A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease
Manuel Romero-Gómez, Eric Lawitz, R Ravi Shankar, Eirum Chaudhri, Jie Liu, Raymond L H Lam, Keith D Kaufman, Samuel S Engel, MK-6024 P001 Study Group, Santiago Oscar Bruzone, Maria Jimena Coronel, Fernando M Gruz, Ignacio MacKinnon, Jacob George, Kate Muller, Samuel S Lee, Cyrielle Caussy, Jean Michel Petit, Ziv Ben Ari, Marius Braun, Helena Katchman, Yoav Lurie, Ella Veitsman, Eli Zuckerman, Alessio Aghemo, Stenfania Basili, Anna Ludovica Fracanzani, Antonello Pietrangelo, David Sacerdoti, Jose Francisco Rubio Arce, Alma Laura Ladron de Guevara Cetina, Norberto Carlos Chavez-Tapia, Eira Cerda Reyes, Lourdes Lol-Be Pinzon Te, John R Baker, Jeffrey Ngu, David Orr, Ewa Janczewska, Pawel Matusik, Maciej Murawski Stanislaw Sadurski, Anna Valerievna Akinina, Diana Nodarievna Alpenidze, Pavel Bogomolov, Polina Yurievna Ermakova, Albina V Golovach, Sang Gyune Kim, Jin-Woo Lee, Yong Han Paik, Jun Yong Park, Jong Eun Yeon, Victor Vargas Blasco, Francisco Jose Tinahones Madueno, Jose Luis Calleja Panero, Esther Molina Perez, Manuel Romero-Gómez, Pin-Nan Cheng, Wen-Juei Jeng, Chun-Jen Liu, Filiz Akyuz, Hatice Yasemin Balaban, Metin Basaranoglu, Tevfik Demir, Ramazan Idilman, Tarkan Karakan, Olga Gyrina, Olena Vadimivna Kolesnikova, Sergiy M Pyvovar, Oleksandr Oliinyk, Igor Skrypnyk, Isaac Bassan, William Kelly Bowman, Douglas Scott Denham, Reem Ghalib, Eric J Lawitz, Kathryn Jean Lucas, Rizwana H Mohseni, William Eduardo Sanchez, John Moore Vierling, Manuel Romero-Gómez, Eric Lawitz, R Ravi Shankar, Eirum Chaudhri, Jie Liu, Raymond L H Lam, Keith D Kaufman, Samuel S Engel, MK-6024 P001 Study Group, Santiago Oscar Bruzone, Maria Jimena Coronel, Fernando M Gruz, Ignacio MacKinnon, Jacob George, Kate Muller, Samuel S Lee, Cyrielle Caussy, Jean Michel Petit, Ziv Ben Ari, Marius Braun, Helena Katchman, Yoav Lurie, Ella Veitsman, Eli Zuckerman, Alessio Aghemo, Stenfania Basili, Anna Ludovica Fracanzani, Antonello Pietrangelo, David Sacerdoti, Jose Francisco Rubio Arce, Alma Laura Ladron de Guevara Cetina, Norberto Carlos Chavez-Tapia, Eira Cerda Reyes, Lourdes Lol-Be Pinzon Te, John R Baker, Jeffrey Ngu, David Orr, Ewa Janczewska, Pawel Matusik, Maciej Murawski Stanislaw Sadurski, Anna Valerievna Akinina, Diana Nodarievna Alpenidze, Pavel Bogomolov, Polina Yurievna Ermakova, Albina V Golovach, Sang Gyune Kim, Jin-Woo Lee, Yong Han Paik, Jun Yong Park, Jong Eun Yeon, Victor Vargas Blasco, Francisco Jose Tinahones Madueno, Jose Luis Calleja Panero, Esther Molina Perez, Manuel Romero-Gómez, Pin-Nan Cheng, Wen-Juei Jeng, Chun-Jen Liu, Filiz Akyuz, Hatice Yasemin Balaban, Metin Basaranoglu, Tevfik Demir, Ramazan Idilman, Tarkan Karakan, Olga Gyrina, Olena Vadimivna Kolesnikova, Sergiy M Pyvovar, Oleksandr Oliinyk, Igor Skrypnyk, Isaac Bassan, William Kelly Bowman, Douglas Scott Denham, Reem Ghalib, Eric J Lawitz, Kathryn Jean Lucas, Rizwana H Mohseni, William Eduardo Sanchez, John Moore Vierling
Abstract
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/m2 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.
Trial registration: ClinicalTrials.gov NCT04944992.
Keywords: efinopegdutide; liver fat content; nonalcoholic fatty liver disease; semaglutide.
Copyright © 2023 Manuel Romero-Gómez, 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.
Source: PubMed