Immuno-Oncology’s Signal-to-Noise Problem: Developing ......Jun 14, 2017 · Avelumab 1 1/2 1 2 1 1 1 1 Atezolizumab 1 1 3 1 M Efficacy ... But at ASCO 2017, Combo Data Was Sparse,

Immuno-Oncology’s Signal-to-Noise Problem: Developing Proof of Relevance for Novel MOAs

Jeffrey M. Bockman, PhDSenior Vice PresidentSenior Vice PresidentHead, Oncology PracticeDefined Health

Defined Health Seminar for IRICoRJune 14, 2017

Institut de Recherche en immunologie et en cancérologie -Commercialisation de la RechercheInstitute for Research in Immunology and Cancer-Commercialization of Research

ABSTRACT

Immunotherapy has over the past 5 or so years gone from an exclusion on BioPharma's external innovation list in searches for licensing or M&A opportunities to now being the hottest space that perhaps the industry has ever seen in Oncology (and maybe any therapeutic area). However, while in the past the frenzy over new approaches to treating cancer was often based on meaningful but still mainly incremental benefits (think 25% increase in OS if not simply ORR), the clinical improvements seen across a number of tumor types initially as monotherapy -melanoma, non-small cell, renal, bladder - have been significant, even dramatic, albeit in only a proportion of patients. And here significance refers to long, durable remissions. And these appear to look better still in combination, whether with standard of care (SOC) or other Immunotherapy agents (for example, anti-PDx plus anti-CTLA-4, like ipilimumab plus nivolumab in melanoma). Hence the sheer number of deals that industry has enacted since approval of the first checkpoint inhibitors (Yervoy, Opdivo, Keytruda, etc.), their size especially upfronts, and

Page 2Immuno-Oncology Seminar – June 14, Montreal© Defined Health, 2017

first checkpoint inhibitors (Yervoy, Opdivo, Keytruda, etc.), their size especially upfronts, and stage of deal, increasingly preclinical, have set records. And yet, as the number of clinical trials for the approved agents, novel agents, new modalities, and in particular number of combination studies have skyrocketed to over one thousand, the pace of deals is appearing to slow. Most importantly, the next breakthrough, that will improve the percent of patients with durable remissions in immunoresponsive cancers (so-called hot tumors) or yield good signals in the less immunoresponsive cancers (so-called cold or immune desert and excluded tumors), has yet to be seen, whether with up-and-coming new targets or new combinations. The result of all the first wave of deal activity and the slowing of clinical improvements by the first generation approaches means that novel programs in the hands of early stage biotechs need to have a clear story of differentiation, a supportable value proposition, and a keen understanding of potential positioning--how they might fit into this intensely competitive, highly dynamic space. This presentation will provide a context and lay out some of the challenges, as well some of the ways that newcos can think about strategizing in the new frontier that is Immuno-Oncology.

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 Defined Health, 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 Defined Health, 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,


This report may contain information provided by third parties such as Thomson Reuters, Wolters Kluwer, EvaluatePharma; DH analysis, 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, 2017

What Does the Cancer Market Look Like?


An Amazing Run of Cancer Approvals, 2011-2016 – Not to Mention Year-to-Date 2017


QuintilesIMS

But Almost the Only Thing That Anyone Wants to Hear About Is Immuno-Oncology (IO), or Cancer Immunotherapy (CIT)


Axel Hoos, Nat Rev Drug Discov. 2016 Apr;15(4):235-47.

120

140

160

US Oncology Products Sales:IO vs. Non-IO

Non-IO CAGR (2012-2022): 12%

IO Assets Are Still a Fraction of the Overall Oncology Market, But Growth Far Outweighs That of Non-IO Cancer Drugs

IO CAGR (2012-2022): 43%Total Oncology CAGR (2012-2022): 15%

Total sales of IO assets in 2022 are estimated at $20B in US and $35B WW.

The CAGR of IO products from 2012-2022 is projected to be 43% in US.


0

20

40

60

80

100

120

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Non-IO IO

Non-IO CAGR (2012-2022): 12%

EvaluatePharma; DH Analysis *analysis includes products marketed and in development

25

30

35

US IO Sales by Modality

IO Antibody Revenues Driven by Checkpoint Inhibitor Antibodies Continue to Dominate IO Modalities

Antibodies (Opdivo, Keytruda, Tecentriq, Yervoy) are the fastest growing modality within IO sales, driven by checkpoint inhibitors.


0

5

10

15

20

Sale

s ($

B)

IO Antibody Cell therapy Vaccine or Onc Virus

Small molecule Cytokine or Chemokine


Checkpoint Inhibitors Are Driving Sales, Primarily in Selected Launched Indications: Melanoma, NSCLC, and Bladder Cancer

8000

10000

12000

14000

16000

Multiple myeloma

Glioma

Ovarian cancer

Hodgkin lymphoma

Stomach cancer

Small cell lung cancer (SCLC)

Solid tumour indications

Do

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0

2000

4000

6000

8000

1 2 3 4 5 6 7 8 9 10 11

Solid tumour indications

Head & neck cancers

Non-Hodgkin lymphoma (NHL)

Renal cell carcinoma (RCC)

Melanoma

Bladder cancer

Non-small cell lung cancer (NSCLC)

2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022

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But Why is IO All the Rage?


Just to Make Sure We Are All on the Same Page


Oncotarget. 2014 Dec 30;5(24):12472-508; http://www.cancerresearch.org/news-publications/our-blog/april-2015/whatever-happened-to-coleys-toxins

Just to Make Sure We Are on the Same Page as to the Frontrunners of the Rage


Drew Pardoll, Nat Rev Cancer. 2012 Mar 22;12(4):252-64

Nivolumab Demonstrated Not Just an ORR Better Than Chemotherapy But a Meaningful Percentage of Patients Experienced Durable Remissions


Robert C, et al. N Engl J Med. 2015;372:320-330.; Clinical Care Options

And Nivolumab Plus Ipilimumab Demonstrated a Significant Improvement Over Ipi Alone – Especially in Patients With Low PD-L1 Expression


Clinical Care Options

And Now, First-Line in NSCLC, Pembrolizumab Has Bested Cytotoxic SOC

KEYNOTE-024: International, randomized, open-label, phase 3 trial compared pembrolizumab(administered at a fixed dose of 200 mg every 3 weeks) with the investigator’s choice of cytotoxic chemotherapy as first-line therapy for patients with advanced NSCLC and a PD-L1tumor proportion score of 50% or greater.


N Engl J Med 2016; 375:1823-1833

A Lot of Key Events (Requires Updating Almost Daily)

ProvengeApr, 2010(Prostate)

KeytrudaSept, 2014(Melanoma)

BlincytoDec, 2014(ALL)

KeytrudaOct, 2015(NSCLC)

ImlygicOct, 2015(Melanoma)

Approvals Recent or Expected Approvals

Atezolizumab(Bladder)

Avelumab(Merkel Cell)

CTL019(ALL)

Atezolizumab(RCC) (NSCLC, 2nd line)

Recent and Near-Term I/O Approvals Timeline

Approved Oct 18, 2016


Adis R&D Insight, Clarivate Analytics Cortellis

2015Pre-2015 2016 2017/2018

YervoyMar, 2011(Melanoma)

OpdivoDec, 2014(Melanoma)

OpdivoMar, 2015(NSCLC squamous)

OpdivoOct, 2015(NSCLC Non-squamous)

Opdivo +YervoyOct, 2015(Melanoma)

Opdivo(RCC)

Durvalumab(H&N)

Keytruda(Bladder)

Opdivo +Yervoy(GBM)

Opdivo (H&N)

Durvalumab(NSCLC)

Keytruda(NSCLC, 1st line)

Efficacy Benchmarks: Checkpoints

Efficacy Benchmarks: Marketed Checkpoint Inhibitors


NEJM 2015 Jan 22; 372:320-330; NEJM. 2015 Jun 25; 372(26):2521-2532; J Clin Oncol 34, 2016 (suppl; abstr 9505); NEJM 2015 July 9; 372(2):123-35; NEJM. 2015 Oct 22; 373:1627-1639; Oncologist 2016; 21(5):643-650; Tecentriq PI; NEJM 2015; 373:1803-1813; Lancet Oncology 2016 July; 17(7):956-965; J Clin Oncol 2016; 34 (suppl abstract 7535); J Clin Oncol 2016; 34 (suppl2S; abstract 355)

Efficacy Benchmarks: Checkpoints

Efficacy Benchmarks: Marketed Checkpoint Inhibitors(circle=ORR; diamond=mOS)

Opdivo, ORR 40% vs. dacarbazine, 14%

Opdivo/Yervoy, ORR 58% vs. Yervoy, 19%, Opdivo, 44%

Opdivo vs. docetaxel(ORR 19.5% vs. 10.5%*;mOS 10.7 vs 7.7 mo*)


NEJM 2015 Jan 22; 372:320-330; NEJM. 2015 Jun 25; 372(26):2521-2532; J Clin Oncol 34, 2016 (suppl; abstr 9505); NEJM 2015 July 9; 372(2):123-35; NEJM. 2015 Oct 22; 373:1627-1639; Oncologist 2016; 21(5):643-650; Tecentriq PI; NEJM 2015; 373:1803-1813; Lancet Oncology 2016 July; 17(7):956-965; J Clin Oncol 2016; 34 (suppl abstract 7535); J Clin Oncol 2016; 34 (suppl2S; abstract 355); *squamous and non-squamous NSCLC trials averaged

Keytruda, ORR 33% vs. Yervoy, 12%

Opdivo vs. Everolimus, (ORR 25% vs. 5%; mOS 25 vs. 19.6 mo)

Tecentriq vs. docetaxel(ORR 15% vs. 15%; mOS 12.6 vs. 9.7 mo)

mOS 10.7 vs 7.7 mo*)

But There Have Been Other Trials That Have Failed or Had Marginal Data, Just Among Checkpoints, Let Alone Other Modalities (Like Vaccines)

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Nivolumab 2 3* 1/2 M 3 M* M M 1/2 1/2

Pembrolizumab 1 1 2 2* 2* 1/2 2 M M 2 M 1 2* 2 1/2* 1 2 1 2


Clinicaltrials.gov; DH Analysis

Pembrolizumab 1 1 2 2* 2* 1/2 2 M M 2 M 1 2* 2 1/2* 1 2 1 2

Durvalumab 2 1/2 1/2* 1/2

Avelumab 1 1/2 1 2 1 1 1 1

Atezolizumab 1 1 3 1 M

Efficacy

Negative Positive

Numbers Represent Trial Phase or Market

*Represents a Combo Trial

If there are combination therapies that are earlier but have higher efficacy than monotherapy, the combo therapy is represented

And Major Setbacks, For Example with CHECKMATE-026, While Striking a Major Blow to BMS, Have Not Noticeably Dampened the Fervor


But at ASCO 2017, Combo Data Was Sparse, Modest, or at Best Promising


FierceBiotech; Xconomy

To Understand Deal-Making, One Needs to Appreciate Immuno-Oncology Clinical Development Activity


Hot & Cold Tumors, More & Less Immunoresponsive Cancers, Immunogenic Tumors


Citibank

Elements of Cancer Immunity and the Cancer–Immune Set Point


Dan Chen and Ira Mellman, Nature 2017 Jan 18;541(7637):321-330

PD-1/L1 Make Up a Significant Proportion of Checkpoint Inhibitors in Clinical Development, GITR, OX40, and CD40 Are Key Costim Agonists

9

1

1

11

11 1

US Checkpoint Programsby Target (n=33)

PD-1

PD-L1

CTLA4

LAG3

KIR

5

2

1

11

US Costim Programs by Target (n=19)

GITR

OX40


Adis R&D Insight, Clarivate Analytics Cortellis; DH analysis

5

33

2

2

2

1

PD-L2

TIM3

CD276

NKG2A

PD-1/TGFb

PD-L1/VISTA

TIGIT

Undefined

VISTA

54

2 OX40

CD40

41BB

CD27

CD70

ICOS

Large Portion of IO Pipeline is in in Early Development and Focused on Cancer Vaccines, Cell Therapies, and Cytokines

228

434

44 28

US IO Pipeline by Highest Phase (n=533)

Phase 1

Phase1/2228

33

2121

19

US IO Pipeline by IO Category(n=533)

Cancer vaccine

Other cell therapy

Cytokine


228

44

187

Phase 2

Phase2/3

Phase 3

Pre-registration

Registered

Marketed

Adis R&D Insight, Clarivate Analytics Cortellis; DH Analysis

228

76

52

46

37Cytokine

CAR-T cells

Other IO

Checkpoint

Innate Immunity

Oncolytic virus

Costim

Combination Trials Across the Various IO Platforms are Where the Industry (& Academia) Are Focused


Clinicaltrials.gov, Adis R&D Insight, Clarivate Analytics Cortellis, DH analysis

This Focus Reflects the Significant Clinical Needs for Both Cancers Showing Good Responses/Outcomes As Well As Those Not as Yet Showing Benefit

Checkpoint Antagonists and Costimulatory Agonists Lead the Way for Combinations, seeking to amplify the outcomes in settings like melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC) and bladder cancer. Checkpoint/Costim trials with 1 trial each:

41BB/KIR 41BB/PD-L1 CCR4/41BBCCR4/PD-1

CD27/CTLA4 CD27/PD-1 CD27/PD-L1 CD40/CTLA4 CD40/PD-L1


Clinicaltrials.gov, Adis Insight, Clarivate Analytics Cortellis, DH analysis

CD40/PD-L1 CSF1R/PD-1 CSF1R/PD-L1

CTLA4/PD-1/KIR CXCR4/PD-1GITR/PD-1IDO/CTLA4KIR/CTLA4 KIR/PD-1

OX40/PD-1 OX40/PD-L1/CTLA4

PD-1/KIRPD-1/PD-1 TIM3/PD-1

LAG3LAG3/ACT

NKG2A

The Number of Immuno-Oncology Combination Trials Continues to Grow –Combinations with Checkpoints or Costims Doubled from 2014 to 2015

The number of combination trials involving checkpoint inhibitors or costimulatory agonists more than doubled from 2014 to 2015 (92 trials in 2014, 229 in 2015).

Checkpoint/costim combination trials in 2016 are poised to surpass 2015, with 184 trials from January 2016 – July 2016.

Checkpoint/Costim Combination Trials By Year First Received in clinicaltrials.gov, N=603


Clinicaltrials.gov; DH analysis

Jan -July

Combo Studies with Checkpoints Are Increasing at an Unprecedented Rate


EvauatePharma

A Diversity of Combinations Are Being Pursued


EvaluatePharma

PD-1/L1s Combinations

Costim

CSF1R

Epigenetic modulator

IDO inhibitor

Antibody

3+ Agents Combined Together

Other targeted therapy

Vaccine

Chemotherapy

Kinase Inhibitor

CTLA4

Anti-PD1/L1 Combination Trials(Lg Pharma PD1/L1, Industry Only, P1/2+, n=140)


0 5 10 15 20 25 30 35

Chemokine/Antisense

Chemokine/Chemotherapy

CTLA4/Cytokine

Other PD1/L1

Radiation

Other Checkpoint/Kinase Inhibitor

Antibody (ADC)

Oncolytic virus

Other Checkpoint

PARP Inhibitor

SOC

Undefined

Chemokine

TLR Agonist

Costim

Clinical Trial Count

Phase 1/2

Phase 2

Phase 3

Clinicaltrials.gov; DH analysis *Trials evaluating two different combinations (X+Y vs. X+Z) are noted with a “/”

Rationality…Or Spaghetti


Overall PD1/L1 Clinical Trials Indication Analysis P1+ Show Activity in a Variety of Indications

PD-1/L1 Therapies

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Pembrolizumab 1 1 4 1 1 18 17 5 1 12 1 2 3 8 5 3 4 3 20 6 48 1 3 7 1 1 38 9 5 1 5 9 4 3 62 1 1 2 1

Nivolumab 1 1 5 1 1 4 2 7 1 1 2 1 2 1 5 10 1 4 6 4 6 1 1 37 2 1 2 43 2 4 1 9 4 36

Durvalumab 1 2 8 2 3 1 3 2 3 2 1 6 2 2 2 5 16 3 7 1 2 1 33

Atezolizumab 8 7 2 1 4 1 3 1 2 22 2 1 3 2 1 19

Avelumab 1 2 1 1 2 3 2 2 3

Phase Heat Map (Academic+Industry, Mono+Combo, P1+)


Avelumab 1 2 1 1 2 3 2 2 3

PDR001 1 1 1 7

REGN2810 1 1 1 1

MSB0011359C 2

LY3300054 1

AMP514 1 1

PF6801591 1


Key

P1 P1/2 P2 P2/3 P3

*Agents may be double counted if more than one PD-1/L1 agent per trial

• Pembrolizumab has the farthest reach to different indications, contributed by the great proportion of their trials being academic

• A significant number of trials are still early, looking at multiple solid tumor indications• The greatest activity among PD-1/L1 therapies exists in the marketed indications• Interestingly, the new-comer PD-1/L1 therapies are not targeting too many indications

that are not already being investigated

Other Leading Immuno-Oncology Programs by Indications


QuintilesIMS

Non-IO Still Dominates the Pipeline, But IO Agents are Making Rapid Inroads

While IO shows strong market growth and an increasing presence in oncology treatment, Non-IO compounds still constitute the majority of the overall oncology pipeline.

Within the oncology pipeline, Non-IO and IO compounds are split by approximately two-thirds to one-third, respectively (~1200 Non-IO and ~550 IO agents total).

Oncology Pipeline: IO vs. Non-IO (%)

Oncology Pipeline: IO vs. Non-IO (Count)N=1759


Adis R&D Insight; Clarivate; DH analysis

Oncology Pipeline: IO vs. Non-IO (%)N=1759

Most IO Agents Are Biologics, While Most Non-IO Agentsare Small Molecules

The oncology pipeline is split almost 50/50 between biologics and small molecules, with 893 vs. 852 agents, respectively. A small percentage of the pipeline is other/undefined.

~60% of biologics are IO agents, and ~98% of small molecule agents are Non-IO.

IO vs. Non-IO BiologicsN=893

IO vs. Non-IO Small MoleculeN=852

IO vs. Non-IO OtherN=14


Adis R&D Insight; Clarivate; DH analysis

Small Molecule

Once Barely on Radar, Biologics Now Dominate Leading Productsand Will Increase in Dominance in the Future

Top 10 Selling Products (WW)Percent by Category

2005 vs 2015 vs est. 2022

Biologic

Small

Biologic

SmallMolecule


EvaluatePharma

2005

2015

SmallMolecule

SmallMolecule

SmallMolecule

Biologic

Biologic

Regenerative, etc. ????

2022

Molecule

Biologic

Strategic Mapping of Checkpoint Inhibitors and Costimulatory Agonists Among Major BioPharma: What I Call Combinatorial Optionality

Clinical StageImmuno-OncologyAssets

NVS AZN BMS ROC CELG JNJ MRK PFE AMG GSKMRK KGaA

SNY LLY TAK BAY ABV

Checkpoint II III M M III† I M III I III II I

Costim II I/II II I I II I

Oncolytic virus I M

Cancer vaccine I/II III II II I I III M


Other Cell Therapy II I I** I

CAR-T Cells II II

Innate Immunity I I

Cytokine M II M M M M M II M

Other IO I I II I I M I I M

Adis R&D Insight, Clarivate Analytics Cortellis; DH analysis

NVS, Novartis; AZN, AstraZeneca/MedImmune; BMS, Bristol-Myers Squibb; ROC, Roche/Genentech; CELG, Celgene; JNJ, Johnson & Johnson; MRK, Merck & Co; PFE, Pfizer; AMG, Amgen; GSK, GlaxoSmithKline; MRK KGaA, Merck KGaA; SNY, Sanofi/Regeneron; LLY, Eli Lilly; TAK, Takeda; BAY, Bayer; ABV, Abbvie

Majority of Phase 2+ Trials are Examining Relapse/Refractory Patients, Followed Closely by Those Targeting Front-Line Use

50

3926

24

65 5 532 1

Specific Patient Population - Phase 2+ CTs - Combo/Mono (n=166)

R/R1st LineAdvancedChemo-refractoryChemo-Naïve2nd Line3+ LineCPI-NaïveAll LinesMaintenanceCPI-Refractory



29

18

15

5

43 2 1 1

Specific Patient Population - Phase 2+ CTs -Combo (n=78)

1st Line

R/R

Advanced

Chemo-Naïve

Chemo-refractory

2nd Line

CPI-Naïve

3+ Line

All Lines

32

2011

10

432 2 2 1 1

Specific Patient Population - Phase 2+ CTs -Mono (n=88)

R/RChemo-refractoryAdvanced1st Line3+ LineCPI-Naïve2nd LineMaintenanceAll LinesCPI-RefractoryChemo-Naïve

CPI-Refractory

Many Approved PD-1/L1 Gained Breakthrough Designation or Accelerated Approval and Bypassed Phase 2 and 3; or Skipped From Phase 1 to Phase 3

Almost all the indications that were approved for Keytruda were able to get approval based on Phase 1 data, except for the checkpoint-naïve patient approval that skipped Phase 2 and went straight to a Phase 3 registrational trial.

Melanoma (ipi-refractory) Melanoma (CPI-naïve) NSCLC (PD-L1+/post-platinum) HNSCC (post-platinum r/r)

KeytrudaPhase 1, Accelerated Approval(NCT01295827)

Phase 1(NCT01295827)Phase 3(NCT01866319)

Phase 1, Breakthrough and Accelerated Approval(NCT01295827)

Phase 1b, Accelerated Approval(NCT01848834)

Melanoma (BRAF V600 WT untreated)

Melanoma (BRAF V600 MUT)

NSCLC (squamous, post-platinum)

NSCLC (non-squamous, post-platinum)

RCC (post-angiogenic r/r)

HD (r/r post-HSCT and Adcetris)

For Opdivo, only RCC required the complete Phase 1 2 3 progression, while others skipped Phase 1 or 2.


Clinicaltrials.gov

V600 WT untreated) V600 MUT) post-platinum) post-platinum) r/r) Adcetris)

Opdivo

Phase 1(NCT00730639) and (NCT00441337)Phase 3(NCT01721772)

Phase 1(NCT00730639) and (NCT00441337)Phase 3, Accelerated Approval(NCT01844505)



Phase 1(NCT00730639) and (NCT00441337)Phase 2(NCT01354431)Phase 3, Breakthrough Designation(NCT01668784)

Phase 2, Breakthrough Designation(NCT02181738)

Melanoma (untreated)

Opdivo + Yervoy

Phase 2(NCT01927419)Phase 3(NCT01844505)

Bladder (post-platinum r/r)

Tecentriq

Phase 1(NCT01375842)Phase 2, Accelerated Approval(NCT02108652)

Bladder cancer, being a first indication for Tecentriq, required a Phase 1 and 2, with accelerated approval at Phase 2

Deals, Deals, Deals

Page 42

Appetite for IO Deals Slowing? Considerably Lower Number of Deals Leading Up to ASCO 2017 Compared To Last Year (2016)

22

27

20

25

30

IO Licensing and M&A Deals

2227

80

100

120

Non-IO vs IO Licensing and M&A Deals

Immuno-Oncology

Non-IO


4

0

5

10

15

2015 2016 2017

72 75

114

0

20

40

60

2015 2016 2017

BCIQ

YTD YTD

Deals Galore: Research Collaborations, Licensing & Outright Acquisition –Especially in IO, & As We Will See, Especially at an Early Stage

Between 2011 and 2015, Big Pharma and Mid Pharmaimmuno-oncology transactions were worth $6 billion upfront, $33 billion in milestones and $46 billion in aggregate deal value, according to DatamonitorHealthcare data.

Bristol-Myers dominated the activity: Of the 50 immuno-


MedCity News, Datamonitor Healthcare

Bristol-Myers dominated the activity: Of the 50 immuno-oncology partnerships sealed by Bristol-Myers between 2011 and 2015, 70 percent (35) were aimed at evaluating a combination treatment…

Top 2015 Oncology Deals: Almost All of These Top Deals Are IO


EvaluatePharma, Defined Health

Deal-Making in a Sellers Market Where the Number of Assets Is Increasing Every Day: Targets, Targets Everywhere – The Cancer Immunity Cycle


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

Deal Highlights 2015-2016 Underscore the Overall Intensity of Activity; Many Deals Have Been & Continue to Be are Early Stage

Apr 2015UndisclosedCART/PDL1

P1

Apr 2015$555M

IDO/TDOResearch

June 2015UndisclosedCART/TCRResearch

Oct 2015Undisclosed

CSF1R P1/2

Dec 2015$1.775B

Undisclosed CPsPreclinical

Apr 2015Undisclosed

Undisclosed CPResearch

May 2015$132MCAR T

ResearchJuly 2015

$2.67BLAG-

3/PD1/GITRPC/P1

Nov 2015Undisclosed

CAR TPreclinical

Dec 2015Undisclosed

CTLA-4Research

2015


Apr 2015$1.28BNKG2A

P1/2 Apr 2015 Undisclosed

PD-L1P3

May 2015$360M

TCRResearch

Oct 2015UndisclosedIO Bispecifics

Preclinical

May 2015UndisclosedCART/TCR Research

May 2015$737M

CART/TCRResearch

Sept 2015$795M

PD-1P1

Oct 2015Undisclosed

PD1Research

Dec 2015Undisclosed

CARTResearch

Dec 2015Undisclosed

CARTPreclinical

2015

EvaluatePharma, BCIQ, Company Press Releases, Defined Health

2016

Deal Highlights 2015-2016 Underscore the Overall Intensity of Activity; Many Deals Have Been & Continue to Be are Early Stage

Apr 2016$685M

LRRC32/GARPPC

Jun 2016$2.55B

CD3/CD123PC

Jul 2016$520M

IL8P1/2

Jul 2016$2.56BICOS /

Other CPP1/2

Aug 2016Undisclosed

BCMAPC

Jan 2016Undisclosed

mRNAResearch

Jan 2016UndisclosedTCR mimics

Research

Mar 2016Undisclosed

CARTResearch


EvaluatePharma, Company Websites, Defined Health; BCIQ

2016

May 2016$740M

CD3Research

Jun 2016$200M

mRNA vaccineResearch

Jan 2016$400M

IDO1/TDO2PC

Jul 2016$977M

PD-1 PC

Jul 2016Undisclosed

OncolyticVirus

PC

Sep 2016$250MCTLA4

PC

Jan 2016Undisclosed

Undisclosed IO TargetsPreclinical

Feb 2016$1.7BCAR T

Research

Mar 2016Undisclosed

PD-1Research

MabQuest

Top Oncology Deals by Value: 2017

Rank CompanyDeal Partner/

Product SourceDeal Type Product Upfront* Milestones Total

1 Astellas Ogeda Company Acquisition Fezolinetant 533 320 852

2 Merck Vertex Portfolio Acquisition Multiple 230 - 230

3 Sumitomo Dainippon

Tolero Pharma Company Acquisition Alvocidib 200 580 780

4 Sosei MiNA Therapeutics Acquisition Option MTL-CEBPA 181 310 491

Top 10 Deals by Upfront Value ($M): 2017


Evaluate Pharma; *Upfront includes upfront payment and equity stake

5 Kite Pharma Shanghai Fosun Pharma

Joint Venture KTE-C19 60 175 235

6 Calithera Biosciences

Incyte Development Collaboration

CB-1158 53 430 483

7 Kite Pharma Daiichi Sankyo Development Collaboration

KTE-C19 50 200 250

8 Takeda Exelixis Licensing Agreement Cometriq 50 95 145

9 Pieris Pharma Servier Licensing agreement PRS-332 31 338 369

10 Immatics Amgen Development Collaboration

Multiple 30 500 530

Recent Deal Activity Signifies Doubling Down on Bispecific mAbs, Expanding Access to ACTs and Early investment in mRNA and Microbiome

Date Deal Headline

3/20/2017Bristol-Myers Squibb and CytomX Therapeutics extend worldwide collaboration to discover Probody™ therapeutics for the treatment of cancer and other diseases

12/21/2016 Merus granted Incyte rights to up to 11 bispecific antibody programs that use Merus' BiClonics platform

11/16/2016Bristol-Myers Squibb and Enterome announce immuno-oncology collaboration focused on microbiome-derived biomarkers, drug targets and bioactive molecules

09/21/2016Roche's Genentech unit and BioNTech partner to develop and commercialize personalized mRNA-based immunotherapies that target patient neoantigens to treat cancer

08/11/2016Vedanta Biosciences announces collaboration with the NYU Langone Medical Center to develop microbiome-derived immunotherapies for cancer


immunotherapies for cancer

07/19/2016 Jounce grants Celgene option to license Jounce's immuno-oncology programs including JTX-2011

06/29/2016Moderna and Merck partner to develop and commercialize mRNA-based cancer vaccines that encode patient-specific neoantigens

06/28/2016Xencor grants Novartis rights to develop bispecific antibodies using Xencor's technology including ex-U.S. rights to Xencor'sXmAb14045 and XmAb13676

03/15/2016 Blueprint and Roche partner to discover, develop and commercialize up to five small molecules targeting undisclosed kinases

02/25/2016Precision and Baxalta partner to develop allogenic chimeric antigen receptor (CAR) T cell therapies for up to six undisclosed cancer targets

01/11/2016Moderna partners exclusively with AstraZeneca to discover, develop and co-commercialize one mRNA therapeutic from each of two new joint immuno-oncology programs

01/04/2016 Symphogen and Baxalta partner to develop cancer therapeutics against six undisclosed checkpoint targetsBCIQ

Publication Spikes in Adoptive Cell Therapy, Microbiome and NeoantigensSignify Strides Made in these Fields

400

500

600

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PubMed Search of “Non-Conventional Modality” & “Cancer”


0

100

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2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

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Oligonucleotides Oncolytic Viruses NeoAntigensPubMed, DH Analysis

IO Deals Constitute a Majority of Oncology Deals

2016 IO vs Non-IO Licensing Deals


Evaluate Pharma; DH Analysis

While the Majority of Oncology Deals Remain Non-IO, Total Immuno-Oncology Deal Values Edged Out Non-IO Deals

91

IO Vs Non-IO Distribution (n=246)

$16.6$15.7

$12.0

$14.0

$16.0

$18.0

Total Combined Deal Value (2015-2016)


91

155

IO

Non-IO

Evaluate Pharma; DH analysis

$0.0

$2.0

$4.0

$6.0

$8.0

$10.0

IO Non-IO

USD

(b

ln)

2 1 2

720

Phase Distribution IO Assets (n=91)

Marketed

Approved 21 417

Phase Distribution Non-IO Assets (n=155)

Marketed

Approved

Preclinical and Research Project Deals Made Up the Majority of IO Deals, Whereas Clinical Deals Made Up the Majority of Non-IO Deals


9

13

37

20Filed

Phase III

Phase II

Phase I

Pre-clinical

Research project

11

18

1919

46

Filed

Phase III

Phase II

Phase I

Pre-clinical

Research project


63% Preclinical/ Research Project Deals

60% Phase 1+ Project Deals

15

20

25

$1,500

$2,000

$2,500

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IO vs Non-IO: Average Total Deal Value

The Average Total Deal Value Was Highest in Phase 3 Deals for Non-IO and Highest in Phase 2 Deals for IO


$5

$284

$601

$190

$345$223

$408

$7$66

$516

$102$231 $177

$62

0

5

10

$0

$500

$1,000

Marketed Approved Filed Phase III Phase II Phase I Pre-clinical Research project

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IO Non-IO Non-IO Deal Range # of IO Deals # of Non-IO Deals

Evaluate Pharma; DH Analysis

IO Upfront Deal Value Is Significantly Higher Than Non-IO Deals (Through Phase II)

10

12

14

16

18

20

$250

$300

$350

$400

$450

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IO vs Non-IO: Average Upfront Deal Value

The higher frequency of Non-IO deals in later clinical stages is consistent with the fact that most IO agents are in earlier clinical stages, driven by the hope and frenzy for the IO MOA.


$6

$75

$130

$166

$36$60$68

$15

$82

$13 $18 $13 $40

2

4

6

8

10

$0

$50

$100

$150

$200

Marketed Approved Filed Phase III Phase II Phase I Pre-clinical Research project

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IO Non-IO Non-IO Deal Range # of IO Deals # of Non-IO Deals


The Good, the Bad & the Ugly


Wrap-Up

Page 58

Combinations Have Always Been the Hope for Managing Cancer (Gleevecin CML are the Exceptions), But Now With IO-Based Regimens, There May Be a Real Chance for a Cure in a Substantive Portion of Patients

Improved Overall Survival as a Result of Combination Therapy. Depiction of Kaplan-Meier survival curve with genomically targeted agents (blue line) as compared to standard therapies (purple line), indicating an improvement in median overall survival but lack of durable responses; improved median overall survival and durable responses in a fraction of patients


https://www.elsevier.com/connect/two-major-cancer-therapies-may-work-better-together-say-researchers-at-md-anderson

responses in a fraction of patients treated with immune checkpoint therapy (green line); possibility for improved median overall survival with durable responses for the majority of patients in the setting of combination treatment with genomically targeted agents and immune checkpoint therapy (red line). (Source: Sharma, Allison: Cell, April 2015)

Already the Dreams of Many, Going Back 100 Years, Are Coming True, for Researchers, and Most Importantly for Patients

In science, we dream, too


http://www.notable-quotes.com/s/science_fiction_quotes.html

In science, we dream, too

Acknowledgements

Page 61

The Defined Health Oncology Team & Support Staff

James Lee, PhD, Consultant

Samuel Leyens, Senior Research Analyst

Eva Dixon, Senior Research Analyst

Akash Katakam, Research Analyst

Joel Sandler, PhD, Senior Consultant

Mike Rice, MS, MBA, Senior Consultant


Mike Rice, MS, MBA, Senior Consultant

Documents

Immuno-Oncology’s Signal-to-Noise Problem: Developing ......Jun 14, 2017 · Avelumab 1 1/2 1 2 1 1 1 1 Atezolizumab 1 1 3 1 M Efficacy ... But at ASCO 2017, Combo Data Was Sparse,