A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease

A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease Authors Manuel Romero-Gómez, Eric Lawitz, R. Ravi Shankar, ., Raymond L.H. Lam, Keith D. Kaufman, Samuel S. Engel Correspondence [email protected]om (S.S. Engel). Graphical abstract Efinopegdutide Semaglutide 72.7% 42.3% N = 72 N = 73 LS mean relative reduction from baseline in LFC at week 24 (%) Difference in LS means (90% CI) efinopegdutide vs. semaglutide: 30.4 (22.1, 38.7); p<0.001 100 0 10 20 30 40 50 60 70 80 90 ≥30% ≥50% ≥70% Relative reduction from baseline in LFC at Week 24 Percent of participants 81.9% 77.8% 70.8% 67.1% 43.8% 12.3% n/N = 59/72 n/N = 56/72 n/N = 51/72 n/N = 49/73 n/N = 32/73 n/N = 9/73 100 0 10 20 30 40 50 60 70 80 90 >10% 86.2% 64.2% >5% to ≤10 % 76.6% 39.6% ≤5% 52.4% 13.4% N = 22 N = 23N = 29 N = 30N = 15 N = 18 Percent reduction from baseline in body weight at Week 24 Mean relative reduction from baseline in LFC at week 24 (%) 100 0 10 20 30 40 50 60 70 80 90 Efinopegdutide Semaglutide Primary efficacy endpoint Relative reduction from baseline in LFC at week 24 Participants with an AE, % Safety results Deaths 0Serious drug-related AEs 0 Population characteristics • Males and females • Age: 18 to 70 years • NAFLD with LFC ≥10% by MRI-PDFF • T2DM stratification (yes or no) R 1:1 2.4 mg 5.0 mg 10.0 mg Efinopegdutide SC Q1W 1.0 mg Semaglutide SC Q1W 0.5 mg 0.25 mg Screening period Treatment period Posttreatment period MRI-PDFF Day 1 Wk 1 Wk 2 Wk 3 Wk 4 Wk 8 Wk 12 Wk 16 Wk 20 Wk 24 Wk 28 MRI-PDFF Efficacy results Screening Study design Efinopegdutide n = 72 88.9% Semaglutide n = 73 72.6% Highlights There are no approved therapies for fatty liver disease. Dual glucagon/glucagon-like peptide-1 receptor agonism may be beneficial. Efinopegdutide (dual agonist) improved liver fat content compared with semaglutide. Efinopegdutide’s tolerability profile was similar to that of semaglutide. Efinopegdutide may be an effective treatment for fatty liver disease. 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. https://doi.org/10.1016/j.jhep.2023.05.013 © 2023 Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and The Author(s). Published by Elsevier B.V on Behalf of European Association for the Study of the Liver (EASL) This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). J. Hepatol. 2023, 79, 888–897 Research Article NAFLD and Alcohol-Related Liver Diseases 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 1 , Eric Lawitz 2 , R. Ravi Shankar 3 , Eirum Chaudhri 3 , Jie Liu 3 , Raymond L.H. Lam 3 , Keith D. Kaufman 3 , Samuel S. Engel 3, *, for the MK-6024 P001 Study Group † Journal of Hepatology 2023. vol. 79 j888–897 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 nonalcoholic 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. © 2023 Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and The Author(s). Published by Elsevier B.V on Behalf of European Association for the Study of the Liver (EASL) This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/). Introduction Non-alcoholic fatty liver disease (NAFLD), a condition associated with increased accumulation of triglycerides in the liver, is estimated to affect approximately 30% of the global adult population. 1 NAFLD encompasses a broad spectrum of fatty liver disease, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), a form of fatty liver disease that is associated with chronic inflammation described histologically as steatohepatitis with or without fibrosis. 2 Approximately 20% of the NASH population will progress to cirrhosis, which is associated with increases in rates of hepatocellular carcinoma and all-cause and liver-related mortality. 3 NAFLD is increasingly being recognized as the hepatic manifestation of underlying metabolic dysregulation and is considered a consequence of obesity-related insulin resistance, resulting in increased trafficking of fatty acids from adipose tissue to the liver and de novo hepatic lipogenesis. 4,5 Overweight and obesity are considered the primary pathological drivers of metabolic disease, NAFLD and, by extension, NASH. 5 Currently, there are no approved therapies for the treatment of NASH. Management of NAFLD/NASH is focused on lifestyle modification such as diet and exercise, directed mainly at weight loss. Pioglitazone and high-dose vitamin E (800 IU/day) have been recommended as pharmacotherapies for biopsyproven NASH, with pioglitazone recommended in those with type 2 diabetes mellitus (T2DM) and vitamin E recommended in those without diabetes. 6 Keywords: efinopegdutide; semaglutide; nonalcoholic fatty liver disease; liver fat content. Received 7 April 2023; received in revised form 19 May 2023; accepted 22 May 2023; available online 22 June 2023 * Corresponding author. Address: Merck & Co., Inc., 126 East Lincoln Ave., Rahway, NJ, 07065, USA; Tel.: +1 732 594 0981. E-mail address: [email protected] (S.S. Engel). † List of investigators comprising the MK-6024 P001 Study Group is presented in acknowledgments section. https://doi.org/10.1016/j.jhep.2023.05.013 Journal of Hepatology, October 2023. vol. 79 j888–897 Research Article NAFLD and Alcohol-Related Liver Diseases Glucagon-like peptide-1 (GLP-1) agonism is associated with reductions in serum glucose and weight loss. GLP-1 receptor agonists enhance glucose-stimulated insulin secretion and have become useful treatments for T2DM. At doses that have been developed for diabetes indications (e.g., liraglutide up to 1.8 mg daily, semaglutide up to 2 mg weekly), GLP-1 receptor agonists are associated with weight loss of approximately 3% to 5%, generally attributed to reductions in food intake. More recently, higher dose administration of GLP-1 receptor agonists has been pursued for weight loss indications. At the approved doses for weight loss, liraglutide 3 mg subcutaneously (SC) daily over 56 weeks resulted in weight loss of approximately 7.4%, 7 while semaglutide 2.4 mg SC once weekly over 68 weeks resulted in approximately 15% weight loss. 8 The weight loss associated with GLP-1 agonists has been shown to be associated with decreased hepatic inflammation in patients with NASH. The Liraglutide Efficacy and Action in NASH (LEAN) phase II study showed that 39% (9/23) of participants who received liraglutide 1.8 mg SC daily and who underwent an end of treatment liver biopsy after 48 weeks had resolution of NASH compared with 9% (2/22) in the placebo group. 9 A phase IIb study with semaglutide at 0.1 mg, 0.2 mg, or 0.4 mg SC once daily (total weekly dose of 0.7 mg to 2.8 mg) showed histologic resolution of NASH without worsening of fibrosis in 40.4% to 58.9% of participants compared to placebo (17.2%) after 72 weeks of dosing, albeit without significant improvement in fibrosis. 10 Glucagon receptor activation has a number of effects that may complement the beneficial effects of GLP-1 receptor agonism for the treatment of NASH. 11 Glucagon has been shown to induce weight loss by reducing food intake and increasing energy expenditure. In addition to reducing liver fat content (LFC) indirectly through weight loss, glucagon agonism may also reduce LFC by acting on the liver directly to stimulate fatty acid oxidation and reduce lipogenesis. 12 Efinopegdutide (MK-6024) is a synthetic peptide of oxyntomodulin conjugated to the constant region of human IgG4 that acts as a dual GLP-1 receptor and glucagon receptor agonist, with a GLP-1 receptor:glucagon receptor relative potency of approximately 2:1. Oxyntomodulin, a 37 amino acid peptide product of the proglucagon gene released from L-cells of the small intestine in response to food ingestion, has been shown to decrease appetite and body weight in overweight and obese individuals. 13,14 The effects of efinopegdutide on weight loss were studied in two phase II dose-ranging studies in obese patients with and without T2DM. 15,16 In both studies, treatment with efinopegdutide resulted in a significant, dose-dependent reduction in body weight. 15,16 The present phase IIa study was conducted to compare the efficacy and safety of GLP-1 and glucagon receptor co-agonism with efinopegdutide to GLP-1 agonism alone with semaglutide in patients with NAFLD with and without T2DM, and to generate data on the potential of efinopegdutide as a novel therapy for NASH. Patients and methods Participant selection This study enrolled males and females aged 18 to 70 years. Inclusion criteria included NAFLD based on an LFC of > −10% as assessed by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF), BMI > −25 kg/m 2 and < −50 kg/m 2 , stable body weight (based on self-reporting) defined as < −5% gain or loss of body weight for at least 3 months before screening, and either no history of T2DM or a history of T2DM with glycated hemoglobin (HbA1c) < −8.5% at screening and controlled by diet and/or a stable dose of metformin for the 3 months before screening. Antihyperglycemic agents other than metformin were not permitted. Key exclusion criteria included history or evidence of chronic liver disease other than NAFLD or NASH; known history of cirrhosis (fibrosis stage >3 based on a historical liver biopsy or a liver stiffness score >14 kPa based on a historical FibroScan ® assessment; decompensated liver disease including, but not limited to, history of ascites, esophageal or gastric variceal bleeding, hepatocellular carcinoma, hepatic encephalopathy, splenomegaly, or spontaneous bacterial peritonitis; treatment with any GLP-1 receptor agonist or investigational GLP-1/ glucagon receptor co-agonist within 6 months before screening; treatment with thiazolidinediones (i.e., pioglitazone, rosiglitazone) within 6 months before screening; previous or current use of prescription weight-management medications or over-the-counter weight-loss medications or therapies within the 3 months before screening; treatment with an antihyperlipidemic therapy that was not at a stable dose for at least 1 month before screening; or treatment with >100 IU/day of vitamin E at a dose that was not stable for at least 3 months before screening. Study design This was a phase IIa, randomized, active-comparatorcontrolled (semaglutide; Ozempic ® ), parallel-group, multi-site, open-label study of efinopegdutide in participants with NAFLD (protocol 001; EudraCT: 2020-005136-30; NCT: 04944992). The study protocol was approved by the institutional review board or independent ethics committee at each investigational site and was conducted in accordance with applicable regulations and the ethical principles of Good Clinical Practice as defined by the International Conference on Harmonization and Declaration of Helsinki. Written informed consent was obtained from all participants. The study design is shown in Fig. 1. The duration of the study was approximately 32 weeks, which included a staged screening period of approximately 4 weeks, a 24-week activecomparator-controlled treatment period, and a post-treatment period follow-up visit at approximately 5 weeks after the last dose of study intervention. During the screening period, an MRI-PDFF was performed on all participants who met other screening eligibility requirements. If a participant had an LFC as assessed by MRIPDFF of > −10% as determined by blinded independent central review and all other eligibility criteria had been met, the participant proceeded to randomization. At baseline (Day 1), participants who met eligibility criteria were randomly assigned in a 1:1 ratio to efinopegdutide 10 mg SC once weekly or semaglutide 1 mg SC once weekly, stratified according to concurrent diagnosis of T2DM at the time of randomization. Participants randomized to efinopegdutide 10 mg once weekly or semaglutide 1 mg once weekly followed a 3-step dose-escalation regimen to achieve the planned study dose. Participants randomized to the efinopegdutide 10 mg once Journal of Hepatology, October 2023. vol. 79 j888–897 889 Research Article weekly group were started at a dose of 2.4 mg once weekly from Day 1 to Week 4; the dose was increased to 5 mg once weekly from Week 4 up to Week 8 and then to 10 mg once weekly from Week 8 to Week 24. Participants who could not tolerate the efinopegdutide 10 mg once weekly dose could continue in the study on the efinopegdutide 5 mg once weekly dose. Down-titration below the 5 mg once weekly dose for efinopegdutide was not permitted; study treatment was discontinued in participants unable to tolerate at least the 5 mg once weekly efinopegdutide dose. Participants randomized to the semaglutide 1 mg once weekly treatment group were started at a dose of 0.25 mg once weekly from Day 1 to Week 4; the dose was increased to 0.5 mg once weekly from Week 4 to Week 8 and then to 1 mg once weekly from Week 8 to Week 24. Participants who could not tolerate the semaglutide 1 mg once weekly dose could continue in the study on the semaglutide 0.5 mg once weekly dose. Down-titration below the 0.5 mg once weekly dose for semaglutide was not permitted; study treatment was discontinued in participants unable to tolerate at least the 0.5 mg once weekly semaglutide dose. All participants received dietary and activity counseling at the randomization visit from a qualified health care professional, using diet and activity guidance sheets. At subsequent visits, the site staff reviewed the diet and activity guidance sheets with the participants. Efficacy endpoints The primary efficacy endpoint was the relative reduction from baseline in LFC measured by MRI-PDFF (evaluated by blinded independent central review) after 24 weeks of treatment. Secondary efficacy endpoints included the percent change from baseline in body weight and fasting lipid levels (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides) after 24 weeks of treatment. The following exploratory endpoints supported the primary efficacy endpoint: the proportions of participants with relative reductions from baseline in LFC of > −30%, > −50% and > −70%; the proportion of participants who had achieved normal LFC (<5%); and the mean relative reduction from baseline in LFC by weight-loss categories (percent reductions from baseline in body weight of < −5%, >5% to < −10%, and >10%). Exploratory fibrosis biomarkers included change from baseline at Week 24 in pro-peptide of type III collagen (Pro-C3) and enhanced liver fibrosis (ELF) and a post hoc analysis of change from baseline at Week 24 in fibrosis-4 index (FIB-4). Because the study population included a broad range of participants with NAFLD, many of whom may have had no or minimal fibrosis, the results of these analyses of fibrosis biomarkers should be interpreted with caution. Safety assessments Safety and tolerability were monitored throughout the study by clinical evaluation of adverse events and inspection of other study parameters including physical examinations, 12-lead electrocardiograms, vital signs, and laboratory safety tests. Statistical analysis The efficacy analysis population included all randomized participants who received at least one dose of study intervention and had at least one assessment. The primary efficacy analysis compared the efficacy of efinopegdutide to semaglutide in the relative reduction from baseline in LFC at Week 24. The difference (efinopegdutide minus semaglutide) in means and the associated 90% CI and pvalues were provided based on a longitudinal data analysis model. 17 Efinopegdutide was considered superior to semaglutide if the one-sided pvalue was <0.05. The model-based least squares (LS) mean change from baseline for each treatment group and difference (with CI) between treatment groups at the Week 24 post-baseline time point were summarized. Percent changes in body weight and fasting lipid levels were analyzed using the same longitudinal data analysis model as described for the primary endpoint. The changes from baseline in Pro-C3, ELF, and FIB-4 at Week 24 were summarized descriptively. The safety analysis population consisted of all randomized participants who received at least one dose of study intervention. A sample size of 65 participants per arm provided approximately 99% power to establish that efinopegdutide was superior to semaglutide with respect to the mean relative reduction from baseline in LFC at Week 24, with a one-sided a = 0.05, assuming a true treatment difference of approximately 19.4%, a common SD of 20%, and 10% missing Week 24 data. A sample size of 65 participants per arm provided 80% Population characteristics • Males and females • Age: 18 to 70 years • NAFLD with LFC ≥10% by MRI-PDFF • T2DM stratification (yes or no) R 1:1 2.4 mg 5.0 mg 10.0 mg Efinopegdutide SC Q1W 1.0 mg Semaglutide SC Q1W 0.5 mg 0.25 mg Screening period Treatment period Posttreatment period MRI-PDFF Day 1 wk 1 wk 2 wk 3 wk 4 wk 8 wk 12 wk 16 wk 20 wk 24 wk 28 MRI-PDFF Fig. 1. Study design. LFC, liver fat content; MRI-PDFF, magnetic resonance imaging-estimated proton density fat fraction; NAFLD, non-alcoholic fatty liver disease; R, randomization; T2DM, type 2 diabetes mellitus. 890 Journal of Hepatology, October 2023. vol. 79 j888–897 Efficacy and safety of efinopegdutide in NAFLD power to establish that efinopegdutide was superior to semaglutide by 10% or more with respect to the mean relative reduction from baseline in LFC after 24 weeks. Results This study was performed from 4 August 2021 to 19 October 2022 across 79 centers in 16 countries (Argentina, Australia, Canada, France, Israel, Italy, Mexico, New Zealand, Poland, Russia, South Korea, Spain, Taiwan, Turkiye, Ukraine, and United States). The disposition of participants is shown in Fig. 2. A total of 145 participants were randomized to treatment, of whom 135 completed the study. In the efinopegdutide group, seven participants did not tolerate the target dose of 10 mg once weekly; of those, six down-titrated to and completed the study on a dose of 5 mg once weekly, and one down-titrated to 5 mg once weekly but subsequently discontinued study medication. In the semaglutide group, one participant attempted to up-titrate to the target dose of 1 mg once weekly, but had to down-titrate, and completed the study on a dose of semaglutide 0.5 mg once weekly. One other participant who could not tolerate 0.5 mg once weekly discontinued study medication. Demographics and baseline characteristics The two treatment groups had similar demographics and baseline characteristics (Table 1). Among 145 randomized participants (efinopegdutide, n = 72; semaglutide, n = 73), the majority (55.2%) of participants were male, mean age was 49.5 years, mean BMI was 34.3 kg/m 2 , mean body weight was 97.3 kg, 33.1% of participants had T2DM, and mean LFC was 20.3%. Efficacy At Week 24, treatment with efinopegdutide led to a significantly (p<0.001) greater relative reduction from baseline in LFC compared to semaglutide; the LS mean relative reduction from baseline in LFC was 72.7% (90% CI 66.8–78.7) with efinopegdutide and 42.3% (90% CI 36.5–48.1) with semaglutide (Fig. 3A, Table 2). The difference in the LS mean relative reduction from baseline in LFC at Week 24 in the efinopegdutide group compared to the semaglutide group was 30.4% (90% CI 22.1–38.7; p<0.001) (Fig. 3A, Table 2). The mean relative reduction from baseline in LFC at Week 24 in the efinopegdutide group was superior by 10% or more to that observed in the semaglutide group. Median relative reductions from baseline in LFC at Week 24 were 83.8% with efinopegdutide and 44.4% with semaglutide. A greater proportion of participants achieved a normal LFC level (<5%) at Week 24 with efinopegdutide (66.7%) compared with semaglutide (17.8%). Greater proportions of participants had relative reductions from baseline in LFC at Week 24 of > −30%, > −50% and > −70% with efinopegdutide (81.9%, 77.8%, and 70.8%, respectively) compared with semaglutide (67.1%, 43.8%, and 12.3%, respectively) (Fig. 3B). The LS mean percent reduction from baseline in body weight at Week 24 was 8.5% in the efinopegdutide group compared with 7.1% in the semaglutide group (p= 0.085) (Table 2). Similar percent reductions from baseline in mean body weight were observed in the two treatment groups over time (Fig. 4A). The relative reductions from baseline in LFC at Week 24 by weight-loss category (< −5%, >5% to < −10%, and >10% reduction in body weight from baseline) were greater in the efinopegdutide group (52.4%, 76.6%, and 86.2%, respectively) than in the semaglutide group (13.4%, 39.6%, and 64.2%, respectively) (Fig. 3C). In the efinopegdutide group, LS mean percent reductions from baseline at Week 24 were observed in total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides of 15.2%, 8.1%, 13.0%, and 30.9%, respectively (Table 2). In the semaglutide group, LS mean percent reductions from baseline in total cholesterol, lowRandomized n = 145 Semaglutide n = 73 Completed n = 71 Completed n = 64 Efinopegdutide n = 72 Discontinued n = 8 Lost to follow-upn = 1 Physician decision n = 1 Withdrawal by subject n = 4 Other n = 2 Discontinued n = 2 Lost to follow-up n = 1 Withdrawal by subject n = 1 Screened N = 318 Not randomized n = 173 Screen failure n = 173 Fig. 2. Disposition of participants. Journal of Hepatology, October 2023. vol. 79 j888–897 891 Research Article density lipoprotein cholesterol, and triglycerides of 8.0%, 6.9%, and 23.3%, respectively, and an LS mean percent increase from baseline in high-density lipoprotein cholesterol of 3.6%, were observed at Week 24 (Table 2). Safety Slightly higher incidences of adverse events and drug-related adverse events were observed in the efinopegdutide group, primarily related to an imbalance in gastrointestinal adverse Table 1. Demographics and baseline characteristics. Efinopegdutide Semaglutide Parameter n= 72 n= 73 Sex Male 39 (54.2) 41 (56.2) Female 33 (45.8) 32 (43.8) Age, years 48.1 [11.0] 50.9 [10.9] Race American Indian or Alaska Native 3 (4.2) 2 (2.7) Asian 7 (9.7) 7 (9.6) Black 0 1 (1.4) White 62 (86.1) 63 (86.3) Ethnicity Hispanic or Latino 25 (34.7) 26 (35.6) Not Hispanic or Latino 46 (63.9) 47 (64.4) Unknown 1 (1.4) 0 BMI, kg/m 2 35.2 [5.7] 33.5 [5.0] Body weight, kg 100.2 [18.8] 94.5 [18.9] T2DM (stratification) Yes 24 (33.3) 24 (32.9) No 48 (66.7) 49 (67.1) With T2DM HbA1c % 6.3 [0.7] 6.5 [0.8] FPG, mg/dl 121.9 [33.0] 122.3 [31.0] Without T2DM HbA1c, % 5.7 [0.3] 5.6 [0.4] FPG, mg/dl 101.6 [13.0] 99.1 [11.4] LFC, % 21.1 [8.1] 19.4 [8.1] ALT, IU/L 61.9 [45.4] 54.2 [32.7] AST, IU/L 35.6 [18.9] 36.6 [19.3] Total cholesterol, mmol/L 5.3 [1.1] 5.3 [1.2] High-density lipoprotein cholesterol, mmol/L 1.2 [0.3] 1.2 [0.4] Low-density lipoprotein cholesterol, mmol/L 3.3 [0.9] 3.2 [1.1] Triglycerides, mmol/L 2.0 [0.9] 2.0 [1.0] WBC, 10 9 /L 6.6 [1.6] 6.6 [1.6] Platelet count, 10 9 /L 258.6 [58.8] 256.8 [70.4] Hemoglobin, mmol/L 9.1 [0.8] 9.0 [0.9] Pro-C3, l g/L 53.2 [16.7] 55.9 [16.7] ELF 8.8 [0.9] 9.1 [0.9] Data are presented as n (%) for categorical variables and mean [SD] for continuous variables. ALT, alanine aminotransferase; AST, aspartate aminotransferase; ELF, enhanced liver fibrosis; FPG, fasting plasma glucose; LFC, liver fat content; Pro-C3, pro-peptide of type III collagen; T2DM, type 2 diabetes mellitus; WBC, white blood cell count. C Mean relative reduction from baseline in LFC at week 24 (%) BA Efinopegdutide Semaglutide 72.7% 42.3% LS mean relative reduction from baseline in LFC at week 24 (%) Difference in LS means (90% CI) efinopegdutide vs. semaglutide: 30.4 (22.1, 38.7); p <0.001 ≤5% >5% to ≤10 % >10% 52.4% 76.6% 13.4% 39.6% Efinopegdutide Semaglutide 100 0 10 20 30 40 50 60 70 80 90 ≥30% ≥50% ≥70% Relative reduction from baseline in LFC at Week 24 Percent of participants 81.9% 77.8% 70.8% 67.1% 43.8% 12.3% N = 72 N = 73 n/N = 59/72 n/N = 56/72 n/N = 51/72 n/N = 49/73 n/N = 32/73 n/N = 9/73 100 0 10 20 30 40 50 60 70 80 90 Percent reduction from baseline in body weight at Week 24 86.2% 64.2% N = 15 N = 29N = 18 N = 30 N = 22 N = 23 100 0 10 20 30 40 50 60 70 80 90 Fig. 3. Primary efficacy endpoint. (A) LS mean relative reduction from baseline at Week 24 in LFC, derived from a longitudinal data analysis; (B) proportions of participants with relative reductions from baseline in LFC at Week 24 of > −30%, > −50%, and > −70%; (C) mean relative reductions from baseline in LFC at Week 24 by weight-loss category (< −5%, >5% to < −10%, and >10% reduction in body weight from baseline). LFC, liver fat content; LS, least squares. 892 Journal of Hepatology, October 2023. vol. 79 j888–897 Efficacy and safety of efinopegdutide in NAFLD events (Table 3). There were otherwise no meaningful differences between the two treatment groups in the incidence of overall, serious, or drug-related adverse events, including adverse events that led to discontinuation (Table 3). The overall profile of adverse events reported by at least four participants was similar between the two treatment groups (Table 3). The incidences of nausea and of vomiting were similar between the two treatment groups (Table 3). Three specific adverse events Table 2. Efficacy results. Parameter n Baseline mean (SD) n Week 24 mean (SD) Percent change from baseline at Week 24 n Mean (SD) LS mean (90% CI) a Difference in LS means (90% CI) efinopegdutide vs. semaglutide a ;pvalue b LFC, % Efinopegdutide 72 21.1 (8.1) 65 4.6 (4.5) 72 −74.6 (28.0) −72.7 (−78.7 to −66.8) −30.4 (−38.7 to −22.1); <0.001 Semaglutide 73 19.4 (8.1) 72 11.4 (7.2) 73 −40.9 (27.9) −42.3 (−48.1 to −36.5) Body weight, kg Efinopegdutide 72 100.2 (18.8) 66 91.6 (19.5) 72 −8.7 (5.2) −8.5 (−9.5 to −7.5) −1.4 (−2.7 to −0.1); 0.085 Semaglutide 73 94.5 (18.9) 71 87.4 (19.0) 73 −7.5 (4.3) −7.1 (−8.1 to −6.2) Total cholesterol, mmol/L Efinopegdutide 72 5.3 (1.1) 65 4.4 (1.0) 72 −16.4 (14.8) −15.2 (−18.2 to −12.2) −7.2 (−11.2 to −3.1) Semaglutide 73 5.3 (1.2) 69 4.7 (1.0) 73 −8.6 (15.3) −8.0 (−11.0 to −5.0) High-density lipoprotein cholesterol, mmol/L Efinopegdutide 72 1.2 (0.3) 65 1.1 (0.3) 72 −8.5 (15.3) −8.1 (−11.2 to −5.1) −11.7 (−15.8 to −7.7) Semaglutide 73 1.2 (0.4) 68 1.2 (0.3) 73 2.0 (15.0) 3.6 (0.6 to 6.6) Low-density lipoprotein cholesterol, mmol/L Efinopegdutide 71 3.3 (0.9) 65 2.7 (0.8) 72 −14.9 (19.5) −13.0 (−17.4 to −8.6) −6.1 (−12.0 to −0.1) Semaglutide 73 3.2 (1.1) 67 2.8 (0.9) 73 −8.3 (22.9) −6.9 (−11.3 to −2.6) Triglycerides, mmol/L Efinopegdutide 72 2.0 (0.9) 65 1.3 (0.5) 72 −26.1 (26.0) −30.9 (−35.6 to −25.8) −7.6 (−14.3 to −0.9) Semaglutide 73 2.0 (1.0) 68 1.5 (0.6) 73 −18.6 (27.3) −23.3 (−28.5 to −17.7) For baseline and Week 24, n is the number of participants with non-missing assessments at the specific timepoint. For percent change from baseline, n is the number of randomized participants. LFC, liver fat content; LS, least squares. a Based on a constrained longitudinal data analysis model including terms for treatment, time, stratum (T2DM), and the interactions of treatment by stratum, time by treatment, and time by stratum. b pvalue not computed for total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. Diastolic blood pressure (mmHg) D Mean ± SE change from baseline 2.5 -2.5 -5.0 -7.5 Week 0 1 2 3 4 8 12 16 20 24 FU 0.0 5.0 A Week Body weight B Mean ± SE change from baseline 15 10 5 0 -5 Week Heart rate (bpm) 01234 8 12 16 20 24 FU Systolic blood pressure (mmHg) C Mean ± SE change from baseline 0 -5 -10 -15 Week 01234 8 12 16 20 24 FU LS mean ± SE percent change from baseline Efinopegdutide (baseline = 127.9 mmHg) Semaglutide (baseline = 129.1 mmHg) Efinopegdutide (baseline = 80.5 mmHg) Semaglutide (baseline = 80.2 mmHg) Efinopegdutide (baseline = 100.2 kg) Semaglutide (baseline = 94.5 kg) Efinopegdutide (baseline = 73.2 bpm) Semaglutide (baseline = 71.5 bpm) 0 -8 1234 8 12 16 20 24 -10 -6 -4 -2 0 Fig. 4. Other endpoints. Mean (SE) percent change from baseline over time in (A) body weight and mean (SE) change from baseline over time in (B) heart rate, (C) systolic blood pressure, and (D) diastolic blood pressure. LS, least squares. Journal of Hepatology, October 2023. vol. 79 j888–897 893 Research Article in the gastrointestinal system organ class were reported at a higher incidence with efinopegdutide compared to semaglutide: abdominal pain (12.5% vs. 2.7%, respectively), abdominal pain upper (9.7% vs. 1.4%), and constipation (16.7% vs. 5.5%) (Table 3). An adverse event of a composite of abdominal pain terms (including terms for abdominal pain, abdominal pain upper, abdominal pain lower, or abdominal tenderness) was reported for 17 participants in the efinopegdutide group (23.6%); the majority (13/17) of these participants were reported to have a maximum toxicity grade of 1 while the remainder (4/17) had a maximum toxicity of grade 2. An adverse event of the same composite of abdominal pain terms was reported for three participants in the semaglutide group (4.1%); one of the three participants had a maximum toxicity grade of 2. Constipation was reported as an adverse event for 12 participants in the efinopegdutide group (16.7%) compared to four in the semaglutide group (5.5%). All of the adverse events of constipation were reported to have a toxicity grade of 1 and required a dose reduction in only one participant in the efinopegdutide group. All adverse events of abdominal pain and constipation resolved while participants remained on study treatment. A slightly greater increase from baseline in mean heart rate, and slightly greater reductions from baseline in both mean systolic and mean diastolic blood pressure, were observed with efinopegdutide compared to semaglutide (Fig. 4B-D). There was no notable imbalance in adverse events considered potentially related to changes in heart rate or blood pressure. Laboratory parameters of interest While there was a small imbalance in the number of participants with the adverse event of alanine aminotransferase (ALT) elevation, similar reductions from baseline in mean ALT and mean aspartate aminotransferase were observed in the two treatment groups, which had begun by Week 4 and continued throughout the 24-week treatment period (Fig. 5A,B). A post hoc analysis showed that 45.2% of participants in the efinopegdutide group achieved a reduction from baseline in ALT of > −17 U/L at Week 24 compared with 44.1% of participants in the semaglutide group. The relative reductions from baseline in ALT at Week 24 by weight-loss category (< −5%, >5% to < −10%, and >10% reduction in body weight from baseline) were 18.8%, 26.4%, and 19.9%, respectively, in the efinopegdutide group compared with 2.4%, 24.9%, and 33.2%, respectively, in the semaglutide group (Fig. 5C). At Week 24, treatment with efinopegdutide led to similar changes from baseline in Pro-C3, ELF, and FIB-4 compared to treatment with semaglutide (Table S1). Table 3. Adverse events. Efinopegdutide n= 72 Semaglutide n= 73 n (%) n (%) Adverse events 64 (88.9) 53 (72.6) Drug-related a adverse events 46 (63.9) 35 (47.9) Serious adverse events 1 (1.4) 1 (1.4) Serious drug-related adverse events 0 0 Deaths 000 Discontinued drug due to an adverse event 4 (5.6) 0 Discontinued drug due to a drug-related adverse event 3 (4.2) 0 Discontinued drug due to a serious adverse event 0 0 Discontinued drug due to a serious drug-related adverse event 0 0 Adverse events that occurred in > −4 participants in either treatment group Gastrointestinal adverse events Abdominal distension 4 (5.6) 3 (4.1) Abdominal pain 9 (12.5) 2 (2.7) Abdominal pain upper 7 (9.7) 1 (1.4) Constipation 12 (16.7) 4 (5.5) Diarrhea 12 (16.7) 13 (17.8) Dyspepsia 6 (8.3) 5 (6.8) Flatulence 4 (5.6) 1 (1.4) Gastroesophageal reflux disease 6 (8.3) 5 (6.8) Nausea 20 (27.8) 23 (31.5) Vomiting 12 (16.7) 11 (15.1) General disorders and administration site conditions Fatigue 1 (1.4) 6 (8.2) Infections and infestations COVID-19 8 (11.1) 10 (13.7) Urinary tract infection 4 (5.6) 2 (2.7) Investigations Alanine aminotransferase increased 4 (5.6) 0 Lipase increased 4 (5.6) 3 (4.1) Metabolism and nutrition disorders Decreased appetite 12 (16.7) 11 (15.1) Nervous system disorders Dizziness 4 (5.6) 2 (2.7) Headache 5 (6.9) 5 (6.8) a Considered by the investigator to be related to the drug. 894 Journal of Hepatology, October 2023. vol. 79 j888–897 Efficacy and safety of efinopegdutide in NAFLD Treatment with efinopegdutide was associated with a mean increase from baseline in fasting plasma glucose of 0.01 mmol/ L and a mean change from baseline in HbA1c of 0.0% at Week 24, compared to a mean decrease in fasting plasma glucose of 0.64 mmol/L and a mean decrease in HbA1c of 0.5% with semaglutide. Treatment with efinopegdutide and semaglutide was associated with a mean decrease from baseline in hemoglobin of 0.62 mmol/L and 0.12 mmol/L, respectively, at Week 24. There were no adverse events related to reductions in hemoglobin in either treatment group. There were no meaningful differences for other laboratory assessments. Discussion The present study compared the efficacy and safety of GLP-1 and glucagon receptor co-agonism with efinopegdutide to GLP-1 receptor agonism alone with semaglutide in patients with NAFLD. In this study, both active treatments produced clinically meaningful reductions from baseline in LFC, with efinopegdutide providing a significantly greater reduction in LFC than semaglutide. Treatment with efinopegdutide allowed two-thirds of participants to achieve a normal LFC level (<5%) compared with less than one-fifth of participants on semaglutide. The significantly larger reduction in LFC with efinopegdutide (72.7%) than with semaglutide (42.3%) occurred in spite of both treatments producing similar reductions in body weight. This study was initiated prior to the availability of the higher dose (2.4 mg weekly) of semaglutide that is currently approved for the treatment of obesity and that is being evaluated in a phase III study as a potential therapeutic option for patients with NASH. While the greater magnitude of weight loss observed with higher doses of semaglutide may provide some additional antisteatotic efficacy compared to the dose used in this study, prior studies with higher doses of semaglutide have resulted in relative reductions of liver fat of 36% to 46% at 6 months. 18–20 Both treatments resulted in a majority of participants achieving at least a 30% reduction in LFC, which is generally regarded as the minimum threshold for histologic response in patients with NASH. 21 The substantial proportion of participants achieving over 50% and over 70% reduction in liver fat in the efinopegdutide treatment group, with approximately two-thirds of the population normalizing their liver fat concentration, suggests that robust effects on steatohepatitis may be achievable with co-agonists that target both the GLP-1 receptor and the glucagon receptor. Further studies are needed to evaluate the effects of efinopegdutide on histologic endpoints in patients with NAFLD/NASH. Consistent with the experience with dietary, 22 pharmacologic, 23 and surgical therapies 24,25 for weight loss, participants in both treatment groups with larger body weight reductions had greater reductions in LFC. The relative reductions from baseline in LFC at Week 24 by specific weight-loss category (< −5%, >5% to < −10%, and >10% reduction in body weight from baseline) were all greater in the efinopegdutide group than in the semaglutide group. Of particular note was the magnitude of LFC reduction in participants in the lowest weight-loss category. Among those with < −5% weight loss from baseline, the reduction in LFC with efinopegdutide was 52.4% compared to a reduction of 13.4% in the semaglutide group. These findings suggest that other mechanisms, beyond those related to weight loss, contributed to the greater LFC-reducing effect with efinopegdutide compared to semaglutide. This difference is likely due to the glucagon receptor agonism of efinopegdutide directly stimulating fatty acid oxidation and reducing lipogenesis in the liver. 12 Treatment with efinopegdutide was generally well tolerated. Slightly higher incidences of adverse events and drugrelated adverse events were observed in the efinopegdutide group, primarily related to an imbalance in gastrointestinal adverse events. There were otherwise no meaningful differences between the two treatment groups in the incidence of overall, serious, or drug-related adverse events, including adverse events that led to discontinuation. Dose-dependent gastrointestinal adverse events (predominantly nausea and vomiting) were previously reported in two phase II doseranging studies with efinopegdutide in obese patients with and without T2DM 15,16 and have been well described for GLPA Mean ± SE change from baseline -10 0 -30 -20 Week ALT (IU/L) 01234 8 12 16 20 24 Efinopegdutide (baseline = 61.9) Semaglutide (baseline = 54.2) B Mean ± SE change from baseline -5 0 -15 -10 Week AST (IU/L) 01234 8 12 16 20 24 Efinopegdutide (baseline = 35.6) Semaglutide (baseline = 36.6) C 0 5 10 15 20 25 30 35 40 ≤5% >5% to ≤10 % >10% Mean relative reduction from baseline in ALT at week 24 (%) Relative reduction from baseline in body weight at week 24 18.8% 2.4% 26.4% 24.9% 19.9% 33.2% N = 12 N = 18 N = 28 N = 27 N = 22 N = 23 Efinopegdutide Semaglutide Fig. 5. Laboratory results. Mean (SE) change from baseline over time in (A) ALT and (B) AST; (C) mean relative reductions from baseline in ALT at Week 24 by weight-loss category (< −5%, >5% to < −10%, and >10% reduction in body weight from baseline). ALT, alanine aminotransferase; AST, aspartate aminotransferase. Journal of Hepatology, October 2023. vol. 79 j888–897 895 Research Article