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Pietro Invernizzi

Division of Gastroenterology and

Center for Autoimmune Liver Diseases

University of Milan-Bicocca

Monza, Italy

Athens, 24 March 2018

Primary biliary cholangitis


06/2016 Female (dob 1965) - PBC --> OLT on 03/201707/2016 Female (dob 1952) - PBC + sclerodermia --> on waiting list10/2016 Female (dob 1974) - PBC --> OLT on 09/2017 11/2016 Female (dob 1948) - PBC --> on waiting list05/2017 Female (dob 1962) - PBC + IBD --> on waiting list05/2017 Female (dob 1969) - PBC --> on waiting list06/2017 Male (dob 1943) - PBC + HCC --> OLT on 12/201708/2017 Female (dob 1959) - PBC death on waiting list12/2017 Female (dob 1952) - PBC --> on waiting list07/2017 Male (dob 1988) - PBC + AIH --> under evaluation12/2017 Female (dob 1982) - PBC + AIH --> under evaluation

Patients reffered to liver transplantation (2016-2017):

Primary biliary cholangitis (n=600)

Autoimmune hepatistis (n=250)

Primary sclerosing cholangitis (n=250)

(Cholangiocarcinoma)

BASIC

Genetics/Epigenetics

Immunology

Neuroendocrine

Carcinogenesis

New drugs

TRANSLATIONAL / CLINICAL

Biomarkers

Clinical trials

Epidemiology


Pietro Invernizzi

University of Milan-

Bicocca

Italy

www.easl.e

u

MAY 23 – 24 / 2014. Milan,

Italy

PRIMARY BILIARY CIRRHOSIS

New name

September 2015 - Position paper

“Changing Nomenclature for PBC:

From ‘cirrhosis’ to ‘cholangitis’”

• Hepatology. 2015 Sep 15.

• Gut. 2015 Sep 14.

• Gastroenterology. 2015 Sep 15.

• J Hepatol. 2015 Sep 10.

• Clin Gastroenterol Hepatol. 2015 Sep 16.

• Am J Gastroenterol. 2015 Sep 29.

• Dig Liver Dis. 2015 Sep 23.

• Clin Res Hepatol Gastroenterol. 2015 Oct;39(5):e57-9.

PRIMARY BILIARY CHOLANGITIS

Outline

Genetics

Networks

Novel drugs

?

Pre GWAS 2008 GWAS

HLA story in PBC

HLA story in PBC

Pre GWAS 2008 GWAS

2003

Monocentric

study

Italy

PBC = 186

HC = 558

2008

Multicentric

Study

Italy

PBC = 664

HC = 1992

HLA polymorphisms in Italian PBC

Multicenter Study

HLA PBC Controls Pc Odds Ratio (95% C.I.)

(n=664) (n=1992)

(%) (%)

DRB1*08 7.2 2.3 0.000 3.3 2.4-4.5

DRB1*11 13.6 30.0 0.000 0.4 0.3-0.4

DRB1*13 8.6 11.2 0.000 0.7 0.3-0.9

Invernizzi et al. Hepatology 2008

HLA story in PBC

Pre GWAS 2008 GWAS

2003

Monocentric

study

Italy

PBC = 186

HC = 558

2008

Multicentric

Study

Italy

PBC = 664

HC = 1992

2010

GWAS

Italy

USA

Canada

PBC = 993

HC = 2483

Risk variants:

HLA

IL12A

IL12RB2

IRF5

IKZF3/ORMDL

3

SPIB

Genome-wide association study in PBC

Liu & Invernizzi Nature Genetics 2010

HLA story in PBC

Pre GWAS 2008 GWAS

2003

Monocentric

study

Italy

PBC = 186

HC = 558

2008

Multicentric

Study

Italy

PBC = 664

HC = 1992

2010

GWAS

Italy

USA

Canada

PBC = 993

HC = 2483

2012

HLA-Dense array

Italy

PBC = 676

HC = 1440

HLA associations in PBC Dense array approach

676 Italian PBC

vs.

1440 controls

Results:

DRB1 (*08, *11)

DPB1

Invernizzi et al. Genes Immun 2012

HLA story in PBC

Pre GWAS 2008 GWAS

2003

Monocentric

study

Italy

PBC = 186

HC = 558

2008

Multicentric

Study

Italy

PBC = 664

HC = 1992

2010

GWAS

Italy

USA

Canada

PBC = 993

HC = 2483

2012

HLA-Dense array

Italy

PBC = 676

HC = 2483

Increasing study size

HLA / genetic story in PBC

Pre GWAS 2008 GWAS

2003

Monocentric

study

Italy

PBC = 186

HC = 558

2008

Multicentric

Study

Italy

PBC = 664

HC = 1992

2010

GWAS

Italy

USA

Canada

PBC = 993

HC = 2483

2012

HLA-Dense array

Italy

PBC = 676

HC = 1440

?

CountryDiscovery Discovery Validation Validation

Cases Controls Cases Controls

Canada 480 3,701 903 834

Italy 449 940 300 618

United Kingdom 1,816 5,161 1,792 2,515

United States of

America- - 721 294

Total 2,745 9,802 3,716 4,261

Cordell et al. Nat Commun 2015

International GWAS meta-analysis in PBCDiscovery and validation cohorts

PBC = 6461

Controls = 14.063Six novel risk loci:

2q12.1, 2q36.3, 4p16.3, 5q21.1

5q33.3, 6q23.3

Gene Loci Canada

USA

Italy-

Canada

USA

UK Japan

HLA Yes Yes Yes Yes Yes

IL12A - Yes Yes Yes -

IL12RB2 - Yes Yes Yes -

IRF5/TNPO3 - Yes Yes Yes -

ORMDL3/IK

ZF3

- Yes - Yes Yes

MMEL1 - Yes - Yes -

SPIB - Yes Yes Yes -

DENND1B - - Yes Yes -

CTLA-4 Yes - - -

STAT4 - Yes - Yes -

CD80 - - - Yes Yes

NFKB1 - - - Yes -

IL7R - - - Yes Yes

CXCR5 - - - Yes -

TNFRSF1A - - - Yes -

TNFSF1 - - - - Yes

POU2AF1 - - - - Yes

PBC “gene” list 2017

Increasing study size

Pre-GWAS 2009 2010 2011 2012

Sex chromosomes defects in PBC

Enhanced X monosomy (female)

Preferential X chromosome loss (female)

Increased Y chromosome loss (male)

Haploinsufficiency that unmasks PBC

susceptibility genes

Invernizzi et al. Lancet 2004

Invernizzi et al. J Immunol 2005

Miozzo et al. Hepatology 2007

Lleo et al. J Autoimmun 2013

Canadian & US

GWAS in PBC

US/Canadian

Chinese

Italian

XWAS in PBC

5,000 PBC vs. 10,000 controls

(USA, Canada, Italy, UK, Japan, China)

«XWAS: A Software Toolset for Genetic Data Analysis and

Association Studies of the X Chromosome»

J Hered 2015;106(5):666-71

And now?

Pathogenesis of PBC

Lleo & Invernizzi. J Hepatol 2012

Precision drugs (weapons)

PRECISION DRUGS

• FXR

• PPAR

• ASBT

• Anti-IL 12

• Anti-CXCL10

• Anti-CD20

• Anti-CD40L

• Anti-NOX 1 & 4

Anti-IL12 for PBC

Liu, Invernizzi, et al. Nature Genetics 2010

IL12

Genetic defect

Anti-IL12 for PBC


IL12

Genetic defect

Anti-IL12

Clinical trial

Hirschfield, et al. Hepatology 2016

Outline

Genetics

Networks

Novel drugs

?

Networking story in PBC

2011

PI’s of the Global PBC Study Group (2012)

• Henk van Buuren, Rotterdam representing South of the Netherlands

• Gideon M. Hirschfield, Birmingham, UK

• Harry L.A. Janssen, Toronto, Canada

• Pietro Invernizzi, Milan, Italy

• Andrew L. Mason, Edmonton, Canada

• Cyriel Y. Ponsioen, Amsterdam representing North of the Netherlands

• Annarosa Floreani, Padova, Italy

• Christophe Corpechot, Paris, France

• Marlyn J. Mayo, Texas, USA

• Pier M. Battezzati, Milan, Italy

• Albert Parés, Barcelona, Spain

• Frederik Nevens, Leuven, Belgium

• Andrew K. Burroughs* & Douglas, London, UK

• Kris V. Kowdley, Seattle, USA

• Keith Lindor & Nicholas LaRusso, Rochester& Arizona, USA

Continuous growth

20111st prep meeting

20121st official meeting

n=3377 identified

Data collection

2014New presentations

n=4845 in database

20141st publication

Surrogate endpoint

Gastroenterology

20152nd publication

HCC

GUT

20156th investigator meeting

1 new submission

6 ongoing projects

3-9 new centers

20131st presentations

15 centers in 8 countries

2016n=6253 in database

20153rd publication

Globe score

Gastroenterology

Lammers et al. Gastroenterology 2014


2011 2012

Gender differences in the age-related likelihood

of achieving UDCA response criteria

Proportion of patients who did not meet the

criteria for response to UDCA after a minimum

of 2 years treatment because of the ALT/AST

criterion (2 ULN) related to their age at

diagnosis

Carbone M et al. Gastroenterology 2013

Predictors of response to UDCA

Sex & Age

n=2353


2011 2012

Swiss PBC

Austro-German PBC

2016-17

ERN-RARE LIVER

European Reference

Network

PBC is an heterogeneous disease

Variant syndromes PBC – AIH overlap syndrome may be found in ~10% and thepremature ductopenic variant in ~5% of cases

Autoantibody profile Anti-centromere antibodies (ACA) are found in ~30%, anti-sp100antibodies in ~20-30% and anti-gp210 antibodies in ~10% ofcases

Symptom profile Pruritus is present in 40% and fatigue is present in 45% of cases

Modes of disease progression

Portal hypertensive-type versus hepatocellular failure-typeprogression

Rate of disease progression

Ranging from no overt progression at one end of the spectrum,to ESLD occurring within a few years of diagnosis, at the other

The biochemical response to UDCA Variable; it strongly predicts the long-term outcome.

Challenge

Outline

Genetics

Networks

Novel drugs

?

EASL PBC Guidelines: 2009-2017

2009

•Generalized to Management of

Cholestatic Liver Diseases

•ALP 3 x ULN Paris-I

Barcelona

•Budesonide and Fibrates

2017•First Guidelines Specific to PBC

•Patient-Centric Name Change: PBCirrhosis to PBCholangitis

Overall focus on patients, clinical care &

support

•Clear goal of prevention of complications

•Acknowledgement of FXR pathway

•ALP cut-off (<1.5) and bilirubin GLOBE

UK-PBC

•Forward thinking (non-invasive, risk scores

added as part of diagnosis)

•OCA firmly represented as second line

therapy, in line with SmPC/USPI

•Budesonide and Fibrates

Licensed treatments for PBC

First line: Bile acids

> Ursodeoxycholic acid (UDCA)

> Tauro-UDCA

EASL Clinical Practice Guidelines:

The diagnosis and management of patients with primary biliary cholangitis.

J Hepatol 2017 Jul;67(1):145-172. doi: 10.1016/j.jhep.2017.03.022. Epub 2017 Apr 18

https://www.ncbi.nlm.nih.gov/pubmed/28427765


TUDCA – BA metabolism study

Summary

Biliary enrichment with UDCA was higher during TUDCA

administration (32.6% vs 29.2% during UDCA, p <0.05).

Lithocholic acid concentration was consistently higher in all

biological fluids during UDCA administration

Fecal BA excretion was the major route of elimination of both bile

acids. UDCA accounted for 8% and 23% of the total fecal BA during

TUDCA and UDCA administration, respectively

TUDCA was better absorbed than UDCA

TUDCA underwent reduced biotransformation to more hydrophobic

metabolites (although it was partially deconjugated and

reconjugated with glicine)

Invernizzi et al. Hepatology 1999




> Tauro-UDCA

Italy

China









> Tauro-UDCA

Italy

China

Second line:Obeticolic Acid (OCA)






Fib

rosis

/ d

ucto

pen

ia

Time

Immune-mediated cholangitis

Cholestasis

Immune-

modulatory

drugs

Anti-

cholestatic

drugs&

Cirrhosis

Anti-fibrotic drugs

Immuno-pathogenesis of PBC / ideal therapies

• FXR agonists

(OBETICOLIC ACID)

• PPAR agonists

• FGF19

• BIOLOGICS

FXR agonists

(OBETICOLIC ACID)

Obeticholic acid

Bile Acid

Metabolism

Lipid

Metabolism

Carbohydrate

Metabolism

Controls bile acid

biosynthesis, disposal

and transport

Downregulates hepatic

fatty acid biosynthesis and

VLDL formation

Insulin signaling & sensitivity

and hepatic gluconeogenesis

HO OH

CO2H

INT-747

RXRFXR

Inflammation &

Fibrosis

Anti-inflammatory & anti-

fibrotic effects in the liver,

intestine and kidney

Confidential Draft – Do Not Distribute

Re

sp

on

de

rs

(%

)

0 .5 3 6 9 1 2 O L E

3

O L E

6

O L E

9

O L E

1 2

O L E

1 5

O L E

1 8

O L E

2 1

O L E

2 4

0

2 0

4 0

6 0

8 0

P la c e b o U D C A n =

O C A 5 -1 0 m g U D C A n =

O C A 1 0 m g U D C A n =

M o n th s

D o u b le -B lin d P h a s e

R a n d o m iz e d T r e a tm e n t

O p e n -L a b e l E x te n s io n

A ll R e c e iv e O C A

5 m g T it r a t io n

***

***

***

***

***

***

***

***

*** ***

D B T r e a tm e n t G r o u p

P la c e b o p a t ie n ts s ta r t e d O C A d u r in g th e O L E n = 6 4 6 0 5 9 5 9 5 5 5 5 5 4 5 2

7 3 7 3 7 3 7 3 7 3 /6 6

7 0 7 0 7 0 7 0 7 0 /6 3 6 3 6 2 6 2 6 0 5 7 5 7 5 8 5 7

7 3 7 3 7 3 7 3 7 3 /6 4 6 4 5 9 6 1 5 9 5 8 5 9 5 8 5 7

Significant Increase in OCA-Treated Patients Meeting Primary

Endpoint During the Double-Blind Phase and the OLE

†Number of patients who continued treatment in the OLE after completing the double-blind phase of the study.***p<0.0001; p-values for comparing treatments in the DB phase are obtained using CMH General Association test stratified by randomization strata factor; OLE study ongoing. During the DB patients with missing values were considered non-responders (the n values represent the initial number of patients per treatment group). During the OLE patients with missing values and patients who had discontinued were excluded from the analysis at that timepoint. During the DB phase, 3 patients discontinued from placebo, 7 patients from OCA 5-10 mg, and 9 patients from 10 mg OCA.

†

†

†

Confidential Draft – Do Not Distribute

OCA Treatment Showed Sustained Improvement in ALP

Over Time

***p<0.0001; †p-value for comparing active treatments to placebo is obtained using an ANCOVA model with baseline value as a covariate and fixed effects for treatment and randomization strata factor, p-value based on LS mean difference values; ‡p-value for the within treatment comparisons are obtained using a paired t-test.

Mean (SD) Change from BL (U/L)

Placebo± UDCA

OCA 5-10 mg ± UDCA

OCA 10 mg ± UDCA

∆ 12 Months† -7.7 (88.0) -103.5 (87.0)*** -117.7 (73.3)***

∆ OLE 24 Months‡ -101.0 (87.2)*** -120.9 (96.6)*** -102.5 (79.4)***

0 3 6 9 1 2

0

1 0 0

2 0 0

3 0 0

4 0 0

5 0 0

M o n t h s

Me

an

(

SD

) A

LP

(

U/L

)

A L P 1 . 6 7 x U L N

O L E

3

O L E

6

O L E

1 2

U L N

5 m g T i t r a t i o n

D o u b l e - B l i n d P h a s e

R a n d o m i z e d T r e a t m e n t

O p e n - L a b e l E x t e n s i o n

A l l R e c e i v e O C A

O L E

9

O L E

1 5

O L E

1 8

O L E

2 1

O L E

2 4

O C A 5 - 1 0 m g U D C AP l a c e b o U D C A O C A 1 0 m g U D C A P l a c e b o p a t i e n t s r e c e i v i n g O C A d u r i n g O L E U D C A

© UEG. 2017

OCA adverse effects and caveats

Pruritus

• Common, dose related

Nevens et al NEJM 2016; 375: 631-643

Cholesterol changes

• Decrease in HDL cholesterol

Potential risk of chronic increase

in FGF19

• Increase risk of HCC in mouse

models

Warning in decompensated

cirrhosis*

38

56

68

01

10

*FDA Post-Marketing Letter reporting 19 deaths, 8 with reported causes (7 cases of Child B or C cirrhosis and receiving 5 mg daily;

8 additional cases reported serious liver injury without death (3 cases with Child B or C cirrhosis and receiving 5 mg daily

PPAR agonists

FIBRATES

MDR3PPARa

O-oxidation

enzymes

LTB4

ApoAII

ICAM-I

VCAM1

Anti-

inflammation

Biliary phospholipid

secretion

Inactivation of hydrophobic

bile acids

Protection of BECs

NF-kB

IL-1, IL-6

COX2

PGE E2

Th2

Ig production

AutoimmunityDohmen et al. (modified) WJG 2004

Use of PPAR agonists (fibrates ) in PBC

Author Year Country Patients Months FU Improvement in

Nakai 2000 Japan 10 12 ALP,ALT, GGT, IgM

Kunhara 2000 Japan 12 12 ALP, ALT, GGT, IgM

Kanda 2002 Japan 11 6 ALP

Akbar 2005 Japan 10 12 ALP, ALT, GGT, IgM, Chol

Kita 2006 Japan 22 6 ALP,GGT

Hazzan 2010 Israel 8 4-12 ALP, GGT

Honda 2013 Japan 19 3 ALP, GGT, ALT, Chol, TG, IgM

Lens 2014 Spain 30 12 ALP, GGT, ALT, Chol TG

Reig 2015 Spain 48 38 ALP, GGT, ALT, Chol, TG, pruritus

Hosonuma 2015 Japan 12 96 ALP, Mayo Risk Score

Ohira 2002 Japan 7 6 ALP, GGT IgM

Walker 2009 UK 16 3-4 ALP, IgM

Liberopoulus 2010 Greece 6 2 ALP, GGT

Levy 2011 USA 20 12 ALP. AST, IgM, IL-1, IL-6

Cheung 2015 Canada 46 11 ALP

Hegade 2016 UK 23 21 ALP, Not UK-PBC score

B

E

Z

A

F

E

N

O

2-year multicenter, double-blind, randomized, placebo-

controlled trial of bezafibrate (400 mg/d) + UDCA

Corpechot et al EASL 2017

Inadequate

biochemical

response to

UDCA

(Paris-2 criteria)

Randomization

N=100

Premature termination

N=4

Bezafibrate

400 mg/dl

N=50

Placebo

N=46

Placebo

N=44

Bezafibrate

400 mg/dl

N=50

Bezafibrate

400 mg/dl

N=48

Placebo

N=50


N=2


N=2

Recruiting centers: 21

Recruiting period: 22/10/2012 – 22/10/2014

UDCA 13-15 mg/Kg/d

M0 M3 M6 M9 M12 M15 M18 M21 M24

M24 complete biochemical responsePrimary endpoint


30%

M24 normal alkaline phosphatase levelSecondary endpoint


67%

M2

4 n

orm

alA

LP

Biologics

Immune-related precision drugs (weapons)

PRECISION DRUGS

• Anti-IL 12

• Anti-CXCL10

• Anti-CD20

• Anti-CD40L

• Anti-NOX 1 & 4

Anti-IL12 for PBC


IL12

Genetic defect

Anti-IL12

Clinical trial

Hirschfield, et al. Hepatology 2015

Reduction in ALP

✓ 90 mg s.c. weeks 0,4, and 8 to 20 wks

✓ Median ALP 12% at 6 months

Hirschfield GH et al, Hepatology 2015

Anti-IL 12 for PBC

PIANO Study design

Anti-CXCL10 for PBC

An open label single arm study to investigate the safety and efficacy of multiple

administrations of NI-0801, a fully human anti-CXCL10 monoclonal antibody in

PBC patients with an incomplete response to UDCA.

Invernizzi et al Hep Commun 2018 in press

Tsuda M, et al. Hepatology. 2012

Anti-CD20 (Rituximab) for PBC

CONCLUSIONS:

• depletion of B cells influences

the induction, maintenance

and activation of both B and T

cells

• potential mechanism for

treatment of patients with

PBC with an incomplete

response to UDCA.

Meyer, et al. Am J Gastroenterol. 2013

Anti-CD20 (Rituximab) for PBC

CONCLUSIONS:

• safe and associated with a

significant decrease in

autoantibody production

• had limited biochemical

efficacy

NADPH oxidases (NOX): 7 ROS producing enzymes

NOX enzymes are the only specialized ROS-producing systems

NOX2NOX1 NOX3 NOX4 NOX5 DUOX1/2

NOX1 NOX2 NOX3 NOX4 NOX5 DUOX1/2

O2- O2

- O2- O2

- O2- O2

-

p22phoxp22phox p22phox p22phox

THANKS

DIVISION OF GASTROENTEROLOGY and CENTER FOR AUTOIMMUNE LIVER DISEASESPietro INVERNIZZIMarco CARBONEFrancesca BERNUZZIFederica MALINVERNOMarta GEMMAVincenzo RONCAAlessio GERUSSILaura CRISTOFERIGiulia BONATOVasiliki LIGOURA

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