P181 Safety of seladelpar in patients with primary biliary cholangitis with cirrhosis and clinical signs of portal hypertension: data from the ENHANCE and RESPONSE studies
Bibliographic record
Abstract
Seladelpar is a first-in-class delpar (selective PPAR-delta agonist) indicated in the UK for the treatment of primary biliary cholangitis (PBC) including pruritus in combination with ursodeoxycholic acid (UDCA). In two Phase 3, placebo-controlled studies (ENHANCE [NCT03602560], RESPONSE [NCT04620733]), seladelpar significantly reduced cholestatic markers and pruritus with a safety profile similar to placebo. Here, we present pooled safety data from these studies in a subgroup of patients with cirrhosis and portal hypertension (PHT). Patients with PBC who received UDCA for ≥12 months or were UDCA intolerant, with alkaline phosphatase (ALP) ≥1.67 × upper limit of normal (ULN) and total bilirubin (TB) ≤2 × ULN, were randomised 1:1:1 to daily, oral placebo, seladelpar 5 mg, or seladelpar 10 mg for up to 52 weeks in ENHANCE and 2:1 to seladelpar 10 mg or placebo for 52 weeks in RESPONSE. Cirrhosis was defined by medical history, liver biopsy, transient elastography, laboratory findings, radiological features, or clinical determination by the investigator. Patients with cirrhosis were identified as having signs of PHT at baseline if they had thrombocytopenia (platelet count <140 × 103/µL), low albumin, elevated TB, or history of varices or ascites. Among 56 patients with cirrhosis at baseline across the two studies, 27 had signs of PHT at baseline (21 on seladelpar [15/21 on 10 mg], 6 on placebo). Most patients were female (85%) and White (89%), with a mean (range) age of 55.6 (33–74) years, and baseline mean ALP and TB levels of 319.9 U/L and 1.2 mg/dL. Mean (SD) liver stiffness was 17.4 (3.5) kPa with placebo and 21.0 (11.8) kPa with seladelpar. In total, 5/6 (83%) patients on placebo and 15/21 (71%) patients on seladelpar experienced an adverse event (AE); 2/6 (33%) patients on placebo and 1/21 (5%) patients on seladelpar discontinued treatment due to AEs. Serious AEs occurred in 1/6 (17%) patients on placebo and 1/21 (5%) patients on seladelpar and were deemed unrelated to study drug. Liver-related AEs by a predefined search strategy were similar across patients on placebo (2/6, 33%) or seladelpar (3/21, 14%) and included hepatomegaly, ascites, hyperbilirubinaemia, and portal hypertensive gastropathy. Liver-related laboratory abnormalities by predefined categories occurred in 2/6 (33%) placebo-treated patients and 1/21 (5%) seladelpar-treated patients. In this pooled analysis of patients with PBC and cirrhosis with clinical signs of PHT from the ENHANCE and RESPONSE studies, safety outcomes were overall similar between seladelpar and placebo, with no new safety signals.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.003 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".