HEPATITIS DELTA VIRUS (HDV)

1

Poster, DDW 2017, Abstract #Sa1486

Increased HDV Patient Diagnosis~110,000 Individuals Co-infected with HBV/HDV in U.S.

Newly Diagnosed Patients by ICD-10

4,9464,274

4,841 5,043 5,2595,926

6,8367,442

9,079

2008 2009 2010 2011 2012 2013 2014 2015 2016

Lonafarnib Phase 2Data Presentations

• 15-20 M HDV infected patients worldwide

• 4-6% of HBV infected patients

OVERVIEW

Prevalence

• Most severe form of viral hepatitis

• Always associated with HBV infection

• HDV causes more rapid disease progression

- Compared to HBV mono-infection

• No FDA approved Rx- PEG IFN alpha demonstrates modest benefit

2

(Range 0 - > 60%)

HDV WORLDWIDE PREVALENCE: 15-20 MILLION6% of HBV Population Infected with HDV

2

MIGRATION AND VIRAL HEPATITIS

3

Globalization of Disease

Foreign-born individuals comprise majority of growingHDV positive population in North America and Western Europe…

Germany: Wedemeyer et al., Hepatology 2007Heidrich et al., J Viral Hepatitis 2009

France: Le Gal et al., Hepatology 2007UK: Cross et al., J Med Virol 2008Italy: Stroffolini et al., J Med Virol 2009

Piccolo et al., Eur J Publ Health 2010

MIGRATION INTO WESTERN EUROPE

4

Known Claims for Asylum in 2015 > 1 Million

AT DIAGNOSIS, >50% OF HDV PATIENTS ARE CIRRHOTIC

5

Risk of Hepatocellular Carcinoma, Decompensation, Mortality Increase

Fattovich et al, J Infect Dis, 1987; Fattovich et al, Gut, 2000. Serrano et al, EASL 2011

Survival Evolution from Chronic Active Hepatitis to Cirrhosis

CumulativeSurvival

Progression to Cirrhosis (%)

HBV + HDV

HBV

P = 0.001

HBV + HDV

HBV

P = 0.0002

Follow-up Years Time to Event (Years)

PEG IFN-a HAS MODEST BENEFIT IN HDV

6

Tolerability a Problem, Rebound a Problem, Retreatment a Problem

Mean Change inLog HDV-RNA

Wobse 2014: AASLDWedemeyer 2014: AASLD Week

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0 4 8 12 16 20 24 28 32 36 40 44 48

HIDIT-2: PEG IFN 180 mcg QW + tenofovir

HIDIT – 2 Study

-2.5 log mean reduction in HDV-RNA at 48 weeks

SVR rates ~ 25-30%

HIDIT-2: PEG IFNa 180 mcg QW + tenofovir (N=91)

REDUCING HDV-RNA IMPROVES SURVIVAL

7

Improved Clinical Benefit without Clearance of HDV-RNA

Survival

Interferon-a for 48 weeks with 15 year Follow Up

Farci et al, Gastroenterology 2004: Long-Term Benefit of Interferon-α Therapy of Chronic HDV: Regression of Advanced Hepatic Fibrosis

Years after Termination of Therapy

Proportion ofPatients

Surviving

Change in HDV-RNA

Log Change inSerum HDV-RNA

n=36

P = 0.009

FEWER CLINICAL EVENTS FOLLOWING IFN a

8

151050

1.0

0.8

0.6

0.4

0.2

0

YearsWranke et al. J Hepatology 2016: Does Antiviral Treatment Affect the Clinical Long-term Outcome of Hepatitis Delta?

• Long term clinical outcomes - IFN alfa treatment in HDV

• Retrospective analysis - single cohort study

• 136 anti-HDV positive patients

• Median follow-up: 5.2 years - Range 0.6 -18.8 years

HDV-RNA Loss Improves Long-term Clinical Outcomes

Interferon-a for 48 weeks with up to 18.8 Year Follow Up

NUCs (N=45)

No therapy (N=39)

IFN a (N=52)p < 0.01 vsNUCs

p = 0.02 vsNUCs

p = 0.05 vs no therapyCumulativeEvent FreeSurvival

9

WHAT ENDPOINTS HAVE BEEN USED IN HDV?

9

10

• Primary Endpoint: Reduction in HDV RNA

- ≥ 2 Log Reduction in HDV RNA at EOT

• Secondary Endpoint: Biopsy Confirmed Histologic Improvement

- 2 point improvement in HAI inflammation score without progression in Fibrosis at EOT

- ALT Normalization at EOT

PROPOSED ENDPOINTS IN HDV

White Paper to be submitted by Hepatitis Delta International Network

(HDIN) in October

10

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Uncoating of Virus

Transport to Nucleus

Replication

Assembly

prenylatedLHDAg

Release of Progeny

Cytoplasm

HBV surface antigen

largeHDAg

smalldelta

antigen

large delta

antigenHDV genome

HDV genome

Prenylation

HDV genome

prenylated LHDAg

prenyl moiety

small HDAg

large HDAg

HBsAg

HDV LIFE CYCLE

Jak

Lambda Interferon Receptor

ISG Induction

Antiviral Activity

Lambda Interferon

Stat

12

Uncoating of Virus

Transport to Nucleus

Replication

Assembly

prenylatedLHDAg

Release of Progeny

Cytoplasm

HBV surface antigen

largeHDAg

smalldelta

antigen

large delta

antigenHDV genome

HDV genome

Prenylation

HDV genome

prenylated LHDAg

prenyl moiety

small HDAg

large HDAg

HBsAg

HDV LIFE CYCLE

Entry Inhibitors(i.e. Myrcludex-b)

Jak

Lambda Interferon Receptor

ISG Induction

Antiviral Activity

Lambda Interferon

Stat

X

13

Uncoating of Virus

Transport to Nucleus

Replication

Assembly

prenylatedLHDAg

Release of Progeny

Cytoplasm

HBV surface antigen

largeHDAg

smalldelta

antigen

large delta

antigenHDV genome

HDV genome

Prenylation

HDV genome

prenylated LHDAg

prenyl moiety

small HDAg

large HDAg

HBsAg

HDV LIFE CYCLE

Nucleic Acid Polymers

(i.e. REP 2139) X Jak

Lambda Interferon Receptor

ISG Induction

Antiviral Activity

Lambda Interferon

Stat

14

Uncoating of Virus

Transport to Nucleus

Replication

Assembly

prenylatedLHDAg

Release of Progeny

Cytoplasm

HBV surface antigen

largeHDAg

smalldelta

antigen

large delta

antigenHDV genome

HDV genome

Prenylation

HDV genome

prenylated LHDAg

prenyl moiety

small HDAg

large HDAg

HBsAg

HDV LIFE CYCLE

PrenylationInhibitors

(i.e. lonafarnib)X

Jak

Lambda Interferon Receptor

ISG Induction

Antiviral Activity

Lambda Interferon

Stat

15

Uncoating of Virus

Transport to Nucleus

Replication

Assembly

prenylatedLHDAg

Release of Progeny

Cytoplasm

HBV surface antigen

largeHDAg

smalldelta

antigen

large delta

antigenHDV genome

HDV genome

Prenylation

HDV genome

prenylated LHDAg

prenyl moiety

small HDAg

large HDAg

HBsAg

HDV LIFE CYCLE

Jak

Lambda Interferon Receptor

ISG Induction

Antiviral Activity

Lambda Interferon

Stat