The Future Outlook to DILI Research From The Perspective of China

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1 The Future Outlook to DILI Research From The Perspective of China Yimin Mao Renji Hospital,Shanghai Jiaotong University School of Medicine

2 DILI in General Population Less than 20/100,000 The incidence increased in the elder people

3 Drug Can Cause All Kinds of Liver Injury We Have Ever Known DILI is one of the most common reason for unknown cause liver injury/liver disease

4 DILI in Different Countries

5 DILI-R Research Study Population: Hospitalized Patient during hospitals nationwide which cover all 31 provinces in mainland China involved 29,687 DILI cases in total enrolled

6 DILI Incidence Among Hospitalized Patients DILI incidence ( ) by geographic locations of China South SW North NW East Central NE DILI 3-year incidence:1.75 unpublished data

7 Increasing DILI Incidence Trend of DILI Incidence ( ) of China unpublished data

8 DILI Incidence Higher in Non-tertiary Hospitals DILI incidence ( ) in tertiary and non-tertiary hospitals of China Tertiary Non-tertiary P < unpublished data

9 Top-10 Classes of Suspicious Drug in General Hospitals TCM Anti-biotics (include anti-tb drug) herbs Chinese patent drug anti-tumor drug are major suspicious drugs unpublished data

10 Top-20 Suspicious Drugs unpublished data

11 Compare with WM, DILI Latentperiod is longer for those who Take TCM TCM Westen Medicine P < unpublished data

12 40% DILI Patients Take at Least 2 Suspicious Drugs Unsure 1 suspicious drug 2 suspicious drugs 3 or more unpublished data

13 Live Injury Types Hepatocellular injury Cholestatic injury Mixed injury Unsure unpublished data

14 At Baseline, ALT Above 10xULN Among 30% Patients Missing, unknown unpublished data

15 30% patients meet criteria of Hy's Law Percentage of Hepatocyte injury type of DILI meeting Hy's Law criteria Yes No About 3% patients progressed to liver failure or death unpublished data

16 Liver Histology Presents Many Kinds of Liver Injury Liver histology charateristics Cases and percentage Acute hepatitis 438(28.59%) Chronic hepatitis 239(15.60%) Acute cholestasis 15(0.98%) Chronic cholestasis 10(0.65%) Cholestatic hepatitis 72(4.70%) Granulomatous change 3(0.20%) Macrosteatosis 9(0.59%) Microsteatosis 10(0.65%) NASH 17(1.11%) Coagulation/fusion necrosis 3(0.20%) Non focal necrosis 1(0.07%) Hepatocyte change 44(2.87%) Mixed or miscellaneous liver injury 3(0.20%) Slight nonspecific change 57(3.72%) Absolutely normal 4(0.26%) Massive necrosis 2(0.13%) Other 392(25.59%) Unknown 219(14.30%) Among 1532 cases,chronic DILI are16.25% unpublished data

17 Interventional Research

18 Magnesium Iso-glycyrrhizinate(MgIG) in The Treatment of Subjects with DILI Low dose 100mg/d(N=72) 216 DILI patients High dose 200mg/d(N=72) Tiopronin 100mg/d(N=72) Primary endpoint: ALT normalization at weeks 4 0 w 4 w Randomized, double-blind, multi-doses, active drug controlled, multi-center study

19 Study Subjects

20 Rates of ALT Normalization At Weeks 1-4 Group A: low dose study drug; Group C: high dose study drug Group B: active control P < at Week 2 3 and 4 unpublished data

21 Rates of ALT Normalization At Weeks 1-4 for Subjects Who Stopped Suspicious Drug P < at Week 3 and 4 unpublished data

22 Rates of ALT Normalization At Weeks 1-4 for Subjects Who Cont' with Suspicious Drug P < at Week 2 3 and 4 unpublished data

23 MgIG Approved of the Indication To Treat Acute DILI The only drug approved of DILI indication globally

24 Translational Research Between Basic and Clinical

25 Anti-inflammation Mechanism of MgIG Pro-inflammatory cytokines (TNFα, IL-1β, ) Viruses, Bacteria TLRs, TNFR, IL- 1R Dose dependently inhibit 3 major Inflammatory pathway: PLA2/AA signal channel IG PLA 2 AA IG p38, JNK, ERK MAPK AP-1 IKK IκBα/NF- κ B (p65/p50) IG NF-κB signal channel MAPK/AP-1 signal channel COX LOX PGE, PGI, Cytokines (TNF-α, IL-1β, IL-6) Chemokines (IL-8) TBX 2, LTB 4 Enzymes (inos, COX-2, LOX, PLA 2 ) Inflammatory response 25

26 Bicyclol, Class I new drug of China ALT decrease in CCI4-included liver injury

27 Bicyclol Inhibit expression and activity of inflammatory cytokines 抑制炎症因子表达 60 NF-KB 16 TNF-α 40 **P< *P< Blank control group Oligonucleotide group ** Oligonucleotide + bicyclol group IL-1β Blank control group Dimethylnitrosamine induced injury group * Dimethylnitrosamine + bicyclol group TGF-β 1 60 ***P< *P< * 20 *** 4 0 Blank Control group Ethanol induced injury group Ethanol + bicyclol group Blank control group Dimethylnitrosamine induced injury group [1]cLou XY, Xu N, Yao HP, et al. Bicyclol attenuates pro-inflammatory cytokine and chemokine productions in CpG-DNA-stimulated L02 hepatocytes by inhibiting p65-nf-kb and p38-mapk activation. Pharmazie, 2010, 65(3): [2] Hu QW, Liu GT. Effects of bicyclol on dimethylnitrosamine-induced liver fibrosis in mice and its mechanism of action. Life Science, 2006, 79: [3] Zhao J, Chen H, Li Y. Protective effect of bicyclol on acute alcohol-induced liver injury in mice. European Journal of Pharmacology, 2008, 586: Dimethylnitrosamine + bicyclol group

28 RCT Study on Bicyclol to Treat DILI Has Been Initiated

29 Prospective Research Is Ongoing More than 100 hospitals involved Follow up at least 6 month Collect clinical information Set up sample bank Biomarker research

30 A Professional DILI Platform in China: HepaTox

31 Released The First DILI Clinical Guideline in China

32 Diagnosis Confirm normal ALT The Future Outlook To DILI Translational Research Develop new method for causality assessment Pathogenesis Idiosyncratic animal model Host,drug and enviromental Risk factors Host,drug and enviromental Biomarkers Diagnosis Tolerators, adaptors, susceptibles Prognosis Treatment Regional/Global cooperation is needed

33 Thank you for your attention!