TY - JOUR

T1 - Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study

AU - Hirschfield, Gideon M

AU - Shiffman, Mitchell L

AU - Gulamhusein, Aliya

AU - Kowdley, Kris V

AU - Vierling, John M

AU - Levy, Cynthia

AU - Kremer, Andreas E

AU - Zigmond, Ehud

AU - Andreone, Pietro

AU - Gordon, Stuart C

AU - Bowlus, Christopher L

AU - Lawitz, Eric J

AU - Aspinall, Richard J

AU - Pratt, Daniel S

AU - Raikhelson, Karina

AU - Gonzalez-Huezo, Maria S

AU - Heneghan, Michael A

AU - Jeong, Sook-Hyang

AU - Ladrón de Guevara, Alma L

AU - Mayo, Marlyn J

AU - Dalekos, George N

AU - Drenth, Joost P H

AU - Janczewska, Ewa

AU - Leggett, Barbara A

AU - Nevens, Frederik

AU - Vargas, Victor

AU - Zuckerman, Eli

AU - Corpechot, Christophe

AU - Fassio, Eduardo

AU - Hinrichsen, Holger

AU - Invernizzi, Pietro

AU - Trivedi, Palak J

AU - Forman, Lisa

AU - Jones, David E J

AU - Ryder, Stephen D

AU - Swain, Mark G

AU - Steinberg, Alexandra

AU - Boudes, Pol F

AU - Choi, Yun-Jung

AU - McWherter, Charles A

N1 - Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.

PY - 2023/8/1

Y1 - 2023/8/1

N2 - 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.

AB - 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.

KW - Humans

KW - Liver Cirrhosis, Biliary/drug therapy

KW - Ursodeoxycholic Acid/adverse effects

KW - Acetates

KW - Alkaline Phosphatase

KW - Pruritus/etiology

KW - Cholagogues and Choleretics/adverse effects

UR - https://www.mendeley.com/catalogue/8552c3d0-6506-39a3-97f2-a70ffcb18445/

U2 - 10.1097/HEP.0000000000000395

DO - 10.1097/HEP.0000000000000395

M3 - Article

C2 - 37386786

VL - 78

SP - 397

EP - 415

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 2

ER -