Introduction

MAESTRO-NASH is an ongoing 54-month, randomized, double-blind, placebo-controlled Phase 3 trial evaluating the effect of once-daily 80 or 100 mg resmetirom, an oral thyroid hormone receptor-β selective agonist, compared with placebo in adults with nonalcoholic steatohepatitis (NASH) and fibrosis (ClinicalTrials.gov identifier, NCT03900429).

Aims & Methods

Eligibility required the presence of ≥3 metabolic risk factors, baseline liver stiffness ≥8.5 kPa (measured by FibroScan vibration-controlled transient elastography [VCTE]), baseline hepatic fat ≥8% (measured by magnetic resonance imaging-proton density fat fraction [MRI-PDFF]), biopsy-confirmed NASH with fibrosis stage 1B (F1B), 2 (F2), or 3 (F3), and a nonalcoholic fatty liver disease activity score (NAS) ≥4 with ≥1 in each component (steatosis, ballooning, inflammation). The dual primary endpoints at Week 52 were NASH resolution (achievement of a ballooning score of 0, inflammation score of 0 or 1, and ≥2-point reduction in NAS) with no worsening of fibrosis OR ≥1-stage improvement in fibrosis with no worsening of NAS. The key secondary endpoint was percent change from baseline in low-density lipoprotein cholesterol (LDL-C) at Week 24. Liver biopsies obtained at screening/baseline and Week 52 were read by two central pathologists using glass slides (primary analysis) with results combined via a statistical algorithm to generate a single treatment effect. If the central pathologists disagreed on the response for either primary endpoint, a supportive consensus read using digitized images was conducted.

Results

966 patients were enrolled at ~200 global sites. The modified intent-to-treat population excluded 11 patients who had their biopsy after Week 60 (due to COVID-19 site issues). Demographic and baseline characteristics were age 57 years (11) (mean (SD)); 56% female; 89% white; BMI 36 kg/m² (7); 78% with hypertension; 71% with dyslipidemia; 67% with type 2 diabetes; FibroScan VCTE 13 kPa (7); controlled attenuation parameter (CAP) 348 dB/m (38); hepatic fat 18% (7); 84% with baseline NAS ≥5; 62% with F3, 33% with F2, and 5% with F1B fibrosis at baseline. Both primary endpoints and the key secondary endpoint were achieved with 80 and 100 mg resmetirom (TABLE). A consensus review confirmed the primary analysis results. In addition, similar results were obtained by both central pathologists for the primary endpoints and results were independent of diabetes status or baseline fibrosis stage. Furthermore, additional biopsy endpoints including NASH resolution and fibrosis improvement (combined) and ≥2-stage improvement in fibrosis as well as multiple biomarker endpoints including reduction in ALT, AST, GGT, enhanced liver fibrosis (ELF), hepatic fat (measured by MRI-PDFF), CAP, and FibroScan VCTE were achieved with resmetirom. Resmetirom treatment was well tolerated. A similar number of serious adverse events was reported across the treatment groups. The incidence of diarrhea and nausea was increased in the resmetirom groups at the beginning of therapy.

Conclusion

Both NASH resolution and fibrosis improvement were achieved with 80 and 100 mg resmetirom. Resmetirom was well tolerated over 52 weeks. Overall, the data from MAESTRO-NASH support the potential for resmetirom to provide benefit to patients with NASH and fibrosis.

Disclosure

Jörn M. Schattenberg: investigator for Madrigal Pharmaceuticals.
Pierre Bedossa: consultant for Madrigal Pharmaceuticals.
Cynthia Guy: consultant for Madrigal Pharmaceuticals.
Rohit Loomba: investigator for Madrigal Pharmaceuticals.
Rebecca Taub: employee and stockholder of Madrigal Pharmaceuticals.
Dominic Labriola: employee of Madrigal Pharmaceuticals.
Sam E. Moussa: stockholder of Madrigal Pharmaceuticals.
Guy W. Neff: investigator for Madrigal Pharmaceuticals; speakers’ bureau for Intercept.
Arun J. Sanyal: investigator for Madrigal Pharmaceuticals.
Mazen Noureddin: investigator for Madrigal Pharmaceuticals.
Meena Bansal: investigator for Madrigal Pharmaceuticals.
Naim Alkhouri: Research funding from 89Bio, AbbVie/Allergan, Akero, Better Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Corcept, DSM, Galectin, Genentech, Genfit, Gilead, Hepagene, Healio, Intercept, Inventiva, Ionis, Madrigal, Merck, NGM, Noom, NorthSea, Novo Nordisk, Perspectum, Pfizer, Poxel, Viking, and Zydus; Speaker bureau for AbbVie/Allergan, Alexion, Echosens, Eisai, Exelixis, Gilead, Intercept, Perspectum, Salix, and Theratechnologies; Consultant for AbbVie/Allergan, Echosens, Fibronostics, Gilead, Intercept, Madrigal, Novo Nordisk, Perspectum, Pfizer, and Zydus.
Vlad Ratziu: investigator for Madrigal Pharmaceuticals.
Stephen A. Harrison: Grant and research support from 89 Bio, Boehringer Ingelheim, Akero, Altimmune, Axcella, Corcept, Cymabay, Enyo, Galectin, Galmed, Genentech, Genfit, Gilead, Hepion, Hightide, Intercept, Madrigal, Metacrine, NGM Bio, NorthSea, Poxel, Sagimet, and Viking; consulting adviser for Akero, Altimmune, AstraZeneca, Axcella, Chronic Liver Disease Foundation, Echosens, Genfit, Gilead, GSK, Hepion, Hightide, HistoIndex, Intercept, Madrigal, Medpace, Metacrine, NGM Bio, Northsea, Novartis, Novo Nordisk, Nutrasource, Perspectum, Poxel, Sagimet, Sonic Incytes, Terns, and Viking.

Introduction

In recent years, the detection of Branch Duct Intraductal Papillary Mucinous Neoplasms (BD-IPMN) has increased. The Association of Pancreatology (IAP) approved specific guidelines for their management in Fukuoka in 2017. The rates of malignant degeneration of these lesions remain unclear, raising concerns about the cost-effectiveness of the suggested surveillance strategies.

Aims & Methods

This study aimed to identify the rates of BD-IPMN malignant degeneration and their associated risk factors to propose a new, more cost-effective surveillance strategy. In this multicentric retrospective observational study, clinical and histopathological data of patients with IPMN were collected by four tertiary centers in Northern Italy. Multivariate Cox regression identified factors associated with a higher risk of malignant degeneration. A segmentation analysis aimed to define new dimensional cut-offs for better risk stratification. Demographic and anamnestic data relating to the patient (age, gender, comorbidities based on the Age-Adjusted Charlson Comorbidity-Index (ACCI), imaging, endoscopic examinations, and surgical interventions), to IPMN (presence of Worrisome Features (WF) and High-Risk Stigmata (HRS) as defined by IAP), and surveillance costs were collected. Malignant degeneration was defined as the presence of high-grade dysplasia or invasive neoplasia.

Results

The study enrolled 333 patients, with a total of 1400 visits and a median follow-up of 4 years. IPMN developed malignant degeneration in 3.3% of cases. Cancer risk factors included the presence of HRS (HR 4.4, 95%CI 1.1-17.8, p = 0.04), of at least two WFs (HR 5.8, 95%CI 1.5-22.4, p = 0.01), and cyst size (HR 2.0, 95%CI 1.3-3.0, p < 0.001). The latter discriminated this risk (AUC 0.91, 95%CI 0.84-0.97), and two new cut-offs of 1.5 and 3.0 cm identified three dimensional categories with significantly different neoplastic potential (OR 6.6, 95%CI 1.7-25.4, p = 0.007, OR 9.8, 95%CI 1.1-89.7, p = 0.04). Based on this, we proposed a new surveillance strategy that maintained diagnostic accuracy while reducing the cost per patient for a 3-year follow-up from 670.01 (407.33-1130.32) to 587.01 (347.10-930.28) euro, resulting in a total savings of 11% (p = 0.001).

Conclusion

IPMN malignant degeneration was infrequent. The presence of at least one WF, currently a cornerstone of guideline recommendations, did not independently associate with neoplastic risk, unlike HRS and the presence of at least two WFs. Implementing a follow-up strategy based on operatively identified dimensions (1.5 and 3 cm) could potentially enhance the cost-effectiveness of the 2017 Fukuoka IAP guidelines.