PMID- 37355043 OWN - NLM STAT- MEDLINE DCOM- 20230918 LR - 20230922 IS - 1600-0641 (Electronic) IS - 0168-8278 (Linking) VI - 79 IP - 4 DP - 2023 Oct TI - A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease. PG - 888-897 LID - S0168-8278(23)00342-2 [pii] LID - 10.1016/j.jhep.2023.05.013 [doi] AB - BACKGROUND & AIMS: This study assessed the effects of the glucagon-like peptide-1 (GLP-1)/glucagon receptor co-agonist efinopegdutide relative to the selective GLP-1 receptor agonist semaglutide on liver fat content (LFC) in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: This was a phase IIa, randomized, active-comparator-controlled, parallel-group, open-label study. A magnetic resonance imaging-estimated proton density fat fraction assessment was performed to determine LFC at screening and Week 24. Participants with an LFC of >/=10% at screening were randomized 1:1 to efinopegdutide 10 mg or semaglutide 1 mg, both administered subcutaneously once weekly for 24 weeks. Participants were stratified according to the concurrent diagnosis of type 2 diabetes mellitus (T2DM). Both drugs were titrated to the target dose over an 8-week time period. The primary efficacy endpoint was relative reduction from baseline in LFC (%) after 24 weeks of treatment. RESULTS: Among 145 randomized participants (efinopegdutide n = 72, semaglutide n = 73), 33.1% had T2DM. At baseline, mean BMI was 34.3 kg/m(2) and mean LFC was 20.3%. The least squares (LS) mean relative reduction from baseline in LFC at Week 24 was significantly (p <0.001) greater with efinopegdutide (72.7% [90% CI 66.8-78.7]) than with semaglutide (42.3% [90% CI 36.5-48.1]). Both treatment groups had an LS mean percent reduction from baseline in body weight at Week 24 (efinopegdutide 8.5% vs. semaglutide 7.1%; p = 0.085). Slightly higher incidences of adverse events and drug-related adverse events were observed in the efinopegdutide group compared with the semaglutide group, primarily related to an imbalance in gastrointestinal adverse events. CONCLUSIONS: In patients with NAFLD, treatment with efinopegdutide 10 mg weekly led to a significantly greater reduction in LFC than semaglutide 1 mg weekly. CLINICAL TRIAL NUMBER: EudraCT: 2020-005136-30; NCT: 04944992. IMPACT AND IMPLICATIONS: Currently, there are no approved therapies for non-alcoholic steatohepatitis (NASH). The weight loss associated with glucagon-like peptide-1 (GLP-1) receptor agonists has been shown to decrease hepatic inflammation in patients with NASH. In addition to reducing liver fat content (LFC) indirectly through weight loss, glucagon receptor agonism may also reduce LFC by acting on the liver directly to stimulate fatty acid oxidation and reduce lipogenesis. This study demonstrated that treatment of patients with non-alcoholic fatty liver disease with the GLP-1/glucagon receptor co-agonist efinopegdutide (10 mg weekly) led to a significantly greater reduction in LFC compared to treatment with the GLP-1 receptor agonist semaglutide (1 mg weekly), suggesting that efinopegdutide may be an effective treatment for NASH. CI - Copyright (c) 2023 Manuel Romero-Gomez, Eric Lawitz, R. Ravi Shankar, Eirum Chaudhri, Jie Liu, Raymond L.H. Lam, Keith D. Kaufman, Samuel S. Engel, MK-6024 P001 Study Group. Published by Elsevier B.V. All rights reserved. FAU - Romero-Gomez, Manuel AU - Romero-Gomez M AD - Digestive Diseases Unit and CIBERehd, Virgen del Rocio University Hospital, Institute of Biomedicine of Seville (HUVR/CSIC/US), University of Seville, Seville, Spain. FAU - Lawitz, Eric AU - Lawitz E AD - Texas Liver Institute, University of Texas Health San Antonio, San Antonio, Texas, USA. FAU - Shankar, R Ravi AU - Shankar RR AD - Merck & Co., Inc., Rahway, NJ, USA. FAU - Chaudhri, Eirum AU - Chaudhri E AD - Merck & Co., Inc., Rahway, NJ, USA. FAU - Liu, Jie AU - Liu J AD - Merck & Co., Inc., Rahway, NJ, USA. FAU - Lam, Raymond L H AU - Lam RLH AD - Merck & Co., Inc., Rahway, NJ, USA. FAU - Kaufman, Keith D AU - Kaufman KD AD - Merck & Co., Inc., Rahway, NJ, USA. FAU - Engel, Samuel S AU - Engel SS AD - Merck & Co., Inc., Rahway, NJ, USA. Electronic address: samuel_engel@merck.com. CN - MK-6024 P001 Study Group LA - eng SI - EudraCT/2020-005136-30 SI - ClinicalTrials.gov/NCT04944992 PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20230622 PL - Netherlands TA - J Hepatol JT - Journal of hepatology JID - 8503886 RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) SB - IM MH - Humans MH - Diabetes Mellitus, Type 2/drug therapy/complications MH - *Glucagon-Like Peptide-1 Receptor/agonists/therapeutic use MH - Hypoglycemic Agents/adverse effects MH - *Non-alcoholic Fatty Liver Disease/complications/drug therapy MH - Weight Loss OTO - NOTNLM OT - efinopegdutide OT - liver fat content OT - nonalcoholic fatty liver disease OT - semaglutide FIR - Bruzone, Santiago Oscar IR - Bruzone SO FIR - Coronel, Maria Jimena IR - Coronel MJ FIR - Gruz, Fernando M IR - Gruz FM FIR - MacKinnon, Ignacio IR - MacKinnon I FIR - George, Jacob IR - George J FIR - Muller, Kate IR - Muller K FIR - Lee, Samuel S IR - Lee SS FIR - Caussy, Cyrielle IR - Caussy C FIR - Petit, Jean Michel IR - Petit JM FIR - Ari, Ziv Ben IR - Ari ZB FIR - Braun, Marius IR - Braun M FIR - Katchman, Helena IR - Katchman H FIR - Lurie, Yoav IR - Lurie Y FIR - Veitsman, Ella IR - Veitsman E FIR - Zuckerman, Eli IR - Zuckerman E FIR - Aghemo, Alessio IR - Aghemo A FIR - Basili, Stenfania IR - Basili S FIR - Fracanzani, Anna Ludovica IR - Fracanzani AL FIR - Pietrangelo, Antonello IR - Pietrangelo A FIR - Sacerdoti, David IR - Sacerdoti D FIR - Rubio Arce, Jose Francisco IR - Rubio Arce JF FIR - de Guevara Cetina, Alma Laura Ladron IR - de Guevara Cetina ALL FIR - Chavez-Tapia, Norberto Carlos IR - Chavez-Tapia NC FIR - Reyes, Eira Cerda IR - Reyes EC FIR - Pinzon Te, Lourdes Lol-Be IR - Pinzon Te LL FIR - Baker, John R IR - Baker JR FIR - Ngu, Jeffrey IR - Ngu J FIR - Orr, David IR - Orr D FIR - Janczewska, Ewa IR - Janczewska E FIR - Matusik, Pawel IR - Matusik P FIR - Stanislaw Sadurski, Maciej Murawski IR - Stanislaw Sadurski MM FIR - Akinina, Anna Valerievna IR - Akinina AV FIR - Alpenidze, Diana Nodarievna IR - Alpenidze DN FIR - Bogomolov, Pavel IR - Bogomolov P FIR - Ermakova, Polina Yurievna IR - Ermakova PY FIR - Golovach, Albina V IR - Golovach AV FIR - Kim, Sang Gyune IR - Kim SG FIR - Lee, Jin-Woo IR - Lee JW FIR - Paik, Yong Han IR - Paik YH FIR - Park, Jun Yong IR - Park JY FIR - Yeon, Jong Eun IR - Yeon JE FIR - Blasco, Victor Vargas IR - Blasco VV FIR - Madueno, Francisco Jose Tinahones IR - Madueno FJT FIR - Panero, Jose Luis Calleja IR - Panero JLC FIR - Perez, Esther Molina IR - Perez EM FIR - Romero-Gomez, Manuel IR - Romero-Gomez M FIR - Cheng, Pin-Nan IR - Cheng PN FIR - Jeng, Wen-Juei IR - Jeng WJ FIR - Liu, Chun-Jen IR - Liu CJ FIR - Akyuz, Filiz IR - Akyuz F FIR - Balaban, Hatice Yasemin IR - Balaban HY FIR - Basaranoglu, Metin IR - Basaranoglu M FIR - Demir, Tevfik IR - Demir T FIR - Idilman, Ramazan IR - Idilman R FIR - Karakan, Tarkan IR - Karakan T FIR - Gyrina, Olga IR - Gyrina O FIR - Kolesnikova, Olena Vadimivna IR - Kolesnikova OV FIR - Pyvovar, Sergiy M IR - Pyvovar SM FIR - Oliinyk, Oleksandr IR - Oliinyk O FIR - Skrypnyk, Igor IR - Skrypnyk I FIR - Bassan, Isaac IR - Bassan I FIR - Bowman, William Kelly IR - Bowman WK FIR - Denham, Douglas Scott IR - Denham DS FIR - Ghalib, Reem IR - Ghalib R FIR - Lawitz, Eric J IR - Lawitz EJ FIR - Lucas, Kathryn Jean IR - Lucas KJ FIR - Mohseni, Rizwana H IR - Mohseni RH FIR - Sanchez, William Eduardo IR - Sanchez WE FIR - Vierling, John Moore IR - Vierling JM EDAT- 2023/06/25 01:08 MHDA- 2023/09/18 12:43 CRDT- 2023/06/24 19:15 PHST- 2023/04/07 00:00 [received] PHST- 2023/05/19 00:00 [revised] PHST- 2023/05/22 00:00 [accepted] PHST- 2023/09/18 12:43 [medline] PHST- 2023/06/25 01:08 [pubmed] PHST- 2023/06/24 19:15 [entrez] AID - S0168-8278(23)00342-2 [pii] AID - 10.1016/j.jhep.2023.05.013 [doi] PST - ppublish SO - J Hepatol. 2023 Oct;79(4):888-897. doi: 10.1016/j.jhep.2023.05.013. Epub 2023 Jun 22.