© Defined Health, 2015 Defined Health Immuno-Oncology Webinar, July 23, 2015

BioEurope Spring April 4-6, 2016

Stockholm, Sweden www.therapeuticinsight.com

Defined Health is pleased to present:

Defined Health will also be participating in the following industry events: BioPharm America

September 15 - 17, 2015 | Boston, MA | http://dfndhlth.com/BPA-2015 CRI-CIMT-EATI-AACR - The Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival

September 16 - 19, 2015 | New York, NY | http://dfndhlth.com/CRI-CIMT-EATI-AACR GTCbio's CNS Partnering & Deal-Making Conference

September 18 - 19, 2015 | Philadelphia, PA | http://dfndhlth.com/GTC-CPDMC-2015 The Pharmaceutical Strategy Conference 2015

September 29 - 30, 2015 | New York, NY | http://dfndhlth.com/pharmastrategic LES 2015 Annual Meeting

October 25 - 28, 2015 | New York NY | http://dfndhlth.com/LES-2015 AACR-NCI-EORTCInternational Conference on Molecular Targets and Cancer Therapeutics

November 5 - 9, 2015 | Boston, MA | http://dfndhlth.com/AACR-NCI-EORTC Therapeutic Area Partnerships

November 18 - 20, 2015 | Boston, MA | http://www.iirusa.com/therapeuticareapartnership/home.xml ASH

December 5 - 8, 2015 | Orlando, FL | http://dfndhlth.com/ASH-2015

27th Annual Cancer Progress Conference March 8-9, 2016 New York City

www.cancerprogressbyDH.com

Boosting Immuno-Oncology Therapies to the Next Level: New Combinations & Approaches Moderators: Jeffrey M. Bockman, PhD, Vice President, Defined Health Joel Sandler, PhD, Consultant, Defined Health Panelists: Michael Curran, PhD, Assistant Professor, Department of Immunology; Scientific Director, ORBIT Program, MD Anderson Rachel Humphrey, MD, Vice President, Head of Immuno-Oncology, Eli Lilly and Company

July 23, 2015

© Defined Health, 2015 Defined Health Immuno-Oncology Webinar, July 23, 2015

Disclaimer

The information in this report has been obtained from what are believed to be reliable sources and has been verified whenever possible. Nevertheless, we cannot guarantee the information contained herein as to accuracy or completeness. All expressions of opinion are the responsibility of Cancer Progress, and though current as of the date of this report, are subject to change. The opinions and information set forth herein are expressed solely for the benefit of the addressee and only for the purpose(s) for which the report was produced. Without the prior written consent of Cancer Progress, this report may not be relied on in whole or in part for any other purpose or by any other person or entity, provided that this report may be disclosed where disclosure is required by law. This report may contain information provided by third parties such as Thomson Reuters, Wolters Kluwer, EvaluatePharma, Datamonitor, Informa Healthcare, IMS Health and others with a proprietary interest in the data provided herein. Please note that you are not permitted to redistribute any such third party information without consent from the originator company. Defined Health © 2015

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© Defined Health, 2015 Defined Health Immuno-Oncology Webinar, July 23, 2015

Peak Forecasts of $20-$40 Billion, With Near- to Mid-Term Growth Driven Largely By Immune Checkpoint Inhibitors

• Citigroup analysts have estimated combined peak sales of $35B for immuno-oncology drugs.

• Other analysts are more conservative, with peak estimates ranging from $20-$30B.

• Despite the discrepancy, analysts, Defined Health and leading immuno-oncology KOLs agree that anti-PD-1 and PD-L1 agents will be leading the pack with the greatest revenue potential through 2020.

EvaluatePharma

Citibank

Triangle Insights Group

© Defined Health, 2015 Defined Health Immuno-Oncology Webinar, July 23, 2015

Massive Increase in Research and in Clinical Development

ClinicalTrials.gov, EvaluatePharma, PubMed, Defined Health; *Assumes that final/target enrollment was reached in year of trial initiation

Immuno-Onc PubMed Hits

• In the past few decades, there has been a massive increase in the number of studies examining immuno-oncology therapeutic approaches.

• This trend is mirrored in the clinic, with a huge uptick in the number of patients treated in clinical trials with (and rapid regulatory approval of) agents targeting the PD1/L1 axis.

© Defined Health, 2015 Defined Health Immuno-Oncology Webinar, July 23, 2015

Oncology Meets Immunology: The Cancer-Immunity Cycle per Chen & Mellman

6

Each step of the Cancer-Immunity Cycle requires the coordination of numerous factors, both stimulatory and inhibitory in nature. Stimulatory factors shown in green promote immunity, whereas inhibitors shown in red help keep the process in check and reduce immune activity and/or prevent autoimmunity. Immune checkpoint proteins, such as CTLA4, can inhibit the development of an active immune response by acting primarily at the level of T cell development and proliferation (step 3). We distinguish these from immune rheostat (‘‘immunostat’’) factors, such as PD-L1, can have an inhibitory function that primarily acts to modulate active immune responses in the tumor bed (step 7). Examples of such factors and the primary steps at which they can act are shown. Abbreviations are as follows: IL, interleukin; TNF, tumor necrosis factor; IFN, interferon; CDN, cyclic dinucleotide; ATP, adenosine triphosphate; HMGB1, high-mobility group protein B1; TLR, Toll-like receptor; HVEM, herpes virus entry mediator; GITR, glucocorticoid-induced TNFR family-related gene; CTLA4, cytotoxic T-lympocyte antigen-4; PD-L1, programmed death-ligand 1; CXCL/CCL, chemokine motif ligands; LFA1, lymphocyte function-associated antigen-1; ICAM1, intracellular adhesion molecule 1; VEGF, vascular endothelial growth factor; IDO, indoleamine 2,3-dioxygenase; TGF, transforming growth factor; BTLA, B- and T-lymphocyte attenuator; VISTA, V-domain Ig suppressor of T cell activation; LAG-3, lymphocyte-activation gene 3 protein; MIC, MHC class I polypeptide-related sequence protein; TIM-3, T cell immunoglobulin domain and mucin domain-3. Although not illustrated, it is important to note that intratumoral T regulatory cells, macrophages, and myeloid-derived suppressor cells are key sources of many of these inhibitory factors.

Immunity. 2013 Jul 25;39(1):1-10

© Defined Health, 2015 Defined Health Immuno-Oncology Webinar, July 23, 2015

Checkpoints Likely to Be Foundational

T-Cells Vaccines

Oncolytic Viruses

Costim Agonists (e.g. 4-1-BB agonist mAbs)

Checkpoint Blockade (e.g. anti-PD/L1 mAbs)

Defined Health

• Anti-PD/L-1 agents could well be similar to that of the taxanes being the foundational IO piece of immunotherapy regimens, ultimately across many tumor types and lines of therapy.

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© Defined Health, 2015 Defined Health Immuno-Oncology Webinar, July 23, 2015

Activity Focused on Combinations, & More Immuno-Responsive Cancers, & Unmet Need Remains in Both “Responsive” Settings & In “Non-Responders”

• More immunogenic solid tumors include many tumors that are already being actively targeted by PD1/PDL1 and CTLA-4 inhibitors (melanoma, NSCLC, renal, H&N, gastric, bladder).

• Melanoma has become the proving ground for new IO regimens, largely led by BMS but also others viewing this as a de-risked setting to show some effect.

Citi Research, Clinicaltrials.gov, Defined Health

© Defined Health, 2015 Defined Health Immuno-Oncology Webinar, July 23, 2015

New Paradigm of Cancer Treatment: Next Gen IO Combinations – Shifting the Survival Curves Towards a Functional Cure?

Fred Hutch Cancer Center, Drew Pardoll (2014)

© Defined Health, 2015 Defined Health Immuno-Oncology Webinar, July 23, 2015

Thinking About Positioning IO Agents Across Disease Settings

Courtesy of Michael Curran

© Defined Health, 2015 Defined Health Immuno-Oncology Webinar, July 23, 2015

High Valuations Driven By Need For Access to Complementary I/O assets

EvaluatePharma, Company Website

Immuno-oncology Deal Timeline 2014-2015

2014

Feb 2014 Undisclosed

M&A

June 2014 $350M

NY-ESO-1

Oct 2014 IDO/TDO inhibitor

$150M + $1B

Mar 2014 $350M

Checkpoints

June 2014 Undisclosed checkpoints

June 2014 $265M CAR-T

July 2014 Undisclosed checkpoints

May 2014 $365M

ADU741/GVAX

July 2014 $25M

T-cell therapy

Sept 2014 Undisclosed

CART+ antibodies

Sept 2014 $46.M + $572M

CV9202 + Chemo

Nov 2014 $850M+ $2B

MSB0010718C

Dec 2014 $11M

CAR-TNK IO Combinations

IO + Traditional Therapeutics

© Defined Health, 2015 Defined Health Immuno-Oncology Webinar, July 23, 2015

2015

Jan 2015 $625M

MGD011

Jan 2015 $525M CAR-T

Feb 2015 $339M

TGF-beta

Feb 2015 $800M upfront $450M

milestones IDO1

Feb 2014 Undisclosed

IDO1 + ADXS-HPV

Mar 2015 $975M

Prostvac

Mar 2015 Undisclosed PD1 + GITR

Mar 2015 $941M CAR-T

Mar 2015 $250M

STING agonists

Apr 2015 Undisclosed CART/PDL1

Apr 2015 $350M + 925M

IPH2201

Apr 2015 $555M + $530M

IDO + TDO

High Valuations Driven By Need For Access to Complementary I/O assets

EvaluatePharma, Company Website

Immuno-oncology Deal Timeline 2014-2015

IO Combinations

IO + Traditional Therapeutics

Apr 2015 Celgene will make an upfront

payment of $450 million to AstraZeneca in

relation to MEDI4736

June 2015 Celgene and Juno

Announce Ten-Year Collaboration - Celgene to make initial payment of approximately $1

billion

© Defined Health, 2015 Defined Health Immuno-Oncology Webinar, July 23, 2015

Some Selected IO Activity Just This Week

13

© Defined Health, 2015 Defined Health Immuno-Oncology Webinar, July 23, 2015

Overarching issues

• Will checkpoint agents be foundational? • Combinations - antibodies, ACT, oncolytic viruses, bispecifics • Unique niches for selected IO modalities – one size does not

fit all? • Benchmarks for bringing new agents and combinations

forward – clinical and commercial/strategic challenges and opportunities

• Next gen IO approaches - targets & platforms • Diagnostic approaches for identifying responders • Partnering and business strategies

© Defined Health, 2015 Defined Health Immuno-Oncology Webinar, July 23, 2015

BioEurope Spring April 4-6, 2016

Stockholm, Sweden www.therapeuticinsight.com

Defined Health is pleased to present:

Defined Health will also be participating in the following industry events: BioPharm America

September 15 - 17, 2015 | Boston, MA | http://dfndhlth.com/BPA-2015 CRI-CIMT-EATI-AACR - The Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival

September 16 - 19, 2015 | New York, NY | http://dfndhlth.com/CRI-CIMT-EATI-AACR GTCbio's CNS Partnering & Deal-Making Conference

September 18 - 19, 2015 | Philadelphia, PA | http://dfndhlth.com/GTC-CPDMC-2015 The Pharmaceutical Strategy Conference 2015

September 29 - 30, 2015 | New York, NY | http://dfndhlth.com/pharmastrategic LES 2015 Annual Meeting

October 25 - 28, 2015 | New York NY | http://dfndhlth.com/LES-2015 AACR-NCI-EORTCInternational Conference on Molecular Targets and Cancer Therapeutics

November 5 - 9, 2015 | Boston, MA | http://dfndhlth.com/AACR-NCI-EORTC Therapeutic Area Partnerships

November 18 - 20, 2015 | Boston, MA | http://www.iirusa.com/therapeuticareapartnership/home.xml ASH

December 5 - 8, 2015 | Orlando, FL | http://dfndhlth.com/ASH-2015

27th Annual Cancer Progress Conference March 8-9, 2016 New York City

www.cancerprogressbyDH.com