NASDAQ: ABUS www.arbutusbio.com

Durable inhibition of hepatitis B virusreplication and antigenemia using subcutaneously administered siRNA agentAB-729 in preclinical models

Amy C.H. Lee

EASL International Liver Congress

12 April 2018 Paris, France

2

90MChina

15MEurope

2MUnited States

~900kpeople die every year as a consequence despite the availability of vaccines and antivirals.

257Mpeople are chronically infected with HBV, globally.

Source: Hepatitis B. WHO (2017) http://www.who.int/mediacentre/factsheets/fs204/en/

Key to Therapeutic Success in HBVREDUCE/SUPPRESS VIRAL

DNA & ANTIGENS

Viral Replication

Viral Proteins/HBsAg

cccDNA Formation /Function

RE-AWAKEN/BOOST IMMUNE RESPONSE

Reduced HBsAg

Immunotherapy

A combination approach to these key factors will drive cures

AB-729• Novel RNA interference agent

• Inhibits HBV replication, reduces all HBV transcripts, and lowers all HBV antigens

• Proprietary liver targeting technology

• Durable activity following a single subcutaneous dose

AB-729• Novel RNA interference agent

• Inhibits HBV replication, reduces all HBV transcripts, and lowers all HBV antigens

• Proprietary liver targeting technology

• Durable activity following a single subcutaneous dose

Polymerase, Core Ag, e Ag, pgRNA

sAg

sAg

HBx

siRNA delivery is mediated by a conjugated targeting ligand; GalNAc

AB-729 Mechanism of Action

• Cell uptake via GalNAc interaction with ASGPR

• Asialoglycoprotein Receptor– Helps clear desialylated proteins from serum

• High capacity uptake system– 0.5-1 million copies/cell– Rapid 15 min recycling time

• Advantageous tissue specificity– Highly expressed in hepatocytes– Conserved across species

Nucleus

RecyclingASGPR

RISC loading

Target Protein

X

GalNAc-siRNA

ASGPR

Clathrin-coated pit

mRNA cleavage

0 2 4 6 8 1 0-1

0

1

2

3

4

W e e k s A fte r A d m in is tr a t io n in A A V M ic e

Seru

m H

BsA

g

(Lo

g I

U/m

L)

S a lin e

A B -7 2 9 , 3 m g / k g S C

L L O Q

A R B -1 4 6 7 , 0 .3 m g / k g IV

AB-729 has longer duration of activity than ARB-1467, a Ph2 LNP siRNA agent

Adding New Value to Arbutus HBV Portfolio

1 dosesiRNA

Mean (n=5) ± SD

• This study utilized an early discovery-stage siRNA

• GalNAc delivery provides more durable siRNA activity than LNP – All LNP dose groups had resolved activity before end of study, whereas GalNAc activity persisted

0 1 2 3 4 5 6 7 81

2

3

4

G a lN A c v s L N P D e liv e r y

W e e k s a f te r A d m in is t r a t io n in A A V M ic eSe

rum

HB

sAg

(Lo

g IU

/mL)

S a lin e

0 .0 3 m g / k g L N P -e n c a p s u la t e d IV

0 .1 m g / k g L N P -e n c a p s u la te d IV

0 .3 m g / k g L N P -e n c a p s u la te d IV

1 m g / k g L N P -e n c a p s u la te d IV

1 m g / k g G a lN A c -c o n ju g a te d S C

GalNAc-Conjugates Have More Durable siRNA Activity

1 dosesiRNA

Pooled (n=5) samples

- 1 0 1 2 3

0

2 0

4 0

6 0

8 0

1 0 0

G e n o t y p e B

G e n o t y p e C

G e n o t y p e D

G e n o t y p e A

C o n c e n t r a t i o n ( l o g n M )

% I

nh

ibit

ion

of

HB

sA

g

- 1 0 1 2 3

0

2 0

4 0

6 0

8 0

1 0 0

L A M , T L V r e s i s t a n t

A D V r e s i s t a n t

W i l d t y p e G t D

E T V , L A M , T L V r e s i s t a n t

C o n c e n t r a t i o n ( l o g n M )

AB-729 has Pan-Genotypic ActivityThe siRNA functions well against all tested genotype & Nuc-resistant variants • Targeted HBV genome site is highly conserved across gt A-H

Mean (n=2) ± SD

HBV Variant HBsAg EC50(nM)

Genotype A 11

Genotype B 40

Genotype C 59

Genotype D 62

ETVr L528M/M552V/T532G/S550I 61

TLVr M552V+L528M 89

ADVr A529V 143

Wildtype 73

- 2 - 1 0 1 2 3

- 2 0

0

2 0

4 0

6 0

8 0

1 0 0

T o t a l H B V R N A

C o n c e n t r a t i o n ( L o g 1 0 n M )

To

ta

l H

BV

RN

A*

% i

nh

ibit

ion

A B - 7 2 9

U n c o n j u g a t e d s i R N A o f ' 7 2 9

- 2 - 1 0 1 2 3

- 2 0

0

2 0

4 0

6 0

8 0

1 0 0

S e c r e t e d H B s A g

C o n c e n t r a t i o n ( L o g 1 0 n M )

Se

cr

et

ed

HB

sA

g*

% i

nh

ibit

ion

AB-729 In Vitro Potency

• Effect of ligand-mediated delivery shown with ~2 log right shift versus unconjugated control

• No cytotoxicity detected up to highest AB-729 dose tested

Pleiotropic Effects on HBV Demonstrated in AAV-HBV Mouse Primary Hepatocytes

Mean (n=3) ± SD* Normalized to GAPDH mRNA

AB-729 EC50(nM)

HBsAg (secreted) 16.9

HBeAg (secreted) 10.1

3.5 kb HBV RNA 3.2

Total HBV RNA 4.9

Cytotoxicity > 19,591

CC50/EC50 for sAg > 1,158

• Concentration dependent asialofetuin (ASF) suppression of GalNAc-siRNA effect on multiple HBV markers* verifies drug activity is occurring through ASGPR interaction

• Novel GalNAc ligand conjugates provide excellent avidity for receptor binding

0 1 0 0 2 0 0 3 0 0 4 0 0 5 0 00

5 0 0

1 0 0 0

1 5 0 0

[L ig a n d lin k e d to F lu o ro p h o re ] (n M )

∆ M

ea

n F

luo

resc

en

ce I

nte

nsi

ty ABUS LigandFor ‘729

ABUS Ligand 2

External Ligand

-3 -2 -1 00

2 0

4 0

6 0

8 0

1 0 0

A S F C a n C o m p e t e O u t '7 2 9 A c t iv it yin P r im a r y A A V M o u s e H e p a to c y te s

A S F (L o g 1 0 µ M )

To

tal H

BV

RN

A/G

AP

DH

% in

hib

itio

nConfirmation of Mechanism of Action Asialoglycoprotein Receptor Interaction Demonstrated In Vitro

* sAg, eAg data similar; not shown

Dotted line = ‘729 activity at 0.3 ug/mL in absence of

competitor

Mean (n=3) ± SD

• Clear dose response, achieved max effect detectable in this model

• Supports clinical dosing frequency of 1 month (or more)

0 2 4 6 8 1 0

- 1

0

1

2

3

4

W e e k s A f t e r O n e S C D o s e

Se

ru

m H

Bs

Ag

(Lo

g I

U/

mL

) 1 m g / k g

3 m g / k g

9 m g / k g

L L O Q

S a l i n e

1 d

(right panel, & next slide)

AB-729 In Vivo Single Dose Response & DurationIn AAV Mouse

Liver sections stained for HBsAg

3 mg/kg

9 mg/kg

Saline

Control siRNA 9 mg/kg

‘729 TreatmentControls1 mg/kg

Mean (n=5) ± SD

200 µm

-1

0

1

2

3

4

5

In h ib it io n o f M u lt ip le H B V M a r k e r s b y '7 2 9

LOG

10

In

hib

itio

n#

C o n tro l s iR N A 9 m g / k g

'7 2 9 1 m g / k g

'7 2 9 3 m g / k g

'7 2 9 9 m g / k g

*

**

*

L iv e r 3 .5 k b

H B V R N A

S e ru m

H B V D N A

S e ru m

H B e A g

L iv e r T o ta l

H B V R N A

S e r u m

H B s A g

L iv e r

H B s A g

Pleiotropic Effects of AB-729 on HBV In VivoEffects are consistent with RNAi mechanism of action

• Dose responsive effects on all measured HBV markers

• cccDNA not significantly present in this model; not expected to be directly impacted by RNAi

14 days after single dose treatment in AAV mice (mean of n=5 ± SD) # relative to baseline (serum readouts) or saline control (liver readouts)* indicates signal for ≥1 animal below LLOQ

AB-729• Novel RNA interference agent

• Inhibits HBV replication, reduces all HBV transcripts, and lowers all HBV antigens

• Proprietary GalNAc-conjugate liver targeting technology

• Pan-genotypic activity

• Multi-month duration of surface antigen inhibition after a single SC dose – Significantly improved over ARB-1467, a Phase 2 IV LNP siRNA agent

• Next: Initiate GLP safety studies

Polymerase, Core Ag, e Ag, pgRNA

sAg

sAg

HBx

Acknowledgments – Arbutus Team:Emily ThiXin YeNicholas SneadChris PasetkaHui HuangAndrew KondratowiczJanet PhelpsOwen DalyLuying PeiAngela HussainkhelJoanna PanKaylyn KwokLily ZhangAmy C.H. Lee

Mark WoodAlan MartinLorne PalmerRichard HollandKieu LamAdam JudgeJames Heyes

Holly SteuerAndrzej ArdzinskiLucy WangKim SteverLauren BaileyAndy Cuconati

Sean SempleMerete EisenhardtDunmin MaoRobbin BurnsSunny TangEllen EvangelistaTroy Harasym

Agnes JaroszSara MajeskiCory Abbott Kevin McClintock

Michael J. Sofia