Non-alcoholic fatty liver disease (NAFLD) is a chronic metabolic disease that is complex by etiology and pathogenesis, with a significant fat change in hepatocytes.With the global viral hepatitis, it is effectively controlled.NAFLD has become the primary cause of current chronic liver disease.The global prevalence is as high as 25%[1],About 1/5 of patients will develop into non-alcoholic fatty hepatitis (NASH),Nash will become the main cause of liver transplant in the next 10 years.NASH patients are large,There is no listing of the treatment drug approved by any authority,This represents a huge clinical demand that is not yet satisfied.In recent years,Nash drugs based on various new theories and new targets have entered clinical research.However, its complex pathogenesis, disease heterogeneity, diagnosis barriers, and the choice of treatment endpoints have brought huge challenges to NASH new drugs.The key points of this period focuses on the progress and setbacks in the NASH new drug sector in recent years.And try to analyze the difficulties and future directions of NASH new drug research.

  1 History of NASH new drug research and development at home and abroad

  in 1980,The first time[2]of the US Mei Ou Clinic[2]was first named and reported the pathological characteristics of NASH: hepatocyte fatty degeneration and balloon samples, combined with small inflammation and extracellular fibrosis.NASH will further progress through liver fibrosis to cirrhosis,The disability and mortality rate of patients with NASH were significantly higher than that of simple fatty liver.In recent years,Based on various new theories and new target NASH new drugs enter the clinical trial,And show the level of liver fat, improve liver inflammation,Even the effect of liver fibrosis,Many pharmaceutical companies and biomedicine companies have joined NASH new drug research and development.however,What people seem to have underestimated the complexity of the NASH pathogenesis,NASH New Drug R & D has not been expected.Intercept company’s Farnesoid X receptor (FXR) agonist Drug Oraboxoic acid (OCA) as the world’s first drug, the drug applied for NASH,In June 2020, he was rejected by the US Food and Drug Administration (FDA).The reason is based on the expected benefits of alternative tissue pathological test terminals,And the treatment benefits did not exceed the potential risks (liter LDL-C side effects).The latest data released by Intercept,25 mg group after 2 years,Patient biochemical indicators and non-invasive fibrosis and liver hardening indicators continue to improve,The OCA can eventually be appreciated.In addition,In 2020, there are also many NASH new drug research and development frustrated.May 20020,Genfit announced its peroxane proliferative activation receptor (PPAR) agonist GFT-505 (ELAFIBRANOR) of III clinical failure,And stop the drug development in the NASH field.Gilid also announced its GS-4997 (SelonsertiB) of III clinical failure.August 2020,Albireo Pharma announced that its II clinical trials in Elobixibat were carried out in the ileum bile acid transporter Elobixibat failed.despite this,Many pharmacies are still going to success,It is desirable to overcome the final fortress in the field of Nash.Based on NASH complex pathogenesis,The individual is highly heterogeneous,Diagnostic disorders and difficulties in the treatment endpoint, etc.NASH’s new drug research is still a long way.

  2.1 NASH complex clinical phenotype and multi-target treatment NAFLD is the performance of metabolism syndrome in the liver,Clinically, it is often a combination of different severity of liver and hepatic comorbidity.These complex clinical patterns will not only promote disease progression,The effect of drug efficacy is also not neglected.Some new drugs appear to be effective in the clinical trial,Invalid and harmful to some phenotypes,This limits the use of these drugs to some extent.E.g,Acetidase A carboxylase (ACC) is a key enzyme in fat synthesis.Play an important role in adjustment metabolism.The ACC inhibitor can effectively reduce liver fat content in clinical trials.It will raise the level of plasma triglyceride,Bring the safety hazard of cardiovascular disease,And this defect is difficult to overcome[3]by optimizing the pharmaceutical molecule.Currently,A solution for further development of such drugs is to use it in combination with PPAR or FXR agonists.In addition,FXR agonists and downstream fibroblast growth factors 19 (FGF19) have an elevated ldl-C side effects,It is also an adverse reaction associated with the pathway[4].

  NASH as a long-term chronic disease that combines metabolic abnormalities,More attention should be paid to the tolerance and safety of drugs.How to ensure safety while ensuring medicine,Reach the ideal therapeutic effect,It is a major problem and challenge that is currently facing.Sensitivity increased by Nash patients to drugs caused by drugs,Some drugs may induce liver injury,For example, PPARδ agonist SeladelPar can improve NASH-related indicators,It has increased the risk of interfacial hepatitis.therefore,Negative reactions such as liver and kidney injury should be considered in drug research and development.It also established a corresponding monitoring mechanism in clinical trials.

  From the perspective of biology,A variety of biological signal paths are interleaved with each other.Mutual causal,The same target is often contradictory in different tissues or cells.It has provided new ideas to prevent liver fat changes, inflammation, hepatocyte damage and fibrosis, and compound preparations for clinical phenotype complex NASH treatment.How to maintain these drug regulation in a just balance,It is the difficulty of Nash drug research and development.NASH patients often have different degrees of metabolism related diseases,Therefore, when clinical trials are included,The effectiveness and safety of new drugs, the effectiveness and safety of clinical positioning and pre-clinical research,Thereby selecting patient populations that are truly suitable for inclusion in clinical trials[5].A method of randomization of layered randomization for different complications,Avoid drugs affecting the original disease.Because Nash is related to diet, living habits, and genetic metabolism,It should also focus on the influence of geographical and racial differences on research.2.2 The ultimate goal of clinical ending and new drug research and development alternative terminal NASH drug treatment lies in delaying, blocked, reversing NASH progress,Improve clinical ending,The clinical ending often needs to be reflected in the mortality rate of patients.Most Nash patients have progressed slowly.In the development of cirrhosis, there is a hidden,If you choose all done death and liver related death as the main study end,Need to follow up for 10 to 15 years,The standard of mortality as the success of the drug clinical trial is not reality.Choosing the right treatment endpoint is critical to the evaluation of drug efficacy,The ideal alternative is the end of the NASH, which can predict the future development of the future.And in the treatment, it is sensitive.It can reflect the risk of disease progression.The currently used alternative endpoint is the change of liver displays in NASH patients.The evaluation criteria is the NAFLD Activity Score score system proposed by Nash Clinical Research Network (CRN).The US and European drug regulators believe thatIn the stage III clinical trial,Nash relieves and the liver fibrosis has no deterioration, and the liver fibrosis is improved and NASH has no deterioration.Or Nash is alleviated and the liver fibrosis is improved,It is currently accelerating approval and conditional approved alternative endpoints.However, if the new drug research is based on the endpoint of histological efficacy, acceleration approval is obtained.There is still a need for the study of IV clinical ending to verify the efficacy[6].

  The development of non-invasive diagnostic technology and indicators has always been the focus of Nash basic research and drug development.But Europe and the United States and China’s guidelines clearly regulate,Serum and imaging indicators such as MRI proton density fat fraction,Can only be used for exploratory clinical trials,A key clinical trial must use liver disease pathology results,This brings great difficulties to Nash’s new drug research.

  2.3 Nash animal models and innovative clinical pre-model NASH preoperative research usually use animal experiments to detect the effectiveness and safety of drugs.therefore,Choosing a suitable animal model is also one of the key points of the new drug development.NASH’s clinical phenotype is very complicated,Often coexistees with diabetes, obesity, cardiovascular diseases,Currently,Few models can integrate the characteristics of multi-disease coexistence.Simultaneously,The individual differences between the experimental animals are large.It is difficult to find the perfect model of simulating human Nash pathological features, pathogenesis and complications.The FDA guide emphasizes the correct NASH animal model to reflect the specific mechanism of action of the drug.Such animal models are more instructive for subsequent clinical trials.Other innovative clinical models are also research hotspots in the NASH field.With the development of 3D cell culture technology,The 3D cell model will gradually replace the traditional experimental animals to become a new hotspot for the preclinical experimental model.Compared to animal models,The engineering hepatocyte model has controllable parameters,The result is intuitive, efficient, etc.Has a large development potential[7].

  3 new mechanism, new target, new drug

  Nash is the hot field of new drug research and development.New drugs invested in in recent years have an endless.PPAR receptors are a nuclear receptor that regulates metabolitability, cell differentiation and immunflammation.It is also a hot NASH treatment target[8]in recent years.A PPARα / γ double agonist Saroglitazar has taken the lead in approved listing in India.This is also the first drug in the world who approves Nash for the treatment of non-hepatic sclerosis.But the drug has not been widely accepted internationally[9].Oltipraz as a liver X receptor α (LXRα) inhibitor,By suppressing the activity of LXRα to play the effect of dosing fatness,It has been approved by the FDA to the treatment of NASH and liver fibrosis III clinical trials.In a Phase II clinical trial[10],Liver fat content ≥ 20% patients with Nash patients using O’Popra after 24 weeks,The liver fat content decreased sharply.Insulin resistance and the liver enzyme did not change significantly.Thyroid hormone β receptors are currently more optimistic about treatment targets.Thyroid hormone receptor β agonists improve Nash by promoting liver fat metabolism and reducing lipoxity.Among them, MGL-3196 and VK2809 have entered the post-clinical stage.And showed a more significant effect of reducing liver fat content[11].There is still a need for strong evidence to clarify the pathogenesis of Nash combined with thyroid dysfunction.Thyroid hormone replacement therapy and drug combination that affects other mechanisms of Nash may achieve better therapeutic effects.FGF19 and FGF21 are combined with FGFR / Klotho receptors,Polypeptide hormones with metabolic ability.An assessment of the FGF19 analogue (NGM282) test for histological changes in NASH patients[12]showed thatNGM282 can improve NASH histological characteristics, NAS scores, fibrotic scores and biochemical indicators.Recent research[13]shows thatFGF21 can also significantly improve lipid metabolism disorders,Including LDL-C, HDL-C,There is a great potential for the treatment of obesity, atherosclerosis, diabetic blood vessel complications, fatty liver and other metabolic diseases.The FGF21 can enter the hub across the blood brain barrier.Systemic regulation of glycolid metabolism,Promote energy consumption,The induced mass is lowered.Pegbelfermin (BMS-986036) is an FGF21 analog,Half-life is longer,Can be administered once a week,And have significant ability to reduce the patient’s liver fat fraction[14].The FGFR1 agonist of the analog FGF21 function is also a recent research and development hotspot.It is noteworthy that,The FGF21 level in Nash patients is elevated.The different effects of FGF21 in physiological state and pharmacological action remain to be further studied.If you use FGF21 long-term use, it is necessary to decline its sensitivity, and it is necessary to continuously increase the drug dose.It may bring a series of security issues.Steaidoyluxil concentrated enzyme 1 (SCD-1) is a key enzyme that functions in the process of liver fat production.The saturated fatty acid can be converted to a monoquest fatty acid.In recent years,SCD-1 has become a main study target of NAFLD diet metabolic model[15].Inhibition of SCD-1 can reduce the synthesis of fatty acids,Increase the oxidation of fatty acids,Reduce the storage of triglycerides and fatty acids in the liver.A double blind, multi-center, placebo control test[15]shows thatUse 300 mg of peanutaltinylpoxy acid per day to treat NAFLD patients,The patient’s liver fat can be significantly reduced.Currently,The periodic clinical studies of the periodic tetrakenylidel bile acids are in progress,This test will further verify the effect of peanut tetrakenylbenamide on the degree of liver inflammation and fibrosis in patients with NASH.

  4 new use,Meet the current clinical needs

  Based on the current status of NASH new drug research,Old drugs are also a shortcut for Nash drug research and development.About 3/4 of obesity and 2 diabetes patients have NAFLD,NAFLD and type 2 diabetes have insulin resistance to this common pathogenesis.Some hypoglycemic drugs that have been launched are controlling blood sugar while controlling blood sugar.It is also possible to benefit from NAFLD patients.The treatment target of these drugs is mainly focused on improving insulin resistance and liver fat metabolism.

  Guglose-like peptide 1 (GLP-1) analog is currently used in diabetes treatment,Can effectively control blood sugar, improve metabolism,There is also a significant role in improving liver inflammation, fat degeneration and fibrosis.And reduce the patient ALT, AST level.A liraglutide – placebo control test[16]showed thatLila rides have a role in the treatment of NASH and improve liver fibrosis.Compared with the placebo group,The liver-fat degeneration and hepatocyte balloon samples of lipulutum hybrid group have improved.In a 72-week III merger, F1 ~ 3 periodic patients with NASH patients in Nash patients[17],It was found that 1 time per day was injected.4 mg Somaglutide can achieve up to 59% of Nash relief rate and deteriorated without fibrosis.Sodium-glucose coat the transporter of transporter 2 (SGLT-2) inhibitor and GLP-1 agonist,It is currently optimistic to reposition a listing drug for NASH treatment.SGLT-2 inhibitors mainly absorb the renovation of glucose by inhibiting renal tubules.Increase urinary glucose excretion,Thereby reducing blood sugar.Existing research[18]shows thatDapagliflozin improves liver fatty degeneration of type 2 diabetes mellitus with NAFLD.It also alleviates the degree of fibrosis in severe hepatic fibrosis.A multi-center, random, placebo-controlled clinical trial[19]is working,Used to assess the effectiveness and safety of Damuji net treatment NASH.The test mainly assess Nash patients were 12 months after receiving the net 10 mg / d after receiving Dague.Whether the hepatic histological score is improved,The results will be announced in November 2021.A study for patients with type 2 diabetes and NAFLD showed thatUse the CANagliflozin to significantly decrease the FIB-4 index and ferritin levels (hepatolel should be labeled),It is suggested that it may have improved hepatic fibrosis[20][21]shows that24 cases were treated with GLP-1 analog or diptopeptidin 4 inhibitors,ALT level still continues to rise NALFD patients,After adding IPRAGLIFLOZIN,About half of the patient ALT level and fibrified Index-4 (FIB-4) score significantly decreased.This study suggests that the SGLT-2 inhibitor has potentially synergistic effect on the treatment of diabetes mellitus with NAFLD patients.

  The mechanism of action of these hypoglycemic agents is improving insulin resistance.Therefore, for 2 diabetes, patients with Nafld / Nash,In the case of excluding the contraindication,It can be considered priority.However, the adaption of these drugs does not include NAFLD / NASH.The applications in patients with non-diabetes NAFLD / NASH should still be cautious.Relevant research needs to be further carried out in Nash patients with non-diabetes.To accumulate more clinical evidence.

  Current NASH New Drug R & D remain mainly concentrated in small molecules, polypeptides and mono-antibodies.With the development of medical technology,Relevant drugs such as RNA drugs, gene therapies and intestinal flora are rising.Especially RNA drugs,It is the hotspot developing since 2019.Non-encoded RNA (Mir103 / 107) targeted to regulate insulin sensitivity (Mir103 / 107),Currently entered clinical research[22].Hepatic hardening stem cell therapy is also one of the popular areas worthy of attention.NASH complex pathogenesis means that it can break up one by one in different targets during treatment.When treating NASH in the future,Individualized treatment programs can be formulated according to the patient’s condition.Nash is a multi-factor disease.Recommend different pathogenesis,A variety of drug combined with a variety of drugs is used in accordance with different action targets. NASH is an important research direction.Nash’s combined treatment has a variety of options,Including regulating metabolic drugs, anti-inflammatory drugs, anti-fibrotic drugs and hypoglycemic agents.At present, the combination of various drugs has also been put into Phase II clinical trials.It may have breakthroughs compared to single medication.

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  Corporate

  He Yi Ning, Shi Junping. Non-alcoholic fatty hepatitis new drug research and development: an unmet clinical demand[J]. Clinical hepatobiliary magazine, 2021, 37 (6): 1241-1244.

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