Antibody Drug Conjugates Deep dive into new technologies ...

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Antibody Drug Conjugates

Deep dive into new technologies and drug candidates (Post-ASCO Update)

DISCLOSURE APPENDIX AT THE BACK OF THIS REPORT CONTAINS IMPORTANT DISCLOSURES, ANALYST CERTIFICATIONS, AND THE STATUS OF NON-US ANALYSTS. US Disclosure: Credit Suisse does and seeks to do business with companies covered in its research reports. As a result, investors should be aware that the Firm may have a conflict of interest that could affect the objectivity of this report. Investors should consider this report as only a single factor in making their investment decision.

Research Analysts

Ravi Mehrotra

(212)-325-3487

[email protected]

Lee Kalowski

(212)-325-9683

[email protected]

Koon Ching

(212)-325-6286

[email protected]

Anuj Shah

(212)-325-6931

[email protected]

Jason Kantor

(415)-249-7942

[email protected]

Jeremiah Shepard

(415)-249-7933

[email protected]

June 19, 2014

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• Updated Phase I data for IMGN853 and IMGN529 – Still working out tox issues

• Phase II results for ROMULUS trial comparing Roche’s “Pina” to “Palo” – Both have

solid efficacy in DLBCL and FL. Palo appears to be moving forward in FL. Both have

significant neuropathy concerns

• Data for anti-CD19 ADCs SAR3419 (Phase II) and SGN-CD19A (Phase I) – Both are

active but have ocular toxicity. SGN-CD19A may have higher CR rate in more

refractory patients. Unclear what Sanofi’s plans are for SAR3419

• First clinical data for ABT-414 – Highly encouraging CR and 2 PRs in refractory

glioblastoma. Ocular tox is an issue

• Phase I data for Roche’s anti-NaPi2b ADC – Very encouraging 41% ORR in ovarian

cancer. Moved into randomized Phase II vs. Doxil

• Adcetris in 1st line HL – Impressive 91% ORR (83% CR) after only two doses of

Adcetris in 1st line prior to ABVD

• Other updates/new data for Roche’s anti-STEAP1 ADC and anti-mesothelin ADC,

Takeda’s MLN0264 (anti-GCC) for GI malignancies, and PGNX’s anti-PSMA ADC

Updates post ASCO 2014:

Sources: Company data, Credit Suisse research

3

• Roche/IMGN: Kadcyla MARIANNE Phase III data in first line metastatic breast cancer (H2:14). Key to expansion into 1st line; Combo data with Perjeta could define highest

efficacy combination.

• SGEN: Adcetris AETHERA Phase III (Q4:14), and SGN-CD33A Phase I update likely at ASH (Dec 2014). Potential to expand market for Adcetris; could lead to longer treatment

duration.

• Roche/SGEN: Data from multiple programs likely at ASH 2014

• Sanofi/IMGN: Coltuximab Ravtansine (SAR3419) Phase II MYRALL data in ALL likely at ASH 2014 (Dec 2014). Will also be critical to see whether Sanofi moves this program

forward in either DLBCL or ALL.

• IMGN: First IMGN289 clinical data at cancer meeting (H2:14), and additional updates possible for IMGN853 and IMGN529. Currently no clear winner in the pipeline. IMGN289

(anti-EGFR) could become IMGN’s next driver.

Key Readouts for ADCs in 2014


4

The Future of ADCs

1. Overview of antibody drug conjugates

2. Pipeline of ADCs in development

3. Addressing current challenges with new technologies

4. ADC innovators – Who are the players?

5. Key players – Roche, Seattle Genetics, ImmunoGen

6. Key ADCs in development (Updated)

ADC Overview A Three Part Technology – Antibody, Drug, and Linker

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Overview of ADCs ADCs can provide additional activity/efficacy over naked antibodies

• ADCs build on antibody therapeutics characteristics

o High specificity

o Long half-life

o Reduced immunogenicity with current antibody technology

o Well understood biological function

• ADCs have lower toxicity compared to naked drugs; enables use of higher potency

drugs.

• ADCs have been clinically validated (Kadcyla, Adcetris). Most ADC programs are

Phase I or early Phase II - potential for many more approved ADCs in next 3-5 years.

• Some ADCs have rescued failed antibodies (ie SGN-30, the mAb in Adcetris).


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Three key components:

Antibody

• Needs to be highly specific for tumor cells

• Targeting normal cells will lead to toxicity

• Needs to be internalized by tumor cells

Drug

• Needs to be high potency

• Limited drug molecules get to the tumor cell

so must be very active

Linker

• Needs to be stable in plasma but released in

target cells

• Multiple chemistries can be employed for this

purpose. More potent drugs require more

stable linkers

ADCs: A Three Component System


8

Current State-of-the-Art: Two Approved ADCs

Adcetris Kadcyla

Company Seattle Genetics Roche/ImmunoGen

Target CD30 Her2

Indication r/r Hodgkin lymphoma &

ALCL

2nd line Her2+

metastatic breast cancer

Potential expansion 1st line HL and ALCL, r/r DLBCL, CTCL

1st line mBC, adjuvant BC, gastric cancer

Toxin Monomethyl auristatin E

(MMAE)

Mertansine (DM1)

Drug class Tubulin inhibitor Tubulin inhibitor

Linker Cleavable valine-

cirtrulline linker

Non-cleavable thioether

linker

Approximate # of drugs

per antibody Mostly 4 (0,2,4,6,8) ~3.5 average


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Next Generation Innovations

Antibody

• Probody – antibody prodrug format to enhance specificity at tumor sites

Toxin

• DNA crosslinking toxins - more potent, different mechanism, and different potential toxicity/resistance profile; Examples: Pyrrolobenzodiazepine (PBD) dimer, DGN462

Linker

• Site specific conjugation – multiple technologies allow for precise drug number and linker location

• Non-native amino acids – modified antibodies allow for site specific linking; unique linker chemistry; potential for two different drugs loaded on one antibody

• Fleximers – Large hydrophilic linker system; multi-drug binding sites; can significantly increase drug number

Looking to improve efficacy and safety


Pipeline of ADCs in Development A large number of programs advancing in development

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Clinical Stage Antibody Drug Conjugates 37 ADCs in clinical development, including 2 marketed drugs


Conjugate Company Antigen, Drug Indication Technology from Stage of Development

Adcetris (Brentuximab vedotin, SGN-35) Seattle Genetics CD30, vcMMAE Hodgkin's lymphoma, sALCL Seattle Genetics Marketed

Kadcyla (Ado-trastuzumab emtansine, T-DM1) Genentech Her2, DM1 Her2+ breast cancer ImmunoGen Marketed

Inotuzumab ozogamicin (CMC-544) Pfizer CD22, CalichDMH ALL, DLBCL (Phase II) Pfizer Phase III

Glembatumumab vedotin (CDX-011) Celldex GPNMB, vcMMAE Triple negative breast cancer Seattle Genetics Phase II (pivotal)

Coltuximab ravtansine (SAR3419) Sanofi Aventis CD19, DM4, dilsufide DLBCL, ALL ImmunoGen Phase II

PSMA ADC Progenics PSMA, vcMMAE Prostate cancer, GBM Seattle Genetics Phase II

Pinatuzumab vedotin (DCDT2980S, RG7593) Genentech CD22, MMAE fNHL, DLBCL Seattle Genetics Phase II

Polatuzumab vedotin (DCDS4501A, RG7596) Genentech CD79b, MMAE fNHL, DLBCL Seattle Genetics Phase II

Labetuzumab-SN-38 (IMMU-130) Immunomedics CEACAM5, SN38 Colorectal cancer Immunomedics Phase II

hRS7-SN-38 (IMMU-132) Immunomedics Trop-2/EGP-1, SN38 Epithelial cancers Immunomedics Phase II

RG7599 (DNIB0600A) Genentech NaPi2b Ovarian, NSCLC Seattle Genetics Phase II

BT-062 Biotest AG CD138, DM4, dilsufide Multiple myeloma, triple-neg BC ImmunoGen Phase I/II

Milatuzumab -Dox Immunomedics CD74, doxorubicin Multiple myeloma, NHL, CLL Immunomedics Phase I/II

ABT-414 AbbVie EGFRvIII Squamous cell cancer, glioblastoma Seattle Genetics Phase I/II

SAR566658 Sanofi Aventis CA6, DM4, dilsufide Ovarian, breast ImmunoGen Phase I

AGS-16C3F Astellas ENPP3, mcMMAF Renal cell cancer Seattle Genetics Phase I

RG7450 (DST3086S) Genentech STEAP1, MMAE Prostate cancer Seattle Genetics Phase I

RG7598 Genentech not disclosed (FcRL5?) Multiple myeloma Seattle Genetics Phase I

RG7458 (DMUC5754A) Genentech MUC16, MMAE Ovarian, pancreatic Seattle Genetics Phase I

RG7600 (DMOT4039A) Genentech Mesolthelin, MMAE Pancreatic, ovarian Seattle Genetics Phase I

RG7636 Genentech ETBR Melanoma Seattle Genetics Phase I

ASG-22ME Astellas/SGEN Nectin-4, MMAE Solid tumors Seattle Genetics Phase I

BAY 94-9343 Bayer Mesothelin, DM4, dilsufide Ovarian, pancreatic ImmunoGen Phase I

AMG 172 Amgen (Abgenix) CD27L Renal cell cancer ImmunoGen Phase I

AMG 595 Amgen (Abgenix) EGFRvIII Glioma ImmunoGen Phase I

IMGN529 ImmunoGen CD37, DM1 (non cleavable) B-cell lymphoma ImmunoGen Phase I

IMGN853 ImmunoGen FOLR1, DM4, dilsufide Ovarian ImmunoGen Phase I

MLN0264 Millennium Guanyl cyclase C, MMAE Gastric cancer Seattle Genetics Phase I

SGN-CD19A Seattle Genetics CD19, mcMMAF B-cell lymphoma Seattle Genetics Phase I

ASG-15ME Astellas/SGEN SLITRK6, MMAE Bladder, lung cancer Seattle Genetics Phase I

SGN-CD33a Seattle Genetics CD33, PDBD AML Seattle Genetics Phase I

IMGN289 ImmunoGen EGFR NSCLC, head and neck cancer ImmunoGen Phase I

PF-06263507 Pfizer 5T4 (TPBG), MMAF Solid tumors Seattle Genetics Phase I

SGN-LIV1A Seattle Genetics LIV-1, vcMMAE Breast cancer Seattle Genetics Phase I

HuMax-TF ADC (TF-011-vcMMAE) Genmab Tissue Factor, MMAE Solid and hematologic tumors Seattle Genetics Phase I

AGS67E Astellas CD37, MMAE B-cell lymphoma Seattle Genetics Phase I

RG7841 Genentech not disclosed Solid tumors Seattle Genetics Phase I

12

Vast majority of ADCs in the clinic utilize SGEN or IMGN technology

Main ADC Platforms


13

Partnerships for ADCs SGEN and IMGN are the dominant technology platforms

Roche*

SGEN IMGN

AbbVie

Astellas

Sanofi

Amgen

Biotest

Bayer

Millennium

Celldex

Pfizer

*Roche has 1 marketed drug (Kadcyla) with IMGN, but appears to have selected SGEN’s platform for further development (8 clinical programs.

Genmab

Daiichi Sankyo

Progenics

MedImmune

Oxford Biotherapeutics

GlaxoSmithKline

Novartis

Eli Lilly

Cytomx Celgene

Sutro

Biopharma

Mersana

Endo ADC

Therapeutics


14

SGEN and IMGN technologies SGEN and IMGN have a mix of partnered and proprietary programs in the clinic.

SGEN Compounds in the Clinic

Roche Sanofi Sanofi Biotest

Proprietary

Amgen

Bayer

0

2

4

6

8

10

12

14

16

18

Phase I Phase II Marketed

IMGN Compounds in the Clinic


Proprietary

Proprietary

50/50 dev.

Roche

Roche

Celldex

Progenics

AbbVie

Astellas

Millennium

Genmab

0

2

4

6

8

10

12

14

16

18

Phase I Phase II Marketed

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• Amgen: Its deal with IMGN came through its acquisition of Abgenix. Amgen has subsequently moved two ADC into the clinic using IMGN’s technology.

• AstraZeneca: Bought Spirogen in 2013 and takes equity stake ADC Therapeutics. Builds on antibody expertise of Medimmune. First major move into ADC space.

• Astellas: Bought Agensys, which had a 50/50 co-development with SGEN. Subsequently expanded to multi-target license deal. Currently has 3 ADCs in the clinic.

• AbbVie: Total of three deals with SGEN starting prior to ABBV spin out. Initially a single-target deal, expanded twice to multi-target deals. Total of $58M in upfronts.

• Pfizer: Wyeth developed the first approved ADC Mylotarg. Pfizer acquired Wyeth and still has proprietary development of ADCs.

• Roche: Technology deals with both SGEN and IMGN as well as significant internal research and development (proprietary format – Thiomab – failed in clinic). Kadcyla approved and 9

other ADCs in development.

• Sanofi: Aventis had a broad R&D collaboration with IMGN from 2003 to 2008. From that deal it gained its two clinical stage ADCs, which continue to advance. Sanofi subsequently

took a license to another ADC target stemming from a separate 2006 agreement.

How Some of the Bigger Companies are Accessing ADCs


Addressing Current Challenges with New Technologies Focus on drugs and linkers

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Increasing Potency Through Higher Drug : Antibody Ratio

Current ADCs have a range of drugs:

• Adcetris has mostly 4 per antibody

(range 0-8)

• Kadcyla has ~3.5 on average per antibody

Increased drugs/linkers can lead to:

• ADC instability

• Decreased half-life

• Aggregation during manufacturing

• Liabilities depend on physical

properties of the drug and linker

Solution(s)

Fleximers: Mersana linkers are large biodegradable polymers that can

increase drug:antibody ratio many fold.

More soluble drug/linkers may allow

higher drug:antibody ratios

Site specific conjugation allows

attachment of a specific number of drugs. This may not always lead to more drug per antibody, but can avoid

some of the problems associated with overloading antibodies

More drugs should make ADCs more potent, but there are problems


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SGEN - Adcetris

Conjugates to cysteine by first breaking the

disulfide (S-S) bonds between the heavy and

light chains

Maximum of 8 sites per antibody (4 disulfide

bonds)

Optimal ratio is ~2-4 drugs per antibody for

Adcetris

IMGN - Kadcyla

Conjugates to lysine

Approximately 80-100 possible sites

More than 1M possible combinations

Average ratio is approximately 3.5 for

Kadcyla

Drug : Antibody Ratio Current State of Art

Mixtures vary in both drug : antibody ratio and site of conjugation

Sources: Company data, Sutro presentation, Credit Suisse research

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Fleximer

Polymer is highly water soluble (hydrophilic)

Large number of drugs can be loaded on the polymer (even hydrophobic drugs)

Polymer/drug conjugate can then be linked to the antibody

Polymer/drug can be linked to other types of targeting agents (e.g. antibody fragments)

Drug : Antibody Ratio – Possible Solutions

Mersana’s Fleximer SGEN – More soluble drug/ linkers

More soluble “standard” format

New linker with PEG for increased drug loading

Sources: Company data, Mersana presentation, AACR 2014 posters, Credit Suisse research

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More Uniform ADCs Through Site Specific Conjugation

Current ADCs have a range of drugs:

• Mixtures may include inactive variants or

variants with undesirable PK or safety

• Methods to achieve “optimal” loading may

leave some antibodies with no drug

• Some newer drugs (e.g. PBD dimers) may

have physical properties that lead to

aggregation if drug:antibody ratio is too high

Solution(s):

Genentech developed Thiomabs – failed due

to toxicity

SGEN is using site specific conjugation for

its PBD dimer conjugates (SGN-CD70A and

SGN-CD33A)

Sutro, Allozyne, and Ambrx introduce non-

native amino acids for site specific

conjugation

Other site specific approaches are being

Redwood Biosciences and others

Current ADCs are mixtures with varied drug numbers and conjugation sites

Site specific conjugates may be theoretically more potent if “undesirable” conjugates add toxicity while “desirable” conjugates are more potent. This has yet to be proven in the clinic

Sources: Company data, Sutro presentation, Credit Suisse research

21

Improving Safety and Efficacy

Current challenges:

• Drug resistance can develop against the toxin

(e.g. efflux pumps)

• Peripheral neuropathy is seen with some

tubulin agents (e.g. Adcetris)

• Ocular toxicity has been seen with multiple

ADCs using two different toxins (MMAF and

DM4)

Solution(s):

New drugs may be less

sensitive to efflux pumps

and / or combining two

drugs with different

mechanisms of action

DNA targeting agents

(ie PBD dimers) may not

have peripheral neuropathy

(likely something

different)

Ocular toxicity being addressed by steroid eye

drops and alternative dosing strategies. Best

solution is likely new toxins (i.e. not MMAF and

DM4).

Current ADCs have liabilities – New drugs and linkers may improve profile

Improvements in l inkers and toxins are l ikely to enhance the safety of ADCs


22

Improving Safety and Efficacy – Ocular Toxicity

Significant ocular toxicity with MMAF and DM4 conjugates


Frequent at low grade

Dose dependent

Blurred vision range from 20-50%

Generally reversible

Attempts to mitigate with dosing

changes and steroid prophylaxis

Eye toxicity may raise bar for clinical

activity to achieve good risk/benefit

• IMGN853

• SAR3419 • SGN-CD19a

• ABT-414

• AGS-16M8F • SAR566658

Variety of manifestations:

• Blurred vision

• Dry eye

• Keratopathy

• Keratitis

• Corneal deposits

• Foreign body sensation

• Photophobia

• Eye pain

Some examples:

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Drug payloads beyond auristatins and maytansines

Tubulysin believed to be 10-

100X more potent than

auristatins; still targets tubulin

Ingenica has conjugated this

payload to an ADC

More potent payload could

allow for greater efficacy with

ADC targeting antigens with

low expression

Tubulysin T4

DNA alkylating agent

Induces double strand breaks

that leads to cell death

Several companies have

licensed this drug payload

and are using with its ADC

technology

DNA alkylating agent; active

at picomolar range

Binds to the DNA minor

groove

Synthon has developed fully

synthetic derivatives,

providing greater flexibility for

manufacturing

Pyrrolobenzodiazepine Duocarmycins


//upload.wikimedia.org/wikipedia/commons/0/09/(+)-Duocarmycin_A.svg

http://www.igenica.com/

https://www.google.com/url?q=http://www.stephanemery.demon.co.uk/portfolio2.htm&sa=U&ei=PD5gU7GxFsmwyQHk8IDIBQ&ved=0CDoQ9QEwBg&usg=AFQjCNHrfcBpVzOvqarRlFCW0V1vxXj_wQ

ADC Innovators – Who are the Players? (A-Z) Next generation technologies from new players and current leaders

25

Allozyne: Site-specific ADCs via non-natural amino acids

Allozyne incorporates non-

natural azide amino acids into

antibodies

Regulates the drug/antibody

ratio and location of the drug to

the azide

May improve ADC PK – in vitro

experiments demonstrate that

the ADCs are stable at 37

degrees Celsius in human

serum for at least 1 month

AzAb technology uses engineered “az ide handles” for conjugation

Allozyne is a privately held company. Its most advanced ADC program is preclinical


http://www.allozyne.com/home

26

Ambrx: Site-specific ADCs via non-natural amino acids

Ambrx developed sets of tRNA/tRNA synthetase pairs in engineered cells lines to incorporate

non-native amino acid into proteins (e.g. antibodies)

Non-native amino acids can be used for site specific drug conjugations

This technology is also being examined in other protein therapeutics

Ambrx is a pioneer in employing nnAAs

Ambrx is a privately held company. Its most advanced ADC program is preclinical


27

CytomX Therapeutics Probody technology

ADCs are highly specific for their target, but some targets may also be found on normal

tissue (e.g. skin, heart, etc.) leading to unwanted toxicity

Probodies are modified antibodies that are unable to bind their target unless they are

cleaved by proteases, which are often found in and around tumors

ADC Probodies are “activated” at the site of the tumor, potentially reducing toxicity in

other tissues

CytomX and IMGN have a collaboration to share each others technology

CytomX is a privately held company. Its most advanced ADC program is preclinical.


28

ImmunoGen, Inc.

Marketed drug Kadcyla uses IMGN

technology

3 proprietary drugs in the clinic awaiting

proof of efficacy (& safety)

Two drug formats in the clinic (DM1 & DM4)

New linkers block efflux pumps – combat

drug resistance (e.g. IMGN853)

New DNA binding agents in development

(IGN)

Partnership with CytomX provides access to

Probody technology

Variety of drugs and l inkers in the clinic

Linker chemistry can thwart drug efflux pumps


New DNA-binding toxins

Charged linker

improves solubility

29

Ingenica : Site-specific ADCs using natural cysteines

Conjugation to natural cysteine (like

SGEN)

Novel linker binds both cysteines of a

disulfide pair.

Can achieve homogeneous linkage of 4

drugs per antibody (4 disulfide pairs per

antibody)

The covalent bonds between the light

and heavy chain is maintained, which

may enhance stability

Alternative linkers can achieve 8 drugs

per antibody

Ingenica takes proven conjugation chemistry and improves it to make homogenous ADCs

Ingenica is a privately held company. Its most advanced ADC program is preclinical

Working with multiple payloads

Compatible with proven payloads (MMAE, MMAF)

Working with proprietary tubulysin derivative


http://www.igenica.com/

30

Meditope Biosciences: Linking drug payload via keyhole

Key discovery – There is a pocket in the Fab

portion of Erbitux which can specifically and

non-covalently bind a peptide called a meditope

Application – A portion of the Erbitux antibody

is grafted into any other antibody, providing a

docking station for the meditope

Meditopes with attached toxins can be site-

specifically bound to these modified antibodies.

The attachment is non-covalent, site-specific,

and has a fixed drug number.

Non-covalent binding of drug/ linker payload to antibody in highly specific manner

Meditope is a privately held company. We are unaware of any specified drug candidates.


31

Mersana Therapeutics: Fleximers

Highly water soluble (hydrophilic) linker technology, Fleximer, allows for many drugs conjugated drug, increasing drug:antibody ratio

Fleximer technology can allow up to 20 drugs per l inker

Can use Fleximer technology to add payloads to other types of molecules

Mersana is a privately held company. Its most advanced ADC program is preclinical

Polymer/drug can be linked to other types of targeting agents (e.g. antibody fragments)

Versati le Fleximer technology


32

Redwood Bioscience: Site-specific conjugation

Redwood engineers antibodies to

contain new cysteines

The new cysteines are modified

with an enzyme to remove the

sulphur group and create an

“aldehyde tag” that is amenable to

specific chemistry to attach the

drug payload

Different variations with the

technology are possible

Incorporates a cysteine at a specific site to target conjugation SMARTag technology

Redwood is a privately held company.


http://www.redwoodbioscience.com/

33

Seattle Genetics – Developing a deep ADC tool box

New linkers with differential drug release

Site specific conjugation with PBD payload

Inclusion of PEG molecule as a side chain can improve ADC PK and potency

Improved soluble form of MMAF + Linker:

Marketed proprietary ADC - Adcetris

6 wholly owned or co-developed drugs

in the clinic

13 partners with 16 drugs in the clinic

Three drug formats in the clinic

(MMAE, MMAF, PBD)

New linkers in development


34

Sutro Biopharma: Site-specific ADCs

Sutro is developing a cell-free system

for protein synthesis

Cell-free systems allow for

substitution of non-native amino acids

Non-native amino acids provide

location for site specific conjugation

and allow for specific conjugation of

two different payloads

Cell free systems may also provide for

a cheap and efficient method to scan

for an optimal conjugation site on a

monoclonal antibody

Cell-free production gives greater control for adding non-native am ino acids


Sutro is a privately held company. Its most advanced ADC is preclinical

Non-native amino acids allow for site specific conjugation of more than one toxin

35

Synthon: SpaceLink linker technology

Unique modification to alter the PK of the drug/ linker once it is released from the ADC

Very potent DNA alkylator (duocarmycin)

is not activated until it is released from

ADC

Proprietary linker chemistry

Releases drug in a precursor format.

Drug subsequently converted to active

form.

Unique mechanism may provide safety

advantage

Synthon is a privately held company. Its most advanced ADC is preclinical


Key Player – Genentech/Roche

37

Genentech / Roche – Leader in ADC Development

Roche – Working appears to be working

exclusively with SGEN technology now

Drug Payloads MMAE, MMAF

Number of clinical program (stage)

9 partnered programs with SGEN technology

Key programs Anti-CD22 and Anti-CD79b for

NHL, RG7458 (MUC16-MMAE) for ovarian to Ph II

Genentech was an early adopter of ADC technology signing deals with IMGN (2000) and SGEN (2002) and conducting significant internal development

• Kadcyla approved for 2nd line Her2 positive


• Phase III data in 1st line Her2 positive

metastatic breast cancer in H2:14

• Potential multi-billion dollar franchise

• Biggest pipeline of ADCs in the industry

• 9 other ADCs in clinical development using

SGEN’s technology


38

Development Candidates Use SGEN Technology

Source: Roche Q1:14 earnings slide deck.

9 ADCs in development

• Solid tumors: Pancreatic, ovarian, melanoma, lung, prostate

• Hem/onc: NHL and multiple myeloma

• Most advanced has completed Phase II (anti-CD22 and anti-CD79b)

39

Kadcyla: A Key Part of Roche’s Her2 Franchise

New standard of care in relapsed Her2-positive metastatic breast cancer

Key part of growing Her2 franchise at Roche

First-l ine data expected in 2014 – MARIANNE trial

Expansion into adjuvant and neo-adjuvant

Source: Roche Q1:14 earnings slide deck.

40

Kadcyla: Positive Phase III TH3RESA Trial

Clear win on PFS, OS, ORR, and safety

• PFS: HR 0.528, median 6.2m vs. 3.3m

• OS: HR 0.552, median not reached vs. 14.9m

• ORR: 31.3% vs. 8.6%

Metastatic breast cancer failed 2 or more prior Her2 agents

Source: ECCO 2013 presentation.

41

Kadcyla: Positive Phase III EMILIA Data

2nd l ine metastatic breast cancer

Clear win on PFS, OS, ORR, DOR, and safety

• PFS: HR 0.65, median 9.6m vs. 6.4m

• OS: HR 0.621, median not reached vs. 23.3m

• ORR: 43.6% vs. 30.8%, DOR 12.6m vs. 6.5m

• Grade ≥3 AE: 40.8% vs. 57.0%

Source: ASCO 2012 presentation.

42

Kadcyla: Robust Phase III Program in Earlier Lines

MARIANNE is the next data readout

Adjuvant trials are key to market expansion


Key Player – Seattle Genetics

44

Seattle Genetics (SGEN)

• Adcetris approved for relapsed/refractory

Hodgkin lymphoma and ALCL

• 23 clinical-stage programs total (1 marketed,

6 Phase II, 16 Phase I)

• 6 proprietary programs or 50/50 co-

development in the clinic

• 3 toxins in the clinic (MMAE, MMAF,

PBD dimer)

• 13 technology and development

partners

• Genentech has 9 ADCs in the clinic

with SGEN’s technology

SGEN was founded in 1998 on ADC technology spun out of Bristol Myers Squibb. This first generation ADC technology was improved at SGEN and the entire pipeline at SGEN now comprises internally developed technology

Upfront Additional

Partner Payment Milestones Royalties Terms Date

Single target deals

Genmab Undisclosed Undisclosed Mid-single digit Single target/opt-in rights Apr-11

Abbott $8M $200M Undisclosed Single target Mar-11

Pfizer $8M $200M Undisclosed Single target Jan-11

Genmab Undisclosed Undisclosed Mid-single digit Single target/opt-in rights Sep-10

Millennium $4M Undisclosed Mid-single digit Single target Mar-09

Daiichi Sankyo $4M Undisclosed Mid-single digit Single target Jul-08

Progenics $2M Undisclosed Undisclosed Single target Jun-05

MedImmune $2M / $1.5M Undisclosed Undisclosed Single/added one target Apr-05

Bayer $2M Undisclosed Undisclosed Single target Sep-04

Celldex $2M $28M Undisclosed Single target Jun-04

Multi-target deals

AbbVie* $25M $225M/target mid- to high-single digit Multiple targets Jan-14

Abbott* $25M $220M/target mid- to high-single digit Multiple targets Oct-12

Oxford Biother. NA Undisclosed Undisclosed Multitarget/alternating options for sole

development

Sep-11

Genentech* $12M $900M Mid-single digit Multiple targets Aug-10

GlaxoSmithKline $12M $390M Mid-single digit Multiple targets Dec-09

Astellas* $12M $350M 50:50 profit/cost sharing Multiple targets/Co-develop opt-in rights Nov-09

SGEN technology partnerships


45

SGEN Products and Pipeline Potential Adcetris sales

MMAE MMAF PDBD

Mechanism anti-tubulin anti-tubulin DNA crosslinker

SGEN Adcetris SGN-CD19A SGN-CD33A

candidates ASG-22ME

ASG-15ME

SGN-LIV1A

Other CDX-011 AGS-16C3F

candidates PSMA ADC PF-06263507

RG7593 (CD22)

RG7458 (Muc16)

Comments Clinical, regulatory,

and commercial

validation with Adcetris

Side effects:

Neutropenia and

peripheral neuropathy

Ocular toxicity seen

with SGN-CD19A and

one other MMAF ADC

No clinical data

available


Product Stage Cancer Indication Partner Structure

Adcetris (brentuximab vedotin) Marketed Relapsed/refractory HL and ALCL Millennium/Takeda Regional partner

Phase III Post-transplant Hodgkin lymphoma

Phase III Relapsed CTCL (MF, pcALCL)

Phase III 1st line HL and ALCL (with chemo)

Phase II 1st line HL (monotherapy in elderly)

Phase II CD30+ cancers

CDX-011 (glembatumumab vedotin) Phase II

(pivotal)

Triple negative breast cancer Celldex Technology license

RG7593 (anti-CD22; pinatuzumab

vedotin)

Phase II fNHL, DLBCL Genentech Technology license

RG7596 (anti-CD79b; polatuzumab

vedotin)

Phase II fNHL, DLBCL Genentech Technology license

PSMA ADC Phase II Prostate cancer Progenics Technology license

RG7599 (anti-NaPi) Phase II Ovarian, NSCLC Genentech Technology license

ABT-414 Phase I/II Gliobastoma AbbVie Technology license

RG7600 Phase I Pancreatic, ovarian Genentech Technology license

RG7636 (anti-ETBR) Phase I Melanoma (metastatic or unresectable) Genentech Technology license

RG7450 (anti-STEAP1) Phase I Prostate cancer Genentech Technology license

RG7458 (anti-MUC16) Phase I Ovarian Genentech Technology license

RG7598 Phase I Multiple myeloma Genentech Technology license

RG7841 Phase I Solid tumors Genentech Technology license

AGS-16M8F Phase I Kidney cancer Astellas Technology license

ASG-22ME Phase I Solid tumors Astellas 50/50 co-development

MLN0264 Phase I Gastric cancer Millennium/Takeda Technology license

SGN-CD19A Phase I Hematologic malignancies Proprietary

ASG-15ME Phase I Bladder and lung cancer Astellas 50/50 co-development

SGN-CD33A Phase I AML Proprietary

HuMax-TF-ADC Phase I Not disclosed Genmab 50/50 option for SGEN

AGS67E Phase I Not disclosed Astellas Technology license

SGN-LIV1A Phase I Breat cancer Proprietary

PF-06263507 (anti-5T4) Phase I Solid tumors Pfizer Technology license

SGN-CD75a Preclinical Renal cell and NHL Proprietary

46

Adcetris – Consistent Efficacy and Safety in HL and ALCL

1st Line ALCL – Pivotal Phase II

Source: ASH 2010

1st Line HL – Pivotal Phase II

47

Robust Activity in 1st Line Hodgkin Lymphoma and ALCL

Phase I 1st l ine Hodgkin lymphoma w/AVD chemo 1st l ine elder HL - single agent

Source: ASH 2012, ASH 2013, ASCO 2014

89% ORR (17/19) (12 CR, 5 PR)

Phase I 1st l ine ALCL w/CHP chemo

Early favorable Early unfavorable Advanced

No response 0 0 1

Partial matabolic response 0 1 0

Complete metabolic response 7 3 0

CR Rate 100% 75% 0%

Response by risk stratification

Phase II 1st l ine Hodgkin lymphoma: Adcetris (2 cycles)

Objective response N %

Complete metabolic response 10 83%

Partial metabolic response 1 8%

Disease progression 1 8%

48

Seattle Genetics: Redefining front-line therapy

SGEN is enrolling trials in first-line HL and first-line MTCL

Both trials add Adcetris to chemotherapy

Both trials replace one component of multi-agent chemotherapy with Adcetris

ECHELON-1 is ABVD vs Adcetris + AVD

ECHELON-2 is CHOP vs Adcetris + CHP

ECHELON-2 Phase III MTCL Front-l ine

Source: ASH 2010

ECHELON-1 Phase III HL Front-l ine

49

SGEN is conducting trials in post-transplant

maintenance HL (AETHERA) and relapsed

CTCL (ALCANZA)

Both trials test Adcetris monotherapy

AETHERA is Adcetris vs placebo

ALCANZA is Adcetris vs physicians choice

Seattle Genetics: Expanding in relapsed lymphoma

AETHERA Phase III Post-transplant maintenance

ALCANZA Phase III Relapsed CTCL

AETHERA data expected in Q4:14


Key Player – ImmunoGen, Inc.

51

ImmunoGen, Inc.

• Kadcyla is approved for 2nd line Her2+


• IMGN gets 3-5% royalty from Kadcyla

• 3 proprietary ADCs in development

• 7 partnered ADCs in development

IMGN was founded in 1981 and has been a leader in the development of ADC technologies including the first ADC for solid tumors (Kadcyla) with partner Genentech

Partner Scope Upfront

Additional

Milestones Royalties Date

Eli Lily Multi-target $20M $200M mid-single to

low-double

digit

Dec. 2011

Novartis Multi-target $45M $200M undisclosed Oct 2010

Bayer Single target $4M $170.5M undisclosed Oct 2008

Sanofi-aventis2 Multi-target $2M $30M undisclosed Dec. 2006

Biotest AG

(IMGN has opt-

in rights)

Single target

(opt-in rights)

$1M $35.5M undisclosed Jul 2006

Sanofi-aventis1 Multi-target undisclose

d

$21.5M undisclosed Jul 2003

Abgenix

(Amgen)3

Multi-target $1M $34M undisclosed Sept 2000

Genentech

(Roche)

Multi-target $2M $44M tiered mid-

single digit

May 2000

1 executed three licenses for SAR3419 (CD19), SAR650984 (CD38), SAR566658 (DS6)

2 extended in August, 2011 for a $2M extension fee

3 executed two single-target licenses for AMG 595, AMG 172 in September, 2009

4.3% 500 1,000 1,500 2,000 2,500 3,000

500 3.4% 3.8% 4.1% 4.3% 4.4% 4.5%

1,000 3.8% 4.0% 4.2% 4.3% 4.4% 4.5%

1,500 4.1% 4.2% 4.3% 4.4% 4.5% 4.5%

2,000 4.3% 4.3% 4.4% 4.5% 4.5% 4.6%

2,500 4.4% 4.4% 4.5% 4.5% 4.6% 4.6%

3,000 4.5% 4.5% 4.5% 4.6% 4.6% 4.7%

Ex-U

S S

ale

s

US Sales of T-DM1 ($M)

Kadcyla royalty


52

IMGN Pipeline and Key Proprietary Programs

IMGN

Drug Payloads DM1, DM4, DGN46

Number of clinical

program (stage)

10 (1 marketed, 2 Phase II, 7

Phase I)

Key programs IMGN289 (EGFR), IM853 (folate receptor)

Product Indication Stage Partner

Kadcyla (T-DM1) Her2+ mBC (prior Herceptin/Taxane) Marketed Roche

1st line Her2+ mBC Phase III

Gastric Phase II/III

Adjuvant BC Phase III

SAR-3419 (anti-CD19-DM4) DLBCL Phase II Sanofi-aventis

BT-062 TAP Multiple myeloma Phase I/II Biotest AG (IMGN has opt-in rights)

SAR650984 (anti-CD38) Hematological malignancies Phase I Sanofi-aventis

SAR-566658 (anti-DS6-DM4) Breast, ovarian, lung Phase I Sanofi-aventis

BAY 94-9343 (anti-mesothelin) Ovarian, pancreatic, mesothelioma Phase I Bayer HealthCare

IMGN529 (anti-CD37-DM1) Non-Hodgkin's lymphoma Phase I Proprietary

IMGN853 (anti-FOLR1) Ovarian cancer Phase I Proprietary

AMG 595 (anti-EGFRvIII) Glioma Phase I Amgen (Abgenix)

AMG 172 Renal cell cancer Phase I Amgen (Abgenix)

IMGN289 (anti-EGFR) Solid tumors Phase I Proprietary

Key proprietary programs


Name IMGN529 IMGN853 IMGN289

Target CD37 Folate Receptor-alpha EGFR

Drug payload DM1 DM4 DM1

Disease NHL Ovarian, endometrial Solid tumors

Stage Phase I Phase I Phase I

Timing Data at ASCO Data at ASCO Cancer meeting H2:14

Comments Neutropenia (including

febrile neutropenia) seen

at low doses. Steroid

prophylaxis has been added

and dose escalation

continues

Dosing strategies to reduce

ocular toxicity and optimize

anti-tumor activity --

adjusted ideal body weight

and weekly vs. every three

week dosing

EGFR validated target, but

key concern is skin tox

Key ADCs in Development Most ADCs are in Phase I development, so clinical data is limited

54

Pinatuzumab vedotin (RG7593/DCDT2980S)

Initial Phase I Results from ASH 2013 – Responses at doses > 1.8 mg/kg

Anti-CD22 MMAE

Genentech program; technology from SGEN

92-patient Phase I in NHL/CLL complete – Data at ASCO 2013

Phase II ROMULUS trial compared anti-CD22 and anti-CD79b ADCs head to head – Data presented at ASCO 2014

Side effects appear sim ilar to Adcetris – Neutropenia and peripheral neuropathy

Source: ASH 2013

55

Polatuzumab vedotin (RG7596 / DCDS4501A)

Initial Phase I Results from ASH 2013 – Responses at doses > 1.8 mg/kg

Anti-CD79B MMAE


95-patient Phase I in NHL/CLL complete – Data at ASCO 2013

Phase II ROMULUS trial compared anti-CD22 and anti-CD79b ADCs head to head – Data presented at ASCO 2014

Side effects appear sim ilar to Adcetris – Neutropenia and peripheral neuropathy

Source: ASH 2013

56

First Head-to-Head Trial of Two ADCs Anti-CD22 and anti-CD79b competing internally at Genentech

Innovative trial designed to pick best candidate to advance to pivotal trials

Cross-over helps assess value of developing both drugs for sequential therapy

Head-to-head trial of two Phase II drugs

Source: ASCO 2014

57

Data from ROMULUS Head-to-Head Trial at ASCO Both drugs were highly active in FL and DLBCL

Plans to take anti -CD79b forward in FL

R + Pinatuzumab (anti -CD22) responses better in DLBCL

R + Polatuzumab (anti -CD79b) responses better in FL

Source: ASCO 2014

58

Data from ROMULUS Head-to-Head Trial at ASCO Toxicity profile suggests peripheral neuropathy may limit duration of therapy

Treatment discontinuation for AEs was

31-38% for DLBCL and 60-71% for FL

Peripheral neuropathy was the most

common reason for discontinuation

(43-60% of FL)

Not all the peripheral neuropathy was

reversed

25-39% had ongoing neuropathy at

study entry, so these results are difficult

to interpret

Peripheral neuropathy was most common reason for discontinuation

Source: ASCO 2014

59

Coltuximab Ravtansine (SAR3419) Anti-CD19 DM4

Sanofi licensed drug from IMGN

Phase II STARLYTE trial: 55 r/r DLBCL patients – Data at ASCO 2014

ORR of 38-44% in r/r DLBCL

Few Grade 3&4 AEs

Manageable ocular events Grade 1&2

STARLYTE ORR, ASCO 2014

Duration of response – ASH 2014

Treatment Emergent AE’s – ASH 2014

Source: ASCO 2014

60

SGN-CD19A in DLBCL & MCL

Anti-CD19 MMAF

Target on all B-cells

Ongoing Phase I in NHL (DLBCL and MCL)

Initial Phase I data: ORR 30% (11/37), CR

16% (6/37)

Dose expansion ongoing at 3, 4, and 5 mg/kg

Prophylactic steroid eye drops added to mitigate

ocular toxicity – awaiting update

Ocular toxicity is an issue: question wil l be risk/benefit

Initial efficacy reported at ASCO

Source: ASCO 2014

High single-agent CR rate

61

SGN-CD19A in ALL & Lymphomas Phase I in ALL showed proof of

efficacy: 3 CR/CRp

Ocular toxicity emerged as a safety

concern; protocol changed to mandate

steroid eye drop prophylaxis

Data from DLBCL Phase I expected at

ASCO. ALL poster stated that multiple

CRs were seen in DLBCL.

Ocular toxicity is an issue

Dose-dependent efficacy in Phase I

Source: ASH 2013

62

RG7599 (DNIB06004A)

Anti-NaPi2b MMAE


Target highly expressed on ovarian cancer NSCLC, and papillary thyroid cancer

49-patient Phase I in ovarian and lung cancer presented at ASCO 2014

Source: ASCO 2014

Best responses seen in ovarian; correlates to NaPi2b expression

Ongoing trials

• Phase Ia – current trial enrolling NSCLC patients with fewer prior therapies

• Phase Ib – Platinum-sensitive ovarian cancer in combination with carboplatin +/- Avastin

• Phase II – randomized trial vs. Doxil in platinum resistant ovarian cancer

Peripheral neuropathy is mostly grade 1 & 2

Roche advancing development

63

Data from Phase I with anti-NaPi2b ADC (DNIB06004A)

Time on study roughly correlates with IHC

41% ORR in ovarian cancer with IHC 2 / 3+ (7/17) 0% in IHC 0 (0/1)

10% ORR in NSCLC with IHC 2 / 3+ (2/21) 0% in IHC 0 (0/5)

Source: ASCO 2014

Very encouraging single agent activity in ovarian cancer – prompted Phase II vs. Doxil

Activity not ideal, testing in earlier l ines of NSCLC in hopes of achieving higher response rate

64

ABT-414: Anti-EGFR ADC Antibody to activated EGFR or mutant EGFRvIII

linked to MMAF (EGFR activated in many

glioblastomas)

High antitumor activity in preclinical models

with either wild type EGFR or EGFRvIII

Drug dosed in combination w/ temozolomide

(TMZ)

Animal models suggested synergy with

temozolomide and radiation therapy

Study design

Status of evaluable patients

DLTs- 1.25 mg/kg dose being evaluated

Source: ASCO 2014

http://www.google.com/url?url=http://www.thepharmaletter.com/article/abbvie-files-for-eu-marketing-approval-for-its-all-oral-interferon-free-hepatitis-c-therapy&rct=j&frm=1&q=&esrc=s&sa=U&ei=TTSPU-GULc-yyAS904Fo&ved=0CCgQ9QEwAw&usg=AFQjCNH_PyY9rKfyaA6Z8qgfipfb_fevBg

65

ABT-414 + Temozolomide in Glioblastoma Phase I Single Arm Study Data presented at ASCO

1 CR and 3 PRs out of 15 patients

All responses in pts w/ TMZ refractory

disease – hard to treat patient population

Ocular toxicity an issue for this ADC too

Promising Activity Demonstrated in Early Study

Source: ASCO 2014

http://www.google.com/url?url=http://www.thepharmaletter.com/article/abbvie-files-for-eu-marketing-approval-for-its-all-oral-interferon-free-hepatitis-c-therapy&rct=j&frm=1&q=&esrc=s&sa=U&ei=TTSPU-GULc-yyAS904Fo&ved=0CCgQ9QEwAw&usg=AFQjCNH_PyY9rKfyaA6Z8qgfipfb_fevBg

66

PSMA ADC Progenics’ ADC for metastatic castration-resistant prostate cancer

Anti-PSMA MMAE; Technology from SGEN

Updated Phase II data in taxane-refractory

metastatic CRPC presented at ASCO 2014

Ongoing clinical work in chemotherapy naïve CRPC

patients

PGNX is co-developing a PSMA imaging agent

Phase II PSA response rates and CTC results for taxane experienced patients

Phase II RECIST response rates – updated at 2014 ASCO

Source: ASCO 2014

67

IMGN853: Anti-Folate Receptor

Clinical benefit enriched in ovarian cancer above threshold

Source: ASCO 2014

Phase I ongoing to optimize safety and efficacy

Anti-FRα DM4; proprietary

ImmunoGen drug

Folate receptor is up regulated on

a large number of solid tumors

including ovarian, lung, and breast

Efforts ongoing to optimize dosing

strategy to increase efficacy and

decrease ocular toxicity

68

IMGN853: Anti-Folate Receptor

Changed mg/kg dosing from total body weight (TBW) to adjusted ideal body weight (AIBW) to lower variability in drug levels and reduce toxicity

Dose limited by ocular toxicity- reduced w/ AIBW

Ocular AEs reported w/ AIBW dosing

Source: ASCO 2014

Ocular tox associated with high early exposure

Ocular AEs reported w/ TBW dosing

Ocular toxicity issue not yet solved

May require weekly dosing to get low early levels to reduce tox and higher sustained levels for better efficacy

69

IMGN289: Anti-EGFR ADC

Targets EGFR like Erbitux and Vectibix

Designed to lack skin toxicity – could be key

differentiator

Clear clinical path if safe and effective in Phase I

Expansion cohorts to test tumors known to be

sensitive to EGFR antibodies

Ongoing Phase I dose escalation

Preclinical data supports safety difference

Antibody selected for

lack of skin toxicity

Source: ASCO 2014

Awaiting key Phase I data

70

IMGN529: Anti-CD37 ADC

CD37 is found on B-cell NHL (similar to

CD20 – target of Rituxan)

Antibody alone has anti-cancer activity

similar to Rituxan in vitro

ADC format increases potency further

2 PRs observed in ongoing Phase I

Neutropenia is main toxicity

Initial Phase I dose escalation

Evidence of activity at low doses

DLT is early onset neutropenia, which IMGN believes to be caused by cytokine release.

Peri-infusional steroids added to protocol

Unclear how high drug can be dosed.

With peri-infusional steroids

Source: ASCO 2014

IMGN reported 2 PRs out of 28 patients (7%), both at low doses (0.2 and 0.4 mg/kg).

• DLBCL patient w/ 3 prior treatments, PR at cycle 3. Stopped after 4 cycles.

• Transformed FL w/ 3 prior treatments. PR at cycle 3, but progressed after cycle 5

Optimizing safety and efficacy

71

MLN0264: Anti-Guanylyl cyclase C (GCC) ADC Anti-GCC MMAE; technology from SGEN

GCC found on intestinal epithelial tumor cells

Phase I ongoing

Study design

Prelim inary response indicates antitumor activity

Neutropenia is the DLT; MTD is 1.8 mg/kg

Neuropathy not reported in >10% of patients

28 pts evaluable for response, 1 PR (gastric

cancer at 1.8mg/kg), SD in 13 pts, including

3 patients who received 4 or more cycles.

Modest response rate but still early

DLT at 1.8mg/kg- Grade 4 neutropenia

Source: ASCO 2014

http://www.millennium.com/Default.aspx

72

Inotuzumab ozogamicin (CMC-544)

Phase I trial of IO in r/ r ALL Anti-CD22 ADC; proprietary technology

CD22 is a B-cell marker. Target indications are NHL and ALL

Phase III of CMC-544 + Rituxan in relapsed DLBCL stopped early for futility

Phase III ongoing in relapsed/refractory ALL

Source: Cancer; 2013

Updated data in NHL and ALL presented at ASCO

Not included in slide deck

73

Glembatumumab vedotin (CDX-011)

Pivotal Phase II METRIC Study

Source: EMERGE Update 2013 SABCS

Anti-GPNMB ADC; Technology from

SGEN

Pivotal METRIC trial in triple-negative

breast cancer initiated in Dec. 2013

Phase II in melanoma (66 pt) and

squamous cell lung cancer (55 pt)

planned

EMERGE Phase II Data

74

IMMU-132 & IMMU-130: SN38 Conjugates

IMMU-132

Anti-TROP-2; proprietary SN38 conjugate

Phase I/II in a variety of solid tumors

Phase II ongoing

IMMU-132 Phase I/ II anti -tumor activity

IMMU-130

Anti-CEACAM5; proprietary SN38 conjugate

PR and tumor shrinkage seen in Phase I

Phase II ongoing in relapsed metastatic

colorectal cancer

IMMU-130 Phase I data

Source: ASCO 2014

75

SAR566658: Anti-CA6 ADC

Signals of activity in Phase I Ocular toxicity seen as with other DM4 ADCs

Phase I continues for SAR566658

Phase I is reported to be 150 patients, so we expect Sanofi will test across different dosing strategies and potential expansion cohorts

Target tumor type for further studies not determined

Ocular toxicity is a dose limiting concern

Source: AACR-EORTC 2013

76

RG7450 (DSTP3086S)

Anti-STEAP1 MMAE


61-patient Phase I ongoing in prostate cancer; Interim data presented on 60 patients at ASCO 2014

Recommended Ph II dose (2.4 mg/kg every 3 wks)

Time on Study- dose reductions indicated by color change

Source: ASCO 2014

Best response by cohort

22% (10/45) pts dosed at >2 mg/kg had a PSA decline ≥ 50%

8% (2/26) RECIST evaluable pts (>2mg/kg) had PRs (all at 2.8mg/kg)

Concern is that giving up higher efficacy (at 2.8 mg/kg) due to toxicity concern and going with lower dose (at 2.4 mg/kg)

77

Indatuximab Ravtansine (BT062)

Anti-CD138 DM4

Biotest drug; technology from IMGN

Currently in 49-patient Phase I/II

Trial completion expected in H1:15

Combination trial in multiple myeloma with Revlim id/dexamethasone – ASH 2013

ORR 75% in Len/Dex refractory pts ORR 89% at MTD

Source: Company data, Credit Suisse research

Companies Mentioned (Price as of 19-Jun-2014)

AbbVie Inc. (ABBV.N, $54.24) Amgen Inc. (AMGN.OQ, $117.59) Bayer (BAYGn.DE, €103.45) Celgene Corp. (CELG.OQ, $166.34) Celldex (CLDX.OQ, $16.76) Daiichi Sankyo (4568.T, ¥1,830) Eli Lilly & Co. (LLY.N, $59.77) Endo Health Solutions (ENDP.OQ, $67.81) GENMAB (GEN.CO, Dkr227.1) ImmunoGen, Inc. (IMGN.OQ, $12.95) Immunomedics (IMMU.OQ, $3.67) Novartis (NOVN.VX, SFr81.2) Pfizer (PFE.N, $29.54) Progenics Pharm (PGNX.OQ, $4.35) Roche (ROG.VX, SFr266.4) Sanofi (SASY.PA, €79.54) Seattle Genetics (SGEN.OQ, $40.81) Takeda Pharmaceutical (4502.T, ¥4,876)

Disclosure Appendix

Important Global Disclosures

I, Jason Kantor, PhD, certify that (1) the views expressed in this report accurately reflect my personal views about all of the subject companies and securities and (2) no part of my compensation was, is or will be directly or indirectly related to the specific recommendations or views expressed in this report.

The analyst(s) responsible for preparing this research report received Compensation that is based upon various factors including Credit Suisse's total revenues, a portion of which are generated by Credit Suisse's investment banking activities

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Restricted 3%

*For purposes of the NYSE and NASD ratings distribution disclosure requirements, our stock ratings of Outperform, Neutral, an d Underperform most closely correspond to Buy, Hold, and Sell, respectively; however, the meanings are not the same, as our stock ratings are determined on a relative basis. (Please refer to def initions above.) An investor's decision to buy or sell a security should be based on investment objectives, current holdings, and o ther individual factors.

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See the Companies Mentioned section for full company names

The subject company (ENDP.OQ, ROG.VX, IMGN.OQ, AMGN.OQ, BAYGn.DE, LLY.N, 4568.T, PFE.N, CELG.OQ, NOVN.VX, SGEN.OQ, ABBV.N, 4502.T) currently is, or was during the 12-month period preceding the date of distribution of this report, a client of Credit Suisse.

Credit Suisse provided investment banking services to the subject company (ENDP.OQ, AMGN.OQ, BAYGn.DE, LLY.N, PFE.N, CELG.OQ, NOVN.VX) within the past 12 months.

Credit Suisse provided non-investment banking services to the subject company (ROG.VX, IMGN.OQ, AMGN.OQ, BAYGn.DE, LLY.N, 4568.T, PFE.N, CELG.OQ, NOVN.VX, 4502.T) within the past 12 months

Credit Suisse has managed or co-managed a public offering of securities for the subject company (AMGN.OQ, BAYGn.DE, PFE.N, CELG.OQ, NOVN.VX) within the past 12 months.

Credit Suisse has received investment banking related compensation from the subject company (ENDP.OQ, AMGN.OQ, BAYGn.DE, LLY.N, PFE.N, CELG.OQ, NOVN.VX) within the past 12 months

Credit Suisse expects to receive or intends to seek investment banking related compensation from the subject company (ENDP.OQ, IMGN.OQ, AMGN.OQ, BAYGn.DE, LLY.N, PFE.N, CELG.OQ, NOVN.VX, SGEN.OQ, ABBV.N, 4502.T) within the next 3 months.

Credit Suisse has received compensation for products and services other than investment banking services from the subject company (ROG.VX, IMGN.OQ, AMGN.OQ, BAYGn.DE, LLY.N, 4568.T, PFE.N, CELG.OQ, NOVN.VX, 4502.T) within the past 12 months

As of the date of this report, Credit Suisse makes a market in the following subject companies (ENDP.OQ, IMGN.OQ, AMGN.OQ, LLY.N, PFE.N, CELG.OQ, SGEN.OQ, ABBV.N, 4502.T).

As of the end of the preceding month, Credit Suisse beneficially own 1% or more of a class of common equity securities of (NOVN.VX).

As of the date of this report, an analyst involved in the preparation of this report has the following material conflict of interest with the subject company (PFE.N). As of the date of this report, an analyst involved in the preparation of this report, Vamil Divan, has following material conflicts of interest with the subject company. The analyst or a member of the analyst's household has a long position in the common stock Pfizer (PFE.N). A member of the analyst's household is an employee of Pfizer (PFE.N).

As of the date of this report, an analyst involved in the preparation of this report has the following material conflict of interest with the subject company (PFE.N). As of the date of this report, an analyst involved in the preparation of this report, Ronak Shah, has the following material conflict of interest with the subject company. The analyst has a long position in the common stock Pfizer (PFE.N).

For other important disclosures concerning companies featured in this report, including price charts, please visit the website at https://rave.credit-suisse.com/disclosures or call +1 (877) 291-2683.

Important Regional Disclosures

Singapore recipients should contact Credit Suisse AG, Singapore Branch for any matters arising from this research report.

The analyst(s) involved in the preparation of this report have not visited the material operations of the subject company (ENDP.OQ, ROG.VX, IMGN.OQ, AMGN.OQ, BAYGn.DE, LLY.N, 4568.T, PFE.N, PFE.N, PFE.N, CELG.OQ, NOVN.VX, SGEN.OQ, ABBV.N, 4502.T, SASY.PA) within the past 12 months

Restrictions on certain Canadian securities are indicated by the following abbreviations: NVS--Non-Voting shares; RVS--Restricted Voting Shares; SVS--Subordinate Voting Shares.

Individuals receiving this report from a Canadian investment dealer that is not affiliated with Credit Suisse should be advised that this report may not contain regulatory disclosures the non-affiliated Canadian investment dealer would be required to make if this were its own report.

For Credit Suisse Securities (Canada), Inc.'s policies and procedures regarding the dissemination of equity research, please visit http://www.csfb.com/legal_terms/canada_research_policy.shtml.

The following disclosed European company/ies have estimates that comply with IFRS: (SASY.PA).

Credit Suisse has acted as lead manager or syndicate member in a public offering of securities for the subject company (AMGN.OQ, BAYGn.DE, PFE.N, CELG.OQ, NOVN.VX) within the past 3 years.

As of the date of this report, Credit Suisse acts as a market maker or liquidity provider in the equities securities that are the subject of this report.

Principal is not guaranteed in the case of equities because equity prices are variable.

Commission is the commission rate or the amount agreed with a customer when setting up an account or at any time after that.

For Credit Suisse disclosure information on other companies mentioned in this report, please visit the website at https://rave.credit-suisse.com/disclosures or call +1 (877) 291-2683.

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