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BORTEZOMIB IMPROVES CIRRHOSIS THROUGH INDUCING THE APOPTOSIS OF ACTIVATED HEPATIC STELLATE CELLS

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Introduction

Cirrhosis is a world-widely prevalent disease with a high global burden: approximately one million deaths worldwide are attributed to cirrhosis each year, and cirrhosis is the 11th leading cause of death¹. Fibrosis and cirrhosis develop after a long period of persistent inflammation, which can be caused by a variety of factors such as hepatitis B or C virus, obesity, high alcohol consumption, autoimmune diseases, cholestatic diseases, and so on². However, current clinical treatments for cirrhosis are mainly focused on improving complications such as portal hypertension. Although some patients with early-stage fibrosis may benefit from treatment to remove the cause of fibrosis, there is currently no effective treatment for advanced fibrosis or cirrhosis itself. Bortezomib (B) is a reversible inhibitor of the chymotrypsin-like site of the 20S proteolytic core within the 26S proteasome and is currently mainly used to treat multiple myeloma³. B has been shown to improve fibrosis of the skin, lungs and kidneys^{4, 5}.

Aims & Methods

We aimed to evaluate the efficacy of B to improve advanced parenchymal and biliary liver fibrosis in rats and potential underlying mechanisms. Advanced liver fibrosis was induced in 8-week-old rats by intraperitoneal injection of thioacetamide (TAA) for 12 weeks or bile duct ligation (BDL) for 3 weeks. Rats with advanced fibrosis were divided into 2 groups: intravenous injection of B at 0.1 mg/kg in PBS (B) or injection of PBS alone three times a week for 3 weeks (fibrotic controls, FC). Age matched rats with no intervention served as normal controls (NC). Portal vein pressure was measured after anesthesia before sacrifice. Liver and renal function parameters were determined to evaluate liver inflammation and potential toxicity of B. HE and Masson staining were used to evaluate liver inflammation and fibrosis. Liver collagen was quantified via hydroxyproline content. Fibrosis-related gene and protein expression were determined by RT-qPCR and Western blot. Liver samples were subjected to NGS analysis. LX-2 human hepatic stellate cells and LO2 human hepatocytes were cultured with different concentrations of B for 24 h. Cell apoptosis was quantified via flow cytometry.

Results

B treatment induced a decreased portal vein pressure (mmHg), though the p-values did not yet reach statistical significance in the two fibrosis models (B vs FC: TAA, 6.86 ± 0.76 vs 11.42 ± 2.37; BDL, 9.49 ± 2.92 vs 18.57 ± 16.83). On the other hand, B treatment decreased ALT and AST in both fibrosis models, while serum creatinine and bilirubin levels remained unchanged, indicating a beneficial effect of B on liver function with no apparent liver or renal toxicity. Morphometry and biochemical quantification showed a significant amelioration of fibrosis, as evidenced by liver hydroxyproline content and Masson-positive area. Gene set enrichment analysis indicated the upregulation of pro-inflammation-related Ugt2b7 and anti-proliferation-related gene Marvled1; while the key regulator in ubiquitin-mediated proteolysis and cell cycle pathways Cdc20 decreased after treatment with B, so did the Cdc20 protein. B-treated hepatic stellate cells but not hepatocytes showed prominent apoptosis.

Conclusion

Bortezomib induces activated hepatic stellate cell apoptosis and has a prominent antifibrotic potential in parenchymal and biliary fibrosis.

References

1. Gines P, Krag A, Abraldes JG, Sola E, Fabrellas N, Kamath PS. Liver cirrhosis. Lancet. 2021;398(10308):1359-76.
2. Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol. 2014;14(3):181-94.
3. Tan CRC, Abdul-Majeed S, Cael B, Barta SK. Clinical Pharmacokinetics and Pharmacodynamics of Bortezomib. Clin Pharmacokinet. 2019;58(2):157-68.
4. Fineschi S, Bongiovanni M, Donati Y, Djaafar S, Naso F, Goffin L, et al. In vivo investigations on anti-fibrotic potential of proteasome inhibition in lung and skin fibrosis. Am J Respir Cell Mol Biol. 2008;39(4):458-65.
5. Zeniya M, Mori T, Yui N, Nomura N, Mandai S, Isobe K, et al. The proteasome inhibitor bortezomib attenuates renal fibrosis in mice via the suppression of TGF-beta1. Sci Rep. 2017;7(1):13086.

BORTEZOMIB IMPROVES CIRRHOSIS THROUGH INDUCING THE APOPTOSIS OF ACTIVATED HEPATIC STELLATE CELLS

Ling Wu 1, Feng Li 2, Xiaoquan Huang 3, Detlef Schuppan 4, Shiyao Chen 5

1 Zhongshan Hospital, Fudan University, Shanghai, China|||University Medical Center, Johannes Gutenberg University, Mainz, Germany

2 Zhongshan Hospital, Fudan University, Shanghai, China|||Minhang Hospital, Fudan University, Shanghai, China

3 Minhang Hospital, Fudan University, Shanghai, China

4 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States|||University Medical Center, Johannes Gutenberg University, Mainz, Germany

5 Minhang Hospital, Fudan University, Shanghai, China|||Zhongshan Hospital, Fudan University, Shanghai, China

Event

UEG Week Vienna 2024

Topics

Hepatobiliary IBD Immunology Mechanisms & Personalised Medicine Pancreas

Submission format

Abstract

Session

Basic mechanisms of disease in liver, pancreas and intestine

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

UEG Presentation

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Panel discussion: Cystic pancreatic lesions

Event

UEG Postgraduate Teaching Programme Berlin 2025

Topics

Endoscopy Histopathology Pancreas

Session

Cystic pancreatic lesions

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

UEG Presentation

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Summary: Liver and pregnancy - Beware of dangerous liaisons

Christophe Moreno 1

1 Hôpital Erasme (gastro) - Hôpital Erasme (gastro); Maransart/BE, Brussels, Belgium

Event

UEG Postgraduate Teaching Programme Berlin 2025

Topics

Hepatobiliary Paediatrics

Session

Liver and pregnancy: Beware of dangerous liaisons

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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How to assess portal hypertension: HVPG or anything else but HVPG

Annalisa Berzigotti 1, Thomas Reiberger 2

1 Inselspital, University Hospital of Berne, Berne, Switzerland

2 Medical University of Vienna, Vienna, Austria

Event

UEG Postgraduate Teaching Programme 2023

Topics

Digestive Oncology Hepatobiliary

Session

Complications of cirrhosis and liver cancer

Published

2023

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“Sustainable” radiological follow-up of BD-IPMN: New sequences for MRI? Who, how and when?

Christine Cannataci 1

1 Mater Dei Hospital, Msida, Malta

Event

UEG Postgraduate Teaching Programme Berlin 2025

Topics

Endoscopy Histopathology Pancreas

Session

Cystic pancreatic lesions

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Undertstanding genetic causes of liver and bile duct diseases: Treatment implications

Verena Keitel-Anselmino 1

1 University Hospital Magdeburg, Magdeburg, Germany

Event

UEG Week Berlin 2025

Topics

Hepatobiliary Mechanisms & Personalised Medicine

Session

Infectious and rare hepatitis

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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A RANDOMIZED CONTROLLED PHASE 3 TRIAL OF RESMETIROM IN NONALCOHOLIC STEATOHEPATITIS: 52-WEEK DATA FROM MAESTRO-NASH

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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.

	Resmetirom 80 mg (n=316)	p-value	Resmetirom 100 mg (n=321)	p-value	Placebo (n=318)
Dual Primary Endpoints (Week 52)
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	26%	<0.0001	30%	<0.0001	10%
≥1-stage improvement in fibrosis with no worsening of NAS	24%	0.0002	26%	<0.0001	14%
Key Secondary Endpoint (Week 24)
Percent change from baseline in LDL-C	-12%	<0.0001	-16%	<0.0001	1%

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.

A RANDOMIZED CONTROLLED PHASE 3 TRIAL OF RESMETIROM IN NONALCOHOLIC STEATOHEPATITIS: 52-WEEK DATA FROM MAESTRO-NASH

Jörn Schattenberg 1, Pierre Bedossa 2, Cynthia D. Guy 3, Rohit Loomba 4, Rebecca Taub 5, Dominic Labriola 5, Sam E. Moussa 6, Guy W. Neff 7, Arun J Sanyal 8, Mazen Noureddin 9, Meena Bansal 10, Naim Alkhouri 11, Vlad Ratziu 12, Stephen A. Harrison 13

1 Universitätsmedizin Mainz, Mainz, Germany

2 Université Paris-Diderot Hopital Beaujon, Paria, France

3 Duke University Medical Center, Durham, United States

4 University of California San Diego, San Diego, United States

5 Madrigal Pharmaceuticals, Conshohocken, United States

6 University of Arizona for Medical Sciences, Tucson, United States

7 Covenant Metabolic Specialists, Sarasota, United States

8 Virginia Commonwealth University School of Medicine, Richmond, United States

9 Cedars-Sinai Medical Center, Los Angeles, United States

10 Mt Sinai, New York, United States

11 Arizona Liver Health, Tucson, United States

12 Hôpital Pitié Salpêtrière, Paris, France

13 Pinnacle Clinical Research, San Antonio, United States

Event

UEG Week Copenhagen 2023

Topics

Hepatobiliary

Submission format

Abstract

Session

Opening Plenary

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

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