2024 Is A Historic Year for Fatty Liver Disease. What’s Next?

Published by Biotech Connection Singapore on

Written by:

Karen He, Senior Manager, Intelligence Exchange, A*STAR

Phyllis Phuah, Communications Lead, Biotech Connection Singapore

Jessica Kabigting, Communications Lead, Biotech Connection Singapore

Zara Chung, Vice-President, Biotech Connection Singapore

 

On 14 March 2024, the U.S. Food and Drug Administration (FDA) approved the first treatment for noncirrhotic non-alcoholic steatohepatitis (NASH) with moderate to advanced liver scarring, to be used along with diet and exercise.[1] NASH is the more serious stage of non-alcoholic fatty liver disease (NAFLD), a silent killer affecting up to 40% of the population in Singapore.[2]

 

Introduction

In recent years, non-alcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disorder across the globe. NAFLD affects more than 30% of adults worldwide, and its incidence is growing.[3] This presents a significant health and economic burden to societies.

NAFLD starts off with the accumulation of excess fat, usually > 5%, within the liver, which causes liver hepatocytes to become stressed. This may then progress to more severe non-alcoholic steatohepatitis (NASH) in 20-30% of patients, where inflammation in the liver leads to scar tissue formation, or fibrosis, which restricts blood flow over time. As fibrosis progresses, NASH may develop into cirrhosis, liver failure or even liver cancer.  Liver fibrosis is typically classified into 4 stages based on the amount of scarring, with F1 reflecting mild fibrosis and some collagen deposition, F2 reflecting moderate fibrosis and the beginning of bridge formation, F3 reflecting significant fibrosis with numerous bridges, and F4 reflecting severe fibrosis, or cirrhosis (Figure 1). Furthermore, aside from liver disease, patients with NAFLD also face increased mortality due to extra-hepatic complications such as cardiovascular disease.

 

Figure 1. NASH is a chronic and progressive liver disease. Created with Biorender.com

 

In Singapore, it is estimated that up to 40% of the population has NAFLD, which is significantly above the global average. Furthermore, almost 10% of all liver transplants were NAFLD-related.[4] The disease burden of NAFLD is now widely recognised in Asia. In particular, a higher prevalence in Southeast Asia has also been noted. This has been attributed to rapid urbanisation which has brought about changes in lifestyle, such as the adoption of high-fat, high-sugar dietary habits, and an increase in sedentary behaviour. Not only are there rising numbers living with obesity and diabetes in Asia, but Asians are also known to suffer from metabolic abnormalities such as NAFLD at a lower body mass index (BMI). Genetic factors could explain this trend; studies have shown that even amongst Asian ethnic groups, NAFLD has a higher incidence amongst Malay and Indian ethnic groups vs. the Chinese ethnic population.[5]

 

From NAFLD to MASLD

The term NAFLD was initially coined to describe a fatty liver condition observed in patients that was not attributable to alcohol consumption, medications, or other known causes of chronic liver disease. However, over the years, there has been a growing appreciation that metabolic diseases like obesity, type 2 diabetes, and dyslipidaemia are intricately intertwined with NAFLD. This new understanding has rendered the definition of NAFLD (largely based on exclusion criteria) obsolete.

In 2020, Eslam et al. proposed the new term of metabolic dysfunction-associated steatotic liver disease (MASLD), to better reflect the current understanding of this disease and its strong association with metabolic dysfunction.[6] MASLD is diagnosed based on the presence of hepatic steatosis and at least one of three conditions—obesity, type 2 diabetes, or at least two metabolic risk abnormalities. The more severe form of MASLD was also renamed to metabolic dysfunction-associated steatohepatitis (MASH). Experts hope that the change in nomenclature along with the new understanding will help to more accurately define patient populations and support drug discovery efforts into new therapeutic avenues.

 

Therapeutic Landscape

Until recently, there had been no approved drugs in the U.S. or Europe for the treatment of NAFLD/MASLD or NASH/MASH. Saroglitazar, a dual peroxisome proliferator-activated receptor (PPAR) agonist marketed by Zydus-Cadila Group, was the only drug approved for the treatment of NAFLD and NASH based on positive results of two phase 3 trials in Indian patients.[7] Approval was only granted in 2020 and limited to India. With the FDA’s accelerated approval of resmetirom on 14 March 2024, this has become history. Resmetirom (Rezdiffra™) is a thyroid hormone receptor β (THR-β) agonist marketed by Madrigal Pharmaceuticals. In a phase 3 trial involving NASH patients with liver fibrosis of stages F1B to F3, resmetirom achieved both primary endpoints at 52 weeks (viz. NASH resolution with no worsening of fibrosis, and an improvement in fibrosis by at least one stage with no worsening of the NAFLD activity score). In addition, it also met a key secondary endpoint, demonstrating significant improvement in low-density lipoprotein (LDL) cholesterol levels at week 24 versus placebo.[8] It is noteworthy that FDA does not require a liver biopsy to determine a patient’s eligibility for resmetirom,[9] reducing the hurdle for resmetirom to be prescribed to patients.

While resmetirom enjoys a first-mover advantage, hundreds of pipeline drugs are currently under development for MASH. These are in various stages of maturity, ranging from early discovery to late clinical stage. The number of new clinical trials registered for MASH has been increasing over the past 10 years and has been at a historically high level since 2019 (Figure 2). Based on molecule type, small molecule drugs are the most common in the clinical MASH pipeline, followed by proteins or peptides, and oligonucleotides (Figure 3).

 

Figure 2. Number of new clinical trials registered for MASH from 2010 to 2024. Source: GlobalData. Accessed on 21 February 2024.

 

Figure 3. MASH pipeline drugs by molecule type in clinical phase 1-3 and pre-registration stage. Source: GlobalData. Accessed on 21 February 2024.

 

The pipeline drugs target various mechanisms of action (MoAs), with metabolic hormones such as glucagon-like peptide 1 (GLP-1) or glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, farnesoid X receptor (FXR) agonists, fibroblast growth factor (FGF) analogues, PPAR modulators, and THR-β agonists being the top 5 most investigated MoAs.[10] These account for over 30% of the clinical MASH pipeline.[11] While GLP-1 receptor agonists are thought to have a systemic effect on the liver via glycaemic control and weight loss,[12] FXR agonists, FGF analogues, PPAR modulators, and THR-β agonists target lipid metabolism in the liver directly by decreasing de novo lipogenesis and lipotoxicity, as well as increasing energy expenditure and fatty acid oxidation.[13]

The success of GLP-1 receptor agonists in treating diabetes and obesity has made Eli Lilly and Novo Nordisk the largest two pharmaceutical companies by market capitalization to date.[14] While Novo Nordisk’s GLP-1 receptor agonist, semaglutide, achieved the primary endpoint of NASH resolution at 72 weeks in a phase 2 trial involving NASH patients with liver fibrosis of stages F1 to F3, it missed the confirmatory secondary endpoint of an improvement of at least one fibrosis stage versus placebo.[15] Recently, Eli Lilly announced that its dual GIP/GLP-1 receptor co-agonist, tirzepatide, has helped up to 74% of MASH patients with liver fibrosis of stages F2 to F3 achieve MASH resolution at 52 weeks in a phase 2 trial, compared to 12.6% in the placebo group. However, limited data was released for improvement in the fibrosis stage.[16] As both MASH resolution and fibrosis improvement are important considerations for regulatory approval in the U.S. and Europe, it remains to be seen if this class of drugs could repeat its success in the NASH market.

According to GlobalData, the global MASH market is expected to reach $28.4 billion by 2032, at a compound annual growth rate (CAGR) of 42.6% from 2022 to 2032. However, not all large pharmaceutical companies are interested in gaining a slice of the market. AstraZeneca, Novo Nordisk, Eli Lilly, Merck, GSK, Boehringer Ingelheim, and Gilead Sciences are the only few sponsoring at least one active clinical trial in MASH. They also face immediate competition from small biotech companies with pipeline drugs in active phase 3 trials such as Akero Therapeutics, Inventiva, and 89bio (Table 1). Interestingly, while all three small biotechs are developing small molecule or protein drugs, 4 out of these 7 large pharmas also have oligonucleotides on their clinical MASH pipeline. Boehringer Ingelheim is keen to join them, inking two recent deals potentially worth more than $3 billion in total with biotech companies to develop oligonucleotide-based MASH treatments.[17],[18] Different from the MoAs described above, antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) can target genetic variants associated with MASH at the RNA level, paving the way to personalised medicine. The large pharmas’ bet seems to be paying off. Ionis Pharmaceuticals, a leader in antisense technology, announced right before the FDA’s approval of resmetirom that its ION224 achieved the primary endpoint of liver histologic improvement and the key secondary endpoint of MASH resolution at 51 weeks in a phase 2 study.[19] ION224 is an investigational ASO designed to reduce the production of diacylglycerol acyltransferase 2 (DGAT2), a key enzyme in triglyceride synthesis in the liver.

 

Table 1. Leading large pharma and small biotech companies with active late-stage clinical trials in MASH (non-exhaustive list; *large pharma with internal oligonucleotide pipeline). Source: GlobalData and company websites. Accessed on 21 February 2024.

Company

Most Advanced NASH Pipeline

Modality

Target

Development Status

AstraZeneca*

Mitiperstat

Small molecule

Myeloperoxidase

Phase 2

AZD2693

Oligonucleotide

Patatin-like phospholipase domain-containing 3 (PNPLA3)

Phase 2

Novo Nordisk*

Semaglutide

Peptide

GLP-1 receptor

Phase 3

Eli Lilly*

Tirzepatide

Peptide

GLP-1 and GIP receptor

Phase 2

Merck

Efinopegdutide

Peptide

GLP-1 and glucagon receptor

Phase 2

GSK*

GSK4532990

Oligonucleotide

17-beta hydroxysteroid dehydrogenase 13 (HSD17B13)

Phase 2

Boehringer Ingelheim

Survodutide

Peptide

GLP-1 and glucagon receptor

Phase 3

Gilead Sciences

Fixed-dose combination of cilofexor and firsocostat

Small molecule

FXR and acetyl-CoA carboxylase (ACC)

Phase 2

Akero Therapeutics

Efruxifermin

Protein

FGF receptor

Phase 3

Inventiva

Lanifibranor

Small molecule

PPAR

Phase 3

89bio

Pegozafermin

Protein

FGF receptor

Phase 3

 

Local efforts to address MASLD/MASH

Singapore’s capabilities span the full value chain of MASH/MASLD, from cohort studies enabling the discovery of new biomarkers and therapeutic targets, to diagnostics and the development of disease models. Such efforts will benefit the expected growing incidence of NAFLD/MASLD and NASH/MASH in Singapore, given our rapidly ageing population.

First announced in 2020, the Ensemble of Multi-disciplinary Systems and Integrated Omics for NAFLD (EMULSION) programme is a strategic collaboration between A*STAR’s Genome Institute of Singapore (GIS), NUS Yong Loo Lin School of Medicine and Novo Nordisk, involving clinicians from various healthcare groups.

According to Prof. Ng Huck Hui, a Co-Principal Investigator of the programme, EMULSION is the first ever large-scale steatotic liver genomics study based on a Singapore cohort. EMULSION addresses the significant need for an Asian-centric study, as previous research has highlighted that Asian NAFLD displays clinical features that are different from those linked to Western NAFLD (e.g. lower BMI, younger patients, increased complication rates).[20],[21] 

Under EMULSION, samples are collected from NASH, NAFLD and cirrhotic patients, as well as healthy individuals. Gene expression changes across these different groups are then profiled, with the goal of discovering new biomarkers and novel therapeutic targets to address NAFLD/NASH. The data can also be correlated to clinical information, such as patient BMI. The EMULSION programme has already gathered data from more than 400 patients. Extended sample collection and data analysis are currently in progress.[22] 

Assoc. Prof. Torsten Wüstefeld of GIS and NTU Lee Kong Chian School of Medicine is an investigator of the EMULSION programme who conducts in vivo functional genetic screens to identify novel therapeutic targets for liver disease. He is the scientific co-founder of Lerna Biopharma (formerly known as Cargene Therapeutics), whose lead target was discovered through this target identification platform and validated with the EMULSION cohort data. In November 2023, Lerna announced its first-in-class siRNA drug, LR1, which promotes liver regeneration based on this target.[23]In the area of MASLD/MASH diagnostics, a digital pathology spin-off from A*STAR called HistoIndex has developed qFibrosis – an automated approach to assess liver fibrosis – that could address concerns regarding the subjectivity of qualitative histopathological assessment of biopsy samples.[24] Their approach uses label-free second harmonic generation (SHG) microscopy, thereby eliminating the need for conventional stains during biopsy processing. This allows for the visualisation of collagen fibrils in the biopsy sample, which is associated with increased liver stiffness and is indicative of pathological fibrosis progression.[25] The images obtained from HistoIndex’s proprietary Genesis®200 microscopy system are then analysed with their HistoHepa© AI algorithm and cloud-based analytics, in order to extract quantitative features such as collagen fibre count, as well as cross-linking and co-localisation of fibres with features of MASLD in varying spatial zones of the sample. This technology has been used in Phase 2 and 3 clinical trials by pharmaceutical companies such as Novartis, AbbVie, and Madrigal Pharmaceuticals. HistoIndex also collaborates with A*STAR’s GIS for preclinical studies and validation of in vivo and in vitro models for MASH. 

The development of disease models is also highly useful in elucidating the molecular pathways that drive MASLD/MASH disease progression, and several groups in Singapore are working on this area. Prof. Hanry Yu from NUS spearheaded efforts in creating the SteatoChip, a microfluidic device exhibiting features of NAFLD. The SteatoChip serves as a 3D cellular niche with a controlled microenvironment for growing liver organoids, which enables scalable and reproducible drug testing studies.[26]

 

Future Opportunities

The recent FDA approval of resmetirom without requiring liver biopsy for prescription has been groundbreaking in the field of steatotic liver disease research. Nonetheless, many challenges are still present in the diagnosis and treatment of MASLD/MASH. Singapore’s population remains largely unaware of the prevalence of the disease and its metabolic associations, as well as the importance of diagnosing and treating this disease. Improving public knowledge of MASLD/MASH would not only allow for greater inclusivity and support of patients, but also aid in early diagnosis when only low-grade symptoms (e.g. fatigue, pain, sleep disturbances, and psychological and abdominal symptoms) manifest. Early diagnosis and preventative interventions when the disease is still reversible, would greatly improve patient outcomes.

In terms of therapeutics, although resmetirom was superior to the placebo group in a phase 3 trial, its placebo-adjusted response rate for either NASH resolution or fibrosis improvement at 52 weeks was modest (approximately 25-30% in both dosage groups vs. 10-15% in the placebo group).[27] This opens the door for other promising drug candidates to compete for “best-in-class” rather than “first-in-class”.

Given the complex pathophysiology of MASH, combination therapies, which currently form only 8% of the clinical-stage pipeline, could be a promising strategy. IQVIA expects the prominence of combination therapies to increase significantly, especially as more of the over 40 MoAs being investigated emerge as validated therapeutic approaches.

Differential targeting of early- and late-stage MASH could be a strategy too. Resmetirom is currently approved to treat MASH with moderate to advanced liver fibrosis (stages F2 to F3). While the large F1 patient population would be an attractive market segment to target, GLP-1 receptor agonists which have proven effective for key drivers of MASH could make this segment challenging for new entrants. On the other hand, the F4 patient population is relatively small with a limited phase 3 clinical pipeline, suggesting a high unmet need in this niche high-risk group.  

As the MASH drug pipeline is getting crowded, it may be worthwhile to look at opportunities at other points of a patient journey. Liver biopsies have long served as the gold standard for clinical diagnosis and disease staging. However, liver biopsies are costly and invasive. They also pose potential sampling errors and higher risk of patient complications. There is work underway to develop better alternatives. One such example is FibroScan®, a U.S. FDA-approved liver screening device that utilises transient elastography (an ultrasound-based modality) to measure liver stiffness and steatosis.[28] FibroScan provides point-of-care screening and takes only 5-7 minutes, enabling clinicians to make decisions during patients’ visits.[29] Blood-based biomarkers are also being explored as a form of non-invasive test (NIT). An example is the enhanced liver fibrosis (ELF) test, which combines pro-collagen III N-terminal peptide, hyaluronic acid, and tissue inhibitor of metalloproteinase 1 to assess the risk of MASH progression in patients with advanced fibrosis (stages F3 to F4) to cirrhosis. Despite the promising outcomes of NITs, detecting early fibrosis stages with accuracy still appears to be a challenge.[30] Combining both imaging-based and blood-based biomarkers could potentially improve the accuracy and reliability of MASH diagnosis and eventually replace biopsy-based efficacy endpoints in clinical trials, which currently pose major barriers to MASH drug development. In addition to diagnostic tests, predictive biomarkers to identify likely responders for a given treatment is another exciting opportunity, especially with more drugs expected to be available to patients in the near future.

 

 

INSIGHTS FROM THE INTERVIEW WITH ASSOC. PROF. TORSTEN WÜSTEFELD

Research Directions

While it is important to identify common robust targets for all MASH patients, the response rate for different subgroups may vary due to various factors. Based on preliminary analysis of the EMULSION data, there seem to be differences among the Chinese, Malay, and Indian ethnic groups, suggesting a potential genetic factor behind the disease. Gender could play a part, too, as there are differences in the body fat distribution between the male and the female. These are interesting research areas to look into.

With the new name “MASH” to indicate a metabolic association, it is time to think beyond the liver and consider other organs as well, such as the cardiovascular system. More research is needed to better understand the disease and treat patients in a more systematic manner.

Therapeutics

Oligonucleotide-based therapy is a promising modality for MASH treatment. GalNAc-siRNA conjugates enable specific delivery to hepatocytes for an efficient knockdown, resulting in less toxicity in other organs. In addition, this knockdown effect could last for several months with just one injection, making it ideal for the treatment of chronic diseases such as MASH. However, for acute conditions which require fast interventions, siRNA may not be suitable since it has to wait for the turnover of existing proteins to show a knockdown effect. 

As the field is changing rapidly, treating simple steatosis without inflammation and fibrosis is no longer a concern. Therapeutic start-ups entering this field may want to target late-stage disease with advanced fibrosis, which demands different therapeutic targets from the early stage and is considered a bigger challenge in view of past failures in clinical trials.

Diagnostics

While imaging techniques such as ultrasound are useful for the diagnosis of MASH, they may not be suitable for population-wide screening as the equipment is expensive and limited. On the other hand, blood-based tests can be easily integrated into the workflows of diagnostic labs to allow cheap screening of the population and monitoring of disease progression. It could also be valuable to develop general fibrosis tests for chronic conditions beyond MASH.

 

MESSAGES FROM DR. MARK MUTHIAH

  • Senior Consultant, Division of Gastroenterology & Hepatology, Department of Medicine, National University Hospital
  • ​​Medical Director & Senior Consultant, Adult Liver Transplantation Programme, National University Centre for Organ Transplantation, National University Hospital
  • Assistant Professor, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore

“MASLD is a growing public health burden in Singapore. Previously, our top cause of liver transplant, end-stage liver failure, and liver cancer was hepatitis B, and now it is overtaken by MASLD. While liver biopsy is the gold standard for MASH diagnosis, patients do not want to be biopsied, especially when there is no drug available. Today, other than weight loss, which is often not sustainable, the best treatments I can offer my patients are clinical trials. As a patient, the best thing you want is to do a cheap and non-invasive diagnostic test at the GP, receive a safe and effective drug for treatment, and repeat the test sometime later to show you are disease-free. Unfortunately, we do not have that now. The choice of NITs depends on the context of use. For population screening, cheap NITs with high negative predictive value will be ideal, which means if the result is negative, it is truly negative. While current clinical trials classify patients based on fibrosis status, the patient population is much more heterogeneous and requires a more granular definition of phenotype. In the Singapore context, the top three unmet needs in my view are first, biomarker development to identify who will benefit from the treatment; second, treatment for the cirrhotic MASH patients; and third, screening and detection of MASH-related hepatocellular carcinoma (HCC). At the end of the day, we need to define our patient cohorts with ‘hard’ clinical outcomes, e.g., who will develop liver failure vs. who will not, rather than surrogate endpoints such as MASH resolution and fibrosis improvement. For those who are interested, you are welcome to join our ‘Singapore MASLD Symposium’ to be held on 25 July 2024, which will discuss the challenges and opportunities in this space with a focus on the limitations of current therapeutics this year.”

 

References:

[1] Source: FDA. Accessed on 14 March 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-liver-scarring-due-fatty-liver-disease

[2] Goh G. B., et al. (2016). Perceptions of non-alcoholic fatty liver disease – an Asian community-based study. Gastroenterology report. 4(2), 131-5.

[3] Le, M. H., et al. (2022). 2019 Global NAFLD prevalence: a systematic review and meta-analysis. Clinical Gastroenterology and Hepatology, 20(12), 2809-2817.

[4] Tan, E. K., et al. (2018). Liver transplant waitlist outcomes and the allocation of hepatocellular carcinoma model for end-stage liver disease exception points at a low-volume center. In Transplantation Proceedings (Vol. 50, No. 10, pp. 3564-3570). Elsevier.

[5] Estes, C., et al. (2020). Modelling NAFLD disease burden in four Asian regions—2019‐2030. Alimentary pharmacology & therapeutics, 51(8), 801-811.  

[6] Eslam, M., et al. (2020). A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. Journal of hepatology, 73(1), 202-209.

[7] Source: Zydus. Accessed on 12 March 2024. https://www.zyduslife.com/public/pdf/pressrelease/Zydus_announces_the_approval_of_Saroglitazar_Mg_for_the_treatment_of_Non_Alcoholic_Fatty_Liver_Disease_in_India_30_12_2020.pdf

[8] Harrison, S. A., et al. (2024). A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. New England Journal of Medicine390(6), 497-509.

[9] Source: FDA. Accessed on 14 March 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217785s000lbl.pdf

[10] Source: IQVIA. Accessed on 10 March 2024. https://www.iqvia.com/library/white-papers/emerging-from-the-shadows-a-new-era-for-nash

[11] Source: GlobalData. Accessed on 21 February 2024.

[12] Harrison, S. A., et al. (2023). Clinical trial landscape in NASH. Clinical Gastroenterology and Hepatology.

[13] Tilg, H., et al. (2023). NASH drug treatment development: challenges and lessons. The Lancet Gastroenterology & Hepatology.

[14] Source: CompaniesMarketcap. Accessed on 17 March 2024. https://companiesmarketcap.com/pharmaceuticals/largest-pharmaceutical-companies-by-market-cap

[15] Newsome, P. N., et al. (2021). A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. New England Journal of Medicine384(12), 1113-1124.

[16] Source: Questex. Accessed on 6 February 2024. https://www.fiercepharma.com/pharma/eli-lilly-touts-tirzepatide-midstage-nash-win-despite-lesser-anti-scarring-effect

[17] Source: Questex. Accessed on 3 January 2024. https://www.fiercebiotech.com/biotech/boehringer-bets-2b-biobucks-unlock-sirna-targets-nash-treatments

[18] Source: Questex. Accessed on 22 April 2024. https://www.fiercebiotech.com/biotech/boehringer-signs-13b-deal-rna-biotech-ochre-bio-team-tackle-mash

[19] Source: Ionis Pharmaceuticals. Accessed on 13 March 2024. https://ir.ionispharma.com/news-releases/news-release-details/ionis-announces-positive-results-phase-2-study-ion224

[20] Aslam, F., et al., (2019) Prevalence of NAFLD in a Singaporean cohort using non-invasive multiparametric MRI. Singapore Hepatology Conference, 7-8 June.

[21] Wilman, H.R., et al. (2017). Characterisation of liver fat in the UK Biobank cohort. PLoS ONE 12(2): e0172921.

[22] Source: A*STAR. Accessed on 30 April 2024. https://www.a-star.edu.sg/bmsipo/success-stories/enabling-the-fight-against-asian-liver-fat

[23] Source: BioSpace. Accessed on 18 March 2024. https://www.biospace.com/article/releases/lerna-bio-unveils-its-first-in-class-solution-to-combat-liver-failure/

[24] Source: HistoIndex. Accessed on 18 March 2024. https://www.histoindex.com/

[25] Luangmonkong, T., et al. (2023). Targeting collagen homeostasis for the treatment of liver fibrosis: Opportunities and challenges. Biochemical Pharmacology, 115740.

[26] Teng, Y., et al. (2021). A scalable and sensitive steatosis chip with long-term perfusion of in situ differentiated HepaRG organoids. Biomaterials, 275, 120904.

[27] Source: Madrigal Pharmaceuticals. Accessed on 15 March 2024.  https://ir.madrigalpharma.com/static-files/f3971a3b-c0ce-4db8-93e7-ac46afabb42a

[28] Source: Memorial Sloan Kettering Cancer Center. Accessed on 18 March 2024. https://www.mskcc.org/cancer-care/patient-education/understanding-your-fibroscan-results

[29] Afdhal, N. H. (2012). Fibroscan (transient elastography) for the measurement of liver fibrosis. Gastroenterology & hepatology, 8(9), 605.

[30] Martinou, E., et al. (2022). Diagnostic modalities of non-alcoholic fatty liver disease: from biochemical biomarkers to multi-omics non-invasive approaches. Diagnostics, 12(2), 407.

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