A Review of Selected Presentations From the American Association for the Study of Liver Diseases 2024 Liver Meeting
November 15-19, 2024 • San Diego, California
Phase 3 ESSENCE Trial: Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis
Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) that has been extensively studied in a wide spectrum of cardiometabolic diseases.1,2 As cardiovascular disease is the leading cause of mortality in metabolic dysfunction-associated steatotic liver disease (MASLD), it has been surmised that agents that result in improvements in cardiometabolic risk factors would also result in improved MASLD outcomes, including an improved liver condition.3,4 Indeed, a randomized placebo-controlled phase 2 trial demonstrated that among 320 patients with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis stage 1 to 3, semaglutide 0.4 mg once daily was associated with a significantly higher percentage of patients who achieved MASH resolution with no worsening of fibrosis compared with placebo (59% vs 17%; P<.001).5 These data led to the design of the ESSENCE trial, an ongoing phase 3, randomized, controlled trial comparing once-weekly subcutaneous semaglutide 2.4 mg vs placebo in patients with biopsy-defined MASH and fibrosis stage 2 or 3.4 Patients were randomized in a 2 to 1 ratio to treatment with semaglutide, which was initiated at a dose of 0.25 mg and titrated up over 16 weeks to a final dose of 2.4 mg once-weekly, or placebo. The ESSENCE study plans to treat patients for up to 240 weeks.
In a late-breaking abstract, Newsome and colleagues presented efficacy data from the first 800 participants who completed 72 weeks of treatment alongside a more up-to-date safety dataset.6 This 72-week phase 1 of the ESSENCE study was evaluated against 2 primary endpoints—resolution of steatohepatitis with no worsening of liver fibrosis, and improvement in liver fibrosis with no worsening of steatohepatitis. Resolution of steatohepatitis was defined as a Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) of 0 or 1 for inflammation, 0 for ballooning, and any value for steatosis. An improvement in fibrosis was defined as a 1 grade or higher improvement. No worsening of steatohepatitis was defined as no increase from baseline in NAS for ballooning, inflammation, or steatosis. The 2 primary endpoints were analyzed using a Cochran-Mantel-Haenszel test, stratified by both baseline diabetes status as well as fibrosis stage.
Among the first 800 randomized patients, 534 were randomized to treatment with semaglutide; at week 72, 88% remained on treatment and 87% had a biopsy. Baseline characteristics were well balanced across the semaglutide and placebo arms. The mean age was 56.3 years in the semaglutide arm and 55.4 years in the placebo arm; 58.6% and 54.1%, respectively, were female. At baseline, 55.4% of semaglutide-treated patients and 56.8% of placebo-treated patients had type 2 diabetes, and the mean body mass index (BMI) was 34.3 and 35.0, respectively. Approximately two-thirds of patients in each arm had fibrosis stage 3 (68.4% in the semaglutide arm and 69.5% in the placebo arm).
The primary endpoint of resolution of steatohepatitis with no worsening of fibrosis was achieved in semaglutide- vs placebo-treated patients, respectively (62.9% vs 34.1%) (Figure 1). These results were considered to be highly significant, with an estimated difference in respondent proportions (EDP) of 28.9 percentage points (P<.0001). A similarly significant improvement in the other primary endpoint of improvement in liver fibrosis with no worsening of steatohepatitis was also observed in the semaglutide vs placebo arms (37.0% vs 22.5%; an EDP of 14.5 percentage points; P<.0001).
Results from several confirmatory secondary endpoints were also reported. One of these, patients who achieved both resolution of steatohepatitis and a 1-stage improvement in liver fibrosis, was significantly improved in the semaglutide arm compared with the placebo arm (32.8% vs 16.2%; P<.0001). Not unexpectedly, the mean change from baseline in body weight was significantly improved among semaglutide-treated patients vs placebo-treated patients (–10.5 vs –2.0, respectively; P<.0001). In contrast, the confirmatory secondary endpoint of mean change from baseline in bodily pain, chosen because it was significantly impacted in the phase 2 trial, did not achieve statistical significance in this study (0.9 vs –0.5 in the semaglutide vs placebo arms; P=.0488; a higher score represents an improvement in bodily pain).
A consistent effect of semaglutide on liver enzyme levels was observed, with a 30% to 40% placebo-adjusted reduction with semaglutide compared with placebo. These included a 40% decrease in alanine aminotransferase (ALT), 30% decrease in aspartate aminotransferase (AST), and 40% decrease in gamma-glutamyl transferase (GGT); P<.0001 vs placebo for all comparisons. The same was true for the noninvasive measurements of fibrosis, including changes in liver stiffness values assessed by vibration-controlled transient elastography (FibroScan), which was improved by a decrease of 20%; change in Enhanced Liver Fibrosis score, which was improved by a decrease of 0.6 units; and change in Pro-C3 level, which was improved by a decrease of 20%. An evaluation of cardiometabolic risk parameters showed significant improvements with semaglutide vs placebo across nearly all measures, including systolic and diastolic blood pressures, dyslipidemia (except low-density lipoprotein cholesterol), and highly sensitive C-reactive protein.
Between the semaglutide and placebo arms, there was no increase in serious nor fatal adverse events (AEs). Discontinuations owing to AEs were also not significantly increased with semaglutide vs placebo. In accordance with previous safety findings with semaglutide, gastrointestinal side effects were more commonly found in patients receiving semaglutide vs placebo, including nausea (36.3% vs 13.2%), diarrhea (26.9% vs 12.2%), and constipation (22.3% vs 8.4%). With regard to a specific AE, an increase in gallbladder-related disorders was noted (2.5% vs 1.5%).
These data led the study authors to conclude that semaglutide was associated with superior MASH-related outcomes compared with placebo.
References
1. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al; SELECT Trial Investigators. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-2232.
2. Husain M, Birkenfeld AL, Donsmark M, et al; PIONEER 6 Investigators. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019;381(9):841-851.
3. Gato S, García-Fernández V, Gil-Gómez A, et al. Navigating the link between non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and cardiometabolic syndrome. Eur Cardiol. 2024;19:e03.
4. Newsome PN, Sanyal AJ, Engebretsen KA, et al. Semaglutide 2.4 mg in participants with metabolic dysfunction-associated steatohepatitis: baseline characteristics and design of the phase 3 ESSENCE trial. Aliment Pharmacol Ther. 2024;60(11-12):1525-1533.
5. Newsome PN, Buchholtz K, Cusi K, et al; NN9931-4296 Investigators. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021;384(12):1113-1124.
6. Newsome PN, Sanyal A, Kliers I, et al. Phase 3 ESSENCE trial: semaglutide in metabolic dysfunction-associated steatohepatitis (MASH) [AASLD abstract 5018]. Presented at: The Liver Meeting; November 15-19, 2024; San Diego, CA.
Effect of Resmetirom or Placebo in NASH Fibrosis Patients With <5% or ≥5% Weight Loss and/or on Baseline GLP-1 Therapy in the MAESTRO-NASH 52-Week Serial Liver Biopsy Study
In MASH, the function of the thyroid hormone receptor beta (THR-β) is reduced, causing a reduction in mitochondrial function and β-oxidation of fatty acids, resulting in an increase in fibrosis. The oral agent resmetirom, a liver-directed THR-β–selective agonist, was approved by the US Food and Drug Administration (FDA) in March 2024 for the treatment of adults with noncirrhotic MASH with moderate to advanced liver fibrosis (consistent with stage F2 or F3 fibrosis), based on the results of the MAESTRO-NASH phase 3 trial.1-3 Noureddin and colleagues summarized the results from the MAESTRO-NASH study on the effect of resmetirom in patients with biopsy-confirmed MASH and fibrosis with weight loss or GLP-1 therapy.4 (Note: the term MASH replaces NASH throughout except when used in a trial name).
The aim of the ongoing 54-month, randomized, double-blind, placebo-controlled MAESTRO-NASH trial is 2-fold: to determine the effects of resmetirom compared with placebo on GLP-1 therapy at baseline, and to determine the effect of at least 5% weight loss on liver biopsy endpoints with or without GLP-1 baseline therapy. At baseline, 13% to 17% of patients in the treatment groups were receiving stable GLP-1 therapy for at least 6 months prior to randomization. All of the patients receiving GLP-1 therapy in the MAESTRO-NASH study had type 2 diabetes, with multiple GLP-1 therapies used. Other diabetic therapies associated with weight loss included sodium-glucose cotransporter 2 (SGLT2) inhibitors.
To be eligible for study enrollment, patients were required to have the presence of 3 or more metabolic risk factors, as well as diagnosed MASH on biopsy with a NAS of 4 or greater (with ≥1 in each component), fibrosis stage F1, F2, or F3, and 8% or more hepatic fat by magnetic resonance imaging proton density fat fraction (MRI-PDFF). A total of 966 patients with biopsy-confirmed MASH were randomized in a 1:1:1 ratio to treatment with either resmetirom 80 mg, resmetirom 100 mg, or placebo, each administered orally once daily. Additionally, patients were counseled on moderate diet and exercise at each study visit. Dual histologic primary endpoints were both assessed at week 52—MASH resolution and fibrosis improvement. MASH resolution was defined as a ballooning score equal to 0, an inflammation score equal to 0 or 1, and a reduction in NAS of at least 2 points, with no worsening of fibrosis. Fibrosis improvement was defined as at least a 1 stage improvement in fibrosis, with no worsening of NAS.
Among patients with diabetes, there were no meaningful differences in baseline characteristics between patients treated with either GLP-1 or SGLT2 therapy. The most common dose was 1 mg semaglutide or comparable (dulaglutide). At baseline, fibrosis stage 3 was more common in patients with diabetes (64.1%) and patients receiving GLP-1 therapy (67.9%) compared with patients without diabetes (52.7%). The same was true for hypertension (83.3%, 84.7%, and 67.4%, respectively) and dyslipidemia (79.8%, 85.4%, and 54.2%, respectively). More patients who were diabetic (58.1%) and diabetic receiving GLP-1 therapy (61.3%) were being treated with a statin at baseline compared with nondiabetic patients (30.4%). In contrast, this group of patients had lower liver enzymes (mean ALT: 52.1 U/L, 45.6 U/L, and 62.1 U/L; mean AST: 38.8 U/L, 34.3 U/L, and 45.7 U/L). Patients on GLP-1 therapy at baseline showed no difference in baseline MRI-PDFF or body weight.
Among patients with diabetes who were treated with either dose of resmetirom plus GLP-1 therapy, liver biopsy responses were equivalent to those in patients with diabetes who were not receiving these therapies. For patients on GLP-1 therapy, the coprimary endpoint of MASH resolution was achieved in 27% and 39% of patients treated with resmetirom 80 mg and resmetirom 100 mg, respectively, compared with 32% and 38% of patients not treated with GLP-1 therapy. Similarly, the other coprimary endpoint of fibrosis improvement was achieved in 29% and 20% of patients treated with resmetirom 80 mg and resmetirom 100 mg, respectively, compared with 29% and 32% of patients not receiving GLP-1 therapy.
A similar trend was observed in patients with diabetes who were treated with either dose of resmetirom plus SGLT2 therapy. In patients treated with SGLT2 therapy, MASH resolution was achieved in 36% and 43% of patients treated with resmetirom 80 mg and resmetirom 100 mg, respectively, compared with 29% and 37% of patients not treated with SGLT2 therapy. Similarly, fibrosis improvement was achieved in 22% and 28% of patients treated with resmetirom 80 mg and resmetirom 100 mg, respectively, compared with 31% and 30% of patients not receiving SGLT2 therapy.
Further, neither diabetes drug impacted MRI-PDFF reduction at week 52 by resmetirom. At week 52, the MRI-PDFF reduction overall (regardless of diabetes drug) was –44% and –50% among patients with no diabetes treated with resmetirom 80 mg and resmetirom 100 mg, respectively, and was –41% and –52% among patients with diabetes treated with resmetirom 80 mg and resmetirom 100 mg, respectively. When analyzing the MRI-PDFF reduction in patients with diabetes, there was no difference between patients with GLP-1 therapy (–36% in resmetirom 80 mg– and –52% in resmetirom 100 mg–treated patients) and without GLP-1 therapy (–41% in resmetirom 80 mg– and –52% in resmetirom 100 mg–treated patients). Similar outcomes were noted for patients with diabetes treated with either SGLT2 therapy or insulin.
Weight loss of 5% or more at week 52 was observed more frequently in resmetirom- as compared with placebo-treated patients (17% and 22% in the resmetirom 80 mg and 100 mg groups, respectively). Among patients who achieved a 5% or more weight loss, the median weight loss was 7%. Weight loss of 5% or more that was achieved by diet and exercise occurred in approximately 22% of patients treated with either dose of resmetirom, compared with 12% of patients treated with placebo. GLP-1 treatment was not associated with weight loss; rates of weight loss of 5% or more or less than 5% were 14% vs 15%, respectively, for patients on GLP-1 therapy.
Weight loss of 5% or more was associated with high rates of MASH resolution and fibrosis improvement among resmetirom-treated patients. Among patients treated with resmetirom 100 mg specifically, a 5% or more weight loss was associated with increased fibrosis improvement (42%) and MASH resolution (58%) on liver biopsy (Figure 2). Similar outcomes were also reported among patients treated with resmetirom 80 mg. Compared with placebo, 3-fold more patients who were treated with resmetirom and had achieved a 5% or more weight loss had also achieved the coprimary endpoints of MASH resolution or fibrosis improvement.
MRI-PDFF reduction in patients with 5% or more weight loss improved at week 52 relative to week 16; there was no change between week 16 and week 52 in patients with less than 5% weight loss. Among resmetirom-treated patients, 98% with 5% or more weight loss had a 30% or higher MRI-PDFF reduction. The study authors concluded that relatively small amounts of weight loss (≥5%) could enhance the effects of resmetirom on outcomes such as MASH resolution and liver fibrosis improvement.
References
1. Kelly MJ, Pietranico-Cole S, Larigan JD, et al. Discovery of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), a highly selective thyroid hormone receptor β agonist in clinical trials for the treatment of dyslipidemia. J Med Chem. 2014;57(10):3912-3923.
2. Harrison SA, Ratziu V, Anstee QM, et al. Design of the phase 3 MAESTRO clinical program to evaluate resmetirom for the treatment of nonalcoholic steatohepatitis. Aliment Pharmacol Ther. 2024;59(1):51-63.
3. 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.
4. Noureddin M, Rinella M, Taub R, et al. Effect of resmetirom or placebo in NASH fibrosis patients with <5% or ≥5% weight loss and/or on baseline GLP-1 therapy in the MAESTRO-NASH 52 week serial liver biopsy study [AASLD abstract 132]. Hepatology. 2024;80(suppl 1).
Use of Glucagon-Like Peptide-1 Receptor Agonists in Patients With MASLD in a Real-World Setting Is Associated With Slower Disease Progression and Lower All-Cause Mortality
GLP-1 RAs, currently used in the treatment of type 2 diabetes and obesity, are also under investigation for their potential to reduce the risk for cirrhosis and other complications in patients with MASLD.1,2 Barritt and colleagues presented a study in which they evaluated the association between the use of GLP-1 RAs and MASLD outcomes.3
TARGET-NASH, a real-world longitudinal observational cohort study, included patients with MASLD who were receiving usual care at academic and community sites across the United States. Once enrolled, participants consented to provide access to their prior 3 years of medical records and were then prospectively followed. A detailed curation of these data was conducted using human in-the-loop and automated methodologies, encompassing electronic health records, clinician narratives, laboratory results, imaging, and pathology reports.
A set of real-world definitions was used to define the disease states for this study.4 If a patient had a biopsy, this would be used to define their disease as either metabolic dysfunction-associated steatotic liver (MASL), MASH, or MASH cirrhosis. Without a biopsy, MASH was defined as the presence of hepatic steatosis on imaging (computed tomography, ultrasound, or MRI), presence of at least one cardiometabolic risk factor, and elevated ALT. MASH cirrhosis was defined as the presence of one or more cardiovascular risk factors and hepatic steatosis with one of the following: fibrosis stage 4 on liver biopsy; fibrosis stage 3 on liver biopsy and one or more secondary indicators (evidence of ascites, portal hypertension, varices or portal gastropathy, platelet count <140,000, or cirrhosis or splenomegaly on imaging or scans); the presence of 2 or more secondary indicators; FibroScan stiffness result of 12.5 to 15.9 kPa together with one or more secondary indicators; or transient elastography stiffness results (≥16 kPa). Decompensation events were defined either as any ascites, any complications of ascites, hepatic encephalopathy, or variceal bleeding.
The analysis reported here aimed to describe the demographics and clinical characteristics, disease progression, and all-cause mortality among patients with MASLD who were prescribed GLP-1 RAs in real-world clinical practice through the TARGET-NASH study. To be included in the analysis, patients were required to be adults who had been diagnosed with MASL, MASH, or MASH cirrhosis in the 3 years prior to enrollment. Patients were grouped into cohorts defined by their use of GLP-1 treatments; GLP-1 RA users were defined as patients who had received either a GLP-1 RA or GLP-1 RA/glucose-dependent insulinotropic polypeptide for at least 1 year. Exclusion criteria included having 6 months or less of follow-up data, either prevalent liver cancer or liver transplant, or having received a GLP-1 RA for less than 1 year.
After excluding patients, a total of 4219 remained for analysis. These patients were relatively evenly distributed among disease definitions (1311 with MASL, 1331 with MASH, and 1577 with MASH cirrhosis). About 10% of patients met the definition for GLP-1 RA users (375 GLP-1 RA users and 3844 nonusers). Across the disease definitions, 86, 74, and 215 patients in the MASL, MASH, and MASH cirrhosis cohorts were GLP-1 RA users.
According to the patient demographics, as the disease progressed, the age increased. However, within each group, median age was similar between GLP-1 RA users and nonusers. More females accounted for the GLP-1 RA users vs nonusers in both the MASH (74.3% vs 59.6%; P<.05) and the MASH with cirrhosis (65.6% vs 56.8%; P<.05) cohorts. Within the MASH cohort, there were more prevalent cardiovascular events in GLP-1 RA users vs nonusers (21.6% vs 12.6%; P<.05), but not in the MASH with cirrhosis cohort (34.9% vs 32.2%). Hypertension was also more frequent in GLP-1 RA users compared with nonusers in the MASH (67.6% vs 52.4%; P<.05) and MASH with cirrhosis (78.1% vs 71.3%; P<.05) cohorts. Type 2 diabetes mellitus was more common among the GLP-1 RA users vs nonusers in all 3 cohorts (MASL: 80.2% vs 28.0%; MASH: 81.1% vs 33.3%; and MASH with cirrhosis: 93.5% vs 63.4%; P<.05 for all comparisons).
Disease progression events from compensated to decompensated cirrhosis occurred in 33 (20%) of the GLP-1 RA users compared with 217 (23%) of the nonusers. This was calculated to yield a hazard ratio (HR) of 1.69 (95% CI, 1.16-2.46) for the development of a decompensation event among GLP-1 RA users (Figure 3A). By comparison, other factors that increase the risk for disease progression were associated with less of a hazard risk, including non-Hispanic White race (HR, 1.331; 95% CI, 0.981-1.805), female sex (HR, 1.309; 95% CI, 1.008-1.700), the presence of type 2 diabetes (HR, 1.302; 95% CI, 0.972-1.744), and the presence of hypertension (HR, 1.347; 95% CI, 1.012-1.79). The median time of disease progression from compensated to decompensated cirrhosis was 24.2 months vs 21.2 months in the 2 groups.
The number of mortality events observed was 20 (5%) among GLP-1 RA users compared with 243 (6%) among nonusers, which was calculated as an increased risk of death (HR, 2.28; 95% CI, 1.43-3.60) in nonusers (Figure 3B). This was similar to the increased risk of death observed with type 2 diabetes (HR, 2.263; 95% CI, 1.689-3.032) and hypertension (HR, 2.229; 95% CI, 1.635-3.037). This HR was higher than the HR for other factors such as age (61+ years vs 18-60 years; HR, 1.746; 95% CI, 1.341-2.273) and non-Hispanic White race (HR, 1.671; 95% CI, 1.237-2.256).
According to the authors, the limitations for this analysis included the use of real-world data with nonstandardized follow-up, as well as the use of pragmatic disease definitions that were not based on histology. There is also a potential for a healthy user effect among patients who received treatment with GLP-1 RAs, particularly in this nonrandomized study.
References
1. Abushamat LA, Shah PA, Eckel RH, Harrison SA, Barb D. The emerging role of glucagon-like peptide-1 receptor agonists for the treatment of metabolic dysfunction-associated steatohepatitis. Clin Gastroenterol Hepatol. 2024;22(8):1565-1574.
2. Kanwal F, Kramer JR, Li L, et al. GLP-1 receptor agonists and risk for cirrhosis and related complications in patients with metabolic dysfunction-associated steatotic liver disease. JAMA Intern Med. 2024;184(11):1314-1323.
3. Barritt A, Mospan A, Munoz B, et al. Use of glucagon-like peptide 1 receptor agonists (GLP-1 RA) in patients with MASLD in a real-world setting is associated with slower disease progression and lower all-cause mortality [AASLD abstract 772]. Hepatology. 2024;80(suppl 1).
4. Barritt AS IV, Gitlin N, Klein S, et al. Design and rationale for a real-world observational cohort of patients with nonalcoholic fatty liver disease: the TARGET-NASH study. Contemp Clin Trials. 2017;61:33-38.
Assessment of Resmetirom Efficacy (80 mg vs. 100 mg) Stratified by Baseline Body Mass Index and Weight in Patients From the MAESTRO-NASH Trial
Noureddin and colleagues presented a second analysis of the MAESTRO-NASH trial, which focused on the efficacy of resmetirom according to baseline BMI and weight.1 The recommended dosage of resmetirom is based on actual body weight; for patients weighing under 100 kg, the recommended dosage is 80 mg orally once daily, whereas for patients who weigh 100 kg or more, the recommended dosage is 100 mg orally once daily.2
The only variable found to determine exposure to resmetirom among patients with MASH was body weight. Pharmacokinetic modeling indicated that patients with a higher exposure to resmetirom showed a higher rate of sex hormone-binding globulin (SHBG) response (≥120% increase in SHBG) and also a higher rate of MRI-PDFF response (≥30% reduction in MRI-PDFF). More patients treated with resmetirom 100 mg vs resmetirom 80 mg achieved these targets for SHBG and PDFF, with differences between doses occurring primarily in patients with a body weight of 100 kg or more.
Further exposure modeling showed that higher exposure to resmetirom was also associated with higher rates of both MASH and fibrosis responses on biopsy (Figure 4). Among patients weighing less than 100 kg, the rate of MASH resolution was 32% and 36% among patients treated with resmetirom 80 mg and resmetirom 100 mg, respectively. In patients weighing 100 kg or more, the rate of MASH resolution was 27% and 36% in the resmetirom 80 mg and resmetirom 100 mg treatment groups, respectively. For the outcome of fibrosis improvement, among patients weighing less than 100 kg, 35% and 34% achieved fibrosis improvement with resmetirom 80 mg and resmetirom 100 mg, respectively. In patients weighing 100 kg or more, the rate of fibrosis improvement was 23% and 33% in the resmetirom 80 mg and resmetirom 100 mg treatment groups, respectively.
Among patients who had both a baseline and week 52 liver biopsy, equivalent biopsy responses for both MASH resolution (22% with resmetirom 80 mg and 21% with resmetirom 100 mg) and fibrosis improvement (13% with resmetirom 80 mg and 12% with resmetirom 100 mg) were achieved in patients with a BMI less than 35. However, among patients with a higher BMI (≥35), the rates of MASH resolution (10% with resmetirom 80 mg and 20% with resmetirom 100 mg) and fibrosis improvement (7% with resmetirom 80 mg and 11% with resmetirom 100 mg) were both higher with resmetirom 100 mg.
Other biomarkers, such as ALT, FibroScan, and controlled attenuation parameter, showed similar improvements relative to placebo at both resmetirom doses.
The frequency of diarrhea was higher with the resmetirom 100 mg dose compared with the resmetirom 80 mg dose (33.4% vs 27.0%) and was higher with both than with placebo (15.6%). The rate of discontinuation owing to an AE was higher with resmetirom 100 mg (6.8%) but was relatively similar between resmetirom 80 mg (1.9%) and placebo (2.2%). Further, the rate of overall discontinuations of the resmetirom 100 mg dose was highest in the lower body weight group (19% in the <100 kg group compared with 17% in the ≥100 kg group), but the opposite was true for the resmetirom 80 mg dose (10% in the <100 kg group compared with 15% in the ≥100 kg group).
References
1. Noureddin M, Alkhouri N, Taub B, Labriola D, Loomba R. Assessment of resmetirom efficacy (80 mg vs. 100 mg) stratified by baseline body mass index and weight in patients from the MAESTRO-NASH trial [AASLD abstract 1644]. Hepatology. 2024;80(suppl 1).
2. Rezdiffra [package insert]. West Conshohocken, PA: Madrigal Pharmaceuticals, Inc; 2024.
Results From the 52-Week Phase 2b VOYAGE Trial of VK2809 in Patients With Biopsy-Confirmed Non-Alcoholic Steatohepatitis and Fibrosis: A Randomized, Placebo-Controlled Trial
Lian and colleagues presented data from the 52-week phase 2b VOYAGE trial, which evaluated the investigational agent VK2809, a potent and selective THR-β agonist.1,2 VK2809 has been demonstrated to have liver-targeting characteristics, including CYP3A4-mediated cleavage; because CYP3A4 is primarily expressed in the liver, this results in a largely targeted delivery of the drug to the liver tissue.
The VOYAGE study was designed as a 12-month, double-blind, placebo-controlled, phase 2b trial. In this study, patients with biopsy-confirmed MASH were randomized to treatment with either placebo or VK2809 at 1 of 4 doses (1.0 mg once daily, 2.5 mg once daily, 5 mg every other day, or 10 mg every other day). At baseline, patient characteristics were well balanced, with females more prevalent than males across all arms, and age, weight, and BMI consistent across all arms.
The primary endpoint of the VOYAGE study was the change in MRI-PDFF at 3 months. A significant reduction in liver fat was observed at this time point at all doses of VK2809, except 1.0 mg once daily, compared with placebo. Patients experienced up to a 57% median reduction in MRI-PDFF from baseline. Importantly, these reductions in liver fat were sustained or improved through week 52, which showed up to a 56% median reduction in MRI-PDFF from baseline. Up to 85% of patients treated with VK2809 achieved a 30% or more decrease in liver fat at 12 weeks; this was increased to 88% at the week 52 time point. A reduction in liver fat was found to correlate with improved odds of long-term histology benefit.
Resolution of MASH without worsening of fibrosis was observed in up to 75% of patients (Figure 5). At the highest 2 doses of VK2809 (5 mg or 10 mg every other day), a significant proportion of patients achieved a 1-stage or higher improvement in fibrosis, without worsening of MASH. Among this group, similar fibrosis improvement rates were observed among patients with F2 or F3 stages.
The majority (94%) of treatment-emergent AEs reported were mild or moderate, and the rates of discontinuations due to an AE were balanced across the VK2809 doses and in comparison to placebo. The rates of gastrointestinal-related AEs in VK2809-treated patients were similar to placebo-treated patients.
References
1. Lian B, Loomba R, Rodriguez M, et al. Results from the 52 week phase 2b VOYAGE trial of VK2809 in patients with biopsy-confirmed non-alcoholic steatohepatitis and fibrosis: a randomized, placebo-controlled trial [AASLD abstract 5016]. Presented at: The Liver Meeting; November 15-19, 2024; San Diego, CA.
2. Zhou J, Waskowicz LR, Lim A, et al. A liver-specific thyromimetic, VK2809, decreases hepatosteatosis in glycogen storage disease type Ia. Thyroid. 2019;29(8):1158-1167.
Liver Enzymes Reductions From Baseline Over Time in Resmetirom-Treated Patients in a Phase 3 Study, MAESTRO-NASH
Many patients treated with resmetirom may also receive treatment with statins, the latter of which are known to have potentially harmful effects on the liver.1,2 Therefore, Baum and colleagues reported on an analysis of the phase 3 MAESTRO-NASH trial, which aimed to evaluate the effects of resmetirom and statins, alone and in combination, on liver function as assessed by changes in the levels of the liver enzymes ALT, AST, and GGT over time.3
As part of the eligibility criteria for enrollment in MAESTRO-NASH, patients were required to have an AST level of greater than 17 U/L (women) or greater than 20 U/L (men), and were excluded if serum ALT was greater than 250 U/L. At baseline, 49% of the 966 patients were receiving treatment with a statin. These included atorvastatin (23.1%), rosuvastatin (11.8%), simvastatin (6.6%), pravastatin (6.5%), lovastatin (0.7%), and pitavastatin (0.3%). Among the 49% of patients receiving a statin, 13% were receiving treatment with high-intensity statin therapy (rosuvastatin 20 mg; atorvastatin 40 mg) and the remaining 36% were receiving treatment with moderate-to-low-intensity statin therapy (36%).
Among the 473 patients who were receiving statins at baseline, a total of 149 patients were randomized to receive resmetirom 80 mg, 166 received resmetirom 100 mg, and 158 received placebo. At baseline, patients receiving statins had lower liver enzyme levels than patients not receiving statins (median ALT level, 43 U/L vs 54 U/L; median AST level, 33 U/L vs 38 U/L; and median GGT level, 55 U/L vs 51 U/L).
Mild increases in both ALT and AST levels (<1.5-fold over baseline) were apparent at week 4 among statin-treated patients compared with patients not receiving statins, as shown in Figure 6 for ALT. These increases were transient and resolved by week 8, declining thereafter. GGT levels declined from the time resmetirom treatment was initiated.
In patients with ALT levels of 30 U/L or higher at baseline who were receiving a statin, at week 48 the ALT level had declined from baseline by 20% in the resmetirom 80 mg arm and 24% in the resmetirom 100 mg arm (P<.001 vs placebo for both comparisons). Among patients who were not receiving a statin, the week 48 ALT levels had declined from baseline by 37% and 43% in the resmetirom 80 mg and 100 mg arms, respectively (P<.001 vs placebo for both comparisons).
References
1. Newman CB, Preiss D, Tobert JA, et al. Statin safety and associated adverse events: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol. 2019;39(2):e38-e81.
2. Adhyaru BB, Jacobson TA. Safety and efficacy of statin therapy. Nat Rev Cardiol. 2018;15(12):757-769.
3. Baum S, Taub R, Labriola D, Alkhouri N, Noureddin M. Liver enzymes reductions from baseline over time in resmetirom treated patients in a phase 3 study, MAESTRO-NASH [AASLD abstract 1652]. Hepatology. 2024;80(suppl 1).
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
Efimosfermin alfa is a long-acting, once-monthly fibroblast growth factor 21 (FGF21) analogue with an extended half-life of 21 days. In a phase 2a multiple dose/regimen study, efimosfermin alfa led to significant improvements in liver steatosis, markers of liver injury, and fibrosis among patients with MASH.1 Noureddin and colleagues presented results of the histologic assessment of a randomized, double-blind phase 2b study comparing efimosfermin alfa 300 mg once monthly vs placebo.2
To be eligible for the study, patients were required to have biopsy-confirmed MASH with F2 and F3 fibrotic stage. The primary endpoint was safety and tolerability; histologic endpoints were also evaluated, including fibrosis improvement of 1 or more stages without worsening of MASH, MASH resolution without worsening of fibrosis, and fibrosis improvement together with MASH resolution. A total of 84 patients were randomized, with 67 completing study treatment. Baseline characteristics were well balanced between the efimosfermin alfa and placebo arms, with the exception of a higher proportion of patients with diabetes in the efimosfermin alfa group.
Efimosfermin alfa, compared with placebo, achieved statistically significant improvements at week 24 in MASH resolution without worsening of fibrosis (68% vs 29%; P<.01) and fibrosis improvement without worsening of MASH (45% vs 21%; P<.01), as shown in Figure 7. Several biomarkers were also improved with efimosfermin alfa, including MRI-PDFF reduction as well as clinically meaningful glycemic control markers such as glycated hemoglobin.
Efimosfermin alfa was associated with a favorable safety profile; one grade 3 treatment-related AE was reported. Low rates (<5%) of changes in appetite were reported with efimosfermin alfa, and no weight gain was apparent. Few (<5%) injection site reactions occurred.
References
1. Bain G, Clawson A, Lopez-Talavera JC, Odrljin T. BOS-580, a long-acting FGF21 analogue, treatment shows beneficial changes in the circulating lipidome and improves MASEF score in patients with phenotypic metabolic dysfunction-associated steatohepatitis in a phase 2a randomized, placebo-controlled, 12-week study [EASL abstract 621]. J Hepatol. 2024;80(suppl 1).
2. Noureddin M, Kowdley K, 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 [AASLD abstract 5017]. Presented at: The Liver Meeting; November 15-19, 2024; San Diego, CA.
Resmetirom Effects on NASH With Liver Fibrosis in Patients With NASH Genetic Risk Alleles
Another analysis of the MAESTRO-NASH study was presented by Chalasani and colleagues.1 This analysis focused on the impact of particular genotypes (PNPLA3, HSD17B13, TM6SF2, SERPIN [AAT], and MBOAT7) on baseline characteristics and the response to resmetirom. In MAESTRO-NASH, single nucleotide polymorphisms were genotyped in 740 patients across the 3 arms consenting to DNA collection and genetic testing.
A significant proportion of patients in the MAESTRO-NASH study were positive for genetic risk markers, particularly PNPLA3 (22.5% homozygous vs 10.5% in the non-MASH population) and HSD17B13 (65% wild-type vs 52% to 58% in the non-MASH population), as well as TM6SF2. These markers impacted several baseline features, including ethnicity, metabolic features, baseline liver enzyme levels, and lipids.
Higher genetic risk was associated with fewer metabolic risk factors (eg, dyslipidemia, hypertension, and type 2 diabetes) in the noncirrhotic MASH population of MAESTRO-NASH, suggesting that compared with patients without genetic risk factors, patients with higher genetic risk may require less metabolic risk to progress to an equivalent MASH fibrosis stage. However, the presence of MASH risk alleles did not influence the treatment response to resmetirom on liver biopsy, imaging, or other markers of response. In resmetirom-treated patients, the percentage achieving MASH resolution was not impacted by any MASH genetic risk markers (Figure 8), nor was the percentage with fibrosis improvement on liver biopsy.
Reference
1. Chalasani N, Labriola D, Taub R, Anstee Q. Resmetirom effects on NASH with liver fibrosis in patients with NASH genetic risk alleles [AASLD abstract 2070]. Hepatology. 2024;80(suppl 1).
Aerobic Exercise Training Leads to MASH Resolution as Defined by the MASH Resolution Index Without Body Weight Loss
Lifestyle intervention, including dietary changes and increased physical activity, is recommended for all patients with MASLD with a goal of achieving 7% to 10% in weight loss.1 However, the vast majority of patients struggle to achieve this goal. Exercise training specifically has many benefits, several of which occur without significant body weight loss.2 Although these benefits can occur outside the liver, many also impact the liver itself. For example, exercise training can lead to clinically significant reductions in MRI-measured liver fat, and a higher likelihood of achieving a 30% or more reduction in MRI-PDFF, considered a surrogate for histologic improvement.3 Likewise, exercise training lessens MASH activity, even in the context of no body weight loss.4
Channapragrada and colleagues provided an overview of a study which investigated the impact of lifestyle intervention, in the form of aerobic exercise training, on MASH resolution.5 The MASH Resolution Index (MASH-RI)6 was applied in a post hoc analysis of data from the NASHFit trial7 to assess if exercise training can lead to MASH resolution without body weight loss. This NASHFit cohort was comprised mainly of non-Hispanic White women with early-stage MASH. A total of 15 patients received an aerobic exercise intervention, while 8 received standard of care.
This analysis found that exercise training achieved MASH resolution about 3-fold more often and without significant body weight loss (33% vs 13%; P<.01), as shown in Figure 9. Additionally, patients who participated in exercise training showed a greater reduction in MRI-PDFF (–4.3% vs +1.2%) and greater reduction in ALT levels (–14 U/L vs –6 U/L).
According to the study authors, the data demonstrate that sustained exercise training can result in MASH resolution, even without weight loss, and that future work should focus on whether exercise training can lead to liver fibrosis regression and resolution.
References
1. Stine JG, Long MT, Corey KE, et al. American College of Sports Medicine (ACSM) International Multidisciplinary Roundtable report on physical activity and nonalcoholic fatty liver disease. Hepatol Commun. 2023;7(4):e0108.
2. Stine JG, Henry ZH. How to write an exercise prescription to treat metabolic dysfunction-associated steatotic liver disease for the busy clinician. Am J Gastroenterol. 2024;119(6):1007-1010.
3. Stine JG, Loomba R. Magnetic resonance imaging proton density fat fraction as an imaging-based biomarker of treatment response in patients with nonalcoholic steatohepatitis. Clin Liver Dis (Hoboken). 2022;20(6):198-201.
4. Harris SJ, Stine JG. Frailty in liver transplantation: exploring prescribing exercise as medicine to improve patient outcomes. Liver Int. 2024;44(9):2251-2262.
5. Channapragrada T, Hummer B, Chinchilli V, et al. Aerobic exercise training leads to MASH resolution as defined by the MASH Resolution Index without body weight loss [AASLD abstract 1428]. Hepatology. 2024;80(suppl 1).
6. Loomba R, Amangurbanova M, Bettencourt R, et al. MASH Resolution Index: development and validation of a non-invasive score to detect histological resolution of MASH. Gut. 2024;73(8):1343-1349.
7. Stine JG, Schreibman IR, Faust AJ, et al. NASHFit: a randomized controlled trial of an exercise training program to reduce clotting risk in patients with NASH. Hepatology. 2022;76(1):172-185.