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Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study

Lookup NU author(s): Professor David Jones

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Abstract

© 2023 John Wiley and Sons Inc.. All rights reserved.Background and Aims: ENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA). Approach and Results: Patients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (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) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 (p=0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% (p=0.0008); 10 mg: 16.7% (p=0.03); placebo: 4%]. There were no serious treatment-related adverse events. Conclusions: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.

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Author(s): Hirschfield GM, Shiffman ML, Gulamhusein A, Kowdley KV, Vierling JM, Levy C, Kremer AE, Zigmond E, Andreone P, Gordon SC, Bowlus CL, Lawitz EJ, Aspinall RJ, Pratt DS, Raikhelson K, Gonzalez-Huezo MS, Heneghan MA, Jeong S-H, Ladron De Guevara AL, Mayo MJ, Dalekos GN, Drenth JPH, Janczewska E, Leggett BA, Nevens F, Vargas V, Zuckerman E, Corpechot C, Fassio E, Hinrichsen H, Invernizzi P, Trivedi PJ, Forman L, Jones DEJ, Ryder SD, Swain MG, Steinberg A, Boudes PF, Choi Y-J, McWherter CA, Adrover R, Agrawal S, Aigner E, Martinez AA, Alden A-MS, Bellido RJA, Jimenez MAA, Ayoub W, Baum SJ, Ben-Ari Z, Berenguer M, Berg C, Bessone FO, Bonder A, Borg BB, Ruiz CGB, Buggisch P, Panero JLC, Carey EJ, Carmiel-Haggai M, Carubbi F, Grau PC, Ch'ng CL, Cimpoeru N-C, Omana RC, Corless L, Costentin C, Deschenes M, Dorffel Y, Dugalic P, Farrell GC, Fernandez JL, Floreani A, Francque S, Freilich BL, Saldias FAF, Galambos MR, Galati J, Galli A, Ganne-Carrie N, Geyvandova N, Gheorghe L-S, Gilroy R, Goel A, Goeser T, Greenbloom S, Halota W, Harrison SA, Hartleb M, Heo J, Hofer H, Horvath G, Huang JC, Huffman JL, Hunyady B, Johnson S, Kallis Y, Khazanchi A, Kim K-A, Kim SU, Kim YJ, Kohli A, Kontorinis N, Lake JR, Lee KS, Mach T, Manch R, Maor-Kendler Y, Mateescu R-B, Minuk G, Modi AA, Moehlen MW, Rodriguez CM, Cunill RMM, Mouzas I, Muir A, Nagy I, Ngu JH(, Odin J, Ogurtsov P, Pabjan P, Pagadala M, Papp M, Pares A, Peskov A, Peyton A, Phillips J, Porayko M, Post A, Pound DC, Rabinovitz M, Rank K, Reddy KG, Regula J, Riley T, Gomez MR, Safadi R, Sheridan DA, Silva MO, Silveira MG, Sood S, Sporea I, Stanca C, Stauber R, Svorcan P, Tak WY, Taylor RM, Thorburn D, Tobias H, Zekry AT, Trauner M, Triantos C, Veitsman E, Thompson AJV, Verhelst X, Verna EC, Von Der Ohe M, Weilert F, Wiegand J, Yimam KK, Yoon SK, Younes Z, Zivony AS, Zuin M

Publication type: Article

Publication status: Published

Journal: Hepatology

Year: 2023

Volume: 78

Issue: 2

Pages: 397-415

Online publication date: 01/08/2023

Acceptance date: 02/04/2021

Date deposited: 08/08/2023

ISSN (print): 0270-9139

ISSN (electronic): 1527-3350

Publisher: Wolters Kluwer Medknow Publications

URL: https://doi.org/10.1097/HEP.0000000000000395

DOI: 10.1097/HEP.0000000000000395

PubMed id: 37386786

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