Robert H.I. Andtbacka1, Brendan Curti2, Sigrun Hallmeyer3, Zipei Feng4, Christopher Paustian4, Carlo Bifulco4, Bernard Fox4, Mark Grose5, Bronwyn Davies5, Roberta Karpathy5, Darren Shafren5

1 Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; 2 Providence Cancer Center, Portland, OR; 3 Oncology Specialists SC, Park Ridge, IL; 4 Earle A Chiles Research Institute, Providence Cancer Center, Portland, OR; 5 Viralytics Limited, Sydney, Australia.

Characterisation of the oncolytic kinetics of the immunotherapeutic agent, CAVATAKTM, delivered intratumorally in patients with

advanced malignant melanoma.

OVC Boston, MA

June 16, 2015

CAVATAK™ (Coxsackievirus A21) an oncolytic immunotherapeutic agent

2

•  Proprietary formulation of the oncolytic virus, Coxsackievirus A21 •  Targeted to specific receptor over expressed on cancer cells (ICAM-1) •  Kills local and metastatic cells by oncolytic and immunotherapeutic

activity •  Potential application across a range of cancer types

–  Prostate, lung, melanoma, bladder and others •  Well tolerated in patients - to date no treatment-related grade

3 or 4 adverse events •  Potential intravenous as well as intratumoural use •  Potential application as monotherapy or in combination •  Manufactured under cGMP at SAFC, California

Coxsackievirus A21(CVA21) Oncolytic immunotherapeutic modes of action

Day 169 (w24) irPFS Primary endpoint (≥ 22.5%)

(irCR, irPR, irSD)

57 Stage IIIC and IV melanoma patients at least 1 injectable lesion

10 series of multi-intratumoral CVA21 injections (up to 3x108 TCID50)

Day 1,3,5,8,22,43,64,85,106,127

YES

Eligible for Extension study 9 cycles of multi-intratumoral

CVA21 injections (up to 3x108 TCID50) q21 days

NO

6 Weeks later, confirm Disease progression

NO

YES

CALM Phase II CAVATAK in Late stage Melanoma study design

Observation only

Planned Interim DMC analysis: 35 patients

Adverse Event1 Grade 1* n (%)

Grade 2 n(%)

Grade 3 n(%)

Grade 4 n(%)

Injection site pain 16 (28%) 2 (4%)

Tiredness (fatigue) 15 (26%) 2 (4%)

Chills 15 (26%)

Pyrexia 7 (12%)

Injection site erythema 7 (12%)

Pain 6 (11%) 1 (2%)

Myalgia 6 (11%)

Headache 6 (11%)

Hyperhidrosis 5 (9%)

Peripheral edema 1 (2%)

Erythema 1 (2%)

Musculoskeletal stiffness 1 (2%)

Rash 1 (2%)

• only Grade 1 adverse events occurring in 5 or more patients are listed • 1 AE coded using Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0

CALM Phase II trial (VLA-007) Safety and toxicity¶

CALM Phase II trial (VLA-007) Response data

Primary endpoint (≥ 10 pts with irPFS 6 months from 54 evaluable pts)

irPFS 6 months (CR+PR+SD) 38.6% (22 / 57 pts)

Secondary endpoints

Overall response rate (CR+PR, irRECIST 1.1) 28.1% (16 / 57 pts) [8 CR+ 8 PR]

Median time to response 3.4 months (95% CI: 1.5, 4.2)

Median irPFS 5.7 months (95% CI: 2.8, 11.1)

Median Overall Survival 26 months (95% CI: 16.7, NR+)

1-year survival rate 75.4% (43 / 57 pts)

Pt 03-032: Non-injected distant visceral lesion response

Male with metastatic melanoma to left neck and lungs. Injection in left neck.

1.0 x 0.8 cm

1.3 x 0.9 cm

0.5 x 0.2 cm

0.6 x 0.5 cm

Baseline Day 86

Injected

Non-injected Non-injected

Pt 12-002: Local injected and non-injected lesion responses

Male with metastatic melanoma to the leg. Injection in leg lesions .

Baseline Day 85 Injected Non-injected

IIIC IV M1a IV M1b IV M1c

• Analysis excludes patients satisfying protocol criteria but not on study long enough for 6 week tumor response assessment; CR=Complete response, PR= Partial response, SD= Stable disease and PD= Progressive disease

-100

-80

-60

-40

-20

0

20

40

60

80

100

Bes

t per

cent

age

chan

ge in

the

targ

et le

sion

s su

m o

f dia

met

res

rela

tive

to b

asel

ine

CR, PR or SD = 75.4%

CR or PR = 36.8%

VLA-007 (CALM study): Best Percentage changes in Target lesions

VLA-007 (CALM study): Best Percentage change in non-injected lung and liver lesions

-100-80-60-40-20

020406080

100B

est p

erce

ntag

e ch

ange

in in

divi

dual

ta

rget

lung

and

live

r le

sion

s co

mpa

red

to b

asel

ine

SD or PR= 62.5%

PR= 37.5%

Liver lesionsLung lesions

CALM extension cohort

VLA-007 (CALM study): Duration of Response

0 25 50 75 100

125

150

175

200

225

250

275

300

325

350

03-00604-00403-01208-00203-00103-03603-03903-00312-00212-00402-00103-02503-01504-01207-00103-020

Time, days

Indi

vidu

al p

atie

nts

trea

ted

with

CVA

21

X

X

response ongoing

Target lesion excised

Disease progression

Death

No injectable diseasenew therapy

IIICIVM1a

IVM1bIVM1c

+ Serum prior to CAVATAK injection from patients with CR, PR or SD * Preliminary on-going analysis

IL-1β IL-5IL-4

IL-6 IL-7 IL-8

IL-12 IL-17 IFN-γ

VLA-007 (CALM study): Patient Serum Cytokine levels. Anti-viral / anti-tumor immune response ?

CALM Phase II: Extension Cohort

YES

6 Weeks later, confirm Disease progression

Day 169 (w24) irPFS Primary endpoint (≥ 22.5%)

(irCR, irPR, irSD)

57 Stage IIIC and IV melanoma patients at least 1 injectable lesion

10 series of multi-intratumoral CVA21 injections (up to 3x108 TCID50)

Day 1,3,5,8,22,43,64,85,106,127

YES

Eligible for Extension study 9 cycles of multi-intratumoral

CVA21 injections (up to 3x108 TCID50) q21 days

NO

NO

Observation only

13 Stage IIIC and IV melanoma

patients at least 1

injectable lesion • Mandatory

biopsy • Multi-spectral

analysis • NanoString

Immune panel

Pt  03-­‐043  Day  0  (pre-­‐treatment)  

• Male: Stage IIIC with melanoma to the feet • Prior treatment with surgery

Injected N

on-injected

Day  0  

Day  8  (post-­‐treatment)  

Day  8  

Pt  03-­‐043  Multi-spectral analysis NanoString analysis: Immune

profiling panel

CD4CD8

FoxP3

CD163 (

PD-L1 n

eg.)

PD-L1

CD4CD8

FoxP3

CD163 (

PD-L1 n

eg.)

PD-L1

0

750

1500

2250

3000

Num

ber

of p

ositi

ve c

ells

/ m

m2

Pre-treatment (Day 0)

Post-treatment (Day 8)

CD4CD8

FoxP3

CD163 (

PD-L1 n

eg.)

PD-L1

CD4CD8

FoxP3

CD163 (

PD-L1 n

eg.)

PD-L1

0

50

100

150

200

250

Num

ber

of p

ositi

ve c

ells

/ m

m2

Pre-treatment (Day 0)

Post-treatment (Day 8)

Injected

Non-injected

Pt  03-­‐044  Day  0  (pre-­‐treatment)  

• Female: Stage IIIC with melanoma to back • Prior treatment with ipilimumab and talimogene laherparepvec

Injected N

on-injected

Day  0  

Day  8  (post-­‐treatment)  

Day  8  

Pt  03-­‐044  Multi-spectral analysis NanoString analysis: Immune

profiling panel

CD4CD8

FoxP3

CD163 (

PD-L1 n

eg.)

PD-L1

CD4CD8

FoxP3

CD163 (

PD-L1 n

eg.)

PD-L1

0

3000

6000

9000

12000

Num

ber

of p

ositi

ve c

ells

/ m

m2

Pre-treatment (Day 0)

Post-treatment (Day 8)

CD4CD8

FoxP3

CD163 (

PD-L1 n

eg.)

PD-L1

CD4CD8

FoxP3

CD163 (

PD-L1 n

eg.)

PD-L1

0

1500

3000

4500

Num

ber

of p

ositi

ve c

ells

/ m

m2

Pre-treatment (Day 0)

Post-treatment (Day 8)

12000

Injected

Non-injected

Pt  12-­‐010   Day  0  (pre-­‐treatment)  

• Male: Stage IV M1a with melanoma to neck • Prior treatment with ipilimumab and talimogene laherparepvec

Day  8  (post-­‐treatment)  

CD4CD8

FoxP3

CD163 (

PD-L1 n

eg.)

PD-L1

CD4CD8

FoxP3

CD163 (

PD-L1 n

eg.)

PD-L1

0

2000

4000

6000

8000

Num

ber

of p

ositi

ve c

ells

/ m

m2

Pre-treatment (Day 0)

Post-treatment (Day 8)

When treatment with immune checkpoint inhibitors fail

• Reconstitution of the tumour micro-environment with immune cell infiltrates

• Female: Stage IIIC with melanoma to legs • Prior treatment with ipilimumab and pembrolizumab

Pt  04-­‐015   Day  0  (pre-­‐treatment)   Day  8  (post-­‐treatment)  

CD4CD8

FoxP3

CD163 (

PD-L1 n

eg.)

PD-L1

CD4CD8

FoxP3

CD163 (

PD-L1 n

eg.)

PD-L1

0

3000

6000

9000

12000

Num

ber

of p

ositi

ve c

ells

/ m

m2

Pre-treatment (Day 0)

Post-treatment (Day 8)

Pt  04-­‐014   Day  0  (pre-­‐treatment)  

• Male: Stage IV M1c with melanoma to the leg and lungs • Prior treatment with ipilimumab • and pembrolizumab

Day  8  (post-­‐treatment)  

CD4CD8

FoxP3

CD163 (

PD-L1 n

eg.)

PD-L1

CD4CD8

FoxP3

CD163 (

PD-L1 n

eg.)

PD-L1

0

1500

3000

4500

6000N

umbe

r of

pos

itive

cel

ls /

mm

2

Pre-treatment (Day 0)

Post-treatment (Day 8)

•  The CALM study achieved its primary endpoint with 22/57 pts (38.6%) irPFS at 6 months

•  Multi-dose intralesional therapy with CVA21 was generally well tolerated (No Grade 3 or 4 treatment related AEs

•  Responses were observed in injected lesions, non-injected non-visceral lesions and in distant non-injected visceral lesions

•  CVA21 treatment induced notable changes within the tumor microenvironment by inducing increases in immune cell infiltrates and expression of PD-L1

•  CVA21 treatment induces a Th1-gene shift, with increases in interferon-induced genes

CALM Phase II trial: Conclusions

Future Directions

•  CVA21 treatment may be used to in combination with immune checkpoint blockade

•  CVA21 treatment may be used in a rescue strategy to reconstitute the immune cells within the tumor microenvironment of lesions resistant to immune checkpoint blockade

Acknowledgements Many thanks to:

•  The CALM study patients and families

•  CALM study investigators

•  CALM study Clinical Trials Research Staff

•  Viralytics Clinical Development team

Roberta Karpathy Leanne Stootman Bronwyn Davies Gough Au Jackie Burgess Rebecca Ingham Erin Green Susanne Johansson Penny Yates Robert Herd Eric Chan Min Quah Yvonne Vern Vee Richard Barry