Year in review

NASH and NAFLD therapeutics in 2023 https://doi.org/10.1038/s41574-023-00939-9

A pivotal year for NAFLD

and NASH therapeutics
Jean-François Dufour Check for updates

The metabolic dysfunction that characterizes In a publication in Nature Medicine this year, the American consor-
tium Non-Invasive Biomarkers for Metabolic Liver Disease (NIMBLE)
obesity and type 2 diabetes mellitus affects not published an evaluation of the diagnostic performance of circulating
only the heart and kidneys, but also the liver. biomarkers for NASH and for fibrosis in NASH4 (here and below, termi-
nology follows that of the cited papers). Selected panels were evaluated
Although lifestyle modification remains the in an observational cohort of about 1,000 individuals with NAFLD. One
cornerstone in the management of metabolic panel, NIS-4, is based on the determination of four parameters: miR-
liver diseases, the field has progressed this year, 34a-5p, YKL-40, α2-macroglobulin and HbA1c, which assess glycaemic
control and fibrosis progression. This panel had an area under the
with a new definition, validation of non-invasive receiver operating characteristic curve (AUROC) of 0.81 (with 1 being
biomarkers and numerous clinical trials. perfect accuracy) for identifying patients with at-risk NASH, defined
by the presence of NASH with at least stage 2 fibrosis. The ELF panel
In the past two decades, tremendous therapeutic advances have been and Fibrometer VCTE panel both had an AUROC of >0.8 for clinically
achieved in the treatment of patients with liver disease. For example, significant fibrosis (stage 2 or higher), advanced fibrosis (stage 3 or
chronic hepatitis B can be prevented with vaccination and second-line higher) and cirrhosis (stage 4). This work opens the way towards the
treatments are available for patients with primary biliary cholangitis. validation and qualification of biomarkers to diagnose patients with
Several lines of systemic therapies can be used nowadays to treat patient NASH. Since the selection of these biomarkers, new panels have been
with hepatocellular carcinoma, and in the field of liver transplantation, proposed. These panels — for example, the FAST panel, which includes
machine perfusion allows improved preservation and selection of liver stiffness, controlled attenuated parameters and serum levels of
grafts. The next frontier in hepatology is non-alcoholic steatohepatitis aspartate aminotransferase5 — should be evaluated for their diagnostic
(NASH). Owing to high rates of obesity, type 2 diabetes mellitus and accuracy.
sedentary lifestyles, 25% of the world population now has non-alcoholic The context in which these panels will be used has to be consid-
fatty liver disease (NAFLD), and about 10% of these individuals progress ered in their validation. General practitioners need to be able to use
to the severe form of the disease (NASH). diagnostic biomarkers in the context of the primary care setting. In a
This year, this terminology undergoing a change (Fig. 1). It is time publication in The Lancet Gastroenterology and Hepatology, the Euro-
to abandon the term ‘NASH’1. The disease has been renamed ‘metab­ pean consortium Liver Investigation: Testing Marker Utility in Steato-
olic dysfunction-associated steatohepatitis’ (MASH) and NAFLD is hepatitis (LITMUS) performed a meta-analysis of individual participant
now named ‘metabolic dysfunction-associated steatotic liver disease’ data for the performance of liver stiffness as a prognostic measure
(MASLD)2. This new nomenclature is less stigmatizing than the previ- for NAFLD outcomes, measured by vibration-controlled transient
ous terminology. In addition, this change enables MASLD and MASH elastography (LSM-VCTE) and fibrosis-4 index (FIB-4; based on serum
to be diagnosed in patients who also consume high levels of alcohol, levels of aminotransferases, platelet count and age)6. The meta-analysis
a frequent clinical situation that is now referred to as ‘metabolic and included 2,518 patients with biopsy-proven NAFLD from 25 studies.
alcohol-related liver disease’ (MetALD). As important as this change The primary outcome was a composite end point (all-cause mortal-
of nomenclature is, it does not affect the two major challenges we are ity, development of hepatocellular carcinoma, liver transplantation
facing in the management of these patients, namely, diagnosis and or cirrhosis complications). The time-dependent AUROCs at 5 years
treatment.
The diagnosis of MASH/NASH is based on three histological
­features: steatosis, lobular inflammation and hepatocellular balloon-
ing, the identification of which requires performing a liver biopsy.
Key advances
This diagnostic approach has major limitations, such as random •• Panels of non-invasive biomarkers have the potential to diagnose
sampling (as the biopsy area might not necessarily be representa- patients with NASH and those with NASH and fibrosis4.
tive of the whole liver); interpretation variability; the high cost of •• Panels of non-invasive biomarkers have predictive value for
the procedure; and limited logistic accessibility and acceptability by the outcomes, especially those capturing the degree of fibrosis6.
patients. Moreover, this definition does not take into account fibrosis, •• Drugs targeting new targets, such as thyroid hormone receptor-β
the most important feature in terms of patient outcomes. Fibrosis is the and fibroblast growth factor 21, showed positive results in
parameter that dictates prognosis3. Therefore, there is an urgent clinical trials8,9.
and unmet need to develop and validate non-invasive biomarkers for •• There is a high degree of variability in the responses of the
MASH/NASH. We need diagnostic biomarkers, and we need predictive placebo groups in these trials8,9.
biomarkers (Fig. 1).

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 Name improvement: ‘N for M’ In a second phase IIb multicentre, randomized, double-blind,
• Change from ‘non-alcoholic’ to ‘metabolic’ placebo-controlled trial, patient with biopsy-confirmed NASH and
• Reduce stigma histological stage F2 or F3 fibrosis were randomly assigned to receive
• Open to non-invasive diagnosis
• Avoid diagnosis of exclusion placebo or efruxifermin subcutaneously once weekly9. Efruxifermin is
a human IgG1 Fc–FGF21 fusion protein. In this trial, 20% of the patients
Non-invasive tests in the placebo group had an improvement in fibrosis of at least one
• Diagnose patients in need of intervention stage and no worsening of NASH by week 24 versus 41% of the patients
• Identify patients at risk of complications Progress in MASH
• Rely less on liver biopsy therapies in 2023 in the 50-mg efruxifermin group. This smaller trial confirms that FGF21
• Consider the context of use is an attractive approach to treat patients with NASH. However, mono-
therapy to treat NASH with response rates below 50% is unlikely to
Drug therapy be enough to ensure effective management of NASH and combina-
• Positive phase III trial with THR-β agonist
• Ongoing advanced-phase trials with:
tion therapies will probably be required10. It is interesting to note the
• GLP1 agonist variability in the placebo groups between the studies. The first study
• Pan-PPAR agonist reports a 7% improvement in fibrosis in the placebo group and the
• FGF21 agonist
second study reports a 20% improvement of fibrosis.
Fig. 1 | Key advances in 2023 in MASH therapeutics. The disease was renamed Both the settings of the clinical trials as well as the trial character-
to have a non-exclusionary diagnosis that better captures its metabolic nature. istics were different for these studies; nevertheless, they illustrate a
Publications demonstrated that non-invasive biomarkers can be used to recurrent observation and point of discussion in the field: the impres-
diagnose metabolic dysfunction-associated steatohepatitis (MASH) and predict sive differences in the response rates in the placebo groups between
its outcomes. Randomized controlled trials showed positive results in phase III clinical trials. This variability relates partially to the inaccuracy of our
for resmetirom and in phase II for fibroblast growth factor 21 (FGF21) agonists. current gold standard, liver biopsy, to assess patient response to MASH
GLP1, glucagon-like peptide 1; PPAR, peroxisome proliferator-activated receptor;
therapeutics. These inaccuracies in random sampling and interpreta-
THR-β, thyroid hormone receptor-β.
tion are why the validation and qualification of non-invasive markers
to diagnose MASH and to monitor response to treatment are essential to
address the pandemic of patients with MASH in the future.
were 0.76 for LSM-VCTE and 0.74 for FIB-4. Notably, the histology had
a time-dependent AUROC at 5 years of 0.72. This work demonstrates Jean-François Dufour
that non-invasive tests performed as well as histology, if not better, Center for Digestive Diseases Lausanne, Lausanne, Switzerland.
at predicting clinical outcomes. Such publications demonstrate the e-mail: [email protected]
viability of using biomarkers to diagnose patients with NASH without
having to perform a liver biopsy, and the potential of non-invasive Published online: 14 December 2023
tests to identify patients at risk who need to be prioritized for
treatment. References
1. Dufour, J. F. Time to abandon NASH? Hepatology 63, 9–10 (2016).
There is currently no approved therapy to treat patients with 2. Rinella, M. E. et al. A multisociety Delphi consensus statement on new fatty liver disease
NASH. Several drugs evaluated in phase III clinical trials have failed; nomenclature. Hepatology 78, 1966–1986 (2023).
however, in 2023, new drugs have shown promising effects. Results 3. Angulo, P. et al. Liver fibrosis, but no other histologic features, is associated with
long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology
from the phase III clinical trial with resmetirom, a thyroid hormone 149, 389–97.e10 (2015).
receptor-β agonist were published7. The drug has a significant effect 4. Sanyal, A. J. et al. Diagnostic performance of circulating biomarkers for non-alcoholic
steatohepatitis. Nat. Med. 29, 2656–2664 (2023).
on NASH resolution and on improvement of fibrosis in comparison to
5. Ravaioli, F. et al. Diagnostic accuracy of FibroScan-AST (FAST) score for the non-invasive
the placebo group7. identification of patients with fibrotic non-alcoholic steatohepatitis: a systematic review
Publications of phase II trials also showed the potential of and meta-analysis. Gut 72, 1399–1409 (2023).
6. Mózes, F. E. et al. Performance of non-invasive tests and histology for the prediction
drugs with another mechanism of action. In a phase IIb multicentre,
of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual
double-blind, 24-week trial, patients with biopsy-confirmed NASH participant data meta-analysis. Lancet Gastroenterol. Hepatol. 8, 704–713 (2023).
with stage 2 or stage 3 fibrosis were randomized to receive either sub- 7. Harrison, S. A. et al. Resmetirom for nonalcoholic fatty liver disease: a randomized,
double-blind, placebo-controlled phase 3 trial. Nat. Med. 29, 2919–2928 (2023).
cutaneous pegozafermin or placebo8. Pegozafermin is a long-acting
8. Loomba, R. et al. Randomized, controlled trial of the FGF21 analogue pegozafermin
glycopegylated fibroblast growth factor 21 (FGF21) analogue. FGF21 in NASH. N. Engl. J. Med. 389, 998–1008 (2023).
regulates lipid and glucose metabolism and energy expenditure and 9. Harrison, S. A. et al. Safety and efficacy of once-weekly efruxifermin versus placebo
in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind,
so has multiple effects that could be beneficial in patients with NASH. placebo-controlled, phase 2b trial. Lancet Gastroenterol. Hepatol. 8, 1080–1093 (2023).
As reported in this publication in the New England Journal of Medicine, 10. Dufour, J. F., Caussy, C. & Loomba, R. Combination therapy for non-alcoholic
fibrosis improvement occurred in 7% in the placebo group and in 22% steatohepatitis: rationale, opportunities and challenges. Gut 69, 1877–1884
(2020).
in the group that received 15 mg of pegozafermin. NASH resolution
occurred in 2% in the placebo group and in 37% in the 15-mg pegoza- Competing interests
fermin group, and these differences were statistically significant. The J.-F.D. declares the following competing interests: participation on advisory committees
for Alentis, Astra-Zeneca, Bayer, Bristol-Myers Squibb, Enyo, Esai, Genfit, Intercept, Inventiva,
safety profile was favourable, with common adverse effects being Ipsen, Lilly, Madrigal, Merck, Novartis, Novo-Nordisk and Roche. Speaking and teaching
gastrointestinal (specifically nausea and diarrhoea). engagements for Astra-Zeneca, Bristol-Myers Squibb, Intercept, Ipsen and Roche.

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