Anti-fibrotic Therapy in

Hepatitis C

Scott Friedman, M.D.Fishberg Professor of Medicine Chief, Division of Liver Diseases Mount Sinai School of Medicine

Hot Topics in Liver DiseaseHouston, Oct 9, 2010

Hepatic Fibrosis is the Liver’s Wound Healing Response to Many Chronic Injuries

FIBROSIS FIBROSIS Inherited Metabolic Disorders

Excess Vitamin A

Cholestatic Disorders

Immune Disorders

Drugs

Hepatitis Hepatitis

VirusesViruses AlcoholAlcoholNASHNASH

Natural History of Chronic Liver Disease

Chronic hepatitiswith fibrosis

10-50 yrs

Cirrhosis Cirrhosis Normal liverNormal liver

HepatocellularHepatocellular

CarcinomaCarcinoma

LiverLiver

TransplantTransplant

Chronic hepatitis - ~300 million worldwideHCC - fastest rising tumor incidence

OverviewOverview

Challenge # 1: We need better markers of fibrosis stage and activity

Challenge # 2: What makes cirrhosis reversible?

Challenge # 3: We need a ‘proof-of-concept’ anti-fibrotic trial!

Challenge #1: We need better markers of

fibrosis stage and activity!

•• Too much sampling variability and Too much sampling variability and

invasiveness assinvasiveness ass’’d with liver biopsyd with liver biopsy

•• We need markers that are We need markers that are sensitivesensitive, , specific specific

and and respond quickly respond quickly to changes in fibrogenic to changes in fibrogenic

activityactivity

Diagnosis of Hepatic Fibrosis -Current Status

•• Lack of robust, standardized endpointsLack of robust, standardized endpoints is currently is currently the the limiting factorlimiting factor in antifibrotic trials in antifibrotic trials -- need is URGENTneed is URGENT

•• We need We need BIOMARKERSBIOMARKERS, not , not SURROGATESSURROGATES..

•• NonNon--invasive tests (e.g., invasive tests (e.g., ELF, FibrotestELF, Fibrotest) are increasingly ) are increasingly specific for early or late stages, but 25specific for early or late stages, but 25--50% indeterminate 50% indeterminate rate in intermediate stages. rate in intermediate stages.

–– Offer an Offer an ‘‘integratedintegrated’’ readout of fibrosis. readout of fibrosis.

–– May not be sufficient for individual managementMay not be sufficient for individual management

–– BUTBUT, they predict outcomes better than biopsy!, they predict outcomes better than biopsy!

Probe

Liver

ROI

Vibrator

Ribs

Transducter

Fibrosis Assessment with Fibrosis Assessment with

FibroscanFibroscan®®

• Measurements are performed on the

• right lobe of the liver in intercostal position

• The patient is lying supine with the right arm placed behind his head

• Examination time is about 5 minutes

• Interobserver reproducibility

CVS < 10 %,

L = 4 cm Ø = 1 cm

Courtesy of M. Ziol

Sandrin et al, Ultrasound in Biol Med,2003Sandrin et al, Ultrasound in Biol Med,2003

Transient Elastography for Assessment of Hepatic Fibrosis

• Correlates with “stiffness”

• R= 0.71

• ROC= 0.88 for sign fibrosis > F2

• ROC= 0.99 for cirrhosis (F4)

0

5

10

15

20

25

30

Colonne 2

F4

F3

F2

F1

F0

F0F1

F2

F3

F4

Area of fibrosis (%)Area of fibrosis (%) (27 patients)(27 patients)

Principles of 13C Breath Testing

Substrate targets a Substrate targets a

metabolic/biochemical metabolic/biochemical

process which is process which is

affected by presence of affected by presence of

the suspected diseasethe suspected disease

Measure Measure

basebase--line line 1313C/C/1212CC

Drink Drink 1313C marked C marked

substratesubstrate

Rate and magnitude of Rate and magnitude of

change in change in 1313C/C/1212C in C in

exhaled breath exhaled breath

correlates to presence correlates to presence

and severity of the and severity of the

diseasedisease

Human ExhalationHuman Exhalation

1313COCO221212COCO22

1%1% 99%99%

Constant ratio:Constant ratio:1313COCO22

1212COCO2278%78%--NN22

16%16%--OO22

5%5%--COCO22Co

nce

pt

Co

nce

pt

Meth

od

Meth

od

Readout of Methacetin Breath Readout of Methacetin Breath

Test:Test:

Challenge # 2:

What makes Cirrhosis Reversible?

• Not all cirrhosis is the same

• Classification of cirrhosis was never sufficiently refined because it was considered irreversible

• Effective anti-viral therapies have established that even cirrhosis is reversible

Cirrhosis is Reversible!

Evidence in:

• HBV

• HCV

• Secondary biliary cirrhosis

• AIH

• PBC

• Wilson’s disease

• Thalassemia after bone marrow xplant

• Animal models

Improvement in Necroinflammation andFibrosis from Long-term Entecavir Therapy

Chang, Hepatology , 2010

Reversibility of Cirrhosis Following Treatment of Hepatitis C

Poynard et al, Gastroenterology 2002; 122:1303-1313

No

. P

ati

en

tsN

o. P

ati

en

ts

Mallet, V. et. al. Ann Intern MedMallet, V. et. al. Ann Intern Med2008;149:3992008;149:399--403403

Hepatitis C SVR Improves Clinical Outcomes in Cirrhotics, Especially if Cirrhosis Reverses

Responders vsResponders vs

NonNon--RespondersRespondersReversers vsReversers vs

NonNon--ReversersReversers

Improving Liver Fibrosis has a Functional Impact

Roberts et al, Clin Gastro Hep, 2007Roberts et al, Clin Gastro Hep, 2007

SVR of Hepatitis C Lowers HVPG

Hepatic Stellate cell Activation Hepatic Stellate cell Activation --

A Central Event in Liver FibrosisA Central Event in Liver Fibrosis

Normal LiverNormal LiverActivated HSC Activated HSC

with Fibrosis with Fibrosis

Friedman SL and Arthur, Friedman SL and Arthur, Science and MedicineScience and Medicine, 2002, 2002

Pathways of Stellate cell ActivationPathways of Stellate cell Activation

Natural History of Natural History of

Chronic Liver DiseaseChronic Liver Disease

Chronic hepatitisChronic hepatitis

with fibrosiswith fibrosis

1010--50 yrs50 yrs

Cirrhosis Cirrhosis Normal liverNormal liver

HepatocellularHepatocellular

CarcinomaCarcinoma

LiverLiver

TransplantTransplant

AntifibroticAntifibrotic

TherapyTherapy

Challenge # 3 -We need anti-fibrotic treatment in a

‘proof-of-concept’ trial!!

•• Pharma has a short attention span when Pharma has a short attention span when drugs fail (e.g., sepsis therapies, stroke drugs fail (e.g., sepsis therapies, stroke prevention)prevention)

•• Better antiviral therapies for HCV & HBV Better antiviral therapies for HCV & HBV diminish enthusiasm for antidiminish enthusiasm for anti--fibroticsfibrotics

•• ButBut, many pts still need anti, many pts still need anti--fibroticsfibrotics

•• A A ‘‘proof of conceptproof of concept’’ trial will have an trial will have an energizing effect on the fieldenergizing effect on the field

Emerging Therapies for Hepatic Fibrosis

1. Reduce primary disease

2. Downregulate early stellate cell activation

3. Inhibit properties of activated stellate cells: e.g., proliferation, contractility, fibrogenesis

4. Stimulate stellate cell apoptosis

5. Degrade “scar” matrix

Resolution

Friedman SL, J Biol Chem, 2000

Reduce Primary Disease: •• AntiviralsAntivirals

•• Metabolic therapy Metabolic therapy

HCV, NASH

Resolution

Reduce Injury

•• HGF mimeticsHGF mimetics

•• Antioxidants Antioxidants

•• FXR ligands FXR ligands

“Hepatoprotectants”

Resolution

Proliferation

•• PDGFPDGF--R antagonists (MoAb, Gleevec)R antagonists (MoAb, Gleevec)

•• RTK antagonists RTK antagonists –– e.g., e.g., SorafenibSorafenib

Resolution

Contractility

•• ETET--1 & ET1 & ET--1 receptor antagonists1 receptor antagonists

(Bosentan, Thelin)(Bosentan, Thelin)

Resolution

Fibrogenesis

• TGFβ1 & TGFβ1 receptor antagonists

• Hepatocyte growth factor agonists

• AT-Receptor antagonists, ACE Inhibitors

• Adioponectin

• Cannabinoid R1 antagonists

ResolutionHSC Chemotaxis

••PDGFPDGF--R antagonistsR antagonists

••Chemokine antagonistsChemokine antagonists

•• ChemokineChemokine--R antagonistsR antagonists

••Integrin antagonists Integrin antagonists

RESOLUTION

APOPTOSIS?

REVERSION?

INJURY

••Apoptotic ligands, e.g, TRAIL Apoptotic ligands, e.g, TRAIL

••TIMP antagonistsTIMP antagonists

•• Cannabinoids Cannabinoids

Future Advances in Chronic Hepatitis and Hepatic Fibrosis - 2010

• Improved genetic markers of disease risk

• Better non-invasive markers of injury and fibrosis

• Regenerative therapies for acute and chronic liver failure

• Continued refinements in therapies for viral hepatitis - shorter durations, better AE profiles

• Long term antifibrotics, alone or in combination

• Earlier dx and more cures of HCC