PP254 - LIVER INJURY PATTERNS IN INTESTINAL FAILURE–ASSOCIATED LIVER DISEASE (IFALD): BASELINE INSIGHTS FROM A PHASE 2 STUDY

PP254

LIVER INJURY PATTERNS IN INTESTINAL FAILURE–ASSOCIATED LIVER DISEASE (IFALD): BASELINE INSIGHTS FROM A PHASE 2 STUDY

F. Joly^1,*, M. Mundi², S. Lal³, D. Kirby⁴, K. Iyer⁵, P. B. Jeppesen⁶, C. Beysen⁷, D. Fraser⁷, T. Skjaeret⁷, S. Jeannin⁷, T. Vanuytsel⁸ on behalf of Investigator Study Group

¹Beaujon Hospital, APHP, University of Paris, Paris, France, ²Mayo Clinic, Rochester MN, United States, ³University of Manchester, Manchester, United Kingdom, ⁴Cleveland Clinic, Cleveland, ⁵Mount Sinai, New York, United States, ⁶Rigshospitalet, Copenhagen, Denmark, ⁷NorthSea Therapeutic B.V., Amsterdam, Netherlands, ⁸KU Leuven, Leuven, Belgium

Rationale: IFALD is a serious complication of chronic intestinal failure and patterns of liver injury are poorly characterized. We report baseline liver biochemistry profiles of IFALD patients enrolled in a Phase 2 study of orziloben, a structurally engineered fatty acid analogue targeting multiple mechanisms underlying IFALD via fatty acid–sensitive receptors involved in bile acid metabolism, hepatic inflammation and fibrosis.

Methods: This randomized, placebo-controlled trial enrolled IFALD patients receiving parenteral nutrition (PN) at international academic centers. IFALD was defined by persistent (≥6 months) elevations in ≥1 of five liver tests: alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST) (≥1.5×upper limit of normal (ULN)) or total bilirubin (>1×ULN). Severe IFALD (total bilirubin >2.5 mg/dL, ALP >10×ULN, ALT or AST >5×ULN) was excluded.

Results: Thirty-three IFALD patients (mean age 47 years, weight 62 kilograms, 61% female) were enrolled. Short bowel syndrome was present in 25 patients, and intestinal dysmotility in 12 patients. Screening lab results (mean ± standard deviation) were: ALP 242 ± 115 units/liter ( U/L), GGT 164 ± 168 U/L, ALT 71 ± 46 U/L, AST 55 ± 30 U/L, total bilirubin 17 ± 9 µmol/L. Overall, 24 patients (73%) met ≥2 criteria, 15 (45%) met ≥3 criteria, 7 (21%) met ≥4 criteria, and 2 (6%) met all five liver test criteria. ALP or GGT elevation ≥1.5×ULN occurred in 30/33 patients (91%), including 14 patients (42%) with both elevated and 11 patients (33%) with isolated GGT elevation. ALT ≥1.5×ULN was observed in 14 patients (42%) and AST ≥1.5×ULN in 12 (36%). Total bilirubin >1×ULN was seen in 10 patients (30%).

Conclusion: In this cohort, IFALD was predominantly cholestatic with frequent concurrent hepatocellular injury, supporting the need for therapies targeting multiple disease phenotypes.

Disclosure of Interest: F. Joly Consultant for: NorthSea Therapeutics B.V., M. Mundi Consultant for: NorthSea Therapeutics B.V., S. Lal Consultant for: NorthSea Therapeutics B.V., D. Kirby Consultant for: NorthSea Therapeutics B.V., K. Iyer Consultant for: NorthSea Therapeutics B.V., P. Jeppesen Consultant for: NorthSea Therapeutics B.V., C. Beysen Other: Employee of NorthSea Therapeutics B.V., D. Fraser Other: Employee of NorthSea Therapeutics B.V., T. Skjaeret Other: Employee of NorthSea Therapeutics B.V., S. Jeannin Other: Employee of NorthSea Therapeutics B.V., T. Vanuytsel Consultant for: NorthSea Therapeutics B.V.