Inventory of Nash new drugs under development in China

Nonalcoholic fatty liver disease (NAFLD) is a metabolic stress-induced liver injury closely related to insulin resistance and genetic predisposition It is one of the major liver diseases in the world The disease spectrum includes Nash According to the literature, the prevalence of non-alcoholic fatty liver disease is 25.24%, and the incidence rate of NASH is 3 to 5% Among them, the incidence of cirrhosis in NASH patients within 10-15 years is as high as 15% - 25% At present, there is no effective treatment drug on the market According to Deutsche Bank, once Nash is launched, its global market size will reach US $35-40 billion by 2025, which shows the great clinical demand The development of Nash new drugs has already become a new blue ocean for pharmaceutical companies all over the world to look forward to in the future, and it is no exception in China At present, there are more than 10 domestic enterprises in this field This paper reviews the latest development of Nash new drug development of some domestic enterprises with public information In February 2019, Geli, through its subsidiaries, reached a strategic cooperation and exclusive development agreement in Greater China with 3-V Biosciences on tvb-2640 (code asc40) Tvb-2640 is a fatty acid synthetase (FASN) inhibitor, which is the world's first and soon to enter the second phase of clinical treatment of Nash candidate drugs In May this year, the Nash drug was administered to the first patient with nonalcoholic steatohepatitis in a phase 2 clinical study In this randomized, placebo-controlled phase 2 clinical study, Geli and 3-V Biosciences jointly conducted registration submission, clinical trial site selection and trial monitoring in China In this study, the researchers will evaluate the role of tvb-2640 in 90 patients with NASH in the United States and 25-30 patients with NASH in China The subjects met the requirement of liver fat content ≥ 8% at baseline, accompanied by liver fibrosis F1-F3 The primary end point was the effect of tvb-2640 on liver fat synthesis after 12 weeks of daily administration compared to baseline The researchers will also assess the effects of the drug on plasma triglycerides, liver enzymes, inflammation and fibrosis related biomarkers Recently, the official website of the drug evaluation center showed that the registration application of tvb-2640 for imported drugs had been accepted In addition to tvb-2640, there is also a leading compound for NASH in the research product line of Geli, which is in the preclinical research stage According to golly.com, fatty hepatitis and antiviral platform and nucleic acid interference are the three major scientific researches of the company, which is committed to developing new breakthrough drugs targeting Nash Topaz bio is a global biopharmaceutical company located in Shanghai, which is committed to the research and development of new drugs in the field of liver disease and cancer At present, the company is developing five products in the field of nonalcoholic steatohepatitis, among which tern-101, an agonist of FXR, is conducting phase 1 clinical trial in Europe According to the official website of tuozhen biology, fxris a nuclear receptor expressed in large quantities in liver and small intestine Bile acids are the natural ligands of FXRs The binding of bile acids to FXRs and the activation of FXRs are very important for the regulation of cellular pathways of bile acid synthesis, lipid metabolism, inflammation and fibrosis Research shows that tern-101 is a high-efficiency non bile acids fxragonist, which is currently being developed for the treatment of NASH The second Nash drug of tuozhen biology is tern-201, an inhibitor of semicarbazide sensitive amine oxidase (SSAO) According to the official website of tuozhen biology, SSAO, also known as vascular adhesion protein-1, is an amine oxidase with dual functions, which can promote the recruitment of leukocytes in the liver and lead to increased oxidative stress, inflammation and liver fibrosis Inhibition of SSAO is expected to be an effective drug in the treatment of NAFLD, Nash and other chronic fibrotic liver diseases Tern-201 is a potent SSAO inhibitor, which has the potential to treat Nash by reducing oxidative stress and leukocyte recruitment in the liver In April this year, tuozhen biology released preclinical data of two key projects at the 2019 hepatology conference In a preclinical model of nonalcoholic steatohepatitis, tern-101 reduced inflammation, ballooning of hepatocytes, and fibrosis, while tern-201 reduced activity score and fibrosis of nonalcoholic fatty liver disease These data further enhance the confidence of tuozhen biology The third Nash new drug of tuozhen biology is an ASK1 inhibitor According to the official website of tuozhen biology, apoptosis signal regulated kinase 1 (ASK1) is a member of mitogen activated protein kinase family, which can be activated by many factors, including oxidative stress and endoplasmic reticulum stress, and lead to the activation of downstream p38 and c-jun amino terminal kinase pathway ASK1 pathway is found to be activated in the liver of NASH patients, which can induce a series of stress reactions, thus aggravating liver inflammation, apoptosis and fibrosis At present, topaz is exploring the pharmacological inhibition of ASK1 as a new treatment for patients with NAFLD and NASH The fourth Nash new drug of tuozhen biology is a thyroid hormone receptor β (THR - β) agonist According to the official website of tuozhen biology, thyroid hormone can regulate the metabolism of plasma cholesterol, triglyceride and lipid in various tissues including liver Selective activation of thyroid hormone receptors in the liver is expected to regulate the dyslipidemia associated with NASH The reduction of steatosis in the liver may significantly improve Nash because it eliminates the key drivers of inflammation Topaz is looking for a new treatment to selectively activate thr - β in the liver The fifth Nash new drug of tuozhen biology has not disclosed the target, and it is still in the discovery stage Zhongsheng Pharmaceutical Co., Ltd has been developing Nash new drugs for a long time At the same time, there are three small molecule innovative drugs, zsp1601, zsp0678 and zsym008, which act on different pharmacological mechanisms and course stages In October 2017, Zhongsheng pharmaceutical received the clinical trial approval of zsp1601 According to the announcement of Zhongsheng pharmaceutical, zsp1601 is the first innovative drug approved for clinical use in the treatment of NASH in China, and also an innovative drug with clear mechanism and independent intellectual property rights for the treatment of NASH The results of preclinical study showed that zsp1601 could improve the liver pathological changes of Nash animal model in a dose-dependent manner, including ballooning, steatosis and inflammation of liver tissue It showed significant anti-inflammatory and anti fibrosis effects in multiple liver fibrosis animal models, especially in the mouse Nash model induced by CDAA, its anti fibrosis effect was significantly better than that in the United States which has entered clinical practice The results of the toxicity study of GLP showed that it had a good safety window and good pharmacokinetic properties In view of its significant anti fibrosis effect, the announcement shows that zsp1601 may become an effective treatment option for NASH and organ fibrosis in the future, and the combination of zsp1601 and other drugs with different mechanisms of action may become a new method for NASH treatment At present, zsp1601 is in phase 1 clinical research stage, and the research and development progress is in line with expectations In April this year, Zhongsheng pharmaceutical announced that zsp0678, another Nash new drug, had received the notice of clinical trial and was intended to be used for nonalcoholic steatohepatitis At the same time, the company cooperates with Sichuan University to build a Nash efficacy evaluation platform At present, the company has initially established a efficacy evaluation model, and has started the exploratory research of joint administration to help the innovation and research of Nash products Junshengtai junshengtai's htd1801 is an oral multifunctional small molecule drug independently developed by the company's team, which can be used to treat primary sclerosing cholangitis and NAFLD / NASH In animal experiments, htd1801 can improve the histological characteristics of liver, reduce inflammation, reduce the level of liver cholesterol and triglyceride, and reduce the level of LDL cholesterol in serum and improve insulin sensitivity In October last year, Jun Shengtai announced that htd1801 was allowed to carry out phase 2 clinical trial of non-alcoholic steatohepatitis in the United States, which is the second phase 2 clinical trial conducted by Jun Shengtai in the United States In November of the same year, FDA granted the fast track qualification of the drug, which further promoted the development and approval process of the drug According to Professor Stephen Harrison, the chief researcher of htd1801 clinical phase 2 trial and a famous international hepatologist, and considering the multiple target mechanism of htd1801, multiple preclinical efficacy research data including primate models, and the predictable safety, htd1801 has the potential to become an important choice in the field of Nash treatment, especially for diabetes mellitus NASH patients with metabolic syndrome such as hyperlipidemia Previously, FDA also granted htd1801 orphan drug qualification and fast track qualification for the treatment of primary sclerosing cholangitis (PSC) Currently, the product is undergoing randomized, double-blind, placebo-controlled clinical phase 2 trials for PSC in the United States, and phase 1 trials for primary biliary cholangitis (PBC) Micro core bio nonalcoholic fatty liver is an area of active distribution of micro core bio In the preclinical study, ciglitaz sodium, an original anti type 2 diabetes drug independently developed by ciglitaz sodium, showed significant activity in reducing fatty degeneration, inflammatory infiltration and fibrosis of liver tissue in nonalcoholic fatty liver model In the future, it will further carry out clinical trial research on Nash In addition, microchip biology has also completed the screening and evaluation of cs17919, a small molecular inhibitor of ASK1 kinase, and cs27186, a NR receptor selective agonist, in which compound cs17919 has applied for related patents The clinical objectives of cs17919 and cs27186 are mainly aimed at nonalcoholic fatty liver and related metabolic diseases, and it is expected that cs17919 and cs27186 will be further expanded in the field of metabolic related diseases in combination with ciglitazidine sodium Paige bio Paige bio is a biomedical company focusing on the development of innovative drugs, which is dedicated to the development of metabolic and tumor class 1 innovative drugs for the treatment of type 2 diabetes, non-alcoholic fatty liver, obesity and other diseases Pb-718 is a GLP-1 / GCG double target agonist, which has a clear mechanism of regulating glucose metabolism and fat metabolism In preclinical trials, pb-718 has shown a unique therapeutic advantage, targeting non-alcoholic fatty liver and obesity At present, the product is in the United States and China for ind declaration Previously, pb-718 received special support for major new drug development during the 12th Five Year Plan period Zhengda Tianqing has a new drug with the R & D code of tqa3526 The indications to be developed are primary biliary cholangitis and nonalcoholic steatohepatitis At present, the drug is carrying out a phase 1A clinical trial (Registration No ctr20182250) of tolerance and pharmacokinetics in healthy subjects According to the clinical trial registered on the information publicity platform, the study was first publicized in November 2018, and 70 subjects are planned to be enrolled Gst-hg151 is a global innovative drug for the treatment of NASH Preclinical studies have shown the effect of improving liver function and significant anti fibrosis effect Guangshengtang has global intellectual property rights for the drug, and has applied for two PCT international patents for the project In April this year, guangshengtang received the notice of clinical trial from the State Drug Administration on the global innovative drugs that can reverse gst-hg151 non-alcoholic fatty liver disease and liver fibrosis According to the announcement of guangshengtang, this is a milestone achievement of professional cooperative research and development of guangshengtang for three years, and also another important achievement after the company's transformation to an innovative pharmaceutical enterprise relaying the approval of gst-hg161 new targeted drugs for liver cancer In August 2018, kangzhe pharmaceutical announced that the Group signed an agreement with can fit through its wholly-owned subsidiary