Madrigal Pharmaceuticals (United States)

<h3>Introduction</h3> Resmetirom, a selective thyroid hormone receptor beta agonist, is an approved therapy for metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced liver fibrosis based on improvement in both NASH and fibrosis. MASH cirrhosis with clinically significant portal hypertension (CSPH) leads to major adverse liver outcomes. This analysis aimed to assess the effect of resmetirom over two years of treatment in 122 patients with MASH cirrhosis, with and without CSPH, as defined by Baveno VII criteria. <h3>Methods</h3> A total of 122 patients with Child Pugh A MASH cirrhosis (based on MASH F4 on historic biopsy &gt;66% or clinical diagnosis) were treated with 80 mg resmetirom for up to 2 years (MAESTRO-NAFLD-1(NCT04197479) year 1; open-label extension trial (NCT04951219) (year 2)). Patients were assessed for baseline CSPH (Baveno VII) with FibroScan vibration-controlled transient elastography (VCTE), platelet count and confirmed using magnetic resonance elastography (MRE). Non-invasive biomarkers and imaging were analysed at baseline and out to 2 years. Results are presented as mean change or% change from baseline. <h3>Results</h3> Baseline characteristics and outcomes (changes from baseline) are listed in the table 1. At baseline, 63% of patients were categorized as probable/definitive CSPH (Baveno VII), and at 1 and 2 years, respectively, 20% and 28% of CSPH positive patients no longer met criteria for CSPH. 35% of patients with confirmed F4 at baseline (liver biopsy F4 and/or platelets &lt; 140/MRE≥5 with VCTE≥15) showed a transition from F4 to F3 at year 2 (VCTE &lt;15 and ≥25% decrease from baseline). Discontinuation rate was 8%. Mild gastrointestinal disorders were the most common adverse events. <h3>Discussion</h3> At 2 years of treatment, resmetirom demonstrated significant improvements in non- invasive biomarkers, liver stiffness on imaging and portal hypertension risk in patients with MASH cirrhosis. Resmetirom was safe and well-tolerated in this population. These findings highlight the potential of resmetirom to demonstrate clinical benefit in MAESTRO-NASH OUTCOMES, an ongoing 845 MASH cirrhosis patient clinical outcome study.

Aim:A clinical decision support (CDS) tool for metabolic dysfunction-associated steatohepatitis (MASH) was developed to align health systems with clinical guidelines detailed in the MASH Clinical Care Pathway and improve patients' proactive self-management of their disease. The tool includes a provider-facing web-based application and a mobile application (app) for patients. This protocol outlines a pilot study that will systematically evaluate the implementation of the tool in real-world clinical practice settings.Materials & methods:This implementation research study will use a simultaneous mixed-methods design and is guided by the Consolidated Framework for Implementation Research. The CDS tool for MASH will be piloted for ≥3 months at multiple US-based sites with eligible gastroenterologists and hepatologists (n = 5–10 per site) and their patients (n = 50–100 per site) with MASH or suspected MASH. Each pilot site may choose one or all focus areas within the tool (i.e., risk stratification, screening and referral, or patient care management), based on on-site capabilities. Prior to and at the end of the pilot period, providers and patients will complete quantitative surveys and partake in semi-structured interviews. Outcomes will include understanding the feasibility of implementing the tool in real-world clinical settings, its effectiveness in increasing patient screenings and risk stratification for MASH, its ability to improve provider and patient knowledge of MASH, barriers to adoption of the tool and the tool's capacity to enhance patient engagement and satisfaction with their care.Conclusion:Findings will inform the scalable implementation of the tool to ensure patients at risk for MASH are identified early, referred to specialty care when necessary and managed appropriately. Successful integration of the patient app can contribute to better health outcomes for patients by facilitating their active participation in the management of their condition.

In the version of the article initially published, the reference Chalasani, N. et al. Effects of belapectin, an inhibitor of galectin-3, in patients with nonalcoholic steatohepatitis with cirrhosis and portal hypertension. Gastroenterol. 158 1334-1345 (2020) was missing and has now been added as ref. 111 in the second paragraph of the "HVPG as a surrogate end point" section. Additionally, in the second paragraph of the "Current scenario of clinical trials in MASH" section, the sentence "NAVIGATE (NCT04365868; 357 participants) was a phase IIb-III trial…" has been corrected to "NAVIGATE (NCT04365868; 357 participants) is a phase IIb-III trial…". These corrections have been made to the HTML and PDF versions of the article.

Although metabolic dysfunction-associated steatohepatitis (MASH) is rapidly becoming a leading cause of cirrhosis worldwide, therapeutic options are limited and the number of clinical trials in MASH-related compensated cirrhosis is low as compared to those conducted in earlier disease stages. Moreover, designing clinical trials in MASH cirrhosis presents a series of challenges regarding the understanding and conceptualization of the natural history, regulatory considerations, inclusion criteria, recruitment, end points and trial duration, among others. The first international workshop on the state of the art and future direction of clinical trials in MASH-related compensated cirrhosis was held in April 2023 at Vall d'Hebron University Hospital in Barcelona (Spain) and was attended by a group of international experts on clinical trials from academia, regulatory agencies and industry, encompassing expertise in MASH, cirrhosis, portal hypertension, and regulatory affairs. The presented Roadmap summarizes important content of the workshop on current status, regulatory requirements and end points in MASH-related compensated cirrhosis clinical trials, exploring alternative study designs and highlighting the challenges that should be considered for upcoming studies on MASH cirrhosis.

Metabolic dysfunction-associated steatohepatitis (MASH), formerly nonalcoholic steatohepatitis, is characterized by fat accumulation and inflammation of the liver and may result in progression to cirrhosis and liver-related events. To characterize the impact of cirrhosis and progression to liver-related events on costs and health care resource use (HCRU) among MASH patients in the United States. The study cohort included patients with diagnosed nonalcoholic steatohepatitis (International Classification of Diseases, Tenth Revision, Clinical Modification code K75.81) in Optum's deidentified Clinformatics Data Mart Database (October 2015 to December 2022) and were stratified by baseline cirrhosis status. Among those without cirrhosis at baseline, patients were further stratified by status of progression to cirrhosis during follow-up. Total HCRU and costs per-person per-year (PPPY) were estimated and compared descriptively between the cohorts. In addition, gamma generalized linear models were used to compare costs PPPY between those with vs without cirrhosis at baseline, as well as with vs without progression during follow-up, while adjusting for baseline patient and disease characteristics. Annual costs per person were also longitudinally modeled using gamma generalized linear mixed models to understand longitudinal changes in costs PPPY while accounting for time correlations within individual patients. Lastly, a series of sensitivity analyses were conducted to assess the impact of study design features and clinical variations of total costs PPPY. A total of 28,576 adults were included, and 9,157 (32.0%) had baseline cirrhosis; of the 19,419 without baseline cirrhosis, a total of 4,235 (21.8%) progressed over follow-up. Mean (SD) HCRU and costs PPPY were higher among patients with cirrhosis ($110,403 [$226,037]) than without ($28,340 [$61,472]; P < 0.01) and among those with progression ($58,128 [$102,626]) than without ($20,031 [$39,740]; P < 0.01). Costs remained significantly greater when adjusted for covariates, with a risk ratio (95% CI) of 1.99 (1.89-2.09) when comparing with vs without baseline cirrhosis and 2.28 (2.15-2.42) when comparing with vs without progression over follow-up. Costs increased with each subsequent year, to 21% by year 6 among those with cirrhosis at baseline and 49% among those without baseline cirrhosis who progressed. The financial burden of MASH is substantial and significantly greater among those with cirrhosis or disease progression. Although patients without cirrhosis incur lower burden, the increase over time is greater and associated with progression. Therapies that slow progression may help alleviate the financial burden, and strategies are needed to identify patients with MASH at risk of progressing to cirrhosis.

To the Editor: Harrison et al. (Feb. 8 issue)1 found that resmetirom treatment reduced levels of free thyroxine (FT4) by approximately 16 to 19% in patients with nonalcoholic steatohepatitis (NASH). An increase in the levels of type 1 deiodinase (DIO1) that was due to thyroid hormone receptor beta–selective agonism may have contributed to the decrease in FT4 levels.2 However, increased DIO1 function is associated not only with decreased FT4 levels but also with increased levels of free triiodothyronine (FT3).3 The fact that FT3 levels did not increase with resmetirom therapy suggests that central suppression of the hypothalamic–pituitary–thyroid axis is likely .