An innovative adjunct for treating canine oral melanoma and extending patients survival time

Laurent FISCHER, DVM, PhDMerial R&D

2008, Merial Limited, Duluth, Georgia, US, All rights reservedOslo, Nov 25 2008

Oslo, Nov 23 2008

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Key points

Aggressive neoplasm usually of the oral cavity, nail bed, footpadand mucocutaneous junctions.

4% of all tumors and most common oral tumor in dogs

Metastatic disease (LN, liver, lungs and kidneys) is common and chemo/radio-resistant

Oral and mucosal diseases are the most aggressive forms.Advanced oral patients have a typical lifespan of 1-5 months withconventional therapies

Other locations are less aggressive

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Stages and typical survival times

YesAnyAnyIV

NoYes> 4 cm*III

NoNo2 4 cmII

NoNo< 2cmI

MetastasisLymphnode

Tumorsize

Stage

WHO staging system for CMM

* Or any size if LN involvement

MacEwen, et. al. Canine Oral Melanoma: Comparison of Surgery Versus Surgery Plus Corynebacteriumparvum. Cancer Investigation 4(5): 397-402, 1986.Reprinted with permission of Informa HealthCare http://www.informaworld.com/lcnv.

Kaplan-Meier Survival with Conventional Therapies

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First line treatment is surgical tumor removal +/- radiation therapy. Chemoadjunct therapy is not effective with minimal impact on OST.

Several attempts to develop adjunct immunotherapies were considered

MacEwen et al. Canine oral melanoma: comparison of surgery versus surgery plus Corynebacteriumparvum. Cancer Invest. 1986;4(5):397-402.

Hogge et al. Preclinical development of human granulocyte-macrophage colony-stimulating factor-transfected melanoma cell vaccine using established canine cell lines and normal dogs. Cancer Gene Ther. 1999;6(1):26-36

Gyorffy et al. Bone marrow-derived dendritic cell vaccination of dogs with naturally occurring melanoma by using human gp100 antigen. J Vet Intern Med. 2005;19(1):56-63.

Alexander et al. Development of an allogeneic whole-cell tumor vaccine expressing xenogeneic gp100 and its implementation in a phase II clinical trial in canine patients with malignant melanoma. Cancer ImmunolImmunother. 2006; 55(4):433-42.

Milner et al. The immune response to disialoganglioside GD3 vaccination in normal dogs: a melanomasurface antigen vaccine. Vet Immunol Immunopathol. 2006; 114(3-4):273-84.

Finocchiaro et al. Cytokine-enhanced vaccine and suicide gene therapy as surgery adjuvant treatments for spontaneous canine melanoma. Gene Ther. 2008; 15(4):267-76.

von Euler H et al. Efficient adenovector CD40 ligand immunotherapy of canine malignant melanoma. J Immunother. 2008; 31(4):377-84.

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No tolerance

Xenogeneicantigen

Human tyrosinase85%

identityCanine tyrosinase

Self antigen

ToleranceNo immunity

Immune system

Antigen

Immunity

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pDNA/huTyr antigen @ 100, 500, 1500ug/vacc1 stage IV patient with survival = ~ 5.5 years. No melanoma on necropsy, death due to hemangiosarcoma

Median OST389d

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An opportunity for increased survival times

Bergman, PJ, et. al. Development of a xenogeneic DNA vaccine program for canine malignant melanoma at the Animal Medical Center. Vaccine 2006:24:4582-4585.

Bergman, et. al. Long- term survival of dogs with advanced malignant melanoma after DNA vaccination with xenogeneic human tyrosinase: a phase I trial. Clinical Cancer Research 2003;9:1284-1290.

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Merial

Memorial SloanKettering Cancer Center

(MSKCC), NYC

Animal Medical Center (AMC), NYC

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Merial developed it s own proprietary plasmidproduction process.

This will facilitate further developments of veterinary vaccines based on plasmid vectorplatform including

Internal R&D programsCollaboration with Academia and/or external partners

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In the US, the USDA has oversight for veterinary products with immune based mechanism of action.

USDA issues Conditional License for products that:Have established full safety requirementsHave a reasonable expectation of efficacyTarget a disease for which there is no licensed vaccine or effective treatmentHave established reliable and consistent manufacturing process

A unique opportunity to address a critical medical needin a limited timeframe

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2001-2004: Initial safety and feasibility assessments conducted in canine patients by the AMC in collaboration with the MSKCC and Merial.Additional safety studies was conducted by Merial in experimental dogs.

2005:Reasonable expectation of efficacy was acknowledged by USDA, based upon the

above work and published data Bergman, et al, Clinical Cancer Research, v9, p1284, Apr 2003. FONSI issued by USDA.

2006: Based on safety assessment in experimental dogs and in client-owned patients, the application for conditional license was approved.

2007:Conditional license issued by USDA

2009 Full license to be issued pending outcome of Clinical Efficacy Trials

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Purified plasmid expressing the human tyrosinase gene

0.4 mL dose (100µg) administered IM with the Canine TransdermalDeviceInitial treatment: 4 doses of vaccine at two week intervalsBooster dose at six month intervals

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Canine Transdermal injection devise

Adjunct therapy for dogs with stage II or III oral CMM with local disease control

negative local lymph nodes or positive lymph nodes that were surgically removed or irradiated.

© 2008 Merial, Limited, Duluth, GA. All rights reserved. VAC-TDA7MELPPT

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Induction of antibodies in canine patients

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Induction of IFN secreting T cells in Beagle dogs

TD IMLo

g1

0 (I

FN

SF

C/5

.10

5P

BM

Cs)

0

0.5

1

1.5

2

2.5 *

*

*

*

**

**

****

**

**

Log

10

(IFN

SFC/5

.10

5PBMCs)

0

0.5

1

1.5

2

2.5 *

*

*

*

Log

10

(IF

NS

FC

/5.1

05

PB

MC

s)

0

0.5

1

1.5

2

2.5 *

*

*

*

**

**

****

**

**

A Goubier, L. Fuhrman, L. Forest, N. Cachet, M. Evrad- Blanchard, J Wolchock, P Bergman, T Leard, V. Juillard, L. Fischer*

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Field Efficacy Trial

58 oral CMM (histopathoconfirmed*) dogs stage II/III with local disease control.

53 historical controls dogs stage II/III (MacEwen et al 99, ClinCancer Research V5, 4249-4258)

Primary variable : survival time of vaccinated vs. controls after surgery and local LNsprimary therapy.

2 years duration of follow up* demonstration of clean margins was not required

Field Safety Trial

Efficacy dogs (n=60) assessed for safety issues until efficacy trial accrual completion

No significant AE has been identified

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Total No. Dogs Enrolled = 58Age Range: 5-16 yearsWeight Range: 3-103 lbsMales and females equally represented7 AKC groups, 26 breeds/types

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5358Total

11(24%*)

19(58%* as of Aug 08)

Alive

Removed from study

Lost to follow up

Death due to unrelated causes

Death due to disease

Outcome

7

7

11

14

Melanoma Vaccinates

NA

1

7

34

McEwen Controls

*Percent surviving excluding those that died of unrelated causes, lost to follow-up, or removed for other reasons.

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Efficacy data as of Aug 08KM survival curve for death due to melanoma

2008, Merial Limited, Duluth, Georgia, US, All rights reserved

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Completion of full licensing procedureexpected 2009

Further follow up on use of the vaccine by veterinary oncologists (specifically in earlystage patients) to further understand the product potential.

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An innovative adjunct for treating canine oral melanomaand extending patients survival time has been developed.

Vaccine is available in the US under a USDA conditionallicensing process. Data supporting full licensure will besubmitted in 2009.

The canine melanoma vaccine also further demonstrates the utility of spontaneous tumors in companion animals as a valid translational model for the evaluation of novel vaccine therapies

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Phil Bergman and team, AMC (now atBrightHeart, NY) Jedd Wolchok and team at MSKCC Ilene Kurzman at Univ. of Wisconsin for generously sharing control group data (MacEwen, 1999). Maribeth Johnson, Medical College of Georgia, for statistical analysis.Greater Houston VeterinarySpecialists, TX

Dr. Steve SusaneckAnimal Cancer Specialists, WA

Dr. Karri MeleoSouthwest Veterinary Oncology, AZ

Dr. Mary Kay KleinDr. Monica JankowskiDr. Pamela Jones

NCSU College of Veterinary Medicine, Dr. Paul Hess

Numerous Merial colleagesProject teamClin Ops AthensBio Dev Lyon and AthensReg Affairs AthensIndustrial DevelopmentMarketing