Corporate Overview - Isarna Therapeutics · Corporate Overview Dr. Philippe Calais Chief Executive...

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1 | 2015-10 Corporate Overview Dr. Philippe Calais Chief Executive Officer October 2015

Transcript of Corporate Overview - Isarna Therapeutics · Corporate Overview Dr. Philippe Calais Chief Executive...

Page 1: Corporate Overview - Isarna Therapeutics · Corporate Overview Dr. Philippe Calais Chief Executive Officer October 2015. 2 | 2015-10 Advancing innovative TGF-β isoform-specific therapies

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Corporate Overview

Dr. Philippe Calais

Chief Executive Officer

October 2015

Page 2: Corporate Overview - Isarna Therapeutics · Corporate Overview Dr. Philippe Calais Chief Executive Officer October 2015. 2 | 2015-10 Advancing innovative TGF-β isoform-specific therapies

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Advancing innovative TGF-β isoform-specific therapies into the clinic

Leader in deciphering TGF-β biology & role in disease pathophysiology

Proprietary research platform for selection of TGF-β isoform-selective ASOs

Exploit key roles of TGF-β isoforms in ophthalmology, fibrosis & oncology to

target unmet medical needs for major & orphan diseases

Strategic partnerships with Santaris/Roche & Sanofi

Trabedersen (1st gen. ASO) asset sale to Autotelic

Agile, semi virtual private Dutch B.V. with US & German affiliates

Executive Summary

ASO: AntiSense Oligonucleotide

Page 3: Corporate Overview - Isarna Therapeutics · Corporate Overview Dr. Philippe Calais Chief Executive Officer October 2015. 2 | 2015-10 Advancing innovative TGF-β isoform-specific therapies

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• Glaucoma*

• Diabetic retinopathy

• Proliferative vitreoretinopathy

• Age-related macular degeneration

• Secondary cataract (PCO)

• Corneal diseases

(pterygium, keratoconus)

ONCOLOGY

TGF-β: Clinical Development Opportunities

• Pancreatic cancer

• Lung cancer

• Renal cancer

• Hepatocellular

• RPPP-based patient selection

OPHTHALMOLOGY

• Breast cancer

• Mesothelioma

• Glioblastoma

• Melanoma

• Kidney fibrosis*

• Idiopathic pulmonary fibrosis*

• Liver cirrhosis

• Osteogenesis imperfecta

• Primary biliary cirrhosis

• Scleroderma

• Other

FIBROSIS/CIRRHOSIS

TGF-β

• Coronary bypass remodeling

CARDIOVASCULAR

• Alzheimer’s disease

• Parkinson’s disease

CNS DISEASE

Selection of high ‘probability-of-success’ diseases

* Selected lead indications

Page 4: Corporate Overview - Isarna Therapeutics · Corporate Overview Dr. Philippe Calais Chief Executive Officer October 2015. 2 | 2015-10 Advancing innovative TGF-β isoform-specific therapies

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Isarna’s Platform Core Differentiating Feature

TGF-β isoform involvement varies according to disease

OPHTHALMOLOGY

-------------------------ONCOLOGY

-------------------------

FIBROSIS

--------------------

Tailored treatments for 3 therapeutic areas

TGF-β2

TGF-β2 TGF-β1

TGF-β3

TGF-β1

TGF-β2

TGF-β1

Page 5: Corporate Overview - Isarna Therapeutics · Corporate Overview Dr. Philippe Calais Chief Executive Officer October 2015. 2 | 2015-10 Advancing innovative TGF-β isoform-specific therapies

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Ophthalmology

TGF-β2

Fibrosis

TGF-β1

Oncology

TGF-β2

TGF-β1

TGF-β + immune mod.

TGF-β3

RPPP

Program Research Preclinical Development Phase 1

Isarna’s Pipeline

ISTH0036

ISTH0047

ISTH1106

ISTH1047

RPPP: Responder Patient Profiling Program

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Potent & selective ASOs with improved drug-like properties vs 1st-gen. ASOs

Efficient target engagement: mRNA, protein & downstream pathways

Biphasic PK profile in biological matrices upon systemic/local injection

Pronounced & long-lasting distribution in organs/tissues

Long-lasting target engagement in selected organs/tissues

TGF-β Inhibitors Common Preclinical Properties

Lipofectamine-mediated transfection

of human A172 glioma cells

Page 7: Corporate Overview - Isarna Therapeutics · Corporate Overview Dr. Philippe Calais Chief Executive Officer October 2015. 2 | 2015-10 Advancing innovative TGF-β isoform-specific therapies

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Ophthalmology

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ISTH0036 Product Rationale in Advanced Glaucoma

TGF-β2

core physiopathologic factor

in glaucoma

Predominant cytokineAqueous & vitreous humor, neuronal retina &

retinal pigmented epithelium

TM function impairment & IOP

increaseTGF-β2 dependent EMT

Direct optic nerve damaging

Post trabeculectomy scarring,

fibrosis & bleb closureCore driver

Elevated levels in

primary open angle glaucoma

TM: Trabecular Meshwork IOP: IntraOcular Pressure EMT: Epithelial Mesenchymal Transition

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58

3

Glaucoma prevalence, in M

Worldwide USA

Glaucoma – High Unmet Medical Need

10% unresponsive to topical treatment

require surgery to control disease

Filtration surgery: last resort standard

procedure

1st filtration surgery failure rate: up to

33% (6mth to 1y)

Repeat surgeries blindness

2nd leading cause for blindness in the world

Optic nerve damage related disease

Results in visual field loss

Increased IOP based upon trabecular meshwork alterations

Page 10: Corporate Overview - Isarna Therapeutics · Corporate Overview Dr. Philippe Calais Chief Executive Officer October 2015. 2 | 2015-10 Advancing innovative TGF-β isoform-specific therapies

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ISTH0036 - Mechanism of Action

Pharmacology: TGF-β2 ASO with potent, selective, sequence- & dose-dependent

downregulation of TGF-β2 mRNA & protein

Administration: Intravitreal injection every 2 months for 12 months

MoA 3-directional properties resulting from TGF-β2 inhibition:

1. Prevention of further IOP rise

through anti-scarring effect

2. Optic nerve head neuroprotection

3. Trabecular meshwork protection

via antifibrotic effect

Disease modifier in glaucoma pathophysiology

See TGF-β isoform common preclinical properties (slide 6)

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ISTH0036 Summary of Preclinical Properties

Increase bleb size & survival* Bleb area collagen deposition reduction*

Antifibrotic & anti-angiogenic effect**

Intravitreal Intracameral

* Mouse glaucoma filtration surgery model ** Mouse choroidal neovascularization model

Intravitreal Intracameral

Inflammation Angiogenesis FibrosisCD45 D5 FITC D14 collagen D28 Sirius red staining D28

Page 12: Corporate Overview - Isarna Therapeutics · Corporate Overview Dr. Philippe Calais Chief Executive Officer October 2015. 2 | 2015-10 Advancing innovative TGF-β isoform-specific therapies

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lSTH0036 - Clinical Development StrategyExpand target indications post GFS Phase I

ISTH0036

GFS Phase I

GFS

(ODD)

Phase II/III

Diabetic

retinopathy

Phase II/III

Wet AMD

Phase II/III

Proliferative

vitreoretinopathy

& secondary

cataract

Phase II/III

GFS: Glaucoma Filtration Surgery ODD: Orphan Drug Designation

• IOP

• Bleb scarring

• Nerve damage

• Proliferative

fibrotic reaction• Pathophysiology • Proliferative fibrotic reaction

• Epithelial cell proliferation

Disease

driver:

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Fibrosis

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TGF-β: Key Driver Role in Fibrotic Disorders

TGF-β1 isoform dominance in fibrosis pathogenesis

Proinflammatory and profibrotic mediators in the initiation and maintenance of fibrosis

Strong scientific evidence for

clinically potent pro-fibrotic effect

Associated with activity of other

cytokines e.g. IL-7, TNF, …

Recognized key role in TGF-β

driven epithelial-mesenchymal

transition

Epithelial cell activation /

proliferation / differentiation

promotion & collagen-producing

myofibroblasts fibrous

connective tissue synthesisModified from Wynn TA, J Exp Med 2011

Entry and

activation TH17 cell

IL-17

EMTMyofibroblasts ECM

Proliferation

Differentiation

FibroblastsEntry and

activationROS

Epithelial cell

Neutrophil

Macrophage

Irritants

γδ T cell

IL-1β

TNFα

TGF-β

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Summary of Preclinical Package & Evidence*

Initial indication

Regulatory

Pronounced anti-fibrotic effects (ophthalmology program)

Preliminary evidence of anti-fibrotic effect; ISTH0047 as prototype:

Common features described previously

Pharmacology efficacy studies underway in PF & KF models

IND/CTA-enabling toxicology program & manufacturing to be completed

Significant collagen deposition reduction

(~56 %) in ISTH0047-treated mice

Liver fibrosis murine model

* Upon systemic administration PF: pulmonary fibrosis KF: kidney fibrosis

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Status of Isarna’s Fibrosis Program

Target severely debilitating, life-threatening diseases

Prioritize high unmet medical needs indications: KF & IPF (ODD)

Expand: liver cirrhosis, osteogenesis imperfecta (ODD)strategy going forward

Single agent or combination withcomplementary therapeutic agent

Complete IND-ready preclinical package for KF & IPF

Optimize & accelerate pipeline development

Target severe & life-threatening diseases*

Development strategy going forward*

Establish partnership or strategic alliance

* Pending financing KF: Kidney Fibrosis IPF: Idiopathic Pulmonary Fibrosis

ISTH1106

TGF-β1 targeting

compound

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Oncology

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TGF-β Role in Immuno-Oncology

Immuno-oncology modalities

Combine immune checkpoint inhibitors

(e.g. PD-1, PD-1L, CTLA-4) with TGF-β

inhibitors

Combination of immune check point

inhibitor CTLA-4 with TGF-β inhibitor

enhances efficacy in in melanoma

model (ASCO 2014)

Combine cancer vaccines with TGF-β

inhibitors

Established role in tumor microenvironment

Peritumoral immunosuppression is a key

driver for tumor growth & metastasis

Variable predominance & cross talk of TGF-

β1, β2 & potentially β3 isoforms

TGF-β2 directed therapy: 1st clinical

evidence of potent antitumor activity

(NSCLC phase III study with belagenpumatucel-L,

ASCO 2014)

Target TGF-β pathway-addicted tumors

Page 19: Corporate Overview - Isarna Therapeutics · Corporate Overview Dr. Philippe Calais Chief Executive Officer October 2015. 2 | 2015-10 Advancing innovative TGF-β isoform-specific therapies

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Summary of Preclinical Package & Evidence*

Established PoC: Evidence of anti-tumor activity in vivo

Common features described previously

Established tolerance and manufacturing completed for ISTH0047**

Results presented at AACR 2013/2014 & ASCO 2014

Specific therapeutic effect on

lung metastasis

No effect on ‘primary’ tumors

(not shown)

* Upon systemic administration ** ISTH0047: previously ASPH_0047

Anti-metastasis potential in lung metastasis mouse models of RCC & breast cancer

Page 20: Corporate Overview - Isarna Therapeutics · Corporate Overview Dr. Philippe Calais Chief Executive Officer October 2015. 2 | 2015-10 Advancing innovative TGF-β isoform-specific therapies

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Establish “Personalized Medicine”

treatment based on TGF-β isoform

expression with specificity to Isarna

isoform treatment

Develop companion diagnostic

Responder Patient Profile Program (RPPP)

For example: TGF-β2 signature in TCGA GBM

Companion diagnostic

Level 3: TGF-βisoform specific ‘activated pathways gene expression signature’ from tumor biopsies

Level 2: TGF-βisoforms and downstream pathways detection

Level 1: Detection of TGF-β isoform mRNAs &/or proteins by ISH or qRT-PCR, or IHC, respectively, in tumor biopsies

Patient selection based on TGF-β tumor expression

Page 21: Corporate Overview - Isarna Therapeutics · Corporate Overview Dr. Philippe Calais Chief Executive Officer October 2015. 2 | 2015-10 Advancing innovative TGF-β isoform-specific therapies

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Isarna’s Strategy in Oncology

Rationale

Target TGF-β pathway-addicted tumors

Select patients with high TGF-β expression

Pipeline development*

ISTH1047: ongoing preclinical dev.

TGF-β2: select new lead compound

Explore TGF-β1/β2 combination

Test dual modality combinations(e.g. check point inhibitors, vaccines)

ODD: mesothelioma, pancreatic cancer

Accelerate pipeline development

* Pending financing

Establish partnership/ strategic alliance

ISTH0047 (TGF-β2)

&

ISTH1047 (TGF-β1)

Page 22: Corporate Overview - Isarna Therapeutics · Corporate Overview Dr. Philippe Calais Chief Executive Officer October 2015. 2 | 2015-10 Advancing innovative TGF-β isoform-specific therapies

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Corporate Information

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Philippe Calais, CEO: Pharm.D, PhD; ICI, Roche, Neurochem, Ambrilia, Univalor

Michel Janicot: Head, Preclinical Research and Development, PhD; Janssen, Sanofi

Eugen Leo: Head, Clinical Development, MD, PhD, MBA; Janssen, Merck-Serono, Micromet

Experienced Management Team Supported byTop Tier Advisors

Alon Harris, PhD, Indiana U., US

David Spalton, MD, London Clinic Eye Centre, UK

Walter Stark, MD, Johns Hopkins Hospital, US

Rohit Varma, MD, U. of Southern California, US

Michael Wormstone, PhD, U. of East Anglia, UK

Rosemary Akhurst, PhD, UCSF, San Francisco, USA

Ugur Sahin, MD, TVZ, TRON, Mainz, Germany

Josep Tabernero, MD, VHIO, Barcelona, Spain

Michael Weller, MD, U. Hospital Zurich, Switzerland

Oncology

Management

Strong Scientific Advisory Board (SAB) leadership

Ophthalmology

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• Corporate restart

• Began new LNA-ASO isoform specific program

• Acquired exclusive rights to LNA (Roche) for TGF-β

• Expanded pipeline to 3 therapeutic areas

• Established Sanofi CMO partnership

Isarna Corporate History Overview

Antisense Pharma

15 years experience targeting TGF-β

with 1st gen ASO

Established Isarna based on next generation TGFβpipeline & new management team

Ophthalmology program clinical stage

- Complete IND for fibrosis & oncology

- Validating partnership

Trabedersen asset sale

- Steps towards public listing

Isarna corporate reorganization as Dutch BV and U.S. corporation

1998 - 2013

Trabedersen glioma

Phase III termination

2H 2012 ------------------- end 2014

2015 +

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www.isarna-therapeutics.com