dur dur-928, an endogenous regulatory molecule, exhibits ...€¦ · 10 mg/kg 50 mg/kg * score...

Hepatic Gene ExpressionPhase I

Phase II

*p<0.05, **p<0.01

AASLD’s Emerging Trends in NAFLD, Washington DC, March 17-18, 2017

DUR-928, an endogenous regulatory molecule, exhibits anti-inflammatory and antifibrotic activity in a mouse model of NASH Mee J. Kim, WeiQi Lin, DURECT Corporation, Cupertino, CA, USA

INTRODUCTION RESULTSNon-alcoholic steatohepatitis (NASH) is marked by the presence offatty liver, inflammation and fibrosis

DUR-928 is an endogenous regulatory molecule that has beenpreviously shown to reduce hepatic lipid accumulation andinflammation in various animal models of non-alcoholic fatty liverdisease (NAFLD)

Phase I – Weeks 5-9 Four weeks of daily oral DUR-928 treatment during the earlystages of NAFLD/NASH exhibited dose-dependent effects:

Significant decrease in NAS

Trend of decrease of liver fibrosis was observed

Significant reduced hepatic expression of Tnfα and trend ofdecrease of Mcp-1

Phase II – Weeks 9-13 Four weeks of daily oral DUR-928 treatment when liver fibrosiswas established resulted in:

Significant decrease in liver fibrosis

Significant decrease in hepatocyte ballooning

Trend of reduced hepatic expression of fibrotic genes,Collagen 1a1 and 3a1

Hepatic nodule formation, which progresses to hepatocellularcarcinoma in this model, was also reduced in total number, sizeand incidence in DUR-928-treated mice

ConclusionsDUR-928 has the capability to improve liver morphology by itsanti-inflammatory and antifibrotic activity in STAMTM mice. Thesedata support the clinical development of DUR-928 for thetreatment of NASH and other inflammatory or fibrotic liverdiseases

The aim of this study was to investigate the efficacy of DUR-928 toameliorate the progression of NASH and liver fibrosis in theSTAMTM mouse model

STAMTM mouse model of NASH1

NASH was induced by a single subcutaneous injection of 200 ugstreptozotocin solution 2 days after birth in male C57BL/6J mice, followedby high fat diet (57 kcal % fat) feeding at 4 weeks of age until end of thestudy

Dosing regimen and schedule Phase I: Weeks 5–9, daily oral doses of 10 or 50 mg/kg DUR-928 orVehicle (n=8-9/treatment group) Phase II: Weeks 9–13, daily oral doses of 50 mg/kg DUR-928 or Vehicle(n=6-8/treatment group) Studies were terminated upon completion of dosing Baseline measurements were collected from untreated STAMTM mice at Week 9

Phenotypic analysis Hematoxylin & eosin (H&E) staining on liver sections andhistopathological analysis by a certified veterinary pathologist wereperformed to generate NAFLD activity scores (NAS) Percent (%) liver fibrosis as measured by presence of Sirius Red stainingand digital quantification Hepatic gene expression analyses by real-time reverse transcriptionquantitative polyermase chain reaction and normalized to Vehicle Statistical analysis: One-way ANOVA with Dunnett’s MultipleComparison

The STAMTM mouse model used in this study was developed and characterizedby SMC Laboratories (Tokyo, Japan)

We acknowledge Drs. Hongwei Wu, Andy Miksztal and Neil Verity for theirscientific contributions to this study

1. Fujii M, Shibazaki Y, Wakamatsu K, Honda Y, Kawauchi Y, et al. (2013) A murinemodel for non-alcoholic steatohepatitis showing evidence of association betweendiabetes and hepatocellular carcinoma. Med Mol Morphol 46: 141–152

SUMMARY & CONCLUSIONS

OBJECTIVE

MATERIALS & METHODS

ACKNOWLEDGEMENTS

DISCLOSURES Mee J. Kim and WeiQi Lin are employees of DURECT Corporation and may hold company stock/options

This presentation includes discussion of an investigational drug not approved for use in humans

REFERENCE

Phase II: DUR-928or Vehicle controlorally once daily

16151413121110987Week 654321

Birth

Fatty liver

NASH Fibrosis Noduledevelopment

Day 2 HCC

Manifestations of NASH pathology

Low-dose STZ

Phase I: DUR-928or Vehicle controlorally once daily

Begin HFD

Effect of DUR-928 on NAFLD Activity Score

Phase I Phase II

Vehi

cle

10 m

g/kg

50 m

g/kg

0

2

4

6

8**

NAF

LD A

ctiv

ity S

core

Vehi

cle

50 m

g/kg

Wee

k 9

Bas

elin

e

0

2

4

6

8

NAF

LD A

ctiv

ity S

core

Steatosis

Lobular In

flammati

on

Hepato

cyte

Ballooning

0.0

0.5

1.0

1.5

2.0

2.5 Vehicle50 mg/kgWeek 9Baseline

*

Scor

e (0

-3)

Steatosis

Lobular In

flammati

on

Hepato

cyte

Ballooning

0.0

0.5

1.0

1.5

2.0

2.5 Vehicle10 mg/kg50 mg/kg

*

Scor

e (0

-3)

Effect of DUR-928 on Liver Fibrosis

Phase I Phase II

Vehicl

e

50 m

g/kg

Week 9

Bas

eline

0.0

0.5

1.0

1.5

2.0

2.5

*

Siriu

s R

ed-p

ositi

ve A

rea

(%)

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5

2.0

2.5 NS

Siriu

s R

ed-p

ositi

ve A

rea

(%)

Sirius Red Staining for Collagen (fibrosis)

Phase I Phase II

Vehicle

10 mg/kg

50 mg/kg

Vehicle

x200

50 mg/kg

x200

x200

Week 9 Baseline

H&E Staining

Phase I Phase II

Vehicle

10 mg/kg

50 mg/kg

Vehicle

50 mg/kg

Week 9 Baseline

Hepatic Nodule FormationBy Week 12, nodule formation starts to occur in STAMTM

mice. Four weeks of 50 mg/kg DUR-928 treatment thatwas concluded at the end of Week 13 (Phase II) wasassociated with reduced size and incidence of nodules

Vehicle DUR-928

Total Number of Nodules

Vehicl

e

DUR-928

0

2

4

6

# N

odul

es O

bser

ved

Total Area of Nodules

Vehicl

e

DUR-928

0

100

200

300

400

500

600

700

Area

(mm

2 )

Incidence of Nodules

Vehicl

e

DUR-928

0

15

30

45

60

Perc

ent (

%)

Tnf

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5*

**

Rel

ativ

e Ex

pres

sion

(nor

mal

ized

to V

ehic

le)

Mcp-1

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5

2.0

Rel

ativ

e Ex

pres

sion

(nor

mal

ized

to V

ehic

le)

Collagen Type 1a1

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5

2.0

Rel

ativ

e Ex

pres

sion

(nor

mal

ized

to V

ehic

le)

Collagen Type 3a1

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5

2.0

Rel

ativ

e Ex

pres

sion

(nor

mal

ized

to V

ehic

le)

Tnf

Vehicl

e

DUR-928

Baseli

ne0.0

0.5

1.0

1.5

Rel

ativ

e Ex

pres

sion

(nor

mal

ized

to V

ehic

le)

Tgf

Vehicl

e

DUR-928

Baseli

ne0.0

0.5

1.0

1.5

Rel

ativ

e Ex

pres

sion

(nor

mal

ized

to V

ehic

le)

Collagen Type 1a1

Vehicl

e

DUR-928

Baseli

ne0.0

0.5

1.0

1.5

Rel

ativ

e Ex

pres

sion

(nor

mal

ized

to V

ehic

le)

Collagen Type 3a1

Vehicl

e

DUR-928

Baseli

ne0.0

0.5

1.0

1.5

Rel

ativ

e Ex

pres

sion

(nor

mal

ized

to V

ehic

le)


Phase II

*p<0.05, **p<0.01


DUR-928, an endogenous regulatory molecule, exhibits anti-inflammatory and antifibroticactivity in a mouse model of NASH MeeJ. Kim, WeiQi Lin, DURECT Corporation, Cupertino, CA, USA

INTRODUCTIONRESULTSNon-alcoholicsteatohepatitis(NASH)ismarkedbythepresenceoffattyliver,inflammationandfibrosis

DUR-928isanendogenousregulatorymoleculethathasbeenpreviouslyshowntoreducehepaticlipidaccumulationandinflammationinvariousanimalmodelsofnon-alcoholicfattyliverdisease(NAFLD)

PhaseI–Weeks5-9FourweeksofdailyoralDUR-928treatmentduringtheearlystagesofNAFLD/NASHexhibiteddose-dependenteffects:

SignificantdecreaseinNAS

Trendofdecreaseofliverfibrosiswasobserved

SignificantreducedhepaticexpressionofTnfαandtrendofdecreaseofMcp-1

PhaseII–Weeks9-13FourweeksofdailyoralDUR-928treatmentwhenliverfibrosiswasestablishedresultedin:

Significantdecreaseinliverfibrosis

Significantdecreaseinhepatocyteballooning

Trendofreducedhepaticexpressionoffibroticgenes,Collagen1a1and3a1

Hepaticnoduleformation,whichprogressestohepatocellularcarcinomainthismodel,wasalsoreducedintotalnumber,sizeandincidenceinDUR-928-treatedmice

ConclusionsDUR-928hasthecapabilitytoimprovelivermorphologybyitsanti-inflammatoryandantifibroticactivityinSTAMTMmice.ThesedatasupporttheclinicaldevelopmentofDUR-928forthetreatmentofNASHandotherinflammatoryorfibroticliverdiseases

TheaimofthisstudywastoinvestigatetheefficacyofDUR-928toamelioratetheprogressionofNASHandliverfibrosisintheSTAMTMmousemodel

STAMTMmousemodelofNASH1

NASHwasinducedbyasinglesubcutaneousinjectionof200ugstreptozotocinsolution2daysafterbirthinmaleC57BL/6Jmice,followedbyhighfatdiet(57kcal%fat)feedingat4weeksofageuntilendofthestudy

DosingregimenandschedulePhaseI:Weeks5–9,dailyoraldosesof10or50mg/kgDUR-928orVehicle(n=8-9/treatmentgroup)PhaseII:Weeks9–13,dailyoraldosesof50mg/kgDUR-928orVehicle(n=6-8/treatmentgroup)Studies were terminated upon completion of dosingBaseline measurements were collected from untreated STAMTMmice at Week 9

PhenotypicanalysisHematoxylin&eosin(H&E)stainingonliversectionsandhistopathologicalanalysisbyacertifiedveterinarypathologistwereperformedtogenerateNAFLDactivityscores(NAS)Percent(%)liverfibrosisasmeasuredbypresenceofSiriusRedstaininganddigitalquantificationHepaticgeneexpressionanalysesbyreal-timereversetranscriptionquantitativepolyermasechainreactionandnormalizedtoVehicleStatisticalanalysis:One-wayANOVAwithDunnett’sMultipleComparison

TheSTAMTMmousemodelusedinthisstudywasdevelopedandcharacterizedbySMCLaboratories(Tokyo,Japan)

WeacknowledgeDrs.HongweiWu,AndyMiksztalandNeilVerityfortheirscientificcontributionstothisstudy

1.FujiiM,ShibazakiY,WakamatsuK,HondaY,KawauchiY,etal.(2013)Amurinemodelfornon-alcoholicsteatohepatitisshowingevidenceofassociationbetweendiabetesandhepatocellularcarcinoma.MedMolMorphol46:141–152


OBJECTIVE

MATERIALS & METHODS

ACKNOWLEDGEMENTS

DISCLOSURESMeeJ. Kim and WeiQi Lin are employees of DURECT Corporation and may hold company stock/options


REFERENCE


16 15 14 13 12 11 10 9 8 7 Week6 5 4 3 2 1

Birth

Fatty liver

NASHFibrosisNoduledevelopment

Day 2HCC


Low-dose STZ


Begin HFD


Phase IPhase II

Vehicle

10 mg/kg

50 mg/kg

0

2

4

6

8**

NAFLD Activity Score

Vehicle

50 mg/kg

Week 9 Baseline

0

2

4

6

8


Steatosis

Lobular In

flammati

on

Hepato

cyte

Ballooning

0.0

0.5

1.0

1.5

2.0

2.5Vehicle50 mg/kgWeek 9Baseline

*

Score (0-3)

Steatosis

Lobular In

flammati

on

Hepato

cyte

Ballooning

0.0

0.5

1.0

1.5

2.0

2.5Vehicle10 mg/kg50 mg/kg

*

Score (0-3)


Phase I Phase II

Vehicl

e

50 m

g/kg

Week 9

Bas

eline

0.0

0.5

1.0

1.5

2.0

2.5

*

Sirius Red-positive Area (%)

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5

2.0

2.5NS



Phase IPhase II

Vehicle

10 mg/kg

50 mg/kg

Vehicle

x200

50 mg/kg

x200

x200

Week 9 Baseline

H&E Staining

Phase IPhase II

Vehicle

10 mg/kg

50 mg/kg

Vehicle

50 mg/kg

Week 9 Baseline

Hepatic Nodule FormationByWeek12,noduleformationstartstooccurinSTAMTM

mice.Fourweeksof50mg/kgDUR-928treatmentthatwasconcludedattheendofWeek13(PhaseII)wasassociatedwithreducedsizeandincidenceofnodules

VehicleDUR-928


Vehicl

e

DUR-928

0

2

4

6

# Nodules Observed


Vehicl

e

DUR-928

0

100

200

300

400

500

600

700

Area (mm

2)


Vehicl

e

DUR-928

0

15

30

45

60

Percent (%)

Tnf

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5*

**

Relative Expression

(normalized to Vehicle)

Mcp-1

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5

2.0

Relative Expression


Collagen Type 1a1

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5

2.0

Relative Expression


Collagen Type 3a1

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5

2.0

Relative Expression


Tnf

Vehicl

e

DUR-928

Baseli

ne0.0

0.5

1.0

1.5

Relative Expression


Tgf

Vehicl

e

DUR-928

Baseli

ne0.0

0.5

1.0

1.5

Relative Expression


Collagen Type 1a1

Vehicl

e

DUR-928

Baseli

ne0.0

0.5

1.0

1.5

Relative Expression


Collagen Type 3a1

Vehicl

e

DUR-928

Baseli

ne0.0

0.5

1.0

1.5

Relative Expression



Phase II

*p<0.05, **p<0.01
























OBJECTIVE

MATERIALS & METHODS

ACKNOWLEDGEMENTS



REFERENCE


16151413121110987Week 654321

Birth

Fatty liver


Day 2 HCC


Low-dose STZ


Begin HFD


Phase I Phase II

Vehicle

10 mg/kg

50 mg/kg

0

2

4

6

8**


Vehicle

50 mg/kg

Week 9 Baseline

0

2

4

6

8


Steatosis

Lobular Inflammation

Hepatocyte Ballooning0.0

0.5

1.0

1.5

2.0

2.5 Vehicle50 mg/kgWeek 9Baseline *

Score (0-3)

Steatosis

Lobular Inflammation

Hepatocyte Ballooning0.0

0.5

1.0

1.5

2.0


*

Score (0-3)


Phase I Phase II

Vehicle

50 mg/kg

Week 9 Baseline 0.0

0.5

1.0

1.5

2.0

2.5

*


Vehicle

10 mg/kg

50 mg/kg0.0

0.5

1.0

1.5

2.0

2.5 NS



Phase I Phase II

Vehicle

10 mg/kg

50 mg/kg

Vehicle

x200

50 mg/kg

x200

x200

Week 9 Baseline

H&E Staining

Phase I Phase II

Vehicle

10 mg/kg

50 mg/kg

Vehicle

50 mg/kg

Week 9 Baseline



Vehicle DUR-928


Vehicle

DUR-9280

2

4

6

# Nodules Observed


Vehicle

DUR-9280

100

200

300

400

500

600

700

Area (mm

2 )


Vehicle

DUR-9280

15

30

45

60

Percent (%)

Tnf

Vehicle

10 mg/kg

50 mg/kg0.0

0.5

1.0

1.5*

**

Relative Expression


Mcp-1

Vehicle

10 mg/kg

50 mg/kg0.0

0.5

1.0

1.5

2.0

Relative Expression


Collagen Type 1a1

Vehicle

10 mg/kg

50 mg/kg0.0

0.5

1.0

1.5

2.0

Relative Expression


Collagen Type 3a1

Vehicle

10 mg/kg

50 mg/kg0.0

0.5

1.0

1.5

2.0

Relative Expression


Tnf

Vehicle

DUR-928

Baseline0.0

0.5

1.0

1.5

Relative Expression


Tgf

Vehicle

DUR-928

Baseline0.0

0.5

1.0

1.5

Relative Expression


Collagen Type 1a1

Vehicle

DUR-928

Baseline0.0

0.5

1.0

1.5

Relative Expression


Collagen Type 3a1

Vehicle

DUR-928

Baseline0.0

0.5

1.0

1.5

Relative Expression



Phase II

*p<0.05, **p<0.01
























OBJECTIVE

MATERIALS & METHODS

ACKNOWLEDGEMENTS



REFERENCE


16 15 14 13 12 11 10 9 8 7 Week6 5 4 3 2 1

Birth

Fatty liver


Day 2HCC


Low-dose STZ


Begin HFD


Phase IPhase II

Vehicle

10 mg/kg

50 mg/kg

0

2

4

6

8**


Vehicle

50 mg/kg

Week 9 Baseline

0

2

4

6

8


Steatosis

Lobular In

flammati

on

Hepato

cyte

Ballooning

0.0

0.5

1.0

1.5

2.0


*

Score (0-3)

Steatosis

Lobular In

flammati

on

Hepato

cyte

Ballooning

0.0

0.5

1.0

1.5

2.0


*

Score (0-3)


Phase I Phase II

Vehicl

e

50 m

g/kg

Week 9

Bas

eline

0.0

0.5

1.0

1.5

2.0

2.5

*


Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5

2.0

2.5NS



Phase IPhase II

Vehicle

10 mg/kg

50 mg/kg

Vehicle

x200

50 mg/kg

x200

x200

Week 9 Baseline

H&E Staining

Phase IPhase II

Vehicle

10 mg/kg

50 mg/kg

Vehicle

50 mg/kg

Week 9 Baseline



VehicleDUR-928


Vehicl

e

DUR-928

0

2

4

6

# Nodules Observed


Vehicl

e

DUR-928

0

100

200

300

400

500

600

700

Area (mm

2)


Vehicl

e

DUR-928

0

15

30

45

60

Percent (%)

Tnf

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5*

**

Relative Expression


Mcp-1

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5

2.0

Relative Expression


Collagen Type 1a1

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5

2.0

Relative Expression


Collagen Type 3a1

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5

2.0

Relative Expression


Tnf

Vehicl

e

DUR-928

Baseli

ne0.0

0.5

1.0

1.5

Relative Expression


Tgf

Vehicl

e

DUR-928

Baseli

ne0.0

0.5

1.0

1.5

Relative Expression


Collagen Type 1a1

Vehicl

e

DUR-928

Baseli

ne0.0

0.5

1.0

1.5

Relative Expression


Collagen Type 3a1

Vehicl

e

DUR-928

Baseli

ne0.0

0.5

1.0

1.5

Relative Expression



Phase II

*p<0.05, **p<0.01
























OBJECTIVE

MATERIALS & METHODS

ACKNOWLEDGEMENTS



REFERENCE


16 15 14 13 12 11 10 9 8 7 Week6 5 4 3 2 1

Birth

Fatty liver


Day 2HCC


Low-dose STZ


Begin HFD


Phase IPhase II

Vehicle

10 mg/kg

50 mg/kg

0

2

4

6

8**


Vehicle

50 mg/kg

Week 9 Baseline

0

2

4

6

8


Steatosis

Lobular In

flammati

on

Hepato

cyte

Ballooning

0.0

0.5

1.0

1.5

2.0


*

Score (0-3)

Steatosis

Lobular In

flammati

on

Hepato

cyte

Ballooning

0.0

0.5

1.0

1.5

2.0


*

Score (0-3)


Phase I Phase II

Vehicl

e

50 m

g/kg

Week 9

Bas

eline

0.0

0.5

1.0

1.5

2.0

2.5

*


Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5

2.0

2.5NS



Phase IPhase II

Vehicle

10 mg/kg

50 mg/kg

Vehicle

x200

50 mg/kg

x200

x200

Week 9 Baseline

H&E Staining

Phase IPhase II

Vehicle

10 mg/kg

50 mg/kg

Vehicle

50 mg/kg

Week 9 Baseline



VehicleDUR-928


Vehicl

e

DUR-928

0

2

4

6

# Nodules Observed


Vehicl

e

DUR-928

0

100

200

300

400

500

600

700

Area (mm

2)


Vehicl

e

DUR-928

0

15

30

45

60

Percent (%)

Tnf

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5*

**

Relative Expression


Mcp-1

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5

2.0

Relative Expression


Collagen Type 1a1

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5

2.0

Relative Expression


Collagen Type 3a1

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5

2.0

Relative Expression


Tnf

Vehicl

e

DUR-928

Baseli

ne0.0

0.5

1.0

1.5

Relative Expression


Tgf

Vehicl

e

DUR-928

Baseli

ne0.0

0.5

1.0

1.5

Relative Expression


Collagen Type 1a1

Vehicl

e

DUR-928

Baseli

ne0.0

0.5

1.0

1.5

Relative Expression


Collagen Type 3a1

Vehicl

e

DUR-928

Baseli

ne0.0

0.5

1.0

1.5

Relative Expression

(normalized to Vehicle)Hepatic Gene Expression

Phase I

Phase II

*p<0.05, **p<0.01
























OBJECTIVE

MATERIALS & METHODS

ACKNOWLEDGEMENTS



REFERENCE


16151413121110987Week 654321

Birth

Fatty liver


Day 2 HCC


Low-dose STZ


Begin HFD


Phase I Phase II

Vehi

cle

10 m

g/kg

50 m

g/kg

0

2

4

6

8**

NAF

LD A

ctiv

ity S

core

Vehi

cle

50 m

g/kg

Wee

k 9

Bas

elin

e

0

2

4

6

8

NAF

LD A

ctiv

ity S

core

Steatosis

Lobular In

flammati

on

Hepato

cyte

Ballooning

0.0

0.5

1.0

1.5

2.0

2.5 Vehicle50 mg/kgWeek 9Baseline

*

Scor

e (0

-3)

Steatosis

Lobular In

flammati

on

Hepato

cyte

Ballooning

0.0

0.5

1.0

1.5

2.0


*

Scor

e (0

-3)


Phase I Phase II

Vehicl

e

50 m

g/kg

Week 9

Bas

eline

0.0

0.5

1.0

1.5

2.0

2.5

*

Siriu

s R

ed-p

ositi

ve A

rea

(%)

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5

2.0

2.5 NS

Siriu

s R

ed-p

ositi

ve A

rea

(%)


Phase I Phase II

Vehicle

10 mg/kg

50 mg/kg

Vehicle

x200

50 mg/kg

x200

x200

Week 9 Baseline

H&E Staining

Phase I Phase II

Vehicle

10 mg/kg

50 mg/kg

Vehicle

50 mg/kg

Week 9 Baseline



Vehicle DUR-928


Vehicl

e

DUR-928

0

2

4

6

# N

odul

es O

bser

ved


Vehicl

e

DUR-928

0

100

200

300

400

500

600

700

Area

(mm

2 )


Vehicl

e

DUR-928

0

15

30

45

60

Perc

ent (

%)

Tnf

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5*

**

Rel

ativ

e Ex

pres

sion

(nor

mal

ized

to V

ehic

le)

Mcp-1

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5

2.0

Rel

ativ

e Ex

pres

sion

(nor

mal

ized

to V

ehic

le)

Collagen Type 1a1

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5

2.0

Rel

ativ

e Ex

pres

sion

(nor

mal

ized

to V

ehic

le)

Collagen Type 3a1

Vehicl

e

10 m

g/kg

50 m

g/kg0.0

0.5

1.0

1.5

2.0

Rel

ativ

e Ex

pres

sion

(nor

mal

ized

to V

ehic

le)

Tnf

Vehicl

e

DUR-928

Baseli

ne0.0

0.5

1.0

1.5

Rel

ativ

e Ex

pres

sion

(nor

mal

ized

to V

ehic

le)

Tgf

Vehicl

e

DUR-928

Baseli

ne0.0

0.5

1.0

1.5

Rel

ativ

e Ex

pres

sion

(nor

mal

ized

to V

ehic

le)

Collagen Type 1a1

Vehicl

e

DUR-928

Baseli

ne0.0

0.5

1.0

1.5

Rel

ativ

e Ex

pres

sion

(nor

mal

ized

to V

ehic

le)

Collagen Type 3a1

Vehicl

e

DUR-928

Baseli

ne0.0

0.5

1.0

1.5

Rel

ativ

e Ex

pres

sion

(nor

mal

ized

to V

ehic

le)

dur dur-928, an endogenous regulatory molecule, exhibits ...€¦ · 10 mg/kg 50 mg/kg * score...

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