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Invisible Killer

The liver is a very magical organ with many functions, such as participating in the synthesis of various proteins, participating in the metabolism of drugs and secreting the bile needed to digest food. In addition, the liver regulates the amount of sugars, proteins and fats that enter the blood circulation.

The liver is essential for the maintenance of normal body functions. Unfortunately, in the past few decades, the incidence of non-alcoholic fatty liver disease (NAFLD) has risen correspondingly with the increase in the number of people with obesity and diabetes.

Non-alcoholic fatty liver disease has become the most common chronic liver disease in the world. Although for most of them, their illness will not continue to progress, but also through reasonable exercise and weight loss can also reverse the course of the disease. However, for a small number of patients, non-alcoholic fatty liver disease caused solely by fat accumulation is just the beginning of a series of more serious diseases.

 

About 30% of patients with nonalcoholic fatty liver disease develop inflammation in the liver, resulting in non-alcoholic steatohepatitis (NASH). About 20% of NASH patients will continue to progress and develop severe liver fibrosis, which may progress to liver cirrhosis or liver cancer that seriously affects liver function.

In China, the incidence of non-alcoholic fatty liver disease in the eastern coastal and urban areas is about 30%, and the incidence in rural areas is 1%. About 30% of these people may develop disease to form non-alcoholic steatohepatitis. Although based on the above figures to calculate that there should be a large number of patients with nonalcoholic steatohepatitis around us, but in fact most people have a very vague concept of the term non-alcoholic steatohepatitis, and even many people have not heard of NASH this kind of disease.

 

But on the other hand, even if the incidence of non-alcoholic steatohepatitis is very high, most patients with non-alcoholic steatohepatitis do not experience obvious symptoms, and the disease itself has no relatively simple detection/diagnosis methods. There is no approved drug for listing. Therefore, the general public’s perception of non-alcoholic steatohepatitis is rather ambiguous.

 

In fact, until the 1980s, nonalcoholic fatty liver disease was considered to be an independent disease. Prior to this, if patients with fatty liver told the doctor that they did not drink alcohol, the doctor would usually think that they were lying. And even if doctors are willing to believe them, these doctors do not think that non-alcoholic hepatic steatosis can lead to serious diseases.

 

However, some studies in the 1990s subverted this perception because researchers found that nonalcoholic fatty liver can also have serious consequences. At present, it is generally considered that non-alcoholic fatty liver disease involves multiple different stages. If the liver has a fat content of more than 5%, it is regarded as fatty liver, and if it is not accompanied by inflammation or the level of inflammation is very low, it means that The condition is still at the lightest stage.

 

In fact, for many people, suffering from fatty liver is not really a big problem. If only simple fat accumulation, most people can continue to normal life, and even before they died will not realize that they have fatty liver disease.

 

However, if accumulated fat causes inflammation to cause swelling and death of the cells, it means that the patient’s condition has progressed to the stage of non-alcoholic steatohepatitis.

 

The progression of non-alcoholic fatty liver disease is very slow and may last for years or even decades. Like other diseases such as high blood pressure or diabetes, this is a slow and silent process. However, unlike diabetes and high blood pressure, doctors can detect these two diseases with rapid and inexpensive detection methods. Non-alcoholic steatohepatitis is difficult to diagnose.

 

Most patients with fibrosis on the liver do not show obvious clinical symptoms. There are currently no simple and reliable biomarkers that can be tested by blood. The most reliable disease detection method can only be achieved through liver biopsy.

 

Moreover, most of the cognition of nonalcoholic fatty liver disease in the past 30 years has also come from tissue biopsy. With the deepening of research, researchers have found that non-alcoholic fatty liver disease is not a completely progressive disease. For example, a patient with non-alcoholic fatty liver disease may directly produce fibrosis without going through the inflammatory process of NASH. And patients with non-alcoholic steatohepatitis can also progress directly to liver cancer without fibrosis.

Non-alcoholic fatty liver disease often occurs in people with obesity and metabolic disorders (BMI over 30), and the risk factors for diabetes and cardiovascular disease also apply to non-alcoholic fatty liver disease. And patients with severe metabolic diseases are also more likely to have liver fibrosis. When BMI is elevated or complications such as metabolic diseases such as diabetes or hypertension occur, the degree of fibrosis is more likely to deteriorate.

The progression of non-alcoholic fatty liver disease is also age-related, in addition to the difference in the storage of fat in the body can also affect the risk of non-alcoholic fatty liver disease progression. For example, those who have excess abdominal fat are more likely to have a higher risk than those who have excess fat in their extremities and hips.

FXR agonists

At present, doctors can only stop or reverse the patient’s liver damage by suggesting lifestyle changes such as proper diet, more exercise, and less alcohol consumption. In fact, the regenerative capacity of the liver is very strong, and the effect of disease control after lifestyle changes is also very obvious. However, studies have found time and time again that it is extremely difficult for patients to change their lifestyle, control their diet and exercise more. Therefore, liver disease experts prefer to use drugs to treat patients with non-alcoholic fatty liver disease.

However, the development of new drugs for non-alcoholic fatty liver is not easy. At present, the pathological study of non-alcoholic fatty liver disease is not very clear, and researchers still do not understand why some patients with non-alcoholic fatty liver disease will progress to inflammation, fibrosis and cirrhosis, while the other part of the patient’s disease is not Will progress.

The heterogeneity of this disease is very strong, the relevant cell signaling pathways are very complicated, and animal models are not able to well simulate human disease characteristics. In addition, the detection of diseases is also very difficult, which has brought about the development of drugs. Great difficulty.

But even if there are many obstacles, pharmaceutical companies still have great enthusiasm for drug development in the field of non-alcoholic fatty liver disease. Analysts predict that by 2025, the non-alcoholic steatohepatitis drug market will reach $15 billion, which alone is enough to attract many pharmaceutical companies to enter the market.

In January 2014, Intercept announced that they had stopped the phase II clinical trial of a non-alcoholic steatohepatitis of Oberoi Cholic acid in advance. The researchers found that patients with non-alcoholic steatohepatitis could improve after 72 weeks of treatment with labocolic acid. The condition of the patient. The clinical trial results were also published in the “The Lancet” of the year and quickly became a hot topic in the pharmaceutical field.

The NIH-funded FLINT study was the largest at the time, using liver biopsies to compare clinical trials of non-alcoholic fatty liver disease before and after treatment. Of the 110 patients who received albechemic acid, 45% had a significant increase in the activity score for non-alcoholic fatty liver disease, and there was no worsening of hepatic fibrosis. Only 23 out of 109 people in the control group increased their scores.

These results also prompted Intercept to begin phase III clinical studies of abechoic acid. However, due to the heterogeneity of patients with non-alcoholic steatohepatitis, the scale of the study is very large. The clinical trial plans to recruit more than 2,000 people, and the enrolled patients must have 2 or 3 phases of liver fibrosis, which means that they The degree of hepatic fibrosis has been more severe, but it has not reached the level of cirrhosis.

The launch of this study is also of great significance to other pharmaceutical companies that are located in this area. Because Intercept will negotiate with the FDA to develop a clinical trial design program, this will plan a blueprint for other companies to follow.

After the publication of the FLINT study, there has been an explosive growth in the field of drug development for non-alcoholic fatty liver disease. After seeing the positive data of Aubecholic acid, many pharmaceutical companies also began to enter this field through a series of transactions.

One of the more famous ones, including Gilead, acquired Nimbus Apollo for a total transaction volume of up to US$1.2 billion to obtain its allosteric inhibitor of acetyl-CoA carboxylase (ACC). Ai Jian also bought two companies, Tobira Therapeutics and Akarna Therapeutics, in one day and made a high profile visit to NASH.

Ombecholic acid is an analog of bile acid chenodeoxycholic acid, a natural ligand of FXR (a farnesoid-like receptor). FXR can be a popular target because at least in theory, FXR agonists can regulate multiple processes of this complex disease, such as the synthesis and transport of bile acids, the breakdown of liver and intestinal lipids, and the maintenance of Blood sugar levels.

Obecholic acid binds to FXR, which is also the main reason for its pharmacological activity. However, methamithylcholine also interacts with other targets, which can lead to the formation of drug side effects.

Omecholic acid has two major side effects in clinical studies. First of all, many patients who have used methambitic acid may experience pruritus. This side effect can be controlled with other drugs, or the drug can be controlled for a certain period of time after the drug is discontinued. However, another side effect seems to be cause for concern, because the study found that abechoic acid can increase LDL, non-alcoholic steatohepatitis may itself belong to high LDL.

 

Although this side-effect can be eliminated by the combination of statins, it also gives other pharmaceutical companies an opportunity to design compounds that are non-bile FXR agonists to increase the safety and effectiveness of the compounds.

 

In addition, another clinical trial of ambecholic acid in Japan did not recapitulate the effectiveness of FLINT. Only the highest dose of the 40 mg group reached the primary endpoint, and the three doses failed to improve liver fibrosis. In terms of efficacy and side effects, nobechoic acid is not an ideal drug, so many other pharmaceutical companies are hoping for a new generation of FXR inhibitors.

Drug combination

 

In fact, in addition to amychoetic acid, the number of drugs used to treat non-alcoholic fatty liver disease in clinical research is very large, and the mechanism of action is very different. This is actually quite understandable, because in theory, all the processes involved in the process of non-alcoholic fatty liver disease are likely to become drug targets.

Moreover, because the risk factors for non-alcoholic steatohepatitis are partially overlapped with pathological processes and many other diseases, pharmaceutical companies are also testing the efficacy of drugs for the treatment of non-alcoholic fatty liver disease in many other fields.

Although there are a large number of drugs being researched, the drugs in the field of non-alcoholic fatty liver disease can generally be divided into four categories. The first is to target metabolic stress caused by excess fat. Followed by the inflammatory process, inhibit cell death. The third category is antifibrotic drugs. The last category is drugs that inhibit the absorption of intestinal fat or target the inflammation associated with intestinal flora.

However, it should be noted that this classification is not absolute. For example, lobecholic acid and PPAR (peroxisome proliferator-activated receptor) agonist elafibranor can act on nuclear receptors and regulate expression of multiple genes and influence Multiple types of disease processes.

PPAR includes three subtypes of PPARα, PPARδ, and PPARγ, and Elafilbranor belongs to the PPARα/δ dual agonist. In Phase IIb clinical trials (GOLDEN-505), treatment of moderate-severe NASH patients with a high dose of 120 mg of Elafibrabra found that the drug relieved NASH without progression of liver fibrosis progression.

Many other drugs that reduce metabolic stress are realized by mimicking endogenous hormones. In 2015, Merck East purchased drugs from NGM that were modified versions of the hormone FGF19, and FGF19 could participate in the FXR signaling pathway. At present, the pharmaceutical industry is also very interested in GLP-1 analogues such as somaglutide for the treatment of type 2 diabetes. Somatostatin is currently in phase II clinical research for the treatment of non-alcoholic steatohepatitis.

At the same time, drugs that can inhibit the enzymes involved in the fatty acid synthesis process are also a direction for the development of non-alcoholic steatohepatitis drugs, such as ACC inhibitors that Gilead acquired from Nimbus, they hope to inhibit the pathological process of NASH by inhibiting harmful fat accumulation. .

In the field of anti-inflammatory, Al-Jian has given great hope to the drug Cannicriviroc, which was acquired from Tobira, a drug that can block the chemokines CCR2 and CCR5, which can participate in the inflammatory process. The drug Emricasan purchased by Novartis from Conatus last year is a caspase pan-inhibitory agent that may also inhibit the inflammatory process.

The selonsertib in the Gilead product line is an ASK1 inhibitor. ASK1 can participate in the process of programmed cell death. By inhibiting this process, selonsertib may reduce the degree of inflammation and liver fibrosis in NASH patients.

The reason why the realization of such a rich product line in the field of non-alcoholic steatohepatitis treatment is that the group of patients with non-alcoholic steatohepatitis is now considered to be strongly heterogeneous and seems to be different from non-alcoholic. The progression of non-alcoholic steatohepatitis in patients with STDs differs significantly, and it is difficult to find a drug that is effective for all patients. Therefore, pharmaceutical companies need different treatments to treat this complex patient population.

It is also for this reason that the big players in the field of non-alcoholic steatohepatitis have been forming NASH’s product lineup long ago.

 

For example, Gilead’s company, as early as 2010, Gilead has already begun to plan the development of non-alcoholic steatohepatitis treatment strategies to target different symptoms of the disease or different pathogenic factors, such as steatosis, fibrosis, Inflammation, abnormal blood sugar and lipid metabolism.

Currently, Gilead has a variety of drugs with different mechanisms of action in clinical studies. In addition to the FXR agonist GS-9674, Gilead also has LOXL2 inhibitors that inhibit fibrosis, selonsertib that inhibits inflammation and fibrosis, and fatty acids that inhibit inflammation. Synthetic process of ACC allosteric inhibitor GS-0976.

Disease detection dilemma

Today, the drug development pipeline for non-alcoholic steatohepatitis is becoming more and more crowded, and researchers are actively looking for ways to better detect liver fibrosis, thus making it easier and more accurate to assess the patient’s condition.

At present, the most reliable detection method for liver fibrosis is still done through liver biopsy, but it is not an ideal disease detection method for patients and doctors.

 

Since many early non-alcoholic fatty liver disease patients do not have obvious disease symptoms, it is not an easy task to convince them to perform percutaneous puncture and liver tissue extraction to determine the degree of fibrosis.

It may be that for many people, they would rather lose weight than do biopsy. For pharmaceutical companies conducting clinical trials, biopsy is expensive and takes a long time.

 

And, more importantly, even if biopsy is the only method that has a relatively high degree of credibility, this method itself has significant flaws. Because fibrosis of the liver is not evenly distributed on the liver, it means that the degree of hepatic fibrosis observed in a sample will depend on where the needle is inserted.

Because of this flaw, the scale of clinical trials using liver biopsy as a means of detection must be large enough to reduce the impact of this difference.

 

Although there are some non-invasive disease detection methods, these methods are not mature enough to provide more reliable diagnostic results. If there is no simple way to reliably detect the level of fat and fibrosis in the liver, even if it is marketed in the future, its application will be limited. Because even if there are effective drugs, many patients can only wait until the disease progresses to liver cirrhosis or advanced fibrosis if they can’t diagnose the patient’s condition effectively.

 

In the past decade or two, more and more doctors have begun to use the diagnostic ultrasound instrument FibroScan to detect liver fibrosis.

FibroScan, a noninvasive disease detection tool based on transient elastography, uses ultrasound to detect the extent of liver stiffness. The accuracy of this method for detecting cirrhosis can reach 90%, but FibroScan is more suitable for distinguishing between severe fibrosis and cirrhosis, and it is difficult to diagnose liver fibrosis positively.

 

For some patients with less severe fibrosis, the diagnostic results of transient elastography are not very reliable, because other physiological factors including fat accumulation in the body will also affect the detection of liver sclerosis, even for meals. The result of the diagnosis has an effect. And, more importantly, the reliability of this tool for the detection of non-alcoholic steatohepatitis is not high.

With the increase in patients’ BMI, the reliability of this test method will gradually decline. When the BMI exceeds 40, the test has almost no value.

 

To increase accuracy, UCSD’s Rohit Loomba began to examine the extent of liver fibrosis using detection methods based on more traditional MRI techniques. Although costly, magnetic resonance elastography (MRE) should be regarded as the best way to detect advanced fibrosis and cirrhosis.

 

MRE has become a potential diagnostic tool in clinical trials, especially when used in conjunction with another MRI-based PDFF to accurately detect hepatic steatosis. In fact, when using MRE-PDFF to monitor the patient’s condition, the doctor will see that the steatosis can disappear after the patient undergoes lifestyle changes.

A healthy lifestyle affects us far more than we think. It is difficult to accurately predict the timing of the first drug to treat non-alcoholic steatohepatitis, but for most patients with fatty liver disease, it may be best to lose weight, control diet, and exercise properly before launching effective drugs. The choice of it.

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