A Review of Selected Presentations From the American Association for the Study of Liver Diseases 2025 Liver Meeting
November 7-11, 2025 • Washington, DC
Two-Year Time Course of Biomarker and Imaging Responses in Patients With Well-Compensated MASH Cirrhosis Treated With Resmetirom
The thyroid hormone receptor β (THR-β) agonist resmetirom has been approved by the US Food and Drug Administration (FDA) for adults with metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced liver scarring without cirrhosis. There are currently no FDA-approved therapies for MASH with compensated cirrhosis, and stage F4 fibrosis is associated with an increased risk of adverse outcomes, including liver-related complications, need for transplantation, and death.1
Through its binding to THR-β, resmetirom may affect multiple biologic processes in the liver, regulating gene expression, reducing inflammation, indirectly blocking stellate cell activation, and reducing fibrosis production.2 Alkhouri and colleagues presented results from the MAESTRO-NAFLD-1 trial evaluating the safety and efficacy of resmetirom in an open-label cohort of patients with well compensated MASH cirrhosis (Child-Pugh A).3 Patients were required to have at least 3 metabolic risk factors and a platelet count of 70,000/μL or higher.
Patients in the cohort received resmetirom 80 mg for 52 weeks. After a variable gap off treatment ranging from 1 month to 1 year (median treatment gap, 77 days), patients could enter a 1-year open-label extension (OLE). Of the 161 patients who completed 52 weeks of treatment, 122 enrolled in the OLE and 113 completed the 2-year study.
Outcomes were presented based on baseline platelet count of 100,000/μL or higher (n=92; high-platelet group) or less than 100,000/μL (n=30; low-platelet group). Median spleen volume was substantially higher in the low-platelet group than the high-platelet group (906.5 mL vs 424.7 mL), which the investigators noted was attributed to advanced portal hypertension. Conversely, multiple measures of fibrosis and liver stiffness were higher in the low-platelet group, including median Agile-4 (0.85 vs 0.56), magnetic resonance elastography (MRE) (5.9 vs 5.1 kPa), vibration-controlled transient elastography (VCTE) (26.4 vs 19.3 kPa), and Fibrosis-4 (3.9 vs 2.0).
In the efficacy analysis, resmetirom was associated with significant reductions in liver stiffness measurement (LSM) as assessed by VCTE after 1 year and 2 years in both groups. In the low-platelet group, the mean change from baseline was -6.2 kPa at year 1 and -7.9 kPa at year 2; in the high-platelet group, the mean changes were -6.5 kPa and -6.4 kPa, respectively (Figure 1). After 2 years, 59% of patients in the low-platelet group and 49% of patients in the high-platelet group were considered LSM responders, with a 25% change in LSM.
At baseline, clinically significant portal hypertension (CSPH) or probable CSPH as assessed by the Baveno CSPH risk score was present in 93% of patients with a platelet count less than 100,000/μL and 36% of patients with a platelet count 100,000/μL or higher. Resmetirom was associated with a shift to a lower CSPH risk score in approximately two-thirds of patients and to a lower Agile-4 score, indicating a lower risk of cirrhosis. During the median 77-day treatment gap between years 1 and 2, there were transient increases in magnetic resonance imaging–proton density fat fraction (MRI-PDFF), apolipoprotein B, and VCTE; however, the reintroduction of resmetirom resulted in restoration of these values to the levels observed at the end of year 1.
Spleen volume decreased at year 1 of resmetirom in both the low-platelet group (median change, -2.4%) and in the high-platelet group (median change, -7.7%) and increased during the treatment gap. The increase was particularly notable in the low-platelet group. During year 2, spleen volume stabilized in the low-platelet group and decreased in the high-platelet group.
There were significant improvements in multiple imaging measures after 2 years, including in MRI-PDFF, controlled attenuation parameter, and MRE, and these improvements occurred across baseline platelet count groups. Liver enzyme levels also reduced significantly with resmetirom treatment, particularly in patients with a high baseline platelet count, as did biomarkers associated with fibrosis, liver injury, and atherogenic lipids.
In the safety analysis, no serious adverse events (AEs) were study drug–related. The most common AEs were diarrhea (37.7%), COVID-19 (31.1%), nausea (31.1%), and urinary tract infection (25.4%). Over 2 years of treatment, no changes in bone mineral density or fracture risk were noted; there were 6 hepatic decompensation events, 5 of which occurred in patients with a baseline platelet count less than 100,000/μL.
References
1. Sanyal AJ, Van Natta ML, Clark J, et al; NASH Clinical Research Network (CRN). Prospective study of outcomes in adults with nonalcoholic fatty liver disease. N Engl J Med. 2021;385(17):1559-1569.
2. Kendall TJ, Jimenez-Ramos M, Turner F, et al. An integrated gene-to-outcome multimodal database for metabolic dysfunction-associated steatotic liver disease. Nat Med. 2023;29(11):2939-2953.
3. Alkhouri N, Taub R, Lu X, et al. Two-year time course of biomarker and imaging responses in patients with well-compensated MASH cirrhosis treated with resmetirom. AASLD abstract 0167. Presented at: The Liver Meeting; November 7-11, 2025; Washington, DC.
Once-Monthly Efimosfermin Alfa for Up to 48 Weeks in MASH With F2/F3 Fibrosis: Results From a Phase 2, Open-Label Extension Study
Efimosfermin is a novel engineered fibroblast growth factor 21 analog that was designed to have an extended half-life to allow for once-monthly dosing.1 Clinical trials are evaluating efimosfermina alfa in patients with MASH. The randomized, double-blind, placebo-controlled, phase 2 trial of patients with MASH with biopsy-confirmed F2/F3 fibrosis reported that, among 65 evaluable patients, efimosfermin alfa 300 mg every 4 weeks was significantly more effective than placebo after 24 weeks of treatment.2 This was assessed by the proportion of patients attaining a fibrosis improvement of 1 stage or higher without worsening of MASH (45% vs 21%; P=.038) and the proportion of patients attaining MASH resolution without worsening of fibrosis (68% vs 29%; P=.002). In the prior safety analysis, the most frequent treatment-emergent AEs were gastrointestinal (GI), including nausea (33% vs 13% with placebo), diarrhea (23% vs 8%), and vomiting (16% vs 3%), and were mostly mild to moderate. The rate of discontinuations owing to AEs in the efimosfermin alfa arm was 4.7%.
Noureddin and colleagues presented additional findings from the trial, including efficacy and safety outcomes through the 24-week OLE in 15 patients originally assigned to efimosfermin alfa and in 18 patients crossing over from the placebo arm.3 Results were reported for the full analysis set, which included patients who received at least 1 dose of study treatment in the OLE, and the biopsy analysis set, which included 11 patients initially assigned to efimosfermin alfa and 17 patients initially assigned to placebo.
Among patients initially assigned to efimosfermin alfa, who had received up to 48 weeks of treatment, 5 of 11 patients (45.5%) had fibrosis improvement of 1 stage or more without worsening of MASH, including 2 patients (18.2%) with new fibrosis improvement. MASH resolution without worsening of fibrosis occurred in 7 patients (63.6%) and was new in 2 patients (18.2%), and 5 patients (45.5%) had fibrosis improvement of 1 stage or more and MASH resolution (Figure 2). Improvements in noninvasive markers of fibrosis included a mean change from baseline in PRO-C3 of -20.1% (n=13), in Enhanced Liver Fibrosis (ELF) score of -0.7 (n=13), and in VCTE LSM of -12.8 kPa. The mean change from baseline in alanine aminotransferase (ALT) was -31.1U/L, and in aspartate aminotransferase (AST) was -29.2 U/L.
There were sustained reductions in liver fat over 48 weeks as assessed by hepatic fat fraction, with a mean change of -50.0% at the end of study (relative reductions of ≥30% and ≥50% were attained by 53.8% and 46.2% of patients, respectively). Nearly 40% of patients (38.5%) attained liver fat normalization (≤5%). Improvements in cardiometabolic profile with efimosfermin alfa at 48 weeks included a mean change from baseline in the following levels: triglycerides, -0.3 mmol/L; high-density lipoprotein cholesterol, 0.1 mmol/L; low-density lipoprotein (LDL-C), 0.1 mmol/L; total cholesterol, 0.1 mmol/L; adiponectin, 79.2% change; and glycated hemoglobin (A1c), -0.5% units in all patients (n=13) and -0.6% units in patients with type 2 diabetes mellitus (T2DM, n=11). Treatment responses in patients initially assigned to placebo who crossed over to efimosfermin alfa were consistent with those observed in patients originally assigned to the study drug.
In the safety analysis, the only serious AE was a case of appendicitis in the OLE that was considered not treatment-related. No patients discontinued treatment during the OLE period owing to AEs, and no antidrug antibodies were detected. Most GI AEs occurred in the first 24 weeks of treatment. Nausea was reported in 20% of patients in the original efimosfermin alfa group and 22% of patients in the crossover group; diarrhea occurred in 13% and 22% of patients, respectively, and vomiting occurred in 13% and 17% of patients, respectively. Two cases of hepatic calcification in the crossover group were considered not treatment-related.
Investigators concluded that once-monthly efimosfermin alfa was associated with fibrosis improvement and MASH resolution after up to 48 weeks in patients with F2/F3 MASH and improvements in noninvasive markers of fibrosis, liver injury, and liver fat through the end of the OLE. The ongoing phase 3 ZENITH-1 (NCT07221227) and ZENITH-2 (NCT07221188) trials are evaluating efimosfermin alfa in patients with biopsy-confirmed F2/F3 MASH.
References
1. Rader DJ, Maratos-Flier E, Nguyen A, et al; CLLF580X2102 Study Team. LLF580, an FGF21 analog, reduces triglycerides and hepatic fat in obese adults with modest hypertriglyceridemia. J Clin Endocrinol Metab. 2022;107(1):e57-e70.
2. Noureddin M, Kowdley KV, Clawson A, et al. Once-monthly efimosfermin alfa (BOS-580) in metabolic dysfunction-associated steatohepatitis with F2/F3 fibrosis: results from a 24 week, randomized, double-blind, placebo-controlled, phase 2 trial. Gastroenterology. 2025;169(suppl):S1647. Abstract 723.
3. Noureddin M, Kowdley KV, Kutch K, Jeglinski B, Koziel MJ, Loomba R. Once-monthly efimosfermin alfa for up to 48 weeks in MASH with F2/F3 fibrosis: results from a phase 2, open-label extension study. AASLD abstract 5011. Presented at: The Liver Meeting; November 7-11, 2025; Washington, DC.
Improvement in Health-Related Quality of Life After Treatment With Resmetirom in Cirrhotic and Noncirrhotic Patients With MASLD: Data From MAESTRO‑NAFLD-1
Metabolic dysfunction-associated steatotic liver disease (MASLD) and MASH are associated with significant impairments in health-related quality of life (HRQL), particularly in patients with advanced fibrosis.1 The MAESTRO-NAFLD-1 trial evaluated resmetirom in patients with MASLD cirrhosis (MASH cirrhosis) or MASLD without cirrhosis (early MASH).2 In the early MASH cohort (VCTE 5.5 up to 8.5 kPa or MRE 2.0 up to 4.0 kPa), 1143 patients were enrolled into a double-blind arm of resmetirom 100 mg (n=325), resmetirom 80 mg (n=327), or placebo (n=320), or an open-label arm of resmetirom 100 mg (n=171). The MASH cirrhosis cohort included 180 patients with well-compensated MASH cirrhosis with no history of decompensation who received open-label resmetirom 80 mg. The median age of patients in the early MASH cohort was 56 years; 43% were male, 53% had T2DM, and the median MRI-PDFF was 18%. The median age of patients in the MASH cirrhosis cohort was 61 years; 38% were male, 73% had T2DM, and the median MRI-PDFF was 9%.
Younossi and colleagues reported on the effects of resmetirom treatment on HRQL in patients with MASLD with and without cirrhosis enrolled in the MAESTRO-NAFLD-1 trial.3 HRQL was assessed using the 17-domain Liver Disease Quality of Life (LDQOL) questionnaire and the 6-domain Chronic Liver Disease Questionnaire–non-alcoholic fatty liver disease (CLDQ-NAFLD). At baseline, HRQL scores in patients with MASH cirrhosis were significantly lower than those of patients with early MASH. In the early MASH cohort, after no differences were found between the double-blind resmetirom arm and the open-label resmetirom arm, the two groups were pooled for subsequent analyses.
In patients with early MASH, 52 weeks of resmetirom was associated with significant improvements over placebo in abdominal symptoms, worry, and health distress scores, and appeared to reduce the extent of declines in physical and emotional role functioning. Patients who attained a 30% or greater reduction in MRI-PDFF after 52 weeks of resmetirom had greater improvements in the Worry and Abdominal Symptoms domains of CLDQ-NAFLD and the Stigma from liver disease domain of the LDQOL than patients in the placebo arm or nonresponders (Figure 3).
Across all domains, HRQL scores were lower in patients with cirrhosis than in patients with early MASH and in patients with biopsy-proven F2 to F3 MASH (per historic data in the MAESTRO-NASH trial).4 The greatest impairments were observed in the Worry, Health Distress, Role Physical, Hopelessness, Physical Functioning, and General Health domains. Among patients with MASH cirrhosis, resmetirom was associated with improvements in the Worry domain of the CLDQ-NAFLD and the Health Distress domain of the LDQOL by week 24, and these improvements were sustained out to year 2 (P<.05). Significant improvements in the Stigma score were observed in patients with MASH cirrhosis with a PDFF response at week 52 (P<.05).
Resmetirom was associated with improvements in selected HRQL scores in patients with MASH cirrhosis and those with early MASH, and these benefits were sustained long-term. The findings suggest that resmetirom addresses patient-reported outcomes in patients with MASLD.
References
1. Younossi ZM, Stepanova M, Anstee QM, et al. Reduced patient-reported outcome scores associate with level of fibrosis in patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2019;17(12):2552-2560.e10.
2. Harrison SA, Taub R, Neff GW, et al. Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial. Nat Med. 2023;29(11):2919-2928.
3. Younossi ZM, Nader F, Labriola D, et al. Improvement in health-related quality of life after treatment with resmetirom in cirrhotic and noncirrhotic patients with MASLD: data from MAESTRO‑NAFLD-1. AASLD abstract 0181. Presented at: The Liver Meeting; November 7-11, 2025; Washington, DC.
4. Younossi ZM, Stepanova M, Racila A, et al. Health-related quality of life (HRQL) assessments in a 52-week, double-blind, randomized, placebo-controlled phase III study of resmetirom (MGL-3196) in patients with metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis. Hepatology. 2025;81(4):1318-1327.
Weight-Dependent and -Independent Effects of Semaglutide in Participants With MASH: Secondary Analysis of the Phase 3 ESSENCE Trial
The phase 3 ESSENCE trial is evaluating the efficacy of semaglutide in patients with biopsy-defined MASH and stage 2 or 3 fibrosis.1 In part 1 of the study, 800 patients were randomly assigned to once weekly semaglutide at 2.4 mg following a 16-week dose escalation (n=534) or to placebo (n=266).1 The mean age of enrolled patients was 56 years; 57% were female, the mean body weight was 24.5 kg, and 55.9% had T2DM. Semaglutide demonstrated significant improvements in liver-related parameters compared with placebo, including a greater proportion of patients attaining resolution of steatohepatitis without worsening of fibrosis (62.9% vs 34.3%; P<.001) and a greater proportion of patients attaining reductions in liver fibrosis without worsening of steatohepatitis (36.8% vs 22.4%; P<.001). Mean changes in body weight were -10.5% and -2.0%, respectively (P<.001).
Newsome and colleagues presented post-hoc analyses investigating the association between body weight reduction and liver outcomes in the ESSENCE trial.2 At week 72, improvements in MASH-related and fibrosis-related endpoints were observed across body weight reduction thresholds. Rates of steatohepatitis resolution without worsening of liver fibrosis among patients receiving semaglutide ranged from 57.1% (43.1% for placebo) in patients with 2% to 5% body weight reduction to 71.5% (56.1% for placebo) in patients with greater than 7% body weight reduction. Rates of improvement in liver fibrosis without worsening of steatohepatitis ranged from 29.3% (22.5% for placebo) in patients with 2% to 5% body weight reduction to 41.8% (37.2% for placebo) in patients with greater than 7% body weight reduction (Figure 4).
Improvements in MASH-related noninvasive test parameters were also observed across body weight reduction thresholds in patients receiving semaglutide, as were improvements in fibrosis-related histologic and noninvasive test responses, including change in ELF scores and VCTE.
The investigators used exploratory mediation analyses to attempt to measure the extent to which the effects of semaglutide on liver parameters were indirect effects (resulting from body weight reduction) or direct effects (not attributed to body weight reduction). They found that MASH-related histologic changes and noninvasive test responses (including histologic resolution of MASH without worsening of liver fibrosis, ALT responses, and FibroScan AST [FAST] responses), as well as fibrosis-related histologic improvement and noninvasive test responses (including improvement in fibrosis without worsening of MASH, VCTE responses, and ELF score responses), were greater in patients receiving semaglutide than in patients receiving placebo, even at a similar amount of weight reduction.
These exploratory findings suggest that factors other than weight reduction may contribute to the liver health benefits observed with semaglutide. However, investigators cautioned that interaction and confounding effects can influence outcomes and may complicate the analysis. They added that a few people on the placebo arm had large amounts of weight loss, which may also complicate the analysis. Moreover, the model requires assumptions that are not always testable. Despite these limitations, the investigators concluded that the benefits of semaglutide on liver health are not driven by weight reduction alone.
References
1. Sanyal AJ, Newsome PN, Kliers I, et al; ESSENCE Study Group. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025;392(21):2089-2099.
2. Newsome PN, Armstrong MJ, Bakulin I, et al. Weight-dependent and -independent effects of semaglutide in participants with MASH: secondary analysis of the phase 3 ESSENCE trial. AASLD abstract 0010. Presented at: The Liver Meeting; November 7-11, 2025; Washington, DC.
Analysis of Baseline PRO-C3 and ELF Components in Patients With MASH/MASLD and MASH Cirrhosis and Correlations Between Change in PRO-C3 and ELF in Resmetirom-Treated Patients From the MAESTRO-NASH Trial
Noninvasive methods, such as ELF and PRO-C3, are used for assessing extent of fibrosis and predicting liver outcomes in patients with MASH. The FDA-approved prognostic biomarker ELF incorporates 3 serum biomarkers—tissue inhibitor of metalloproteinase 1 (TIMP-1), N-terminal propeptide of type III procollagen (P3NP), and hyaluronic acid (HA)—to provide a more reliable marker compared with individual markers.1 PRO-C3 is a clinically validated marker of fibrosis that is independently associated with fibrotic stage. In the MAESTRO-NASH trial in patients with biopsy-confirmed MASH and fibrosis, resmetirom was associated with a reduction in ELF and in 2 of its components—P3NP and TIMP-1—but not HA.2
Bansal and colleagues presented results of an analysis further investigating changes in biomarkers in two trials of resmetirom.3 Baseline ELF scores and ELF components were assessed according to biopsy fibrosis stage in a pooled cohort of patients from the MAESTRO-NASH and MAESTRO-NAFLD-1 trials. Correlations between ELF/P3NP and PRO-C3 at baseline and week 52, and the effect of resmetirom vs placebo on PRO-C3 and P3NP/ELF scores, were evaluated in patients from the MAESTRO-NASH trial who received resmetirom 80 mg, resmetirom 100 mg, or placebo.
In the assessment of ELF components and total scores at baseline, levels of TIMP-1 and P3NP did not increase from stage F0 to F2 but did increase by 20% moving from stage F2 to F3/F4. HA levels in patients with fibrosis stages F0 to F2 were higher in patients with diabetes than in patients without diabetes. Moreover, HA levels nearly doubled (1.9-fold increase) moving from stage F3 to F4, which is the likely reason for the increase in ELF score in patients with F4 fibrosis.
In the analysis of baseline ELF/P3NP and PRO-C3 levels in patients in the MAESTRO-NASH trial, correlations were found between P3NP and PRO-C3 (correlation coefficient, ρ=0.563) and between ELF and PRO-C3 (correlation coefficient, ρ=0.458).
In the assessment of changes in PRO-C3 from baseline to week 52 in patients receiving resmetirom or placebo, both resmetirom dose levels were associated with greater reductions in PRO-C3 over time than placebo, with a mean change of -23.05 ng/mL with resmetirom 100 mg and -17.93 ng/mL with resmetirom 80 mg, compared with -0.19 ng/mL with placebo. Greater PRO-C3 reductions were observed in the subset of patients with F3 fibrosis, with mean changes from baseline to week 52 of -27.42 ng/mL with resmetirom 100 mg, -22.24 ng/mL with resmetirom 80 mg, and -0.50 ng/mL with placebo (Figure 5).
Positive correlations of similar strength were reported in changes from baseline to week 52 in P3NP and ELF, and in changes from baseline to week 52 in PRO-C3 across treatment groups. The findings support including assessments of the individual ELF components when using the ELF test in patients treated for MASH.
References
1. Lai JC, Liang LY, Wong GL. Noninvasive tests for liver fibrosis in 2024: are there different scales for different diseases? Gastroenterol Rep (Oxf). 2024;12:goae024.
2. Harrison SA, Taub R, Neff GW, et al. Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial. Nat Med. 2023;29(11):2919-2928.
3. Bansal M, Taub R, Zhang H, et al. Analysis of baseline PRO-C3 and ELF components in patients with MASH/MASLD and MASH cirrhosis and correlations between change in PRO-C3 and ELF in resmetirom-treated patients from the MAESTRO-NASH trial. AASLD abstract 4074. Presented at: The Liver Meeting; November 7-11, 2025; Washington, DC.
Top-Line Phase 2 Results of DD01, a Dual GLP-1/Glucagon Agonist, Lead to Rapid Improvements in Liver and Metabolic Endpoints in Patients With MASLD/MASH
DD01 is a pegylated glucagon-like peptide-1 (GLP-1)/glucagon dual receptor agonist with a biodistribution preferentially targeting the liver and a half-life of approximately 8 days, allowing for once-weekly dosing. Clinical trials are evaluating DD01 for the treatment of MASLD/MASH and other metabolic disorders.
Noureddin and colleagues presented results from up to 24 weeks of a randomized, placebo-controlled phase 2 study of DD01 in patients with MASLD/MASH.1 The trial enrolled 67 patients with an MRI-PDFF of at least 10% steatosis and metabolic syndrome or with biopsy-confirmed F1 to F3 MASH. Patients were randomly assigned to subcutaneous DD01 40 mg once weekly following a 2-week titration period (n=33) or placebo (n=34). The primary endpoint was the proportion of patients achieving 30% or greater liver fat reduction by MRI-PDFF after 12 weeks of treatment.
The mean age of enrolled patients was 48 to 49 years (59%-67% were female, 61%-65% were Hispanic/Latino), and the mean body mass index (BMI) was 35.7 to 36.6 kg/m2. The majority of patients (79.4%-75.8%) had biopsy-confirmed MASH and F2/3 fibrosis (42.4%-52.9%).
At week 12, the trial met its primary endpoint, with 75.8% of patients in the DD01 arm attaining at least a 30% reduction in liver fat by MRI-PDFF (P<.0001 vs placebo). Nearly half of patients (48.5%) attained normalization with at least 5% liver fat (P<.0001 vs placebo). The mean relative reduction in liver fat was 62.3% in the DD01 arm vs 8.3% in the placebo arm (P<.0001) (Figure 6).
Mean improvements in liver stiffness by MRE at week 12 were significantly greater with DD01 vs placebo in all patients (-19.7% vs -7.2%; P<.01 vs placebo) and in patients with F2/3 fibrosis (-20.1% vs -8.7%). In the overall population, the mean relative change in ALT at week 12 was -35.9% with DD01 and -9.9% with placebo; at week 24, relative changes were -38.15% and -11.7%, respectively. Among patients with F2/3 with MASH, the mean change in ALT at week 12 was -46.7% with DD01 and -15.8% with placebo; relative changes at week 24 were -54.7% and -10.5%, respectively.
Improvements in lipid parameters, including total cholesterol, LDL-C, and triglycerides, were all significantly greater with DD01 compared with placebo at weeks 12 and/or 24, as were reductions in A1c at weeks 12 and 24. DD01 was also associated with significantly greater weight loss compared with placebo. At week 12, 42.4% of patients in the DD01 arm had attained at least 5% weight loss compared with 0% of patients in the placebo arm (P<.0001); by week 24, rates of at least 5% weight loss increased to 51.5% and 8.8%, respectively (P<.0001).
DD01 was well tolerated and GI toxicities were transient, nonsevere, and self-limiting, occurring sporadically over the first 12 weeks of treatment. Three patients discontinued DD01 owing to GI toxicities. The most frequent toxicities were nausea, reported in 54.5% of patients receiving DD01 and 17.6% of patients receiving placebo, diarrhea (27.3% vs 17.6%), constipation (30.3% vs 11.8%), decreased appetite (24.2% vs 5.9%), vomiting (18.2% vs 2.9%), and fatigue (18.2% vs 8.8%). The results support proceeding with phase 2b and 3 trials of DD01.
Reference
1. Noureddin M, Patil R, Rohit Puskoor DD, et al. Top-line phase 2 results of DD01, a dual GLP-1/glucagon agonist, lead to rapid improvements in liver and metabolic endpoints in patients with MASLD/MASH. AASLD abstract 5004. Presented at: The Liver Meeting; November 7-11, 2025; Washington, DC.
Comparison of MAESTRO-NASH and ESSENCE: Effects of Resmetirom and Semaglutide Relative to Placebo on Primary and Secondary Liver Biopsy Endpoints Using Aligned Endpoints and Statistical Methods
The MAESTRO-NASH and ESSENCE trials are ongoing studies evaluating new therapies in patients with MASH.1,2 The MAESTRO-NASH trial enrolled 966 patients including 917 with fibrosis stage 2/3, who were randomly assigned to resmetirom 100 mg (n=323), resmetirom 80 mg (n=322), or placebo (n=321). At week 52, the trial met its dual primary endpoints with both doses of resmetirom demonstrating significantly improvements over placebo in the proportion of patients attaining NASH resolution with no worsening of fibrosis with at least 2-point reduction in nonalcoholic fatty liver disease activity score (NAS) (P<.001 for both vs placebo), and at least 1-stage improvement in fibrosis with no worsening of NAS (P<.001 for both vs placebo).1
The ESSENCE trial enrolled 1197 patients with biopsy-defined MASH and fibrosis stage 2/3 who were randomly assigned to once weekly subcutaneous semaglutide at 2.4 mg (n=534) or placebo (n=266). In an analysis of the first 800 patients, the trial met its primary endpoint, with significantly higher proportions of patients in the semaglutide arm attaining resolution of steatohepatitis without worsening of liver fibrosis (P<.001 vs placebo) and attaining significantly greater reductions in liver fibrosis without worsening of steatohepatitis (P<.001 vs placebo).2
In an exploratory cross-trial analysis, Loomba and colleagues compared responses to drug treatment and placebo in the MAESTRO-NASH and ESSENCE trials using aligned biopsy endpoints and statistical tools. Baseline characteristics between patients with fibrosis stage 2/3 were similar across both trials; the mean age was 56 years in both trials; 57% of patients in both trials were female, and the mean BMI was 35.6 kg/m2 in MAESTRO-NASH and 34.6 kg/m2 in ESSENCE.
When placebo responses were imputed for missing data, the improvements with treatment over placebo in the likelihood of attaining at least 1-stage improvements in fibrosis with no worsening of NAS were similar with resmetirom 100 mg in MAESTRO-NASH (15% difference over placebo, approximate 2.4-fold improvement) as with semaglutide in ESSENCE (14% difference over placebo, approximate 2-fold improvement).
In MAESTRO-NASH, 36% of patients receiving resmetirom 100 mg attained the FDA endpoint of NASH resolution, compared with 13% in the placebo arm (23% difference), whereas in the ESSENCE trial, rates of NASH resolution were 63% with semaglutide and 34% with placebo (29% difference). However, using the more stringent endpoint of NASH resolution with at least 2-point NAS reduction, rates of resolution in the MAESTRO-NASH trial were 30% with resmetirom and 9% with placebo (21% difference) and in the ESSENCE trial were 44% with semaglutide and 19% with placebo (25% difference) (Figure 7).
The proportion of patients attaining a 2-point NAS reduction was 51% with resmetirom 100 mg in MAESTRO-NASH and 50% with semaglutide in ESSENCE, compared with 25% in both placebo arms. Investigators concluded that the similar rates of 2-point NAS reduction in the placebo arms suggest that the high rate of MASH resolution of 34% reported in the ESSENCE trial can be attributed to low NAS in the reassessed baseline biopsies.
The proportion of patients attaining ballooning reduction was numerically higher for patients in the resmetirom 100 mg arm in the MAESTRO-NASH trial than for patients in the semaglutide arm in the ESSENCE trial (66% vs 61%); rates in the placebo arms in both trials were 31% and 40%, respectively, indicating a greater difference from placebo in the resmetirom trial.
Regarding safety, resmetirom was associated with higher rates of diarrhea and nausea vs placebo, and semaglutide was associated with higher rates of nausea, diarrhea, constipation, and vomiting vs placebo. In both trials, the incidence of serious AEs was similar between treatment and placebo arms.
References
1. Harrison SA, Bedossa P, Guy CD, et al; MAESTRO-NASH Investigators. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390(6):497-509.
2. Sanyal AJ, Newsome PN, Kliers I, et al; ESSENCE Study Group. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025;392(21):2089-2099.
3. Loomba R, Taub R, Labriola D, Alkhouri N, Noureddin M. Comparison of MAESTRO-NASH and ESSENCE: effects of resmetirom and semaglutide relative to placebo on primary and secondary liver biopsy endpoints using aligned endpoints and statistical methods. AASLD abstract 4093. Presented at: The Liver Meeting; November 7-11, 2025; Washington, DC.