Yimin Mao

Renji HospitalShanghai Jiaotong University School of Medicine

The Future Outlook to DILI Research From The Perspective of China

DILI in General Population

Less than 20/100,000

The incidence increased in the elder people

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

DILI in Different Countries

DILI-R Research

Study Population: Hospitalized Patient during

2012-2014 303 hospitals nationwide

which cover all 31 provinces in mainland China involved

29,687 DILI cases in total enrolled

DILI Incidence Among Hospitalized Patients

DILI 3-year incidence:1.75

DILI incidence () by geographic locations of China

South SW North NW East Central NE

unpublished data

Increasing DILI Incidence

Trend of DILI Incidence () of China

2012 2013 2014

unpublished data

DILI Incidence Higher in Non-tertiary Hospitals

P < 0.001

Tertiary Non-tertiary

DILI incidence () in tertiary and non-tertiary hospitals of China

unpublished data

Top-10 Classes of Suspicious Drug in General Hospitals

Anti-biotics (include anti-TB drug) herbsChinese patent druganti-tumor drug are

major suspicious drugsunpublished data

TCM

Top-20 Suspicious Drugs

unpublished data

Compare with WM , DILI Latentperiod is longer for those who Take TCM

P < 0.001

TCM Westen Medicine

unpublished data

40% DILI Patients Take at Least 2 Suspicious Drugs

Unsure

1 suspicious drug

2 suspicious drugs

3 or more

unpublished data

Live Injury Types

Hepatocellular injury

Cholestatic injury

Mixed injury

Unsure

unpublished data

At Baseline, ALT Above 10xULN Among 30% Patients

Missing, unknown

unpublished data

30% patients meet criteria of Hy's Law

About 3% patients progressed to liver failure or death

Percentage of Hepatocyte injury type of DILI meeting Hy's Law criteria

YesNo

unpublished data

Liver Histology Presents Many Kinds of Liver Injury

Liver histology charateristics Cases and percentageAcute 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 casesChronic DILI are16.25%unpublished data

Interventional Research

Magnesium Iso-glycyrrhizinate(MgIG) in The Treatment of Subjects with DILI

Low dose 100mg/d(N=72)

High dose 200mg/d(N=72)

Tiopronin 100mg/d(N=72)

216 DILI patients

0 w 4 w

Randomized, double-blind, multi-doses, active drug controlled , multi-center study

Primary endpoint:

ALT normalization at weeks 4

Study Subjects

Rates of ALT Normalization At Weeks 1-4

unpublished data

Group A: low dose study drug;Group C: high dose study drug Group B: active control

P < 0.001 at Week 23 and 4

Rates of ALT Normalization At Weeks 1-4 for Subjects Who Stopped Suspicious Drug

unpublished data

P < 0.001 at Week 3 and 4

Chart1

0.25710.28950.2727

0.57140.50.6667

0.82860.55260.8182

0.88570.65790.8788

Group A

Group B

Group C

alt

W1W2W3W4

Group A27.12%62.71%81.36%84.75%

Group B25.42%45.76%52.54%61.02%

Group C30.36%69.64%78.57%85.71%

Group AGroup BGroup C

84.75%61.02%85.71%

Group AGroup BGroup C

W127.12%25.42%30.36%

W262.71%45.76%69.64%

W381.38%52.54%78.57%

W484.75%61.02%85.71%

Alt[2,5)

W1W2W3W4

Group A33.33%73.33%84.44%86.67%

Group B27.66%46.81%55.32%59.57%

Group C40.54%75.68%81.08%86.49%

ALT5

W1W2W3W4

Group A7.14%28.57%71.43%78.57%

Group B16.67%41.67%41.67%66.67%

Group C10.53%57.89%73.68%84.21%

[2,5]ULN>5ULN

Group A86.67%78.57%

Group B59.57%66.67%

Group C86.49%84.21%

W1W2W3W4

Group A25.71%57.14%82.86%88.57%

Group B28.95%50.00%55.26%65.79%

Group C27.27%66.67%81.82%87.88%

W1W2W3W4

Group A29.17%70.83%79.17%79.17%

Group B19.05%38.10%47.62%52.38%

Group C34.78%73.91%73.91%82.61%

alt

Group A

Group B

Group C

ast

W1W2W3W4

Group A44.83%72.41%75.86%79.31%

Group B32.00%52.00%52.00%48.00%

Group C60.71%82.14%85.71%89.29%

Group A

Group B

Group C

Group A

Group B

Group C

Group A

Group B

Group C

[2,5]ULN

>5ULN

Group A

Group B

Group C

Group A

Group B

Group C

ast

Group A

Group B

Group C

ALT

BaselineW1W2W3W4

Group A203.53103.6866.1559.553.41

Group B168.95124.6992.6180.277.06

Group C221.08103.9954.9752.6646.37

BaselineW1W2W3W4

Group A160.585444038

Group B14496.56256.955

Group C16574.85454239

ALT

Group A

Group B

Group C

AST

BaselineW1W2W3W4

Group A172.1560.1343.2240.1637.18

Group B162.2670.5356.3746.9246.45

Group C222.349.7743.1737.8235.84

Group A

Group B

Group C

AST

Group A

Group B

Group C

ALTuln

BaselineW1W2W3W4

Group A3.751.911.211.141

Group B3.242.381.861.621.55

Group C4.131.981.051.040.9

BaselineW1W2W3W4

Group A31.610.860.760.75

Group B2.761.651.160.970.92

Group C3.441.450.90.830.79

ALTuln

Group A

Group B

Group C

ASTuln

BaselineW1W2W3W4

Group A4.151.411.020.940.88

Group B4.021.721.331.131.12

Group C5.281.181.030.90.85

Group A

Group B

Group C

ASTuln

Group A

Group B

Group C

Rates of ALT Normalization At Weeks 1-4 for Subjects Who Cont' with Suspicious Drug

unpublished data

P < 0.001 at Week 23 and 4

Chart1

0.29170.19050.3478

0.70830.3810.7391

0.79170.47620.7391

0.79170.52380.8261

Group A

Group B

Group C

alt

W1W2W3W4

Group A27.12%62.71%81.36%84.75%

Group B25.42%45.76%52.54%61.02%

Group C30.36%69.64%78.57%85.71%

Group AGroup BGroup C

84.75%61.02%85.71%

Group AGroup BGroup C

W127.12%25.42%30.36%

W262.71%45.76%69.64%

W381.38%52.54%78.57%

W484.75%61.02%85.71%

Alt[2,5)

W1W2W3W4

Group A33.33%73.33%84.44%86.67%

Group B27.66%46.81%55.32%59.57%

Group C40.54%75.68%81.08%86.49%

ALT5

W1W2W3W4

Group A7.14%28.57%71.43%78.57%

Group B16.67%41.67%41.67%66.67%

Group C10.53%57.89%73.68%84.21%

[2,5]ULN>5ULN

Group A86.67%78.57%

Group B59.57%66.67%

Group C86.49%84.21%

W1W2W3W4

Group A25.71%57.14%82.86%88.57%

Group B28.95%50.00%55.26%65.79%

Group C27.27%66.67%81.82%87.88%

W1W2W3W4

Group A29.17%70.83%79.17%79.17%

Group B19.05%38.10%47.62%52.38%

Group C34.78%73.91%73.91%82.61%

alt

Group A

Group B

Group C

ast

W1W2W3W4

Group A44.83%72.41%75.86%79.31%

Group B32.00%52.00%52.00%48.00%

Group C60.71%82.14%85.71%89.29%

Group A

Group B

Group C

Group A

Group B

Group C

Group A

Group B

Group C

[2,5]ULN

>5ULN

Group A

Group B

Group C

Group A

Group B

Group C

ast

Group A

Group B

Group C

ALT

BaselineW1W2W3W4

Group A203.53103.6866.1559.553.41

Group B168.95124.6992.6180.277.06

Group C221.08103.9954.9752.6646.37

BaselineW1W2W3W4

Group A160.585444038

Group B14496.56256.955

Group C16574.85454239

ALT

Group A

Group B

Group C

AST

BaselineW1W2W3W4

Group A172.1560.1343.2240.1637.18

Group B162.2670.5356.3746.9246.45

Group C222.349.7743.1737.8235.84

Group A

Group B

Group C

AST

Group A

Group B

Group C

ALTuln

BaselineW1W2W3W4

Group A3.751.911.211.141

Group B3.242.381.861.621.55

Group C4.131.981.051.040.9

BaselineW1W2W3W4

Group A31.610.860.760.75

Group B2.761.651.160.970.92

Group C3.441.450.90.830.79

ALTuln

Group A

Group B

Group C

ASTuln

BaselineW1W2W3W4

Group A4.151.411.020.940.88

Group B4.021.721.331.131.12

Group C5.281.181.030.90.85

Group A

Group B

Group C

ASTuln

Group A

Group B

Group C

MgIG Approved of the Indication To Treat Acute DILI

The only drug approved of DILI indication globally

Translational Research Between Basic and Clinical

Pro-inflammatory cytokines (TNF, IL-1, )

Viruses, Bacteria

Inflammatory response

TLRs, TNFR, IL-1R

IG IG

IG

p38, JNK, ERKMAPK IKK

PGE, PGI,

TBX2, LTB4

COX

LOX

PLA2

Cytokines (TNF-, IL-1, IL-6)

Chemokines (IL-8)

Enzymes (iNOS, COX-2, LOX, PLA2)

AA AP-1 IB/NF- B(p65/p50)

Dose dependently inhibit 3 major Inflammatory pathway PLA2/AA signal channel

NF-B signal channel

MAPK/AP-1 signal channel

Anti-inflammation Mechanism of MgIG

25

Bicyclol, Class I new drug of China

ALT decrease in CCI4-included liver injury

Bicyclol Inhibit expression and activity of

inflammatory cytokinesNF-KB

Blank control group

Oligonucleotide group

0Oligonucleotide + bicyclol group

20

40

60

**P

RCT Study on Bicyclol to Treat DILI Has Been Initiated

Prospective Research Is Ongoing

More than 100 hospitals involved Follow up at least 6 month Collect clinical information Set up sample bank Biomarker research

A Professional DILI Platform in ChinaHepaTox

www.hepatox.org

Released The First DILI Clinical Guideline in China

The Future Outlook To DILI Translational Research

Diagnosis Confirm normal ALT 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

Thank you for your attention!www.hepatox.org