Future Direction in Hepatology - LSGE...1-Kamar NEJM 2008;2-Péron J Viral Hepat 2007; 3-Dalton Eur J Gastro Hepato 2008; 4- Haim-Boukobza, Coilly, Liver Int, 2015; 5-Dalton, Nat Rev

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Future Direction in HepatologySession: Hepatology

Audrey Coilly, MD, PhDCentre Hepato-BiliairePaul Brousse Hospital, Villejuif FranceParis-Sud, Paris Saclay University

23/12/2019

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Disclosures

AstellasAbbvieBMSInterceptIpsenGileadNovartis

Immunotherapy induced DILI – Audrey Coilly2

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Significant impact on patients’care

3 Future Direction in Hepatology – Audrey Coilly Ascione, A. Liver International. 2017

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Agenda

1. What changes could be expected regarding causes ?2. What treatments will revolutionize this field?3. What tools could be implemented in a very next future?

4 Future Direction in Hepatology – Audrey Coilly

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Agenda



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Decline of viral hepatitis


HCV HBV

Papatheodoridis, GV. J Viral Hepat. 2018

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Repercussion on waiting list for liver transplantation

Flemming, JA. Hepatology. 2017

Register study2003 à 201547,591 WL patients

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Hepatitis E: the neglected one

2 different zones and viruses


HEV-3

HEV-1&2

HEV-4

http://www.cdc.gov/; Kamar, Lancet 2012

http://www.cdc.gov/

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9 Future Direction in Hepatology – Audrey CoillyRein Hepatology; The Global Prevalence of HEV. A Systematic Review. 2014 http://www.who.int/vaccines-documents/

Interhumaine transmissionOro-fecal peril

70,000 deaths/y50% of ALF20% mortality rate during pregnancy

http://www.who.int/vaccines-documents/

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10 Future Direction in Hepatology – Audrey CoillyRein Hepatology; The Global Prevalence of HEV. A Systematic Review. 2014 http://www.who.int/vaccines-documents/

Interhumaine transmissionOro-fecal peril

70,000 deaths/y50% of ALF20% mortality rate during pregnancy

Zoonotic transmissionIngestion of contaminated food

Less severe<5% of ALF

http://www.who.int/vaccines-documents/

© LSG. 2019Mansuy Hepatology 2016, Coilly Transplantation 2013

22%

One of the most frequent viral hepatitis in Western countries

Symptomatic formPatient type: Men 50-55 ans, comorbidities

Severe form1. Chronic infection

2. Acute on chronic liver failure• Acute alcoholic hepatitis

3. Extra-hepatic manifestattions• Neurological as Parsonage Turner Syndrome

Asymptomatique

1-Kamar NEJM 2008;2-Péron J Viral Hepat 2007; 3-Dalton Eur J Gastro Hepato 2008; 4- Haim-Boukobza, Coilly, Liver Int, 2015; 5-Dalton, Nat Rev Neurol. 2016

Clinical presentation

IgM positivity

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Chronic infection

• Described for genotypes 3 and 4 in immunocompromised individuals: transplanted, HIV, chemo and immunotherapies

• Risk of chronic infection after acute infection: 2/3 in solid organtransplant recipients = Persistence of viral RNA> 3 months

To look for any immunosuppressed person with cytolysisCan be rapidly fibrosing: TreatRibavirin low dose 3 months cure 80%

1-Kamar CMR 2014; 2-Kamar Gastroenterology 2011;3-Kamar NEJM 2014

% cirrdecompensated cirrhosis % HCC

Goldberg. Gastroenterology. 2017

UNOS 2003 to 2015

VHC

NASH et OH

VHC

NASH et OH

Raising of ASH and NASH

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The burden of NASH

Estes et al. Hepatology 2018

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Do not forget alcohol…

Williams R et al. Lancet 2018

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Alcohol impact mortality in patients with viral hepatitis

Schwarzinger, M. J Hepatol. 2017

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The real burden is and will be hepatocellular carcinoma


HCC incidence in France

Années

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In acute liver failure… Drug-Induced Liver Injury

2015-2016 in France: 148 liver transplantation- 42.6% acetaminophen toxicity- 8.4% of DILI with other drug

Countries Study desing IncidenceUK Retrospective 2,4/100,000Swedden Retrospective 2,3/100,000Islande Prospective 19/100,000France Prospective 14/100,000

9000 cas/y

Per yearIn general population

Björnsson Semin Liver Dis 2014 34:115; EASL CPG DILI J Hepatol 2019; Larrey, J Hepatol 2019; 70Supp1:258

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Agenda



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HCV therapy inspires the entire field…


Potent drugs, pangenotypic

>95% of sustained virological response

Even in most severe patients

Coilly, Femlee, lancet infectious disease, 2016

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HBV cure will be another challenge…

Levrero et al, CoViRo, 2018

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Myrcludex to treat hepatitis D

23 Future Direction in Hepatology – Audrey Coilly Bogomolov, P. J Hepatol. 2016

Dual therapy with IFN and MYR allows 53% HDV virologicclearance and 27% loss of HBsAg

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Cholestatic liver diseases: 2nd line!

24 Future Direction in Hepatology – Audrey Coilly Corpechot, NEJM, 2018, Nevens, NEJM, 2017

Obeticholic acid Bezafibrate

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Same pathways for NASH treatment


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Regenerate: the first study of a long list…


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Regenerate: the first study of a long list…


Fibrosis NASH features

Arm 25 mg: Pruritus 51%, treatment discontinuation for AE 13%, LDL 17%

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New input in advanced HCC


Lenvatinib (Lenvima®) Eisai/MSD

Pembrolizumab (Keytruda®)MSD

Durvalumab (Imfinzi®) + Tremelimumab

AstraZeneca

Sorafenib (Nexavar®)Bayer

EMA Approval Oct 2007

Regorafenib (Stivarga®)Bayer

EMA Approval Aug 17

Nivolumab (Opdivo®)BMS

Anti-VEGF Antibody

Other CPIs

TKI

CPI

H1 H2 H1 H2 H1 H2 H1 H2 H1 H2 H1 H2 H1 H22017 2018 2019 2020 2021 2022 2023

H1 H2 H1 H2 H1 H2 H1 H2 H1 H2 H1 H2 H1 H2

1 LINE

2 LINE

Tislelizumab (BGB-A317)

BeiGene/Celgene

Note: All timelines are subject to clinical trial results, regulatory reviews and/or reimbursement negotiations.

• Phase III REACH-2 NCT02435433• Global N: 383 • Global Sites: 158 • PE (OS) met Apr 2018• EMA filed Aug 2018• EMA approval Q1-Q2 19 (earliest Feb)

• Phase III Keynote-240 NCT02702401

• Global N: 408• Global Sites: 68• PE Feb 2019• Readout may be delayed to

Q4’19/Q1’20* TBC

• Phase III REFLECT NCT01761266• Global N: 954 • Global Sites: 196 • PE (non inferior OS) met Jan 2017• EMA filed Jul 2017• EMA Approval Aug 2018

• Phase III CM-459 NCT02576509

• Global N: 726 • Global Sites: 154 • PE Oct 2018• Readout est Q1 2019 TBC*

• Phase III HIMALAYA NCT03298451

• Global N:1200 • Global Sites: 244• PE Mar 2020

• Phase III NCT03412773• Global N: 660 • Global Sites: 12 • PE Jan 2022• Preliminary data 2019

TBC*

Bevacizumab (Avastin®) + Atezolizumab (Tecentriq®)

Roche

Nivolumab (Opdivo®)BMS

• Phase 1/II CM-040 NCT01658878

• EMA filing withdrawn Jul 2017

• Phase III IMbrave150 NCT03434379

• Global N: 480• Global Sites: 113• PE May 2021• Assume filing Q2 2021

TBC• Updated Ph 1/2 data

ESMO 2018 (LBA26)

Source: Ipsen Business Insights & Analytics, clinicaltrials.gov, Newport & Biomedtracker (accessed 29/8/2018)No. of sites are regularly updated especially for newer trials.

Estimated Trial Readout Dates* = Based on primary sources

Updated 5 October 2018

Ramucirumab (Cyramza®)Eli Lilly

High AFP only

Other Key Developments

• Phase III PHOCUS Pexa-Vec (oncolytic virus) + Sorafenib (NCT02562755) – ongoing monitoring, however competitive impact to be re-assessed

• Phase I Regorafenib + Pembrolizumab 1L Global (Bay er/MSD) – start June 18 (NCT03347292)

• Phase I Lenvatinib + Pembrolizumab 1L Global (Eisai/MSD) - as of Aug 2018, no. of patients and sites has increased (NCT03006926))

• New Phase II Tislelizumab 2L Global (BeiGene/Celgene) - first patient dosed Apr 2018 (NCT03419897)

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New input in advanced HCC


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Next approaches to treat acute liver failure

Several artificial and bioartificialliver devices are currently tested

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MARS Circuit

Future Direction in Hepatology – Audrey Coilly

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FULMAR Study


Results : Patient Survival(Primary Endpoint : 102 pts ITT analysis)

Saliba, Ann Int Med, 2013

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• The ELAD system• The Dialive system

Increased toxins and cytokines absorption

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Dialive Concept


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HepaStem consists of liver-derivedMesenchymal Stem Cells that are obtained from ethically healthy donatedorgans and expanded in the lab.

Study HEP101*: Multicenter Phase II Safety and Preliminary Efficacy Study of 2 dose regimens of HepaStem in Patients withAcute on Chronic Liver Failure (ACLF 0 and 1) :Low dose High dose

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Promethera concept


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Next approaches to treat chronic liver diseases

34 Future Direction in Hepatology – Audrey Coilly Zein, N. Liver Transplantation. 2013

Bio-printing techniques

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35 Future Direction in Hepatology – Audrey Coilly Baptista PM, hepatology, 2011

Devascularized scaffold

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36 Future Direction in Hepatology – Audrey Coilly Baptista PM, hepatology, 2011

Devascularized scaffold

Stem cellOr neo

cell

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Agenda



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Trends in steatosis measurement

Echo Scan/CT Scan

MRI-PDFF for grading hepaticsteatosis

38

CAP measurement


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Trends in steatosis measurement

Echo Scan/CT Scan

MRI-PDFF for grading hepaticsteatosis

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Spectrophotometer to measure steatosis during harvesting

Future Direction in Hepatology – Audrey Coilly Golse, N, J Hepatol, 2019

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Trends in fibrosis and portal staging

RMI for sur

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Blood test

Future Direction in Hepatology – Audrey Coilly Cales P, J Hepatol, 2017

« Machine learning », algorithm

CirVir CO12

1 2 3 4 5 6 7 8

Moy Moy Moy Moy Moy Moy Moy Moy

Age 59 1 60 7 55 3 54 7 55 7 55 9 55 0 55 6

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Genomic… in several issues

HASIPRO-cohort70 patientsALF of unkonwn cause

Coill A, Gille N, Carot V, Roque-Afonso AM, Work in progress 2019

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In summary

Hepatology is a field perpetual renewal that leads to great improvementin patients’ care over few decades

• Great change in term of epidemiology is currently ongoing with theraising of NASH and the decease od infectious diseases

• New option treatments are already available for NASH and HCC…but change of paradigm is on-going: No control of symptoms only butcontrol of the cause

• New tools will help … but we will have to be friendly withmathematical language

43 Immunotherapy induced DILI – Audrey Coilly

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Acknowledgments

Documents

Future Direction in Hepatology - LSGE...1-Kamar NEJM 2008;2-Péron J Viral Hepat 2007; 3-Dalton Eur J Gastro Hepato 2008; 4- Haim-Boukobza, Coilly, Liver Int, 2015; 5-Dalton, Nat Rev