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Popular track: NASH research conditions and treatment strategies

 Last Update: 2023-02-03
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Non-alcoholic fatty liver disease, NAFLD) has become the most prevalent liver disease in the world, caused by the accumulation of excess fat in the liver, associated with chronic hepatitis and liver cell damage, can lead to fibrosis, eventually leading to cirrhosis and the occurrence of liver cancer, is one of the main causes of end-stage liver disease and liver transplantation, the global incidence is about 25
%.
At present, NASH is becoming the most important cause of
advanced liver disease.
In recent years, with the in-depth study of the complexity of NASH pathophysiology and the successive reports of NASH biomarkers, breakthroughs have been made in the field of NASH
.
Awareness of the importance of lifestyle is also increasing, and some drugs to treat NASH are undergoing clinical trials
.

1 Introduction to NASH indications

In recent years, the prevalence of nonalcoholic fatty liver disease (NAFLD) has increased due to improved living standards and changes in lifestyle and diet
.
presently The proportion of NASH in NAFLD is 10%~30%, and from 2010 to 2021, the data in China's non-alcoholic fatty liver disease diagnosis and treatment guidelines increased by 10%, which can be estimated to increase about 20 million NASH patients
.

Nonalcoholic steatohepatitis (NASH) is a fast-growing and highly pervasive health threat that has become a leading cause
of liver cancer.
NASH is a late form of non-alcoholic fatty liver disease (NAFLD), which is closely related to obesity and metabolic disorders, and tends to occur in middle-aged especially overweight and obese individuals, and its clinical manifestations are steatohepatitis and fatty cirrhosis
.
With the global obesity epidemic, the clinical and economic burden on NASH patients will become significant (Figure 1).

Despite the prevalence of NASH, there is currently no approved treatment
.
While many drugs are in development, difficulties in the classification and identification of accurate biomarkers hinder the approval
of effective therapeutic strategies.

Studies have reported that NAFLD is a complex disease driven by lipotoxicity, insulin resistance and activation of inflammation and immune pathways, and is closely related
to metabolic disorders.
There is growing evidence of a link
between the gut microbiota and the development of insulin resistance and NASH syndrome.
At present, liver biopsy remains the main reference standard
for the diagnosis of NASH hepatitis (steatosis and steatohepatitis).

Figure 1.
NASH Global Pandemic

2 Treatment strategies for NASH

For NASH, the ideal therapeutic effect is to effectively reverse liver damage and fibrosis and improve other metabolic markers or cardiovascular complications (or at least not worsen the latter).

Although there has been a lot of progress in research on the pathogenesis of NASH over the past 10 years, there is still no approved NASH treatment
.
Currently, the main treatment for NASH is lifestyle changes through diet and exercise, with the ultimate goal of losing weight
.

1.
Lifestyle improvement strategies

Currently, the lack of pharmacological intervention strategies for NASH makes lifestyle modification strategies even more important
.
Adopting lifestyle improvement strategies is the best treatment strategy
in the long run.
The best example comes from the Mediterranean diet
.
The Mediterranean diet has been reported to be characterized by a high intake of olive oil, vegetables, fruits and nuts, legumes, whole grains, fish and seafood, and a low intake of red meat, especially processed meats, as well as a reduction in carbohydrate intake, especially sugar (Figure 2).

A recent 18-month trial of 294 participants showed that adding polyphenol-rich greenery could improve the Mediterranean diet
.
The Green Mediterranean diet reduced liver fat by 39 percent, compared to 20 percent on the Mediterranean diet, although weight loss was similar, and both diets performed better
than controls that only provided healthy eating guidelines.
In addition, increased phenolic acid intake (from fruits and vegetables, nuts, green tea, and coffee) was associated with
the prevalence of insulin resistance, NAFLD, and fibrosis as measured by fibrosis markers (fiber tests).
Many studies have shown that a Mediterranean-style diet can help reduce the risk of
heart disease, stroke, and cognitive impairment such as Alzheimer's disease.

Although lifestyle changes do have an effect on liver fat accumulation, there is no evidence that a specific high intake of nutritious vegetarian diets is beneficial
for NASH.
Therefore, calorie restriction is the most appropriate recommendation
for these patients.
In addition, fructose intake should be limited, as fructose is associated with
the progression of NASH and fibrosis.
In addition, patients with NASH should also avoid alcohol
.

Figure 2.
Lifestyle recommendations for NASH patients

2 Surgical strategies

Studies have reported that unhealthy and irregular ways to lose weight, resulting in too rapid weight loss can sometimes be counterproductive
.
This unhealthy way to lose weight can cause fat to break down too quickly, which can induce or exacerbate inflammation, infiltration, or fibrosis
in the liver.
Bariatric surgery
may be considered in these patients with NASH who are not sensitive to behavioral modification.
Studies have shown that bariatric surgery can effectively improve the quality of life and survival time
of patients with NASH.
However, based on the safety problems faced by surgery, further research and verification
are still needed.

3 Drug strategies for the treatment of NASH

With in-depth research on the pathogenesis of NASH The complexity of the pathophysiology of NASH has been found to provide multiple potential drug targets for NASH drug treatment, such as: FXR, FGF21, GLP-1R, PPAR, ASK1, THR-β, etc (Figure 3).

The endpoints of the FDA's late NASH clinical trial focused on the histological endpoint resolved by NASH without fibrosis exacerbation or fibrosis improvement in at least one fibrotic stage and no exacerbation
of steatohepatitis.
Therefore, liver biopsies are repeated at the time of entry into treatment and at the end of treatment to examine the therapeutic effect
of NASH drugs.

Figure 3.
Potential drug targets for the treatment of NASH

At present, the NASH market is highly competitive, attracting many domestic and foreign pharmaceutical companies to deploy R&D in this area (Figure 4).

Among them, Gilead has carried out the most research projects, reaching 18; followed by Novartis with 9; Pfizer followed with 7; Novo Nordisk, Astra Zeneca, and Boehringer Ingelheim has 6 projects in the pipeline each; BMS and Terns have 5 and 4 projects in their
pipelines each.
In addition, the company with three research projects is Eli Lilly, Metacrine, MSD and Roche, among others; The companies with two research projects are AbbVie, Dr.
Falk Pharma and Inventiva Pharma、Inois Pharma, Kowa, etc.
; The remaining companies each have 1 research project
.
In addition, Chinese companies mainly include Dongguang Pharmaceutical (2), Sihuan Pharmaceutical (2), Zhongsheng Pharmaceutical (2), Ascletis Pharmaceutical (1), Junsheng Tai Biotechnology (1), Altron Biotechnology (1) and Zhejiang Pharmaceutical (1).

Figure 4.
Summary of NASH research at home and abroad

Although no drugs for the direct treatment of NASH have been approved, aggressive symptomatic treatment
is recommended for other metabolic diseases (such as hypertension, hyperglycemia, and hyperlipidemia) that are easy to be comorbid in patients with NASH.
Currently, drug development for NASH focuses on the following four broad categories (Figure 5):

1.
Metabolic targets, mainly including improving insulin sensitivity, inhibiting various enzymes of fat production, and improving mitochondrial uptake of fatty acids

2.
Inflammatory targets, including inhibiting inflammatory cell recruitment, blocking inflammatory signaling, reducing oxidation and endoplasmic reticulum stress response, inhibiting apoptosis of hepatocytes, etc

3.
Digestive targets, including regulating hepatoenteric axis circulation, improving bile acid circulation and signaling, and improving intestinal microbiota

4.
Fibrotic targets, including targeting liver astrocytes, reducing collagen deposition in the liver, and enhancing fiber decomposition
.

Figure 5.
Types of NASH drugs

At present, a large number of NASH drugs are in various stages of clinical research, but only a few drugs have entered phase III clinical studies
.
Despite the positive results so far, it could be years before full approval from regulatory agencies such as the FDA
.
The results of some representative NASH drugs in Phase III clinical trials
are described below.

2.
3.
1 Drugs that regulate metabolic homeostasis

Peroxisome proliferator-activating receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily and include the following three subtypes: PPARα, PPARγ, and PPARβ/δ
.
Activation of PPAR-α reduces triglyceride levels and participates in the regulation of energy homeostasis, activation of PPAR-γ causes insulin sensitization and enhances glucose metabolism, while activation of PPAR-β/δ promotes fatty acid metabolism
.

The pan-PPAR agonist Lanilano successfully completed a 24-week IIb trial in which 247 participants participated and met its primary endpoint: a 2-point reduction in SAF activity scores with no increase in fibrosis, and 49% of patients took 1200 mg, compared with 27%
of patients taking placebo.
In addition, the drug also met the secondary endpoint of reducing fibrosis in at least one stage without worsening symptoms (42% for 1200 mg versus 24% for placebo).

Lanilano is well tolerated, although side effects include mild weight gain
.
It has been designated as an FDA breakthrough therapy as a lead candidate in this class, and Phase III studies are currently underway
.

2.
3.
2 Drugs acting on the liver

Studies have shown that thyroid hormone receptors (THR-β) are essential
for homeostasis in the liver through multiple metabolic effects of thyroid hormones.
THR-β agonists have been shown to improve lipid metabolism
.
The THR-β agonist has completed a Phase II trial and is undergoing a Phase III trial at 52 weeks
.
The 36-week phase II study with 125 participants showed an average reduction of 30% in liver fat compared to baseline, resulting in a significant improvement
in NASH.
Preliminary results from one of the phase III trials showed positive results
in liver fat and liver stiffness, as well as reductions in LDL-cholesterol and apolipoprotein.

Farnesol X receptor (FXR) is a ligand-activated transcription factor involved in controlling the synthesis of bile acids (BA) and is central to many pathways in the liver, affecting inflammation, fibrosis, lipid metabolism, and glucose metabolism
.
Obeticholic acid is a selective FXR agonist currently tested
in a phase III trial in 1968 neonates and fibrotic F2-F3 patients.
In an 18-month interim analysis, the drug met at least one endpoint of improvement in fibrosis phase, with no worsening of NASH but no resolution
of NASH.
The main adverse events were pruritus and elevated LDL cholesterol, which responded to
statin therapy.

Aramchol (arachidonic aminocholic acid), a partial inhibitor of the stearyl-coenzyme desaturase (SCD1), has been tested
in a Phase 2b trial that included 247 NASH patients.
At 52 weeks, the maximum dose was 600 mg, the prespecified significant level
of liver fat reduction is not reached by MR spectroscopy.
However, post-hoc analysis showed that Aramchol has the potential to
improve liver histology in patients with high disease activity and prefibrotic stages of cirrhosis.

In addition, there are studies that have shown that NASH increases the risk of
hepatocellular carcinoma (HCC) and other cancers.
About half of patients with NASH-associated HCC do not have cirrhosis and are often diagnosed at an advanced stage of cancer
.

2.
3.
3 GLP1 receptor agonists

GLP1 receptor agonists have a variety of effects on multiple organs and systems, including the pancreas, central nervous system, and liver
.
GLP1 The receptor agonist somaglutide completed a 72-week phase II trial with a total of 320 participants and showed relief of symptoms with no worsening of fibrosis in 56% of patients taking 0.
4 mg, compared to 20%
of patients with placebo.
It could not achieve the secondary outcome of its fibrosis improvement without the worsening
of NASH.
Although in the active treatment group, the number of patients with fibrosis exacerbation was lower
.
This drug results in significant weight loss, with the most common adverse event being gastrointestinal reactions
.
The safety profile of NASH is consistent with what has been observed in other trials and disease areas, and Phase III clinical trials are
ongoing.

3 Summary

Although many breakthroughs have been made in epidemiological research on NASH in recent years, NASH is still an increasingly common and important disease, which brings great challenges
to people's lives and health.
At present, the only effective treatment for NASH is weight loss
.
While there is no shortage of NASH drug candidates, difficulties in diagnosing, staging, and monitoring treatment effects add unprecedented complexity
to the field.
In the future, drug development in the field of NASH should consider drug safety and tolerability, aspects such as
hepatocellular carcinoma risk and cost of treatment.
We look forward to the rapid rise of innovative pharmaceutical companies at home and abroad in the field of NASH to benefit patients
.
In the future, we will wait and see!

References

1、Therapeutic pipeline in nonalcoholic steatohepatitis.
https://doi.
org/10.
1038/s41575-020-00408-y

2、Current therapies and new developments in NASH.
Gut 2022; 71:2123–2134.
doi:10.
1136/gutjnl-2021-326874

3、Nonalcoholic steatohepatitis is the most rapidly increasing indication for liver transplantation in the United States.
Clin Gastroenterol Hepatol 2021; 19:580–9.

4、Global epidemiology of nonalcoholic fatty liver disease-Meta- Analytic assessment of prevalence, incidence, and outcomes.
Hepatology 2016; 64:73–84.

5、From the origin of NASH to the future of metabolic fatty liver disease.
Gut 2021; 70:1570–9.

6.
NAFLD/NASH drug candidates worldwide.
Peptide Research Society

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