Novel MOA: RNA as a Target and a Therapeutic

Cancer Progress by Defined Health New York, NY | March 8 - 9, 2016

Novel MOA: RNA as a Target and a Therapeutic

Moderator: Mike Rice, MS, MBA, Senior Consultant, Defined Health

Panelists: • Andreas G. Bader, PhD, VP, Translational R&D, Mirna Therapeutics • Bob Brown, PhD, Chief Scientific Officer and Senior Vice President, Dicerna • Carlo M. Croce, MD, Distinguished University Professor, The John W. Wolfe

Chair in Human Cancer Genetics, The Ohio State University • Nigel Horscroft, D.Phil, Director, Alliance Management, CureVac AG • Steven M. Kelsey, MD, FRCP, FRCPath, President, Onkaido Therapeutics

Scope of Panel: RNA as a Target and Therapeutic in Oncology

• microRNA (miRNA) – Prognostic biomarker – Therapeutic target

• Augmentation: miRNA mimetics • Inhibition: Anti-miRNA, Decoys

• RNAi (DsiRNA/siRNA, snRNA) – Knockdown of gene expression as drugs for previously

undruggable targets • Messenger RNA (mRNA)

– Alternate delivery of therapeutic proteins, vaccines, mAbs, etc. – Transient augmentation of therapeutic proteins and peptides as

drugs for previously undruggable targets – Immuno-Oncology – TAA, Neoepitopes, etc.

• Nucleic acid delivery and targeting strategies – Chemical modifications, nanoparticles and gene therapy

Cancer Progress by Defined Health New York, NY | March 8 - 9, 2016

Nucleic Acid Technologies in The Continuum of Biologic Therapeutics Platforms

• Immune Modulators

• SMIs

• Chaperones

• Substrate Reduction

• Transcription / Translation enhancers

• Epigenetics

• Plasma/tissue derived proteins

• Recombinant Proteins – Clotting

factors – Cytokines – Hormones – Growth

factors

• Enzyme Replacement

• Plasma derived Polyclonal Igs

• Monoclonal antibodies

• mAB fragments

• Scaffolds

• Intrabodies

• Antisense

• mRNA

• RNAi /siRNA

• miRNA

• Toll modulators • Aptamers

• Ribozyme

• Exon skipping

• Viral vectors ‒ Retro/ ‒ Lentiviral ‒ AdV ‒ AAV

• Non-viral ‒ Plasmids/ ‒ Fragments

• Gene editing with Meganucleases ‒ Zinc Fingers ‒ TALENS ‒ CRISPR/Cas9

• Autologous and allogeneic BMT/Cell therapy

• Other cell sources: e.g. ES, iPS

• Devices ‒ Encapsulation ‒ Scaffolds ‒ Implants ‒ Micro-organs ‒ Aphaeresis

Therapeutic Interventions

Small Molecule Modulators

Protein Augmentation Antibodies Nucleic Acids Gene Correction

& Augmentation Cell Therapy /

Regen Med

mRNA Augmentation is a Broadly Applicable Therapeutic Platform for Cancer and Other Disorders

Ugur Sahin, Katalin Karikó and Özlem Türeci Nature Reviews Drug Discovery 764 | OCTOBER 2014 | VOLUME 13

siRNA (and miRNA) Provides a Way to Specifically Inhibit Intractable Targets

• siRNA: dsRNA is exogenously introduced and is processed by Dicer into siRNA which is loaded into the RISC.

• AGO2, which is a component of RISC, cleaves the passenger strand of siRNA.

• The guide strand then guides the active RISC to the target mRNA.

• The full complementary binding between the guide strand of siRNA and the target mRNA leads to the cleavage of mRNA.

• Many clinical stage siRNA based drugs are targeting long known, but intractable targets:

– Myc – P53 – KRAS – BCR-ABL – Beta Catenin – PLK1 – PKN3 – RRM2

Molecular Therapy Nucleic Acids (2015) 4, e252, Published online 15 September 2015; http://www.scbt.com/gene_silencers.html

miRNA Mimetics and anti-miRNAs Can Modulate Multiple Oncogenic Pathways

• miRNAs control multiple pathways for which one microRNA mimic can regulate numerous oncogenes across multiple cancer pathways and immune evasion pathways.

• Inhibiting the function of oncomirs by use of anti-miR oligonucleotides (AMOs), small molecule inhibitors, miRNA sponges and miRNA masks/target protectors, and promoting the activity of anti-oncomirs through gene therapy or delivery of miRNA mimics can serve as novel therapeutic options against cancer.

Jornal of Pharmacology and Pharmacotherapeutics, 2012 : 3 Issue 3, p217-227

Cancer Progress by Defined Health New York, NY | March 8 - 9, 2016

Majority of RNA Drugs in Development Lead to Message Knockdown

Thomas Reuter’s Cortellis, Adis Insight; DH Analysis

siRNA, 95

Antisense, 50 miRNA, 38

RNAi, 24

RNA Vaccine, 14

TLR Modulator, 12

mRNA, 10 Catalytic RNAs, 3

CAR T/RNA, 3 RNA aptamer, 2

Other, 19

• Emerging approaches augment endogenous mRNA levels or express synthetic constructs (TAAs, CARs) designed to induce antitumor immune response

Preclinical and clinical Stage RNA Pipeline

Cancer Progress by Defined Health New York, NY | March 8 - 9, 2016

1 Marketed RNA CVD Drug: >50 in Development Across All Therapeutic Areas

Preclinical 200

Clinical 3

Phase 1 23

Phase 2 35

Phase 3 6

Registration 2 Marketed

1

Thomas Reuter’s Cortellis, Adis Insight; DH Analysis

Preclinical and clinical Stage RNA Pipeline

Global Sales Forecasts of DNA/RNA Therapeutics

0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

2015 2016 2017 2018 2019 2020

USD

(mln

)

WW Sales of DNA/RNA Therapeutics

Various Systemic Anti-infectives Sensory Organs Respiratory Oncology & Immunomodulators Musculoskeletal Genito-Urinary Gastro-Intestinal Cardiovascular Blood

EvaluatePharma

Kynamro $62M

• Oncology Makes up 6% of DNA/RNA Therapeutic Sales in 2019 and 9% of Sales in 2020

Cancer Progress by Defined Health New York, NY | March 8 - 9, 2016

RNA Therapeutics by Therapeutic Area (Clinical)

22 112

Non-Oncology Oncology

CML Endocrine CLL Brain tumor ALL Sarcoma RCC Multiple myeloma Head and neck tumor Ovary tumor Liver tumor Myelodysplastic syndrome B-cell lymphoma AML Bladder cancer Breast tumor CRC Prostate cancer Pancreas tumor Melanoma Lung tumor Cancer

Recent Deals Have Been Centered Around RNA based Drug Licensing and Collaborations to Gain Access to Technologies

0

2

4

6

8

10

12

2012 2013 2014 2015 2016

Num

ber o

f Dea

ls

RNA Technology Deal Activity by Type Other

Funding

Technology Platform

Delivery Technology

Target Validation

Drug - Early R&D

Drug - Screening/Evaluation

Drug - Licensing

Thompson Reuters Cortellis

Principal Company Partner Company Product/Platform Upfront Milestones

Rosetta Genomics Ltd Mirna Therapeutics Inc MRX-34 $1.6 M Potential payments

BioNTech AG Sanofi Five immunotherapies: synthetic mRNAs

$60 M $300 M per product

CureVac GmbH Boehringer Ingelheim Corp CV-9202 $48 M $590 M

ModeRNA Therapeutics Onkaido Company creation $20 M capital --

Horizon Discovery Group plc

AstraZeneca plc Identification/validation of novel targets

Undisclosed $88 M

Deal Value

Cancer Progress by Defined Health New York, NY | March 8 - 9, 2016

Novel MOA: RNA as a Target and a Therapeutic

Moderator: Mike Rice, MS, MBA, Senior Consultant, Defined Health

Panelists: • Andreas G. Bader, PhD, VP, Translational R&D, Mirna Therapeutics • Bob Brown, PhD, Chief Scientific Officer and Senior Vice President, Dicerna • Carlo M. Croce, MD, Distinguished University Professor, The John W. Wolfe

Chair in Human Cancer Genetics, The Ohio State University • Nigel Horscroft, D.Phil, Director, Alliance Management, CureVac AG • Steven M. Kelsey, MD, FRCP, FRCPath, President, Onkaido Therapeutics