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The exploration path of liver disease NASH

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Among people with obesity, diabetes, and metabolic syndrome, the global prevalence of non-alcoholic fatty liver disease (NAFLD) is as high as 25%, and the prevalence of ordinary adult non-alcoholic fatty liver disease (NASH) is 3% to 6%. It has become an increasingly important factor in cirrhosis, hepatocellular carcinoma and liver transplantation. NAFLD is currently a major stubborn disease for all human beings, which progresses from fatty lesions to NASH, cirrhosis, and finally to liver cancer.
In the United States, the incidence of nonalcoholic fatty liver disease (NAFLD) accounts for about 10%-46% of the total population, and about 10%-30% of patients will develop into NASH. The incidence rate in China has also been increasing in recent years. The epidemiological survey results from Shanghai and Beijing show that the prevalence of NAFLD diagnosed by B-mode ultrasound in ordinary adults has increased from 15% to more than 31% in 10 years. Liver biopsy confirmed that NASH accounted for 41.4% of patients with NAFLD and cirrhosis accounted for 2%. As a traditional liver disease country, my country’s situation is not optimistic. In the foreseeable future, NASH will become a major challenge for global public health.
Non-alcoholic steatohepatitis (NASH), also known as metabolic steatohepatitis, is a further development of non-alcoholic steatohepatitis (NAFL). The pathological changes are similar to alcoholic hepatitis, but there is no clinical syndrome of excessive alcohol consumption, which is more common. In middle age, especially overweight and obese individuals, the etiology is closely related to a series of metabolic disorders, such as diabetes and obesity. The main feature is liver fat accumulation, accompanied by hepatitis and liver damage. These symptoms are reversible. If not controlled and treated, the condition will continue to deteriorate, and gradually develop into liver fibrosis, cirrhosis, and even liver cancer. The subsequent process is irreversible. Although hepatic fibrosis may also be reversed, its treatment is more difficult, and there is no effective drug so far. It is intuitively important to control and cure diseases at the NASH stage. For the treatment of NASH, there is still no effective drug so far, only by controlling body weight, blood lipids, etc. to stabilize the development of the disease.

Liver cancer formation process
Liver cancer formation process

▲The formation of liver cancer
The cause of NASH is more complicated. It is an acquired metabolic disease that is closely related to insulin resistance and genetic susceptibility. As a simple fatty liver develops into a stage of pathological stage of liver fibrosis, the disease is common in type II diabetes, hypertension, hyperlipidemia and Obese patients. The pathogenesis of NASH is not yet clear, and the interaction of genetic susceptibility and multi-metabolism may be its main pathogenesis factor. Recent studies have shown that the onset of NASH is associated with insulin resistance, oxygen stress and lipid peroxidation damage, proinflammatory cytokines, adipokines, and mitochondrial dysfunction.
For NASH, currently the most effective means of relief is weight control and lifestyle adjustment. When the weight loss exceeds 10%, 45% of the patients’ condition improves, 90% of NASH can subside, and diets reduce high-fat and high-sugar foods. Ingestion can also play a certain role. In view of the fact that there are no effective drugs for NASH yet, adjusting the diet structure and losing weight is currently the best treatment.
NASH target drugs
The pathogenesis of NASH is complicated and the course is long. The pathogenesis is still unclear. Therefore, the targets of the drugs under study are relatively scattered, and some of them are even unclear. At present, the main targets of NASH treatment are peroxisome proliferator-activated receptor (PPAR) agonists acting on the regulation of glucose and lipid metabolism, farnesyl derivative X receptor (FXR) agonists acting on the bile acid pathway, Anti-inflammatory chemical chemokine receptor 2 (CCR2)-5 (CCR5) antagonist, selective phosphodiesterase (PDE) inhibitor, anti-apoptotic cysteine aspartic protease (Caspase) ) Inhibitors and 1w’apoptotic signal-regulated kinase 1 (ASK1) inhibitors, etc.
According to the informa database, there are more than 50 drugs used to treat NASH in clinical trials, and many drugs have entered clinical phase 2/3, and the success rate of phase 3 clinical new drugs is low (less than 10%), so NASH field There are no effective drugs on the market.
Characteristics of NASH and difficulties in drug development
NASH can be divided into F0 (no fibrosis) to F4 (cirrhosis) according to the degree of fibrosis. NASH has an insidious onset and slow progress, with an average level of 7-10 years, which is far beyond the normal clinical trial cycle and difficult to diagnose The current gold standard for clinical diagnosis is still liver biopsy (difficult patient recruitment). The main cause of death is cardiovascular disease and extrahepatic malignant tumors. Liver disease death ranks third, so the safety of drugs is extremely high, especially in the cardiovascular direction .
Market prospects and development trends
In view of the fact that steatohepatitis and associated fibrosis have the characteristics of high incidence and lack of effective treatment drugs, the new drug development targets for treating steatohepatitis cover different stages and mechanisms of the front, middle and back of fatty liver, with rich pipelines and broad market prospects. .
At present, there are no new drugs for the effective treatment of fatty liver disease. The preclinical and clinical trials of NAFLD new drug development are facing great challenges. Combination medicine has become an important trend in the treatment of fatty liver and its related complications, and there is a huge demand for the development of new drugs for the effective treatment of fatty liver.
Medici has extensive experience and effective animal models in the evaluation of NASH new drugs, including golden hamsters and rat models induced by high-fat feeding, and mouse models induced by MCD feed. And has an effective evaluation model for the stage of NAFLD fibrosis, including: TAA-induced liver fibrosis (rat), compound factor method-induced rat liver fibrosis model (rat), ConA-induced mouse liver fibrosis (small Rat), porcine serum-induced immune model of rat liver fibrosis (rat), etc.
Medicilon’s Department of Pharmacodynamics is located in the Pharmaceutical Valley Center of Zhangjiang Hi-Tech Park in Shanghai. After years of experience accumulation, multi-party verification and long-term practical tests, Medicilon has established a complete animal model library, which can provide various types according to customer needs. Effective animal models to evaluate the effectiveness of drugs. Experimental animals include non-human primates, dogs, large mice, rabbits, guinea pigs, and small pigs. They can flexibly develop and build various customized models according to the needs of customers to meet customers’ different types of new drug development needs.

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