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
11
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