Viral Hepatitis: The Search for a Cure

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2017 Drug Design and Delivery Symposium “Viral Hepatitis: The Search for a Cure”

Michael Sofia Co-founder and Chief Scientific Officer, Arbutus Biopharma

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Viral Hepatitis: The Search for a Cure

Michael J. Sofia, Chief Scientific Officer Arbutus Biopharma, Inc. 17

Forms of Viral Hepatitis Five forms of viral hepatitis: Hepatitis A, B, C, D, E •

Hepatitis A – Acute self-limiting infection – Contracted by eating contaminated foods – Rarely leads to permanent liver damage

•

Hepatitis B – Acute infection can lead to chronic infection – Contracted by vertical infection or from contaminated blood sources – Lead to liver damage and HCC

•

Hepatitis C – Acute infection can lead to chronic infection – Contracted from contaminated blood sources – Lead to liver damage and HCC

•

Hepatitis D – Occurs only in conjunction with HBV – Leads to a more sever form of HBV-related liver disease

•

Hepatitis E – Typically only an acute self-limiting infection – problem in immune compromised individuals – Fecal to oral transmission route 18

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Chronic Viral Hepatitis: HBV & HCV • Every third person on the planet shows evidence of infection with viral hepatitis • 500 million people are chronically infected with hepatitis B or C • 1 million die every year: 1 every 30 seconds • Globally 57% of cirrhosis and 78% of primary liver cancer are due to these 2 diseases • 80-90% of liver transplants associated with HBV & HCV infection • The majority of those chronically infected are undiagnosed – hepatitis B and C are often asymptomatic for years • The sheer size of the problem is intimidating - as many people are chronically infected with viral hepatitis in 2 African countries as there are people living with HIV/AIDS in the whole world 19

Summary of Epidemiology and Natural History of Chronic Viral Hepatitis •

HCV – – – –

170-200 Million infected 20% lifetime risk of cirrhosis 4% lifetime risk of HCC Leading cause of liver transplant in North America and Europe – No vaccine available

HBV – – – –

2 Billion ever infected ~400 Million infected now 1 Million die each year of HCC or cirrhosis 25% life time risk for each HBsAg+ patient of HCC or cirrhosis – Second most common carcinogen (liver cancer) after cigarettes – Preventive vaccine available

•

20-30 years

•

Normal

Cirrhotic

HCC

Linked to the co-existence of multiple comorbidities

20

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Challenge Question ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT

Which chronic viral disease has the highest worldwide prevalence rate? • HIV • HCV • HBV • None of the above

21

HBV vs HIV vs HCV HIV

HCV

HBV

U.S. Prevalence

1 million

3 million

1.3– 3 million

Worldwide Prevalence

35 million

160 million

350 million

Percent Diagnosed in U.S.

80%

50%

30%

Percent Diagnosed Who Are Treated in U.S.

70%

33%

6-10%

Nature

RNA retrovirus

RNA virus

DNA virus

Virions Produced per Day

1010

1012

1013

Enzyme Targets for Therapy

Multiple

Multiple

One

Curable?

Unclear; lifelong suppression with HAART therapy

Yes

Unclear; lifelong suppression with Nuc therapy

Why Easy / Difficult?

Proviral DNA integrated into host genome, difficult to eliminate

RNA virus existing in the host cytoplasm; can eradicate with cocktail of small molecules DAAs

cccDNA inside the nucleus, also integrated into host genome, difficult to eliminate

Need Immune Component in Therapeutic Regimen for Cure?

Maybe

No

Maybe

Transmission

Infected blood/needles, sex



Vertical Transmission

Yes

No

Yes

Vaccine

No

No

Yes

2115 U.S. Sales

$9.3 billion

$13.3 billion

$700 million

22

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Can it become a disease of the past?

23

HCV: Prevalence, Total Infected, Genotype North America

Europe, Western

Europe, Central

Europe, Eastern

Asia, Central

Asia Pacific, High Income

Caribbean

Asia, Southeast

Asia, East

Latin America, Central

Prevalence (Viremic)

Latin America, Tropical

Latin America, Andean

Total Infected (Viremic)

0.0%-0.6%

0-200K

0.6%-0.8%

200K-650K

0.8%-1.3%

650K-1.9M

1.3%-2.9%

1.9M-3.5M

2.9%-7.8%

Latin America, Southern

Asia, South

North Africa/Middle East

Australasia

3.5M-9.2M

Sub-S Africa, Central

Razavi H, Gower E, Estes C, Hindman S. Global HCV Genotypes. AASLD 2013; 2013 Nov 1-5; Washington, DC, United States.

Sub-S Africa, Southern

Sub-Saharan Africa, West

24

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Growing Burden of Mortality Associated with Viral Hepatitis in the US (1999-2007) • National multiple-cause mortality data 1999-2007

• Mortality rates of HBV, HCV, and HIV; United States 1999-2007

• 73 % of HCV and 59 % of HBV-related deaths in persons aged 45-64 • Co-morbidities associated with increased odds ratio of mortality – – – –

Chronic Liver Disease (32.1;HCV and 34.4;HBV) co-infection with other hepatitis virus (29.9;HCV and 31.5;HBV) Alcohol related (4.6;HCV and 3.7;HBV) HIV co-infection (1.8;HCV and 4.0;HBV)

Holmberg SD , et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. 243

25

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Hepatitis C Virus: Morphology and Characteristics • Nucleic Acid: 9.6 kb ssRNA(+) • Classification: Flaviviridae, Hepacivirus • Genotypes: 1 to 6 • Enveloped • No known viral reservoir • Does not integrate into host genome

27

High Risk of Infection 170 Million Infected Worldwide  Clotting factor treatment prior to 1987  Injection drug use  Injection treatments prior to universal precautions  Long-term hemodialysis

CDC, MMWR 1998; 47:4

1 in 30 Baby Boomers Infected 28

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The Hepatitis C Virus HCV Lifecycle

•

HCV Genome

Error-prone RNA-dependent, RNA polymerase - poor proofreading function - high replication rate in vivo ~9.6 kb genome: 0.1-1 error per RNA synthesized

Replication Rates HCV

HIV

1012

1010-1011

Lindenbach, B and Rice, C., Nature, 2005, 436,933

29

Key Target Areas of Drug Discovery Focus and Key Drugs

Protease Inhibitors NS5A Inhibitors Telaprevir Boceprevir Asunaprevir Grazoprevir Simeprevir Paritaprevir

Daclatasvir Ledipasvir Velpatasvir Ombitasvir Elbasvir

Adapted from : Liver International pages 69-78, 23 DEC 2013 DOI: 10.1111/liv.12423 http://onlinelibrary.wiley.com/doi/10.1111/liv.12423/full#liv12423-fig-0001

Polymerase Inhibitors Nucleosid(t)e Sofosbuvir Non-nucleoside Dasabuvir Beclabuvir

30

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Challenge Question ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT

What was the first IFN-free HCV cure therapy to be approved by the US FDA? • Harvoni® (sofosbuvir + ledipasvir) • Viekira Pak® (ombitasvir + paritaprevir + dasabuvir +ritonavir) • Zepatier® (grazoprevir + elbasvir) • Sovaldi® (sofosbuvir) + RBV 31

FDA Approved IFN-Free HCV Cure Drug Combinations

2013

2014

2015

2016

Year and Order of Approval

2017

32

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The History of HCV Therapy Development

48

100% 90%

80%

24 ~67- 75%

16

60% 40%

~42-46% ~33-36%

08 RBV IFN

0 1989

3x Weekly

~10-11%

+ PEG IFN

3x Weekly

1998

Protease

Sovaldi

+

+

RBV

+ IFN

Weekly

2001

SVR (Genotype 1)

Treatment Duration (Weeks)

~94 - 99%

RBV

10%

RBV

+

+

PEG IFN

Harvoni

PEG IFN

Weekly

2011

20%

Weekly

2013

Daily

0%

2014

Time

33

HCV Curative Therapy Today • IFN-Free curative therapies are a reality • Simple oral fixed-dose and short duration therapies • >95% cure rates across multiple genotypes • High cure rates in difficult to treat patient populations • Patient access is the issue • HCV can become a rare disease in the future 34

34

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Is there a path to a cure?

35

Hepatitis B Virus (HBV)

• • • •

Hepadnaviridae member that primarily infects liver cells DNA virus 100 times more infective than HIV Found in blood and body fluids

• •

Viral reservoir: cccDNA in nucleus of hepatocytes Small segments of viral DNA do integrate but do not code for viral proteins

– Able to survive in dried blood for longer than 1 week

Ott et al. J Pediatr Health Care. 1999;13(5):211-216. Ribeiro, et al. Microbes and Infection. 2002;4:829-835. MMWR. 2003;52:1-33.

36

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Chronic Hepatitis B: By The Numbers MoreGenotypes than 350 million or 1 in(based 20 people worldwide have chronic hepatitis B infection •7 HBV on complete HBV (Compared with the 33 million living with HIV ) genome): A-G – A – World-wide 14 million in Europe 112 million in Asia-Pacific – Bmillion & Cpeople – Asia 1.46-2 in (93 million people in China) the United States are –chronically D – Southern Europe, Middle East infected – E – Africa die eachAmerica, year of HCC or Polynesia – 1FMillion – South cirrhosis time riskand for each HBsAg+ – 25% G –lifeUSA Europe 1

2

3,4

1,2

5

patient of HCC or cirrhosis Second most common carcinogen (liver cancer) after cigarettes

7 HBV Genotypes (based on complete HBV genome): A-G A – World-wide B & C – Asia D – Southern Europe, Middle East E – Africa F – South America, Polynesia G – USA and Europe

1 WHO. Available at: www.who.int/csr/disease/hepatitis/en/. 2 Ferlay et al. Globocan 2002, Cancer incidence, mortality and prevalence worldwide, IARC Press, Lyon 2004. 3 Records of the thematic press conference of the Ministry of Health of the PRC at April 21, 2008, from the website of the Ministry of Health of the People's Republic of China; 4 Ulmer, T et al. (2007). European orientation towards the better management of hepatitis B in Europe; 5. CDC. Hepatitis B FAQs for Health Professionals. Available at http://www.cdc.gov/hepatitis/HBV/HBVfaq.htm#overview.

37

The Hepatitis B Virus

• 4 Promoter elements • 2 enhancer elements • 10 start sites

5 mRNAs: • Pregenomic/core/pol (3.5 kb) • Precore (3.5 kb) • PreS1 (2.4 kb) • PreS2/S (2.1 kb) • X (0.7 kb)

Genome Structure of HBV Source: Gerlich, W. 2013. Virology Journal, 10:239

Glebe, D., et al, Sem. Liver Dis, 33, 2013, 103

38

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Transmission of HBV Horizontal Transmission Host

Vertical Transmission Mother

Recipient

Child-to-Child Contaminated Needles Sexual Health Care Worker Transfusion 6% infected after age 5 years become chronically infected

Perinatal Infant 90% infected infants become chronically infected

No clear risk factors in 20-30% of patients CDC Fact Sheet. http://www.cdc.gov/ncidod/diseases/hepatitis/b/. Accessed: October 2, 2004. Lee. N Engl J Med. 1997;337(24):1733-1745. Lavanchy. J Viral Hepat. 2004;11(2):97-107.

39

Three Phases of Chronic HBV Infection

Source: Gerlich, W. 2013. Virology Journal, 10:239

40

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REVEAL-HBV: Clearance of HBV DNA Reduces Risk of HCC •

REVEAL-HBV study cohort (N = 2946; aged 30-65 yrs) – Pts recruited 1991-1992, serum markers evaluated every 6-12 mos until June 30, 2004; HCC rates followed until December 31, 2008

•

HBV DNA suppression independently associated with significantly reduced risk of HCC – Pts with HBeAg suppression (n = 185) still had high HBV DNA levels and still at high risk of HCC – HBsAg suppression not associated with reduced incidence of HCC, but study not powered to detect difference

•

Greatest reduction in HCC incidence observed among pts with high baseline HBV DNA (≥ 100,000 copies/mL) who cleared HBV DNA during follow-up – HCC incidence highest in pts HBeAg seropositive throughout follow-up

41

HBV Approved Therapies Nucleosides/Nucleotides Tenofovir Alafenamide

VEMLIDY®

Gilead Sciences

2016

Tenofovir

VIREAD®

Gilead Sciences

2006

Telbivudine

TYZEKA™

Idenix/Novartis

2006

Entecavir

BARACLUDE™

Bristol-Myers Squibb

2005

Adefovir Dipivoxil

HEPSERA™

Gilead Sciences

2002

Lamivudine

EPIVIR-HBV®

GlaxoSmithKline

1998

Interferons Peginterferon alfa-2a

PEGASYS®

Roche Laboratories

2005

Interferon alfa-2b recombinant

INTRON® A

Schering/Merck

1992

Preferred Therapies – AASLD Guidelines 42

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7/27/2017

Relative Efficacy of Approved HBV Therapies HBeAg positive

Entecavir1,2

Tenofovir3

PEG-IFN α-2a4,5

n = 354

n = 176

n = 271

HBV DNA undetectable

67%

76%

25%a

HBeAg seroconversion

21%

21%

27%

ALT normalisation

68%

68%

39%

HBsAg loss

2%

3.2%

2.9%b

n = 325

n = 250

n = 177

HBV DNA undetectable

90%

93%

63%a

ALT normalisation

78%

76%

38%

HBsAg loss

0.3%

0%

0.6%b

HBeAg negative

Results at 48 weeks a HBV DNA < 400 copies/mL; b At 72 weeks 1. 2. 3.

Chang T-T, et al. N Engl J Med 2006;354:1001–10. Lai C-L, et al. N Engl J Med 2006;354:1011–20. Marcellin P, et al. N Engl J Med 2008;359:2442–55.

4. 5.

Lau GKK, et al. N Engl J Med 2005;352:2682–95. Marcellin P, et al. N Engl J Med 2004;351:1206–17.

43

HBV DNA change from baseline (log 10 c/mL)

Long-term Therapy is Required to Maintain Viral Suppression +1.0

Therapy 0.0

HBsAg -1.0 -2.0 -3.0

HBVDNA -4.0 Time

cccDNA Werle et al, Gastroenterology 2004

44

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What Does a Cure Look Like? Functional Cure

Absolute Cure

Clinical Scenario

As if recovery after acute HBV infection

As if never infected

HBsAg

Negative

Negative

Anti-HBsAg

Positive

Positive

Serum HBV DNA

Not Detected

Not Detected

HBV cccDNA

Detected, but not transcriptionally active

Not Detected

Hepatic integrated HBV DNA

Detected

Not Detected

Current Status

Achievable in a few patients

Not yet achievable

Jiang, et al., DDW, 2016

45

HBV Chronic Infection Antigen presenting cell

CD4+ T cell

•

1013 virons produced per day

•

Infection is not cytopathic

•

Outcome of infection and severity of associated liver disease are determined by nature and magnitude of host immune response

CD8+ T cell

HBV

Core particle plus strand synthesis

Vesicular transport to cell membrane

Core particle minus strand synthesis

Core assembly and RNA packaging

Core particle (capsid)

Translation

Transcription Repai r

Endoplasmi HBV Viral Life Cycle c reticulum

46 Hepatocyte

Nucleus

Cytoplasm

46

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7/27/2017

HBV and the Host Immune Response

• • • •

Inhibition of innate immune signaling Inhibition of HBV specific T cell responses Inhibition of antibody responses to HBV Outcome: Immune tolerance, chronicity

47

• Control viral replication – Cripple the virus

• Reactivate the host immune response – Release immune tolerance

Absolute Cure

Functional Cure

How to Achieve a Cure?

• Clear cccDNA

48

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HBV Cure: Potential DAA Drug Targets

49

HBV Cure: Emerging Strategies Viral Attachment Inhibition

• Preclinical and Clinical POC • Clinical results modest and variable • Effects in HDV also 50

25

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Entry Inhibition: Myrcludex B 1. Infection of PHH-transplanted uPA/SCID mice with HBV for 3 weeks 2. Treatment of infected mice with Myrcludex B for another 3 weeks blocks HBV spread

Myrcludex B monotherapy in chronically infected patients

Myrcludex reduces HBV DNA by 0.8log (w12) 2016 AASLD/EASL HBV Workshop Sept. 8th 2016

51

Nucleoside Prodrugs Liver Targeted Tenofovir Prodrugs

CMX157

Launched as Vemlidy®

Phase II Clinical Development

Advantages • Increase drug levels in liver • Reduce renal and bone toxicity associated with Tenofovir 52

26

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Inhibition of HBV Capsid Assembly and pgRNA Encapsidation •

Hepatitis B virus replication is strictly dependent upon capsid assembly

Class II

Class I

around pregenomic RNA (pgRNA) prior to rcDNA synthesis and subsequent cccDNA synthesis. •

Assembly of HBV nucleocapsid is dependent on ordered folding of the viral capsid protein.

•

Interfering with HBV capsid assembly with small molecule inhibitors has been shown to translate into antiviral activity in vitro and in vivo and constitutes a novel mechanism that is distinct from the nucleos(t)ide analogues currently available for clinical use.

HBV capsid assembly pathway and examples of inhibitors [core protein allosteric modulators (CpAM)]

53

First Clinical POC of Capsid Inhibitors (NVR-3-778) NVR 3-778 + PEG IFNalpha-2a Combo in treatment naïve HBeAg positive patients

IFN alone NVR 3-778 IFN + NVR

Yuen et al EASL 2016 Oral Presentation O Ar

Summary Table

O O S R N R'

N H

R"

d28 HBV DNA Treatment (log10 from BL) NVR 3-778 -1.72 PegIFNa-2a -1 NVR3 -778 + PegIFN -1.97

d28 HBV RNA (log10 from BL) -0.82 -0.73 -1.51

(NVR 3-778 @ 600 mg BID; Peg-IFN 180 ug/wk)

54

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Capsid Assembly Inhibitor AB-423



Data suggests AB-423 has a dual mode of inhibition:  Inhibits encapsidation of pgRNA during ongoing infection  Inhibits cccDNA synthesis presumably via inhibition of the capsid uncoating step

copy number/cell

4.0 3.0 2.0 1.0 0.0

cccDNA

ETV A B -4 2 3 , 1 0 0 m g / k g B ID A B -4 2 3 + E T V A B -4 2 3 + P e g a s y s

10

1

0 .1 0

7

14

21

28

Day

Dual mode of inhibition by capsid assembly inhibitors Subviral$ par: cles$

Cytoplasm$

Infected Myrcludex B

1.5

V e h ic le 100

S e r u m H B V D N A (% P r e - D o s e )



In vitro AB-423 showed:  additive/synergistic activity in combination with Nucs and RNAi agents  potent activity against HBV NucR variants and pan-genotypic activity  no significant activity against unrelated viruses AB-423 inhibited cccDNA synthesis during de novo HBV infection of C3AhNTCP cells

pgRNA relative level



IFNα

AB-423

Intermediate$ Compartment$

Vesicular$transport$ to$Golgi$and$cell$$ membrane$

HBV$$ virion$

pgRNA

Endoplasmic$ re: culum$ Surface$an: gen$

Mul: vesicular$ $$body$ NTCP$ (receptor)$

1.0

DNA$ synthesis$

x

pgRNA$ Core$ Pol$

Transla: on$ Nucleus$

Core$assembly$ RNA$packaging$ Intracellular$ amplifica: on$

0.5

HBV$ enters$cell$

0.0 Infected Myrcludex

IFN-α

x

Capsid$ disassembly$

ProteinFfree$viral$ DNA$ Repair$

cccDNA$

AB-423

Transcrip: on$

55

Capsid (Core Protein) Assembly Inhibitors Class I Heteroaryldihydropyrimidine (HAP)

Class II Propenamides

Sulfonylbenzamides

56

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7/27/2017

Capsid Assembly Inhibitor Patent Landscape Janssen

Bayer F

O Ar

O

Cl

MeO

N N H

O O S R N R'

N H

Roche

Novira O Ar

O

O O S N

N H

OH

N H

R N N N

n

R"

R"

Ar

F E A N

Ar

F

BAY-41-4109

B D

N H

O O S R N R'

O Ar

O Ar

O O S N

N H

OH

O

O Ar

O O R S N X N H R' X

N H

F

O

N

n NH

Sunshine Lake Pharm

R'

Ar

N H

R"

N H

R

R N

Y X

O O

Ar

Br

EtO

N

N

N H

GLS-4

N R4 O

N

R N R'

Assembly O NH

S

O Ar

O

O N H

N H

O N O

O R N R'

R"

S

HN R

57

Crystal Structure of Bound Capsid Assembly Inhibitor

HAP (Class I) - Proc. Natl. Acad. Sci. 2015, 112, 15196. 58

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HBV Cure: Emerging Strategies Inhibit HBsAg Production or Secretion RNAi Approach • •

Clinical and preclinical POC Potency & safety 

LNP Delivery Triple Trigger



Chol-siRNA



GalNAc-siRNA

Nucleic Acid Polymers Sequestration • •

Clinical POC? MOA?

Small Molecules •

Preclinical in vitro POC

? ~40 mer

59

Controlling S-Antigen Production via RNAi (ARC-520)

• Preclinical study in 9 HBVinfected chimpanzees (9-37y) • NUC pretreatment 8-24w, repeated injections of ARC520 • • • •

•

Dose escalation study (single dose i.v.): 32 HBeAg-, 8 HBeAg+ CHB patients under ENT Well tolerated up to 4 mg/kg under pretreatment with oral antihistamine Reduction of serum HBsAg up to 0.5 log (HBeAg- patients) 0.7 log (HBeAg+ patients) Reduction of HBeAg up to 2 log

Program Terminated do to tox signal

60

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7/27/2017

Controlling S-Antigen Production via RNAi (ARB-1467) PXB Mouse Study • LNP Delivery Technology • Triple trigger RNAi Serum HBsAg TKM-HBV 0.3 mg/kg

120 100 80 60 40 20 0

% Untreated at Day 42

Serum HBsAg as % Baseline

Untreated

Liver cccDNA

0

7

14

21 Day

28

35

HBV DNA Liver Serum

125 100 75 50 25 0

42

Day 42 (terminal analysis) n=5, mean ± SEM

Treatments

Human Clinical Study •

•

Single-dose results show significant reductions in serum HBsAg levels Multi-dose results show a stepwise, additive reduction in serum HBsAg Reductions of ≥ 1.0 log10 in 3/5 patients (after 3 monthly doses at 0.4 mg/kg)

Streinu-Cercel, A., et al., EASL 2017, Abst # SAT-155

61

Controlling sAg via Nucleic Acid Polymers (NAPS) Mono therapy with REP 2139-Ca

Al-Mahtab M, Bazinet M, Vaillant A (2016) Safety and Efficacy of Nucleic Acid Polymers in Monotherapy and Combined with Immunotherapy in Treatment-Naive Bangladeshi Patients with HBeAg+ Chronic Hepatitis B Infection. PLoS ONE 11(6): e0156667. doi:10.1371/

62

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Reducing or Eliminating cccDNA

Virus entry

rcDNA to cccDNA Conversion

cccDNA decay?

 Can inhibition contribute to reduction of cccDNA pool?

pgRNA to rcDNA conversion  Long term nuc treatment results in multi-log reduction of cccDNA pool  IFN treatment inhibits transcription and capsid stability, reduces cccDNA pool

63

cccDNA Formation and Stability What We Know and What We Don’t Know  Chromatization --Complexed with H3 and H4 histones, acetylation regulates HBV replication  Regulation of expression --HBX destabilizes SMC5/6 episomal silencing complex  Capsid conformational shift  rcDNA deproteinization --TDP2 implicated but unconfirmed  Completion of (+) strand and removal of RNA primer ---PolK implicated

--HBX itself is likely transcribed very early, active at low levels  Modulation of cccDNA copy number in non-dividing cells? --IFN/TNF/LTß upregulation of APOBEC3A

 DNA ligation of both strands over gap --Factors? DNA ligase 1+ 3 implicated 64

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Regulating cccDNA Transcription Epigenetic Control of cccDNA HDAC1HDAC1 Sirt1

Sirt1

PCAF

p300

p300 PCAF

Histones

Histones

LOW-REPLICATIVE STATE

HIGH-REPLICATIVE STATE Silencing Interferon alpha, Capsid inhibitors, Epigenome modifyers

 Epigenetic regulation: - Histones acetylases, deacetylases, methyltransferases - Transcription factors - Binding of viral proteins: HBc & HBx

Pollicino et al. Gastroenteroplogy 2006 Levrero et al. J Hepatol, 2009 Lucifora et al, J Hepatol 2012 Belloni et al, PNAS 20O9 Belloni et al, J Clin Invest 2012 65

cccDNA: A Target for Gene Editing Gene Editing Targeted DNA Cleavage Endpoints

Engineered Endonucleases Meganucleases/Homing endonucleases (HEs)

Tal-effector nucleases (TALENs)

Zinc Finger Nucleases (ZFNs)

CRISPR /Cas9

NHEJ – Non-Homologous End-Joining; results in short mutations, insertions and deletions (indels) HR – Homologous Recombination; accompanied by donor DNA, capable to insert / replace sequence Nishimasu et al, Cell 2014 Stone et al, Curr Opin HIV/AIDS 2013

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cccDNA: A Target for Gene Editing Gene Editing: Targeting HBV with CRISPR/Cas9

• Co-transfection of 1.3x WT HBV and sgRNA-Cas9-2A-mCherry plasmid by HDI in mice, followed by monitoring viral markers in mouse blood •

Total HBV DNA and cccDNA exhibit dramatic, increasing reductions over time

67

Immunmodulation: Challenges on the Path to a Cure 1. Heterogeneous host immunity among HBV patients. -what

is a clinical biomarker for host immune re-awakening?

2. Lack of understanding of the immunological function of viral proteins. -all

inhibitory? or stimulatory? HBV cure

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HBV Cure: Potential Immune Modulatory Drug Targets

69

HBV Cure: Emerging Strategies Restoration of Antiviral Immunity

Bertoletti A, Gehring AJ (2013) Immune Therapeutic Strategies in Chronic Hepatitis B Virus Infection: Virus or Inflammation Control?. PLoS Pathog 9(12): e1003784. doi:10.1371/journal.ppat.1003784

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TLR7 Agonist GS-9620 Woodchuck Study HBV DNA Levels

GS-9620 • • •

HBsAg Levels

•

5 mg/kg QOD, 4-8 weeks Mean Max viral load decline of 6.1 2.9, and 5.8 observed sAg levels reduced to undetectable in 100% of animals Reduced sAg levels were sustained after cessation of therapy Human Clinical Study • Discontinued due to lack of efficacy • Dose limiting toxicity?

Menne, S, et al., J. Hepatology, 2015, 62, 1237-1245

71

RIG-I Agonist: SB9200

• Dinucleotide • Reduction in serum HBV DNA • Reduction in sAg levels • Induction of ISGs • Induction of type 1 IFN

Fletcher SP, Menne S (2015) PLOS Pathogens (Sept. 2015).

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STING Activation Controls HBV Replication and Induces Cytokine Production • STING expressed in hepatocytes (low level), antigen presenting cells and T cells • An innate immune adaptor that regulates responses to cytosolic/viral dsDNA D ose 5000

1 23

4000

IL - 6 ( p g /m L )

Dose

7

3000 2000 1000 BLO Q

g 2

5

.5

m

m

g

g

/k

/k

g

1

2 1

2

.5

m

m

IF

g

N

/k

-

d te a e tr U

500

g

0 6

n

S e ru m H B V D N A

L o g 1 0 ( C o p ie s /m L )

8

1 2 3

IP - 1 0 ( p g /m L )

g /k

g

g

/k

m

g

5

m

2 -

2

P M A G c

c

D

G

M

A

X

M

A

P

A

-

-

1

1

U

2

.5

.5

m

m

IF

g

N

/k

-a

d te a e n

tr

g

5

DM XAA

400

cG AM P

300 200 100 BLO Q

DMXAA

2’3’ cGAMP bisphosphorothioate

Mouse STING agonist

Human/multi-species active

g

g

/k

/k

m

1

2

2

5

.5

m

g

g

/k g m 1

U

2

n

.5

m

tr

e

IF

a

N

te

d

-

g

0

DM XAA

cG AM P

Thi, E. et al., ICAR, 2017 Abs # 135

73

HBV Cure: The Drug Discovery Landscape Immune modulation • Toll-like receptors agonists, Gilead, Roche • Anti-PD-1 mAb, BMS, Merck, Roche, Medimmune, others • Vaccine therapy Transgene, Gilead, Roche Innovio, others • STING: ABUS • Cyclophilin: Contravir • RIG-I: Springbank, Rigontec

RNA interference, ABUS, ARWR, ALNY, GSK/Ionis, Arcturus/JNJ

Targeting HBsAg ABUS, Replicor, Roche

Surface proteins

HBx Polymerase

pgRNA

Polymerase inhibitors • Nucleoside :Gilead, BMS, CoCrystal, Contavir

Core

cccDNA

rcDNA Endosome

Entry inhibitors • Lipopeptides, e.g. Myrcludex-B

Targeting cccDNA • ABUS, JNJ, Chromis, Enyo, Intellia, Gilead, Precision Bio

Inhibition of nucleocapsid assembly, JNJ, Assembly, Gilead, Janssen, Roche, ABUS, Enanta, Sunshine Lake

Zoulim F, et al. Antiviral Res 2012;96(2):256–9; HBF Drug Watch, Available at: http://www.hepb.org/professionals/hbf_drug_watch.htm.

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Current Pipeline of Investigational Agents Preclincal

Enanta Capsid

Phase II

Phase III

Launch

ARB-1740 JNJ-379

Aicuris AIC 649

Enyo FXR Chomis cccDNA

Phase I

JnJ/Arcturus RNAi

CoCrystal CRISPR INtellia CRISPR Precision Gene Editing

Dicerna RNAi

Myrcludex B

AB-423 ALN-HBV

CMX157

Assembly ABIH0731 Ionis-HBVrx

NVR3-778 ARB-1467

GS-5801

SB-9200

Tenofovir Alafenamide

REP 9AC’ GS-9620

RG-7834 RIG-I

RNAi

Therapeutic Vax

Cyclophilin Inhibitor

HBsAg Release Inhib.

Nucleotide

Capsid Inhibitor

Viral Entry Inhibitor

TLR

Gene Editing

75

75

Combination Therapy • General belief that no single approach will be sufficient to deliver a cure • As in HCV and HIV combinations of drugs with different MOA will be the solution • Which combination will deliver the ultimate “cure” is yet to be determined

• How to assess combinations pre-clinically that may guide clinical studies is developing 76

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Combination Therapy

S e r u m H B V D N A ( lo g 1 0 c o p ie s / m L )

10

1

V e h ic le fo r A B -4 2 3

8

ETV P e g IF N A R B -1 7 4 0

7

A B -4 2 3 A B -4 2 3 + E T V A B - 4 2 3 + P e g IF N

6

0 .1

A B -4 2 3 + A R B - 1 7 4 0 A B -4 2 3 + A R B -1 7 4 0 + E T V A B -4 2 3 + A R B - 1 7 4 0 + P e g IF N

5

0LLOQ .0 1 00

77

114 4

2 12 1

28

28

35 D ay

6 wk Treatment Phase

S e ru m H B s A g ( lo g 1 0 IU /m L )

S e ru m H B V D N A ( % B a s e lin e )

100

3 54 2 D ay

4429

5469

6 35 6

4 wk Follow-Up

3

2

1 0

7

14

21

28

35

42

49

56

63

70

70

63

70

Dosage

Route

Frequency

(Capsid Assembly inhibitor)

100 mg/kg

PO

BID

ETV (Nuc)

1.2 µg/kg

PO

QD

PegIFN (Immune Stimulator)

30 µg/kg

SQ

2×/wk

ARB-1740 (RNAi)

3 mg/kg

IV

biweekly

AB-423

D ay

6 wk Treatment Phase

4 wk Follow-Up Lee, A., et al., AASLD 2016, Abs # 232

77

Key Challenges in Finding an HBV Cure • How to completely control viral replication? • How to address the virus’ ability to control the host immune response? • How to eradicate the viral reservoir, cccDNA?

• What is the best combination of MOA? • Can significant reduction in the duration of therapy be achieved?

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HBV: Is There a Path to a Cure? • Increased focus by both academic and industry labs well beyond historic levels • Many new targets and strategies under investigation • Increased efforts to understand the virus and how the host immune system responds to the virus

• Combination of drugs with different MOA have the potential to deliver major therapeutic advances 79

A Cure Yet To Be Realized: HBV Entecavir Lamivudine

Adefovir

PegIFN Tenofovir

IFNα as OT

1966

HBV Discovered

1982 1983

1987

HBV cccDNA identified

1992 1994 1998 2002 2003 2004

HEP2.2.15 cells identified

Non-cytolitic immune control

Telbivudine

2006

2008 2010 2011 2012 2013 2016

? CURE

Capsid Inhibitor identified

50 years without a cure

HBV RT identified

But light is at the end of the tunnel

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2017 Drug Design and Delivery Symposium Save the Date for the next webinar!

“Spinal Muscular Atrophy: Novel Approaches for Treatment” Kevin Hodgetts of Harvard Medical School 82

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Inaugural Pharma Leaders Symposium ACS National Meeting in DC Aug. 21, 2017 - 1 to 4 PM Walter E. Washington Convention Center - Room 146C

“ACS Pharma Leaders: Working together to make a difference”  neglected diseases  chemistry collaborations  predictive science Speakers: Richard Connell of Pfizer Lisa Shewchuk of GlaxoSmithKline Bradley Sherborne of Merck Anil Vasudevan and Dale Kempf of AbbVie Peter Warner of The Gates Foundation

Organizers:

Philip Kym of AbbVie, Catherine Peishoff (formerly of GSK), and Wendy Young of Genentech

For more information, Contact: Susan Ainsworth at [email protected]

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Viral Hepatitis: The Search for a Cure

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