial response following the withdrawal of obeticholic acid and availability of selective PPAR agonists, including elafibranor and seladelpar, as well as fenofibrate and bezafibrates as add-on therapy.

• Patients with moderate-to-severe pruritus and associated sleep disturbance, fatigue, and impaired health-related quality of life (HRQoL): Pruritus affects up to 80% of patients with PBC, often worsens at night, and reduces HRQoL, with EQ-5D-5L scores lower in severe pruritus (≥7-10 NRS) (mean [SD]: 0.49 [0.28]) versus mild/moderate pruritus (0.75 [0.17]/0.76 [0.17]). Development focuses on linerixibat assessed in the Phase 2b GLIMMER trial (NCT02966834) and Phase 3 GLISTEN study (NCT04950127), and seladelpar 10 mg in the Phase 3 RESPONSE trial (NCT04620733) in patients with moderate to severe itch (NRS ≥4), severe itch (NRS ≥7) and clinically significant itch (PBC-40 itch ≥7), evaluating Worst Itch Numerical Rating Scale (WI-NRS), Sleep Interference NRS, 5-D itch scale, PBC-40, and Fatigue NRS.

• Patients with high-risk and advanced disease requiring refined stratification: Populations include those with advanced PBC, high baseline liver enzymes levels with mean baseline alkaline phosphatase 2.73 ± 1.95 times the upper limit of normal (× ULN) among responders versus 5.05 ± 3.08 × ULN in non-responders, compensated cirrhosis (Child-Pugh A), ductopenia present in 56.76% (294/518) overall and 24.83% (74/298) with early-stage disease, and non-cirrhotic portal fibrosis in 30/92 (32.6%) pre-cirrhotic patients. Management emphasizes distinguishing between "adequate" and "complete" biochemical response and integrating fibrosis stage, liver stiffness by Vibration-Controlled Transient Elastography (VCTE), ALBI score, and prognostic scores including GLOBE with area under the ROC curve 0.87 (95% CI 0.83-0.95) and 0.867, and UK-PBC with 0.94 (95% CI 0.86-0.99) and 0.899.

• Patients with substantial symptom burden and comorbid psychological impact: Among patients with severe pruritus, 31% had severe depression versus 9/3% with mild/moderate pruritus, with mean EQ-5D-5L score of 0.30 in those with both severe pruritus and depression, and 54% reported severe sleep interference. Strong correlations were found between change from baseline in weekly itch and sleep NRS scores (r = 0.88 [95% confidence interval (CI): 0.83; 0.91]) and monthly scores (r = 0.84 [95% CI: 0.80; 0.87]), supporting meaningful improvement thresholds of ≥3 points in WI-NRS and ≥2.5 points in SI-NRS weekly scores and the importance of evaluating itch and managing depression.

Livdelzi's IDEAL Results: Efficacy and Safety in PBC

Recent studies in primary biliary cholangitis (PBC) have evaluated second-line therapies in patients with inadequate response to ursodeoxycholic acid. These include selective peroxisome proliferator-activated receptor agonists and fibrates, with efficacy assessed by composite biochemical response and alkaline phosphatase normalization.

• ASSURE interim study — seladelpar 10-mg: In patients rolling over from the phase 3, randomized, placebo-controlled, 12-month RESPONSE study or earlier legacy seladelpar studies, the composite response rate at RESPONSE completion was 62% (79/128) with seladelpar and 20% (13/65) with placebo. After 12 months in ASSURE, response rates were 72% (21/29) in patients continuing seladelpar and 94% (15/16) in crossover seladelpar patients, with response rates of 73% (120/164) and 70% (69/99) after 12 and 24 months in legacy trial patients. No seladelpar-related serious adverse events were reported, with durable improvements in cholestatic biomarkers and pruritus with up to 2 years of treatment.

• ENHANCE phase 3 study — seladelpar 5 mg and 10 mg daily: Significantly more patients receiving seladelpar met the composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 3 (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) (p < 0.0001). ALP normalization occurred in 5.4% (p =0.08) and 27.3% (p < 0.0001) with 5 and 10 mg seladelpar versus 0% with placebo, with significant reduction in pruritus numerical rating scale and alanine aminotransferase decrease. There were no serious treatment-related adverse events.

• ELATIVE phase III trial (NCT04526665) — elafibranor: At Week 52, biochemical response was achieved across all subgroups receiving elafibranor (≤ 2× upper limit of normal [ULN]: 86.7%, > 2-≤ 2.5× ULN: 80.0%, > 2.5-≤ 3× ULN: 52.0%, > 3-≤ 4× ULN: 22.2%, > 4× ULN: 18.8%), with ALP normalization only with elafibranor and mean ALP reductions consistent across subgroups (overall CfB: -38.9%).

• BEZURSO phase 3 trial (NCT01654731) — bezafibrate 400 mg daily plus ursodeoxycholic acid: The primary outcome of complete biochemical response at 24 months occurred in 31% assigned to bezafibrate and in 0% assigned to placebo (difference, 31 percentage points; 95% confidence interval, 10 to 50; P<0.001), with normal levels of alkaline phosphatase in 67% versus 2%. Myalgia occurred in 20% in the bezafibrate group and in 10% in the placebo group, with creatinine level increased 5% from baseline in the bezafibrate group and decreased 3% in the placebo group.

Livdelzi's Impact on Evolving PBC Treatment Goals

Primary biliary cholangitis management long consisted of a single treatment: ursodeoxycholic acid, which has been the cornerstone of PBC management, improving survival and delaying disease progression in most patients. However, up to 40% of patients demonstrate an inadequate response to UDCA, with reviews reporting approximately 30-40% with inadequate biochemical response. Patients typically are assessed after 12 months of treatment with UDCA for biochemical markers of response, although evaluation at 6 months has been proposed for patients with more severe disease or symptoms. Major studies have helped better predict disease progression and its response to treatment through the development of prognostic tools, with Barcelona, Paris-1, Paris-2, Rotterdam, Toronto and GLOBE and UK-PBC Risk Scores most robustly validated in external populations, and the continuous models (GLOBE and UK-PBC Risk Scores) serving as the most accurate predictive models.

Obeticholic acid (OCA), a potent farnesoid X receptor agonist, was the first second-line agent approved for patients with PBC and an inadequate response or intolerance to ursodeoxycholic acid, showing efficacy in reducing alkaline phosphatase levels and improving liver biochemistry. In the Italian PBC Registry of 191 patients, significant median reductions of ALP (-32.3%), ALT (-31.4%), and bilirubin (-11.2%) were observed at 12 months, with response rates of 42.9% according to Poise criteria and 11% by normal range criteria. In a Southern European multicentre cohort of 120 patients, 78 patients completed at least 1 year of OCA with significant decrease in alkaline phosphatase of 81.3 U/L, ALT 22.1 U/L and bilirubin 0.12 mg/dL, and 29.5% (23 out of 78) achieved response according to the POISE criteria. Final results of the 5-year POISE long-term safety extension in 193 patients showed the response rate for the POISE primary endpoint was 63% at Month 72, with the most common treatment-emergent adverse event pruritus (70%), while treatment-induced pruritus was the leading cause of OCA discontinuation (67%) in real-world experience.

Over the past five years, the therapeutic arsenal has expanded with the arrival of selective PPAR agonists. Seladelpar, a selective peroxisome proliferator-activated receptor delta (PPAR-δ) agonist, and elafibranor, a dual PPAR-α/δ agonist, have both recently received FDA accelerated approval after demonstrating significant improvements in ALP, biochemical response rates, and pruritus relief in phase 3 trials. In the phase III ELATIVE trial (NCT04526665), 161 patients were randomized 2:1 to elafibranor 80 mg or placebo, with 64.3% (18/28) and 10.7% (3/28) achieving biochemical response and alkaline phosphatase normalization at Week 104 versus no placebo-treated patients, and sustained biochemical improvements through three years with generally well tolerated profile. Fibrates including bezafibrate, fenofibrate and ciprofibrate added to UDCA have shown substantial alkaline phosphatase reductions, with overall response rates to fibrates varying from 39 to 60% and 39-76% at 12 and 24 months, while a systematic review and meta-analysis of eight RCTs (n = 515) showed beneficial effects of PPAR agonists compared with placebo for change in ALP level (SMD = -2.81), GGT level (SMD = -1.29) and TBil level (SMD = -0.77).