PowerPoint Presentation - Confidential - Jefferies v2.pdf · 15 clinical studies, ... Tumor shrinkage by CT scan ( mesothelioma, brain) ... Checkpoint . Inhibitors : Requires existing

Gene Mediated Cytotoxic Immunotherapy (GMCI™)

dvantagene Jefferies 2015 Healthcare Conference

Estuardo Aguilar-Cordova

Chief Executive Officer

June 4, 2015

2 Gene Mediated Cytotoxic Immunotherapy

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Corporate Highlights

Innovative First-in-class next generation immuno-oncology therapeutic platform

Safe and Effective

Recent data from multiple late stage clinical oncology programs

15 clinical studies, 60+ peer reviewed publications

Late Stage Several value inflection points over next 3 years

2 ongoing pivotal registration studies, 3rd launched by 2016

Blockbuster First mover in massive market with severe unmet need

Estimated BLA approval in 2019 with projected $2B+ annual revenues


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Key Clinical Investigators and Advisors Peter T. Scardino MD Chair, Department of Surgery Memorial Sloan Kettering Theodore L. DeWeese, MD Chair, Department of Radiation Oncology Johns Hopkins Medical Institutions E. Antonio Chiocca, MD PhD Chair, Department of Neurosurgery Brigham and Women’s Hospital Mark Bloomston, MD Medical Director, GI Cancer Service Ohio State University Tanios Bekaii-Saab, MD Section Chief , Gastrointestinal Oncology The Ohio State University Steven M. Albelda, MD Associate Chief, Pulmonary, and Critical Care Director, Thoracic Oncology Research Laboratory University of Pennsylvania Daniel H. Sterman, MD Director, Pulmonary, Critical Care, and Sleep Medicine New York University

Advantagene Leadership and Advisors Key Management Estuardo Aguilar-Cordova,MDinf,PhD Chief Executive Officer and Chairman Harvard University, Baylor College of Medicine, Cetus FDA: BRMAC, VRPAC, NIH:RAC Laura Aguilar, MD, PhD Chief Medical Officer Harvard University, Baylor College of Medicine Stephen Rocamboli, JD, CLP Chief Business Officer Fordham Law, Orion Biomedical Fund, WRY&P, Paramount Brian Guzik, PhD, MBA Director, Business Development University of Virginia, UCSD/HHMI, Cornell Capital Partners

Board of Directors Mitchell Finer, PhD CSO bluebird bio; Founder Avalanche Biotechnologies; (Novocell; Gencell; Abgenix; Cell Genesys) Fred Mermelstein, PhD Partner, Leviathan Biopharma (Javelin, PolaRx, Cardiome, Paramount Capital) Udi Merav, PhD CEO enVerid Systems (Luminus Devices; Cliniworks; Stata Venture Partners, Strategic Decisions Group) Normand F. Smith, JD Partner, Burns and Levinson


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(5) Activated T-cells find and kill tumor cells

(4) Adenovirus and TK protein induce APC maturation and proinflammatory cytokine release leading to T-cell activation and expansion

(3) TAAs are taken up by antigen presenting cells (APCs) initiating immune cascade.

(1) Local delivery of AdV-tk to the tumor + oral valacyclovir

(2) TK protein converts valacyclovir to cytotoxic agent leading to tumor cell death and release of tumor associated antigens (TAAs)

Gene Mediated Cytotoxic Immunotherapy (GMCI®) Multi-Pronged Mechanism of Action Combines direct anti-tumor cytotoxicity with in-situ patient-specific vaccination

Recruited APC

Resting T cell

(2)

(4)

(1)

+ VCV

(3)

Tumor

Local Delivery

Systemic Effect

No Antigen Specific Limitations: Release of autologous TAs suppresses tumor immuno-tolerance. Even if TAs change over time, re-treatment will likely be effective.

Local hyper-immunogenic

microenvironment (e.g. cytokines

IL 2, IL 12)

Anti-tumor T cell clonal expansion (5)

Activated T cell

Necrotic and Apoptotic Tumor Cells

Superantigen


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Evidence of Single Agent Activity in Humans Cytotoxicity immune response in multiple tumor types and studies

0.02.04.06.08.0

10.012.014.0

-100 0 100 200 300 400

Tota

l PSA

Day of Treatment

Patient: 11-1

Clinical response Tumor shrinkage by CT scan (mesothelioma, brain) PET response (mesothelioma) Despite limited distribution, long-term effects consistent

with immune mechanism

Cytopathic / Immune effects Widespread necrosis and apoptosis (prostate, brain) Decreased vascularity (prostate, brain) Loss of glandular architecture (prostate) Widespread immune-cell infiltrate

Biochemical markers PSA response Increased PSA doubling time (PSADT) CEA reduction (ovarian) (not shown)

Pre-Rx 2 months post Rx

Vasculitis in Glioma Necrosis in Pre-Prostatectomy

Lymphocytic Infiltrate

17%

70%

0%10%20%30%40%50%60%70%80%

Partial Response Stable Disease

% o

f Pat

ient

s

Biochemical Response

Monotherapy, single dose in 18 XRT failure prostate cancer

patients

Rapid Response and Persistent effects consistent with immune

mechanism

Limited Transduction


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0

20

40

60

80

100

120

140

CD4+ Pre-Tx CD4+ Post-Tx


1A03

2A02

3A01

3A02

3A03

4A01

4A02

Case Number

Clinical Immune Stimulation & Checkpoint Response PaTK01 patient samples

21.4 Fold Average Increase 1.3 Fold Average Increase

Pre AdV-tk Post AdV-tk

CD8+ T-cells CD4+ T-cells

Cells

Per

Hig

h-Po

wer

ed F

ield

Quantification of Cellular Infiltrate

Pre AdV-tk Post AdV-tk Pre AdV-tk Post AdV-tk

PD-L1+ Tumor Cells

General Up-regulation

Cellular Staining


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Cancer Immunotherapy Desirable Characteristics GMCI® fulfillment

Characteristic Rationale GMCI®

“off the shelf” • More accessible than autologous “ex-vivo” therapies • Dramatically lower COGS • Long shelf life

Target multiple antigens

• Single antigen products have limited utility • Low immune-escape rates

Autologous • Patient specific response Non-replicating

• Negligible antigen masking concerns • No “shedding” issues • Low handling, administration and disposal costs

Low Toxicity • Ability to target early stage, low symptomatic disease • Ability to use in combination therapy


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Solid Tumor Cancer Immunotherapy Landscape GMCI® differentiated from other immuno-oncology approaches

Immunotherapy Utility Toxicity COGS

CAR-T Liquid tumors High High

Checkpoint Inhibitors

Requires existing immune response Moderate Moderate

Autologous Cell Vaccines

Patient specific product Low High

Allogeneic Cell Vaccines

Requires cross reactive antigens Generally Low Moderate

Single Antigen Vaccines

Require target antigen

expression Generally Low Low-High

GMCI ® “off the shelf” autologous cancer immunotherapy

Broad Low Low


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Dynamic Pipeline with Staggered Value Milestones

Preclinical Phase 1 Phase 2 Indication Anticipated Milestones

High & Intermediate Risk with XRT

Low risk with Active Surveillance

mFOLFRINOX Combination

Mesothelioma & others

PD1

Malignant Gliomas (GBM)

Phase 3

Completed/Ongoing

Ongoing Ph3 enrollment Accrual 1.5 years post-funding Data Lock 24m post-enrollment

Launch Phase 2 trial 1H2015 Data estimated 1H 2017

Enrollment complete in 2015 Primary data estimated 2016

IND enabling data for PD-1 combination 4Q 2015

Launch Ph1 trial 2016

Launch Study late 2015 Interim Analysis late 2017

Enrollment complete early 2016 Data lock 12m post-enrollment

BLA

1.5yr 2yr

6m 1yr

9m

6m 2yr

2yr

6m

1yr

1yr

Planned Milestones

Prostate

Brain

Pancreas

Lung

Checkpoint Inhibitors Combination


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Newly Diagnosed Prostate Cancer Significant Recurrence Rate with Current Standard of Care

Active Surveillance

XRT or Surgery

Minimal Residual Disease

Newly diagnosed, local prostate cancer

Current Treatment Options

Low-Risk 50%

Intermediate Risk 35%

ADT, XRT or Surgery

High-Risk 15%

ADT, XRT and/or

Surgery

Risk of Failure 10% 25-35% >40%

Risk Stratification

Recurrence

Castration (surgical or chemical)

Castration Resistant

Androgen Responsive

Taxotere, Provenge, Xtandi, Jevtana, Zytiga, Xofigo

Androgen Resistant

2-4 yr 1-2 yr 6m-1yr 6m-1yr

PSA Monitoring to Detect Recurrence

~30% Recurrence

240,000 patients/ year (US) 70,000 patients/year (US) 30,000 deaths/year (US)


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Newly Diagnosed Intermediate-High Risk Prostate Cancer Significant Recurrence Rate with Current Standard of Care

Active Surveillance

XRT or Surgery




Low-Risk 50%


ADT, XRT or Surgery

High-Risk 15%

ADT, XRT and/or

Surgery

Risk of Failure 10% 25-35% >40%

Risk Stratification

Recurrence



Androgen Responsive


Androgen Resistant

2-4 yr 1-2 yr 6m-1yr 6m-1yr

PSA Monitoring to Detect Recurrence

~30% Recurrence


Forecast with ProstAtak®

X

X Immunotherapy to PREVENT

Recurrence

Die of something other than prostate

cancer


entagen

Pre-Prostatectomy Patients- Evidence of Biological Activity Durable response after single administration in high-risk patients

0

5

10

15

20

25

30

-6 12 30 48 66 84 102 120

PSA

(ng/

ml)

Time (mos)

Biochemical Failure (>0.4ng/ml)

• ProstAtak administered pre-prostatectomy

• 10 patients treated • 1 pre-surgery dropout • 3 intermediate or low risk • 6 high risk at surgery

• 6 with positive margins

• 1 with seminal vesicle involvement

• 11.3 year median follow-

up • Durable PSA suppression • No clinical progression • No significant related SAEs

or late toxicities • Avoiding ADT is a clinical

benefit

Rojas-Martinez et al CGT 2013

Summary of Outcomes

Ten Year PSA Follow-Up No Additional Treatment Castration Avoided


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Phase 2 N=71 Newly diagnosed localized prostate

cancer

Arm A (33 pts)

Low-Risk (T1-T2a, Gleason <7, PSA<10)

2 cycles of AdV-tk, valacyclovir (VCV) plus

XRT

Arm B (33 pts)

Intermediate-High-Risk (T2b-T3, Gleason >6,

PSA≥10)

3 cycles of AdV-tk, VCV, androgen deprivation

(ADT), plus XRT

Arm C* (5 pts)

Stage D1 (positive lymph node)

Same as Arm B, plus XRT to pelvic lymphatics

Radiation Therapy Patients- Evidence of Efficacy Simple outpatient procedure delivered with standard of care

Pre-radiotherapy Radiotherapy Post-radiotherapy

First course: 15 days-8 weeks prior to radiotherapy

Second course: 0-3 days prior to radiotherapy

Third course: 15-22 days after previous injection

14 days

+/- Short-term androgen deprivation therapy

14 days 14 days Valacyclovir pills


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ProstAtak® Phase 2 Results Indicate Significant Benefit to Patients Improved Durable Clinical Response

0%

5%

10%

15%

20%

Peeters(2006)

Dearnaley(2007)

Zelefsky(2006)

Advantagene(Teh 2004;

Aguilar, 2006)

16% 15% 11%

0%

Low Risk Group

0%

5%

10%

15%

20%

25%

30%

35%

Peeters(2006)

Dearnaley(2007)

Zelefsky(2006)

D'Amico(2008)

D'Amico(2008)


Aguilar,2006)

21% 21% 22%

34%

25%

5%

Intermediate Risk Group

( - ADT) (+ ADT)

Perc

ent T

reat

men

t Fai

lure

Perc

ent T

reat

men

t Fai

lure

Pe

rcen

t Tre

atm

ent F

ailu

re

5 4.3 7 8.2 8.2 5.7 Median

Follow-Up (Years )

~75% Reduction in Phase 2

0%5%

10%15%20%25%30%35%40%45%

Peeters(2006)

Dearnaley(2007)

Zelefsky(2006)


Aguilar, 2006)

44% 43%

33%

20%

High Risk Group

5 4.3 7 5.7 Median F/U (yrs )

5 4.3 7 5.7 Median F/U (yrs. )

ProstAtak outside 95% C.I. for all risk groups’ Mean Event rate/person*year

Long-Term Freedom From Failure Rates


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Ongoing Pivotal Phase 3 Study in Newly Diagnosed Intermediate and High-risk Patients

Study Co-chairs: Peter Scardino, MD Chief of Surgery Memorial Sloan Kettering Cancer Center

Theodore DeWeese MD Chair of Radiation Oncology Johns Hopkins Medical Institutes

Enroll (711 patients) (newly diagnosed localized prostate cancer)

Stratify

Randomized 2:1

ProstAtak +VCV (3 courses) +XRT Placebo+VCV (3 courses) +XRT

Primary Endpoint: Novel Disease Free Survival Composite Endpoint Secondary Endpoints: PSA nadir, freedom from biochemical failure, prostate cancer specific survival, overall survival, immune stimulation,

quality of life

NCCN risk group categories

+/- Neoadjuvant ADT

Anticipated BLA Approval 2019

Special Protocol Assessment

• Event-driven Disease Free Survival • Event target ~24 months after enrollment


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Active Surveillance

XRT or Surgery




Low-Risk 50%


ADT, XRT or Surgery

High-Risk 15%

ADT, XRT and/or

Surgery

Risk of Failure 10% >40%

Risk Stratification

Recurrence



Androgen Responsive


Androgen Resistant

2-4 yr 1-2 yr 6m-1yr 6m-1yr

~30% Recurrence


Die of something other than prostate

cancer

Forecast with ProstAtak

No Requirement for Radical XRT/Surgery

ProstAtak® alone

(Mexico) ProstAtak®

+XRT (USA)

X

ProstAtak® - The New Standard of Care Immunotherapy for All Newly Diagnosed Local Prostate Cancer

X 25-35%


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ProActive Surveillance™ Study Design is Approved Localized Prostate Cancer in Low-risk Active Surveillance Patients

Minimal Treatment toxicity risk – 2 ProstAtak injections, each followed by 14

days of oral valacyclovir

All future treatment options maintained (Surgery or radiation)

Addresses “PSA anxiety”

Expected primary data availability 12-15 months post last-patient-in

Over 4000 patients screened to date

and 800+ selected as potential candidates

Enroll patients that have chosen Active Surveillance

Stratify by NCCN Risk Group Category

Randomize 2:1 N=156

Surveillance +

ProstAtak

Surveillance +

Placebo

End Points: Primary: PS score*

Secondary: Progression to additional treatment, Pathological response, PSA kinetics, Quality of Life,

and Immune Biomarkers * Proprietary algorithm of biochemical, pathologic and clinical disease measurements agreed with COFEPRIS (Mexico) as approvable and assessed 12 months from randomization


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ProstAtak® Projected Annual Net Sales Localized Intermediate to High Risk Prostate Cancer Only (USA & EU)

12 years market exclusivity for biologics

Additional approval for “Active Surveillance” will increase revenues by ~50% - ~75%


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Malignant Glioma Completed Phase 2 Shows Improved OS

Annual Diagnoses: ~20,000 Annual Deaths: ~15,000 Survival: median < 15 mos; 2yr ~26% Key Products: temozolomide (Merck; Est Peak Sales > $1B)

Program Status Two Phase 1 studies: Recurrent disease and newly diagnosed Phase 2 Study: Newly diagnosed in combination with standard of care Phase 2b: target launch late-2015

Principal Clinical Investigator: E. Antonio Chiocca, M.D, Ph.D. Chairman, Neurosurgery

Overview of 48 Patient Multisite Phase 2 Study

Outcomes compared with preplanned control cohort

No DLT or significant toxicity observed Overall Survival benefit in entire treated population

Dramatic benefit in patients with total resection

(>95% tumor removal)

AdV-tk delivered to tumor cells via tumor bed injection, Valacyclovir prodrug -orally for 14 days


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Intratumoral Immune Stimulation in GBM

CD3+ T-cells CD68+ APC

CD4+ T cells CD8+ T cells

• Stimulates immune response in vivo (Predina et al, 2011, 2012)

• Synergizes with surgery and

XRT (Sukin et al, 2001; Chhikara et al, 2001)

• Potential promotion of

systemic abscopal effect


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Increased Inflammation

Reduced Edema Tumor necrosis

Continued Tumor Reduction Note ventricle increase

Complete Image Response

3 months 6 months 12 months 24 months 36 months 60 months

Pre-Op Immediate Postop

Patient Alive 8+ Years Post Surgery Small Anterior Temporal Lobectomy, Most Tumor Remained and Injected

Progressing Resolution Post-Resection


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Overview of GMCI™ Outcomes: Malignant Glioma Dramatic benefit in patients with total resection

Subtotal vs Total Resection Overall Survival- All Groups

27% Relative Improvement (3.6m Median Survival Benefit)

48% Relative Improvement (8.1m Median Survival Benefit)


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Expanding Advantage in Survival Rate Dramatic benefit in patients with total resection

Study Cohort

N

OS 12 Months

(%)

OS 24 Months

(%)

OS 36 Months

(%)

Median OS

(mos) p value Group Subgroup Treatment

All H

isto

logi

es

(GBM

, AA,

and

AO

) All Resections

GMCI 48 66.7 35.4 18.8* 17.1 (0.0417)

SOC 134 56.7 21.6 7.5 13.5

Gross Total

Resection

GMCI 19 89.5 52.6 31.6* 25.0 (0.0492)

SOC 47 63.8 27.7 6.4 16.9

Subtotal Resection

GMCI 29 51.7 24.1 10.3 13.5 (0.4584)

SOC 87 52.9 18.4 8.0 12.5

GBM

Onl

y

All Resections

GMCI 43 62.8 32.6 14.0 16.7 (0.2073)

SOC 128 57.8 21.9 7.0 13.7

Gross Total

Resection

GMCI 18 88.9 55.6* 33.3* 25.1 (0.0120) SOC 44 63.6 27.3 4.5 16.3

Subtotal Resection

GMCI 25 44.0 16.0 0.0 10.6 (0.2231)

SOC 84 54.8 19.0 8.3 12.8

*Statistically significant (p<0.05) using two-tailed Fisher Exact probably test


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Lung/Malignant Pleural Effusion/Mesothelioma Long-term Mesothelioma Survivors

Annual Diagnoses: ~150,000 Survival: median < 9 mos; 2yr <20% Key Products pemetrexed (Lilly, Est Peak Sales >$2B*)

* approved for NSCLC and Mesothelioma

Pre Treatment 8 Months post 26 Months post 61 Months post

Two long-term Mesothelioma survivors, with no additional treatment –1 greater than 8 years post-treatment –1 greater than 14 years post-treatment

Durable Tumor Responses

Immune Stimulation Molecular and clinical evidence observed

Program Status Phase 1 Study in Mesothelioma Completed Promising evidence of Immune Stimulation, tumor responses, and survival Phase 1/2 Follow-up initiated in 2014 Estimated Completion of Enrollment: Mid 2015

Intrapleural Instillation of Vector

Principal Clinical Investigators Steven M. Albelda MD Associate Chief, Pulmonary Critical Care Daniel H. Sterman, MD Director, Pulmonary Critical Care


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Pancreatic Cancer Increased Survival and Immuno-reactivity with No Increased Toxicity

Program Status Phase 1/2 Study- 24 patients Completed with Positive Data Phase 2b launch estimated 1H2015

• CD8+ lymphocytic infiltrate • Enhanced PD-L1 expression

Immune Stimulation Observed

0

10

20

30

40

50

60

Median PFS(mo)

Median OS(mo)

1-Yr Survival(%)

Toxicity(rel units)

5-FU

5-FU + AdV-tk

Gemcitabine

Annual Diagnoses: ~45,000 Annual Deaths: ~ 40,000 Survival: median < 11 mos; 1yr <50% Key Products: gemcitabine (Lilly, Est Peak Sales $3.5B*) albumin-bound paclitaxel (Celgene, Est Peak Sales $2.1B*)

*Multiple tumor types

Preclinical studies ongoing to enable GMCI + anti-PD1 combination study

0 Wk 3-4 Wk 9 q 3-4mos

AdV-tk

Valacyclovir

Valacyclovir

Arm A: Surgery

CT scans and CA19-9 Arm B: 5-FU Chemoradiation

AdV-tk

Red=Standard of care procedures

Primary Clinical Investigator: Mark Bloomston, MD Tanios Bekaii-Saab, MD Phase 1/2 Study: Completed 24 evaluable pancreatic cancer patients 3 clinical sites: Ohio State University, City of Hope and Scripps

Locally Advanced Pancreatic Cancer

25% Response Rate by RESIST Criteria


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0

20

40

60

80

100

120

140



1A03

2A02

3A01

3A02

3A03

4A01

4A02

Case Number

Clinical Immune Stimulation & Checkpoint Response PaTK01 patient samples

21.4 Fold Average Increase 1.3 Fold Average Increase

Pre AdV-tk Post AdV-tk

CD8+ T-cells CD4+ T-cells

Cells

Per

Hig

h-Po

wer

ed F

ield

Quantification of Cellular Infiltrate

Pre AdV-tk Post AdV-tk Pre AdV-tk Post AdV-tk

PD-L1+ Tumor Cells

General Up-regulation

Cellular Staining

IND enabling studies with GMCI® and checkpoint inhibitors are underway


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Summary

Safe & Effective Multiple Phase 1 and Phase 2 clinical studies complete >350 patients treated, >650 patients doses in multiple oncology settings Long term follow-up data (up to 5-14 years) Blockbuster potential Multiple late stage clinical programs (first line prostate, glioma, pancreas, lung) Significant advancement in prostate first line SOC

Differentiated No marketed products or late stage R&D programs for first line prostate cancer Favorable pharmacoeconomics Experienced Executive Team Successfully designed and completed multiple large clinical trials 14 FTEs Premier KOL’s

Gene Mediated Cytotoxic Immunotherapy (GMCI™)

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Thank You!

Documents

PowerPoint Presentation - Confidential - Jefferies v2.pdf · 15 clinical studies, ... Tumor shrinkage by CT scan ( mesothelioma, brain) ... Checkpoint . Inhibitors : Requires existing