TO FIGHT CANCER ONCOS Program Oncolytic Virotherapy Summit Boston - - PowerPoint PPT Presentation

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TO FIGHT CANCER ONCOS Program Oncolytic Virotherapy Summit Boston - - PowerPoint PPT Presentation

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ACTIVATING THE PATIENTS IMMUNE SYSTEM TO FIGHT CANCER ONCOS Program Oncolytic Virotherapy Summit Boston - 4 December 2019 IMPORTANT NOTICE AND DISCLAIMER This report contains certain forward-looking statements based on uncertainty, since

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SLIDE 1

ACTIVATING THE PATIENT’S IMMUNE SYSTEM TO FIGHT CANCER

ONCOS Program

Oncolytic Virotherapy Summit Boston - 4 December 2019

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SLIDE 2

IMPORTANT NOTICE AND DISCLAIMER

This report contains certain forward-looking statements based on uncertainty, since they relate to events and depend on circumstances that will occur in future and which, by their nature, will have an impact on the results of operations and the financial condition of Targovax. Such forward-looking statements reflect the current views of Targovax and are based on the information currently available to the company. Targovax cannot give any assurance as to the correctness of such statements. There are a number of factors that could cause actual results and developments to differ materially from those expressed or implied in these forward-looking statements. These factors include, among other things, risks or uncertainties associated with the success of future clinical trials; risks relating to personal injury or death in connection with clinical trials or following commercialization of the company’s products, and liability in connection therewith; risks relating to the company’s freedom to operate (competitors patents) in respect of the products it develops; risks of non-approval of patents not yet granted and the company’s ability to adequately protect its intellectual property and know- how; risks relating to obtaining regulatory approval and other regulatory risks relating to the development and future commercialization of the company’s products; risks that research and development will not yield new products that achieve commercial success; risks relating to the company’s ability to successfully commercialize and gain market acceptance for Targovax’ products; risks relating to the future development of the pricing environment and/or regulations for pharmaceutical products; risks relating to the company’s ability to secure additional financing in the future, which may not be available on favorable terms or at all; risks relating to currency fluctuations; risks associated with technological development, growth management, general economic and business conditions; risks relating to the company’s ability to retain key personnel; and risks relating to the impact of competition.

2

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SLIDE 3

Introduction

  • 2. ONCOS-102 Phase I monotherapy data
  • 3. ONCOS-102 Phase I PD1 refractory

melanoma

  • 4. ONCOS Program next steps
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SLIDE 4

TARGOVAX AT A GLANCE

Immune activation by oncolytic viruses Addressing the growing need for immune activators to enhance efficacy in combination with other treatments, such as checkpoint inhibitors ONCOS clinical stage adenovirus platform targeting hard-to-treat solid tumors

4

ONCOS-102 lead clinical asset One of the furthest developed OVs with >180 patients treated to date Four ongoing combination trials with rich news flow the next 3-12 months Encouraging clinical efficacy demonstrated Strong single agent immune activation and clinical data 33% ORR in anti PD-1 refractory melanoma in combination with Keytruda Promising interim data in mesothelioma in combination with chemotherapy Corporate highlights All assets unencumbered Listed on Oslo Stock Exchange: TRVX Market cap USD ~40m

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SLIDE 5

ONCOS IS BASED ON AN ADENOVIRUS SEROTYPE 5 BACKBONE

Highly immunogenic, TLR-9 agonist, stimulates inflammation Well-characterized and well-tolerated, suitable for combinations Versatile DNA backbone, ability to carry multiple transgenes

5

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SLIDE 6

ONCOS-102 IS THE LEAD CLINICAL STAGE ASSET

6

Selective replication in cancer cells ∆24 bp Fiber knob ITR ITR E1A ∆6.7K/gp19K E3 GM-CSF Transgene ∆Ad5 knob Ad3 knob

1

Boosting the immune activation

2

Enhanced infection

  • f cancer cells

3

Rb binding site in E1A removed Transgene insertion site, up to 4.5kb payload Added infectivity via DSG2 and CD46 receptors

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SLIDE 7

ONCOS-102 CLINICAL DEVELOPMENT PROGRAM

7

Compassionate use program 115 patients

  • Combination with Imfinzi
  • Intraperitoneal administration
  • Collaboration w/ AZ, CRI, Ludwig
  • MSKCC + 5 other sites

Various tumors Phase I - monotherapy 12 patients Peritoneal malignancies Phase I/II up to 75 patients Anti-PD1 refractory melanoma Phase I up to 21 patients Mesothelioma Phase I/II 31 patients

  • Combination with Keytruda
  • Part 1 completed with 33% ORR
  • Part 2 with increased dosing ongoing
  • MSKCC + 3 other sites
  • Combination with SoC chemotherapy
  • Randomized design
  • Enrollment completed
  • Data read-out January 2020

Completed Ongoing trial sponsored by Targovax Ongoing trial sponsored by partner

Targovax is also involved in an ongoing combination trial in Prostate cancer were ONCOS-102 is combined with a dendritic cell vaccine (DCVAC). This trial is sponsored by Sotio, a Czech biotech company

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SLIDE 8

ONCOS-102 Phase I monotherapy data

3. ONCOS-102 Phase I PD1 refractory melanoma 4. ONCOS Program next steps

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SLIDE 9

ONCOS-102 CLINICAL DEVELOPMENT PROGRAM

9

Compassionate use program 115 patients

  • Combination with Imfinzi
  • Intraperitoneal administration
  • Collaboration w/ AZ, CRI, Ludwig
  • MSKCC + 5 other sites

Various tumors Phase I - monotherapy 12 patients Peritoneal malignancies Phase I/II up to 75 patients Anti-PD1 refractory melanoma Phase I up to 21 patients Mesothelioma Phase I/II 31 patients

  • Combination with Keytruda
  • Part 1 completed with 33% ORR
  • Part 2 with increased dosing ongoing
  • MSKCC + 3 other sites
  • Combination with SoC chemotherapy
  • Randomized design
  • Enrollment completed
  • Data read-out January 2020

Completed Ongoing trial sponsored by Targovax Ongoing trial sponsored by partner

Targovax is also involved in an ongoing combination trial in Prostate cancer were ONCOS-102 is combined with a dendritic cell vaccine (DCVAC). This trial is sponsored by Sotio, a Czech biotech company

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SLIDE 10

ONCOS-102 Phase I trial design:

  • 12 patients, 7 different solid tumors
  • All refractory to multiple lines of therapy
  • Treatment: ONCOS-102 monotherapy

−

9 injections over 5 months Top-line results:

  • 100% innate immune activation
  • 11/12 patients increase in CD8+ T-cells
  • 40% DCR after 3 months
  • 2 long-term survivors
  • Abscopal effect and lasting systemic

immune responses observed

  • Induction of tumor specific T-cells

ONCOS-102

PHASE I SINGLE AGENT PROOF-OF-CONCEPT

IMMUNE ACTIVATION DEMONSTRATED

10

Pre-treatment Baseline Post-treatment Week 8 Cold tumor turned hot, CD8+ T-cell staining

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SLIDE 11

11

ONCOS-102 Phase I single agent proof-of-concept

MACROPHAGE INFILTRATION CORRELATES WITH SURVIVAL

11

Fold-change CD68+ macrophage count vs. survival CD8+ fold-change from baseline

r = 0.75 p = 0.005

Ranki et al., Journal for Immunotherapy of Cancer 2016, 4(17)

Potent inflammatory immune responses induced by ONCOS-102

  • CD68+ macrophage tumor infiltration

increased in 8 out of 12 patients

  • Highest fold-change in longest surviving

patients

  • Switch from M2 to M1 phenotype,

indicative of type I immune response

  • All patients had robust increases in

systemic pro-inflammatory cytokines

40 0.1 1 1,000 100 10 5 10 15 20

Overall survival (months)

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SLIDE 12

12

ONCOS-102 Phase I single agent proof-of-concept

CD8+ T-CELL INFILTRATION CORRELATES WITH SURVIVAL

12

Fold-change CD8+ T-cell count vs. survival CD8+ fold-change from baseline Overall survival (months)

40 0.1 10,000 1 1,000 100 10 5 10 15 20

r = 0.75 p = 0.005

Ranki et al., Journal for Immunotherapy of Cancer 2016, 4(17)

Case example #2 – Mesothelioma

  • Radio- and chemotherapy refractory
  • 130-fold increase in CD8+ T-cell infiltration
  • 47% reduction of tumor on PET 6 weeks after last

ONCOS-102 injection, survived 18 months Case example #1 – Ovarian cancer

  • Failed on 5 types of chemotherapy
  • >1,000-fold increase in CD8+ T-cell infiltration
  • Stable disease for 3 years, survived for 3.5 years
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SLIDE 13

13

ONCOS-102 Phase I single agent proof-of-concept

INDUCTION OF TUMOR- SPECIFIC T-CELL RESPONSES

13

De novo tumor-specific systemic CD8+ T-cell response

IFNγ ELISPOT assays on T-cells isolated from PBMC

Ranki et al., Journal for Immunotherapy of Cancer 2016, 4(17)

Mesothelioma patient (FI1-14)

  • Example - anti-MAGE-A3 ELISPOT assay
  • MAGE-A3 T-cells detected up to 6 months after start of

treatment Ovarian cancer patient (FI1-19)

  • Example - anti-Mesothelin ELISPOT assay
  • MAGE-A1, MAGE-A3 and NY-ESO-1 CD8+ T-cells also

detected

  • NY-ESO-1 still present at 17 month follow-up
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SLIDE 14

ONCOS Phase I PD-1 refractory melanoma

4. ONCOS Program next steps

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SLIDE 15

ONCOS-102 CLINICAL DEVELOPMENT PROGRAM

15

Compassionate use program 115 patients

  • Combination with Imfinzi
  • Intraperitoneal administration
  • Collaboration w/ AZ, CRI, Ludwig
  • MSKCC + 5 other sites

Various tumors Phase I - monotherapy 12 patients Peritoneal malignancies Phase I/II up to 75 patients Anti-PD1 refractory melanoma Phase I up to 21 patients Mesothelioma Phase I/II 31 patients

  • Combination with Keytruda
  • Part 1 completed with 33% ORR
  • Part 2 with increased dosing ongoing
  • MSKCC + 3 other sites
  • Combination with SoC chemotherapy
  • Randomized design
  • Enrollment completed
  • Data read-out January 2020

Completed Ongoing trial sponsored by Targovax Ongoing trial sponsored by partner

Targovax is also involved in an ongoing combination trial in Prostate cancer were ONCOS-102 is combined with a dendritic cell vaccine (DCVAC). This trial is sponsored by Sotio, a Czech biotech company

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SLIDE 16

LIMITED TREATMENT OPTIONS FOR ANTI PD-1 REFRACTORY MELANOMA

16

Advanced, unresectable melanoma stage III/IV BRAF mutant BRAFi & MEKi ~60-70% ORR BRAF wildtype anti-PD1 ~40% ORR anti-PD1 or anti-PD1 + anti-CTLA4 ~40% ORR anti-CTLA4 or anti-PD1 + anti-CTLA4 ~20% ORR Other IO (eg. T-Vec) Clinical trial 1L 1L 2L 2L 3L

anti-PD1 checkpoint refractory population Few treatment alternatives, high unmet medical need Poor response rates, typically ORR < 20% Rationale for oncolytic virus as priming agent to re-sensitize to anti-PD-1

Other IO (eg. T-Vec) Clinical trial 3L Progression Progression Progression Progression

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SLIDE 17

MELANOMA PHASE I TRIAL DESIGN

ONCOS-102 + KEYTRUDA COMBINATION IN ANTI-PD1 REFRACTORY MELANOMA

17

BL 1 2 3 6 9 12 15 18 21 24 27 Weeks

Part 1 completed: 3x ONCOS-102 injections Sequential treatment Part 2 enrolling: 12x ONCOS-102 injections Combination treatment

BL 1 2 3 6 9 12 15 18 21 24 27 Weeks

ONCOS-102 CPO ONCOS-102 + KEYTRUDA ONCOS-102 CPO KEYTRUDA

CPO: Cyclophosphamide Imaging

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SLIDE 18

ONCOS-102 ANTI-PD1 REFRACTORY MELANOMA

CLINICAL RESPONSE IN 3 OF 9 PATIENTS (33% ORR)

18

Subjects and Disease Stage

* Length of grey bars indicate time from first ONCOS-102 injection to discontinuation/EoS Withdrawn due to clinical PD Response still ongoing at last CT scan ** **

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SLIDE 19

ONCOS-102 ANTI-PD1 REFRACTORY MELANOMA

BEST PERCENTAGE CHANGE IN TARGET LESIONS

Letters and numbers indicating disease stage Preliminary data

19

* Non-target progression / new lesion (PD)

Best % change in tumor burden from baseline

IV III III III IV III IV III III

* * * *

100 80 60 40 20

  • 20
  • 40
  • 60
  • 80
  • 100
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SLIDE 20

ONCOS-102 ANTI-PD1 REFRACTORY MELANOMA

CASE EXAMPLE: PATIENT WITH COMPLETE RESPONSE

20

Progression on Keytruda 3x ONCOS-102 only 3x ONCOS-102 & 2x Keytruda 3x ONCOS-102 & 5x Keytruda 3x ONCOS-102 & 8x Keytruda

Tumor stage at enrolment: Prior therapies: Patient characteristics IIIb T4a, N2b, M0 Surgery (x3) Ipilimumab Dabrafenib + Trametinib Keytruda RECIST 1.1: CR, week 9-27 Tumor response, 1 of 1 injected lesion Baseline Week 3 Week 9 Week 18 Week 27 (EoS)

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SLIDE 21

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Tumor response, 2 of 2 injected lesions Baseline Week 3 Week 9 Week 18 Week 27 (EoS)

Lesion 1 of 2 Lesion 2 of 2 Progression on Keytruda 3x ONCOS-102

  • nly

3x ONCOS-102 & 2x Keytruda 3x ONCOS-102 & 5x Keytruda 3x ONCOS-102 & 8x Keytruda Tumor stage at enrolment: Prior therapies: Patient characteristics IV T4a, N1b, M1 Surgery Talimogene-laherparepvec (T-vec) Ipilimumab Keytruda RECIST 1.1: PR, week 9-27

ONCOS-102 ANTI-PD1 REFRACTORY MELANOMA

CASE EXAMPLE: PATIENT WITH PARTIAL RESPONSE

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SLIDE 22

BROAD UPREGULATION OF PRO-INFLAMMATORY CYTOKINES OBSERVED IN ALL PATIENTS

22 Unpublished company data * Below detection limit (BDL); If baseline was BDL, then baseline set to BDL for reference *

TNFα Systemic expression of pro inflammatory cytokines, -fold change from baseline

  • fold change from baseline

* * * * * * * * * * * *

IL-6 GM-CSF

* *

IFNγ

CR PR PD

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SLIDE 23

INCREASE IN CD8+ T-CELL INFILTRATION APPEARS TO BE NECESSARY, BUT NOT SUFFICIENT, FOR RESPONSE

23 23 Do not post, unpublished company data

  • Week 9 analysis not available

PD: Progressive disease PR= Partial response CR= Complete response

CD8+ T-cell infiltration into injected lesions, -fold change from baseline

CR PR PR PD PD PD PD PD PD Patient response Clinically responding patients

*

All 9 patients had low or very low CD8+ T-cell infiltration at baseline

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SLIDE 24

SYSTEMIC INCREASE IN TUMOR SPECIFIC T-CELLS OBSERVED IN FOUR PATIENTS

24

Presence of systemic tumor antigen specific T-cells IFNγ ELISPOT, spot number / 25,000 cells

* Week 3/9 analysis not performed

BL Week 3 Week 18 50 100 150 200 250 Specific spot number/25000 cells Tumor response, CR MAGE-A1 BL Week 3 Week 9 200 400 600 800 1000 Specific spot number/25000 cells Tumor response, PD MAGE-A1 BL Week 3 Week 9 50 100 150 200 250 Specific spot number/25000 cells Tumor response, PD NY-ESO-1 BL Week 9 50 100 150 200 250 Specific spot number/25000 cells Tumor response, PR* NY-ESO-1

*

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SLIDE 25

ONCOS-102 + KEYTRUDA DATA IN CONTEXT

ANTI-PD1 REFRACTORY MELANOMA BENCHMARK DATA

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18% 36% 24% ORR (12/49 pats.) Cavatak 6% 36% ORR (4/11 pats.) Tilsotomolid Anti-PD1 retreatment

SOURCE: Targovax market analysis, August 2019

Most pats CTLA4 naïve, 10-20% ORR expected

  • IOvance, autologous TIL therapy with IL-2
  • Complex and expensive manufacturing

32% 3% Lifileucel 35% ORR (23/66 pats.) T-cell therapy + anti-PD1 CMP-001 22% 22% 11% 3% ONCOS-102 33% ORR (3/9 pats.) 3% 17% PR SD-101 17% 2% Etinostat CR 25% ORR (21/83 pats.) 21%ORR (6/29 pats.) 19% ORR (10/53 pats.) Anti-CTLA-4 combination Comment

  • Checkmate Pharma, TLR-9 agonist
  • Data from high dose cohort
  • Dynavax, TLR-9 agonist
  • Syndax Pharma, HDAC inhibitor
  • Idera, TLR-9 agonist
  • Merck (Viralytics), Oncolytic virus, up to 20

injections

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SLIDE 26

ONCOS Program Next Steps

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SLIDE 27

27

PIPELINE WITH RICH NEAR-TERM NEWS FLOW

Mesothelioma Combination w/ pemetrexed/cisplatin Melanoma Combination w/Keytruda 3 new viruses Double transgene Product candidate Preclinical Phase I Phase II Phase III Next expected event ONCOS-102 Next-gen ONCOS January 2020 Randomized data 1H 2020 Part 2 data Update by collaborator Update by collaborator 1H 2020 Pre-clinical data Peritoneal metastasis Collaborators: Ludwig, CRI & AZ Combination w/Imfinzi Prostate Collaborator: Sotio Combination w/DCvac

27

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SLIDE 28

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ONCOS-200 SERIES VIRUSES HAVE DOUBLE TRANSGENES AND DISTINCT MODES OF ACTION

ONCOS-214

Enhanced cell killing properties

ONCOS-210 & -212

Inhibition of tumor growth and metabolism

ONCOS-211

Counteract immune- suppressive tumor microenvironment

Mode of action

  • Removal of immune

suppressive molecules from tumor microenvironment

  • Activation of T-cells

Target tumors

  • “Cold” uninflamed

tumors

  • e.g. colorectal
  • Highly invasive or

metabolic tumors

  • e.g. bladder
  • High-stroma tumors
  • e.g. pancreas
  • Interfere with tumor’s ability to

break down surrounding tissue

  • Induce cell cycle arrest
  • Inhibition of angiogenesis
  • Immunogenic cell death
  • Extend cell killing ability to

neighboring non-infected cells

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SLIDE 29

ACTIVATING THE PATIENT’S IMMUNE SYSTEM

TO FIGHT CANCER

CLINICALLY PROVEN

One of the furthest developed

  • ncolytic viruses

Strong single agent data Activation of anti-PD1 resistant tumors

RICH NEWS FLOW

Mesothelioma randomized data January 2020 Melanoma Part 2 data 1H 2020

INNOVATIVE PIPELINE

Next generation virus platform in pre-clinical testing Available for collaborations and partnering