Halozyme TherapeuticsHalozyme Therapeutics

ANALYST AND INVESTOR MEETINGANALYST AND INVESTOR MEETING

THURSDAY, OCTOBER 15, 2009THURSDAY, OCTOBER 15, 2009New YorkNew York

Safe Harbor

The Private Securities Litigation Reform Act of 1995 provides a "safe harbor" for forward-looking statements. Allprovides a safe harbor for forward looking statements. All statements made in this presentation that are not statements of historical fact constitute forward-looking statements. The matters referred to in forward-lookingstatements. The matters referred to in forward looking statements could be affected by the risks and uncertainties of the Company's business. Such risks inherent to the Company’s business will be described in the Company’sCompany s business will be described in the Company s filings, when they occur, with the Securities and Exchange Commission, as well as in its press releases. The Company's actual results may differ materially from thoseCompany s actual results may differ materially from those expressed in or indicated by such forward-looking statement.

2

AGENDA

Jonathan E. Lim, M.D. President & Chief Executive Officer

I t d ti d St t i R iIntroduction and Strategic Review

Robert J. LittleVice President Chief Commercial OfficerVice President, Chief Commercial Officer

Leveraging the Technology Across Multiple Partners

Gregory I Frost Ph DGregory I. Frost, Ph.D.Vice President, Chief Scientific Officer

Discovery and Early Development Pipeline Update

Douglas B. Muchmore, M.D.Vice President, Endocrinology Clinical DevelopmentUltrafast Insulin-PH20 Program – Where We Are Going

3

Introduction & Strategic ReviewIntroduction & Strategic Review

Jonathan E. Lim, M.D.Jonathan E. Lim, M.D.

President & Chief Executive OfficerPresident & Chief Executive Officer

4

Halozyme is Well Positioned to Generate Current and Future Shareholder Value

• Strong technology foundation and pipeline of commercial, partnered, and clinical stage assets with near-term value drivers

– Partnerships with Roche and Baxter worth up to $724 million plusPartnerships with Roche and Baxter worth up to $724 million, plus royalties; near term launches underway (Hylenex) and anticipated (Enhanze GAMMAGARD, Roche)

– Proprietary programs in clinical development that could generate high p y p g p g gvalue partnerships (e.g., Phase 2 Ultrafast Insulin-PH20 Program)

– Investment in high value but low-cost development activities that advance programs to next value inflection pointg

• Innovative biotech company with strong biologics capabilities that can help drive long-term growth

– Scientific focus and expertise in the extracellular matrix (the “Matrix”)– Scientific focus and expertise in the extracellular matrix (the Matrix )

– Expertise in maximizing value from multifunctional Matrix platforms (rHuPH20, HTI-501, rHuMMP1ts)

C lt f ll E ti l t ith t i bi l i

5

– Culture of excellence: Exceptional team with extensive biologics experience and ability to produce complex recombinant proteins

Strong patent protection and

lif l

s

lifecycle extension

Diversified, robust

pipeline/

Validation through existing Novel M

or P

artn

ers pipeline/

portfolioexisting

partnerships

Matrix TheraTo

olbo

x fo Halozyme’s

Technology Foundation Increased

footprint in high growth

De-risked biological rapeuticsB

iolo

gics

T gbiologics market

gprograms

B

Differentiated biologics with best-in-class

potential

Expedited regulatory pathway

6Differentiated Products

Existing Alliances Drive Significant Value

Enhanze Technology with Roche (up to 13 biologic targets)

• Alliance worth up to $612M ($20M up-front; $111M milestones for first 3 p $ ($ p ; $exclusive targets; $470M up-front & milestones for 10 additional targets; $11M equity), plus royalties; $48M received to date

Enhanze Technology with Baxter BioScience (GAMMAGARD)Enhanze Technology with Baxter BioScience (GAMMAGARD)

• Alliance worth up to $47M ($10M up-front; $37M milestones), plus royalties; $10M received to date

HYLENEX with Baxter Medication Delivery

• Alliance worth up to $65M ($10M up-front; $25M milestones; $10M pre-paid royalties; $20M equity) plus royalties; $40M received to date

Nearly $100 million of alliance related cash received to date

paid royalties; $20M equity), plus royalties; $40M received to date

7

Nearly $100 million of alliance related cash received to date

8

Our Vision

To be the best “Matrix Company” in the world by growing our expertise in the science of the extracellular matrix to develop and commercialize meaningful new

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biotechnology products for patients

Halozyme’s Robust Pipeline of Multifunctional Platforms Targeting the Matrix

Matrix Targets Matrix Biologics

HyaluronanPH20 Depot

PEGPH20 PH20 Intravesical

PH20 SC

Collagen rHuMMP1ts

rHuCAT-L

g

OtherOther Matrix modifying Other

Discovery Preclinical Phase 1 Phase 2 Phase 3 Commercial

y gagents

10

Discovery Preclinical Phase 1 Phase 2 Phase 3 Commercial

Development Stage

Our First Multifunctional Enzyme Platform Targets over $10 Billion in Product Opportunities

Analog-PH20Phase 2

HylenexRoche

Biologic#1Hylenexfor drugs

Phase 4

gPhase 1

rHuPH20 Roche Biologics #2 & #3

Enzyme

Hylenexf fl id

Phase 1

for fluidsLaunched

Insulin-PH20

EnhanzeIgG

Phase 3

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PH20Phase 2

Fluids and small molecules Peptides Large molecules

Culture of Excellence: “The Halo Edge”

Att ti ld l bi h t l t t k iti• Attracting world class biopharma talent to key positions

– H. Michael Shepard, Ph.D., VP of Discovery Research (Receptor BioLogix, Canji, Genentech)BioLogix, Canji, Genentech)

– Jonathan Leff, M.D., VP and Chief Medical Officer (Roche, Amgen, Merck)

• ~140 employees from nearly 70 companies with competencies across the drug development value chain, with exception of sales

– Highly committed, passionate workforce that has the capabilities and experience to execute Halozyme’s plan and build a great company

• Successful track record with talent initiativesSuccessful track record with talent initiatives

– Offer acceptance rate was 87% last year; 60% of new employees came from internal referrals

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– Voluntary turnover remains less than 5% (vs. 10.5% industry average; Radford)

With Fewer than 150 Employees, Halozyme Has Solid Biologics R&D Expertise Per Capita

Biologics Experience(Enzymes, MoAbs, Gene Rx)

Expression Systems(Mammalian, Bacterial, Viral)

13

Halozyme’s Growth Strategy Can Generate Value Over Multiple Time Horizons

Value creation

Generate value for patients and shareholders

• Grow partnership and own product revenue

B ild

Develop pipeline of proprietary programs

• Analog-PH20• Insulin-PH20

own product revenue• Other Matrix drugs• Other promising

innovations

Build revenue generating engine

• Roche Enhanzeprograms

Insulin PH20• PEGPH20• PH20 Depot• HTI-501• rHuMMP1tsp g

• EnhanzeGammaGard

• Hylenex

Capabilities • PH20 drug delivery • PH20 drug development • Commercialization in core TA’s

Time

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• Protein engineering • Other Matrix drug development

alone or with partners• Delivery or development of

other promising breakthroughs

HALO Pursuing Multi-Billion Dollar Franchise Opportunities Targeting the MatrixOpportunities Targeting the Matrix

Drug delivery revenue generating engine

Proprietary pipeline targeting the Matrixgenerating engine

• Enhanze Technology with Roche (up to 13 biologic targets)

• Enhanze Technology with

the Matrix• Ultrafast Insulin-PH20 (diabetes)• PEGPH20 (NME, solid tumors)

Chemophase (bladder cancer)Enhanze Technology with Baxter BioScience(GAMMAGARD)

• HYLENEX with Baxter

• Chemophase (bladder cancer)• HTI-501 (NME, dermatology)

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Medication delivery

Commercial Opportunities –Leveraging the Technology Across Multiple

Commercial Opportunities –Leveraging the Technology Across MultipleLeveraging the Technology Across Multiple

PartnersLeveraging the Technology Across Multiple

Partners

Robert J. Little

Vice President, Chief Commercial Officer

Robert J. Little

Vice President, Chief Commercial Officer

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Leveraging the rHuPH20 Technology Through Drug Delivery Deals

rHuPH20 technology can be used with a broad range of

Through Drug Delivery Deals

rHuPH20 technology can be used with a broad range of injectable pharmaceutical products to improve delivery and optimize value

• Technology can be applied to multiple pharmaceuticals, especially biologics, to transform them from intravenous (IV) to subcutaneous (SC) administration

• Deals provide attractive non-dilutive cash through upfront, milestone, and royalty payments

• Cash generated from deals helps to fund Halozyme’sproprietary pipeline

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Enhanze Technology:For Partners with Injectable Biologics and DrugsFor Partners with Injectable Biologics and Drugs

Value proposition

• Deliver more drug to intended targetsDeliver more drug to intended targets • Allow drugs to work faster • Increased volume of drug at each injection

Increased efficacy

• Change route of administration (IV to SC)• Reduce adverse injection site reactions

Convenience and j

• Decrease pain and tissue distortion upon injectionand compliance

• Provide competitive differentiation and reduce COGS• Enable cost-effective self-administration of physician

delivered drugsEconomic benefits

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• Extend lifecycle of products coming off patent

Enhanze Technology Platform De-Risked Through Progress of Roche and Baxter CollaborationsProgress of Roche and Baxter Collaborations

• Preclinical Safety – high dose chronic and reproductive toxcompleted in several animal species

• Product Development – numerous stable formulations of biologics with PH20

• Regulatory Affairs – U.S. and EU regulatory pathways more clarified

• Clinical Development Enhanze GAMMAGARD in pivotal• Clinical Development – Enhanze GAMMAGARD in pivotal Phase 3, other clinical studies underway

• Manufacturing – two API manufacturing sites established, 2nd

ti ll li d l l t dgeneration cell line and scale-up completed

• Commercial – reimbursement and pricing research with partners completed

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Three Partnered Programs Based on Halozyme’s Drug Delivery TechnologyHalozyme s Drug Delivery Technology

1 Enhanze Technology with Roche (up to 13 biologic targets)1. Enhanze Technology with Roche (up to 13 biologic targets)

2. Enhanze Technology with Baxter BioScience (GAMMAGARD)

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( )

3. HYLENEX with Baxter Medication Delivery

Roche Enhanze Technology Alliance Moving Forward

• Three targets in Phase 1 clinical trials including third

Moving Forward

Three targets in Phase 1 clinical trials, including third target which began in September 2009

• Exercised exclusive global rights to a fourth biologicExercised exclusive global rights to a fourth biologic target in December 2008 and fifth target in June 2009

• Initiation of additional Roche clinical trial plus milestoneInitiation of additional Roche clinical trial plus milestone possible in 2009

• Clinical progress also expected in 2010Clinical progress also expected in 2010

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Recent Public Disclosures Reflect Strong Momentum of Roche-Halo Progress

• 4th exclusive biologic target elected

Momentum of Roche Halo Progress

$612M partnership signed, 3 exclusive biologic targets elected (Dec06)

target elected• 1st Phase 1 (n=70, mid-09

completion)• Annual maintenance fees(Dec08)

5th exclusive biologic target elected(Jun09)

3rd Phase 1 begins (Sep09)

YE06 YE07 YE08 YE09

2nd Phase 1 (n=48, mid-09 completion)

Additional Roche clinical trial plus milestone possible

CMC, including manufacturing scale-up, nonclinical, toxicology, and other development activities for product candidates formulated with PH20 (not disclosed) p )

(Jan09) p

(2H09) ( )

Baxter BioScience - Enhanze GAMMAGARD Addressable IgG Market Forecast at $8-$9 BillionAddressable IgG Market Forecast at $8 $9 Billion

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Market Size Reflects The Broad Clinical Applications Of IgGSource: Baxter

Baxter BioScience - Enhanze GAMMAGARD Development Plan Moving Forward Rapidly

• Current market dominated by IV administration

• SC IgG available limited by low bioavailability (62%) and need for weekly

Development Plan Moving Forward Rapidly

• SC IgG available - limited by low bioavailability (62%) and need for weekly dosing at multiple injection sites

• Phase 1/2a trial showed SC bioavailability equal to 92% of IV administration with dosing of up to 61 2 grams (612 ml) IgG together with PH20 at up to 300with dosing of up to 61.2 grams (612 ml) IgG together with PH20 at up to 300 mL per hour

• Pivotal Phase 3 for GAMMAGARD with PH20 began December 2008; fully enrolled with ~ 80 patients in July 2009 ahead of planenrolled with ~ 80 patients in July 2009, ahead of plan

• Final clinical study reports planned in 1H11

• Pre-launch activities initiated with physician, patient and payer research p y p p yunderway

• SC GAMMAGARD offers convenient, once monthly, self-administration in a single SC injection site; could become gold standard in large growing market

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g j g g g g

HYLENEX –Franchise Potential Could be Worth up to $500MFranchise Potential Could be Worth up to $500M

• $200M U.S. market opportunity in pediatric hydration alone 4.0

Addressable U.S. ED Visits (M)

• 2.4M ED (emergency department) visits potentially addressable by HYLENEX 1.6

• Potential for $500M franchise

– Adult hydration

– Ex-U.S. markets

2.4

Ex U.S. markets

– Delivery of small molecule drugs (e.g., pain, infection)

• Paradigm shift in ED medical• Paradigm shift in ED medical practice means slow, gradual uptake and acceptance

ED pediatric visits for dehydration only

Successful ORT

Total IV procedures (incl. ORT failures)

25

Source: BaxterORT: Oral rehydration therapy

only failures)

HYLENEX – Clinically Meaningful Rehydration Demonstrated in INFUSE Peds 1 StudyDemonstrated in INFUSE Peds 1 Study

26Allen, C.H., et al, Recombinant Human Hyaluronidase-Enabled Subcutaneous Pediatric Rehydration, Pediatrics, 2009;124;e859-e868.

HYLENEX – Favorably Perceived By 9 out of 10 Healthcare Providers and PatientsHealthcare Providers and Patients

27Allen, C.H., et al, Recombinant Human Hyaluronidase-Enabled Subcutaneous Pediatric Rehydration, Pediatrics, 2009;124;e859-e868.

HYLENEX – Encouraging Interim Results at ACEP from INFUSE PEDS 2 Studyfrom INFUSE PEDS 2 Study

28

HYLENEX – Fully Resourced Launch in Pediatric Hydration UnderwayPediatric Hydration Underway

• Product launched for pediatric hydration at ACEP in Boston on Oct 5thon Oct 5th

• Two sales forces - dedicated HYLENEX specialty team and existing Baxter IV team supported by formulary specialists in lplace

• 90% acceptance rate onto target formularies, even prior to published data

• Full team of clinical and scientific medical science liaisons established

L d ith lti l k• Large advocacy program with multiple speaker programs have been underway for several months

• Leading national and regional KOLs on board

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g g

HYLENEX –An Emerging Strong Value PropositionAn Emerging Strong Value Proposition

• Enables rehydration with less stress for parents and childreny p

• Makes infusion simple and efficient

• Facilitates clinically meaningful hydration

• Potentially benefits over 2 million pediatric patients each year in the U.S. alone

• P i d f bl b 9/10 h lth id d t IV• Perceived favorably by 9/10 healthcare providers compared to IV

• Additional post-marketing clinical data being developed

• Building a new standard of care for rehydration paradigm shift• Building a new standard of care for rehydration, paradigm shift

• HYLENEX safe and well tolerated in clinical experience

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Strong Alliances Generate Non-dilutive Cash and Leverage TechnologyCash and Leverage Technology

• Three alliances with Roche and Baxter have provided $98 million of cash so far

• Ability to leverage the technology platform multiple times through additional alliances

• rHuPH20 drug delivery platform being evaluated by nearly every large biopharma company

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Discovery and Early Development Pi li U d t

Discovery and Early Development Pi li U d tPipeline UpdatePipeline Update

Gregory I. Frost, Ph.D.

Vice President , Chief Scientific Officer

Gregory I. Frost, Ph.D.

Vice President , Chief Scientific Officer

32

ECM: Breaking it DownECM: Breaking it Down5 classes of macromolecules5 classes of macromolecules

1. Collagens2. Elastic fibers1. Collagens2. Elastic fibers 3. Hyaluronan3. Hyaluronan3. Hyaluronan

4. Proteoglycans5. Adhesive glycoproteins

3. Hyaluronan4. Proteoglycans5. Adhesive glycoproteins

33

rHuPH20 SC Preclinical

through CommercialCommercial

rHuPH20-Intravesical

Phase 2

rHuMMP1tsConditional CollagenaseDiscovery

MatrixBiologics

Research

Biologics

PEGPH20rHuCAT-L

Conditional P t i

Phase 1

PH20 Depot

ProteinasePreclinical

34

Preclinical

How Halozyme is Targeting the Matrix EnvironmentHow Halozyme is Targeting the Matrix Environment

DiseaseDelivery ECM

Current Matrix Targets

CandidateEnzymes

Mechanism of Action Potential Applications

COLLAGENS rHuCAT-L Focal Proteolysis CelluliteDupuytren’s ContractureFib irHuMMP1ts FibrosisKeloids/Scarring

rHuPH20Transient FocalHydrolysis

SC administration: Fluids, Peptides and Biologics Chemotherapy Delivery

HYALURONAN PH20 Depot

Chemotherapy Delivery

Prolonged Focal Hydrolysis

Postsurgical Edema, Benign Prostatic Hypertrophy (BPH)Chemonucleolysis

35

PEGPH20Chemonucleolysis

Prolonged Systemic Hydrolysis

Solid Tumors

Matrix Target: Collagen

Type I Collagen - Abundant in skin, tendon, ligament bone cornea – 88-99% of total collagenligament, bone, cornea 88 99% of total collagen

36

Fibrous Septae:A Potential Target for Enzymatic Contouring?A Potential Target for Enzymatic Contouring?

P t ti l A h Ch llPotential Approaches1) Surgical subscision2) Enzymatic subscision

Challenge: Temporal spatial control of enzyme activity

37

Enzymatic Subscision: Focal Digestion of Fibrous Septae with Collagenolytic Enzymes

DimpleDimple

Fibrous Septae with Collagenolytic Enzymes

TARGETTARGET

fibrous septae FibrousSeptae

FibrousSeptae

38

create dimplesSeptaeSeptae

rHuCathepsin-L (rHuCAT-L) is a Recombinant Human Lysosomal Cysteine EndopeptidaseHuman Lysosomal Cysteine Endopeptidase

• Cathepsin-L: an enzyme naturally regulated by an acidic cellular environment

• Active at acidic pH but rapidly inactivated at physiological pH in p y g pthe extracellular space

• Very efficient ‘collagenase’ at pH 5 0 (~pH of lidocaine)5.0 ( pH of lidocaine)

olla

gen

Type

I C

opH 5.0pH 5.0

T

Enzyme ‘On’ Enzyme ‘Off’

Dimple

Concept:Temporal Spatial Control of Collagenolytic Activity

1- rHuCAT-L enzyme injected in an active stateformulated in artificial lysosomal buffer

Dimple Collagenolytic Activity

formulated in artificial lysosomal buffer

2- Enzyme cleaves fibrous septae

3 Body’s natural pH in the Matrix3- Body s natural pH in the Matrixinactivates rHuCAT-L as it diffusesaway from injection siteAdipocytes

4- Dimple relieved as septae lysed

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fibrous septae create dimples

Fibrous Septae

rHuCAT-L Treatment Leads to pH Conditional Release of Collagen Fragments In VivoRelease of Collagen Fragments In Vivo

C B ff C ll

Rodent perfusion model Porcine model

CATL pH 5

Buffer pH 5

CollagenasepH 7.5

ss

3.5

4.0

pH 7.4

pH 5 0

gros

eprol

ine

2.0

2.5

3.0pH 5.0

pH 7.4 + CATL

pH 5.0 + CATL

Tric

hrom

e

Hyd

roxy

p(u

g/m

L)

0 5

1.0

1.5

septae lysis septae lysisseptae control

0.0

0.5

0 min 8 min 16 min

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rHuCAT-L Progressing Towards the Clinic

• rHuCAT-L cell bank• Fermentation process development• Downstream process development• IND enabling CMC activities• cGMP production of clinical batches• GLP toxicology• GLP toxicology• Final pharmacology and secondary indication

evaluation • IND filing

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Second Collagenase Program: rHuMMP1ts(Temperature Specific MMP1 Analog)(Temperature Specific MMP1 Analog)

MMP1 (Matrix Metalloproteinase 1)

• Prototypical interstitial human collagenaseyp g

• Selectively degrades interstitial collagens (I/III)

• Little activity towards blood vessel collagen (IV)

• Can temporal spatial enzyme activity be engineered to increase safety at pharmacologically relevant doses?

I/III

e I/III

rHuMMP1Control (Dermis H&E)

agen

 Type 

ollagen Typ

Bacterial Collagenase(positive control)

4343In situ collagen release In situ collagen release

by MMP1

Coll Co

By High Throughput Single AA Mutagenesis, Temperature Specific MMP1 Analogs Identified

Product Concept:stru

cted

• 199 amino acid (AA) protein • All potential single amino

acid substitutions screened• 8 strong hits identified

Product Concept:Inject enzyme at room temperature. Digestion of target until body temperature warms enzyme to i ti tN

A’s

Con

s

8 strong hits identified inactivate

WildtypetsAnalog >40 X 20/37

tsAnalog >40 X 20/37

2985

cD

N

Wildtype >40 X 20/37 >40 X 20/37

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Value of New Matrix Platforms

• A positive extension of Halozyme’s expertise in Matrix p y penzymes, proteins, and delivery

• A novel biologic compound generating engine outside the realm of monoclonal antibodies, creating a new class of potential breakthrough therapies

Generation of new high value therapeutic biologics• Generation of new high value therapeutic biologics beyond HA and hyaluronidase

45

Matrix Target: Hyaluronan in the Tumor Microenvironment• Tumor extends beyond the cancer cells• Tumor extends beyond the cancer cells • Many tumors contain reactive stromal matrix that facilitates tumor progression • Treating the tumor as an organ opens up new opportunities for therapeutic

intervention (beyond angiogenesis)( y g g )

VESSELSVESSELSTUMOR CELLSTUMOR CELLS

STROMASTROMASTROMASTROMA

PEGPH20

Example: Stromal Matrix Occupies Most of the Pancreatic Cancer Microenvironment

Duct T3N0M0 Duct TxN0M0 Duct T3N0M0 Normal

Pancreatic Cancer Microenvironment

40x

200x

HA( ) HA(+)BROWNBlue

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HA(+++) HA(+)

* Representative images of HA/ Hematoxylin on pancreatic tumor tissue

BROWN (HA rich Stroma)

Blue(Tumor Cells)

PEGPH20: Background

Section from Metastatic Breast Cancer

• The Matrix comprises the majority of tumor volume in many tumors

Tumor Matrix

tumor volume in many tumors

• The functions of the Matrix– Support structure for the cancer

Tumor Matrix

pp– Storage for growth factors and

cytokines– Altered composition during growth

and tissue remodelingTumor Matrix and tissue remodeling

• Halozyme’s PEGPH20 degrades Matrix by removing the hyaluronan component

Nest of Malignant Cells

of the Matrix

• Enhances malignant cell vulnerability to Chemotherapy

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– Chemotherapy– Biotherapeutics– Immune system

Hyaluronan Overproduction is Common in MalignancyCommon in Malignancy

87% HA High

46% HA HighAll HA overexpressing tumors tested in46% HA High tumors tested in xenograft models respondto PEGPH20 and enhance activity of chemotherapeutic

49

PEGPH20 – HA Degradation May Represent A Novel Mechanism for Cancer Treatment

• HA rich halos found

A Novel Mechanism for Cancer Treatment

• HA-rich halos found on many types of aggressive tumors (breast prostate

TUMOR CELLHalo (breast, prostate,

pancreatic)

• PEGPH20 collapses

CELLHalo

pHA dependent pericellular halos on tumor cells

HA+ Enzyme=Halo degraded PEGPH20

• Modulates resistance to chemotherapy

TUMOR CELL

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PC3 Xenografts (H&E) PC3 X ft (H&E)

Removal of Hyaluronan from the Tumor Matrix Alters Tissue Structure

PC3 Xenografts (H&E) PC3 Xenografts (H&E)

PEGPH20 i.v 8hrs

TUMORWITH HA

TUMOR WITHOUT HA

WITH HA

PC3 Xenografts (Alcian Blue Stain) PC3 Xenografts (Alcian Blue Stain)

PEGPH20 i.v 8hrs

51

Removal of Hyaluronan from the Tumor Matrix Rapidly Reduces Tumor Interstitial Fluid Pressure (IFP)Rapidly Reduces Tumor Interstitial Fluid Pressure (IFP)

1.11.2

0 70.80.91.0

umor

IFP + API Buffer

>80% reduction in

0.40.50.60.7

Dos

ed

mal

ized

Tu tumor IFP within

1st hour

0.10.20.30.4 D

Nor

m

+ PEGPH20

-20 0 20 40 60 80 100 120

0.0

Time after injection (min)

52* IM PC3 tumor pressure in tumor bearing mice measured 20 minutes prior and for 2 hours following IV

injection of 10,000 units of PEGPH20 (n=3), or Carrier Buffer (n=3)

Time after injection (min)

Combinations of PEGPH20 with Docetaxel or Liposomal Doxorubicin Demonstrates Significantly Improved Anti-Tumor Activity

2000

2500

3000

Vehicle

PEGPH2015 mg/kg(m

m3 )

Tumor Activity

2000

2500

3000

Vehicle

PEG PH20mm

3 )

1000

1500 Taxotere10 mg/kg

15 mg/kg

PEGPH20

(0/6)

(4/7)Tum

or V

olum

e

1000

1500

PEG-PH20

Doxil

Tum

or V

olum

e (m

-2 0 2 4 6 8 12 14 16 18 20 22 24 26 28 30 32 34 363 7 100

500

Time (days)

+ Tax

T+P T+PP P

(4/7)T

6 9 15 18 21 24 27 30 33 360 3 5 7 10 12 14140

500 Doxil + PEG-PH20

D+P D+P D+PP P P P

Time (Days)

6015 mg/kg PEGPH20

g)

Tumor IFP Drug AccumulationStromal MatrixPre-dose Post-dose

10

20

30

40

50

umor

IFP

(mm

HgPre dose Post dose

53

0 1200

10

Time (minutes)

Tu

PEGPH20 enzyme removes matrix substrate in tumor

PEGPH20 + Gemcitabine Shows Activity

BXPC-3 Tumor Line• HALO++ w/Aggrecan

(%TGI=21% at D18)

D18-Data(1 Round of Rx)

Tumor Tissue• HA Stroma+ / Tumor

Cells+(%TGI=62% at D18)

Cells+

Superior Effect of PEGPH20+Gemcitabine

D28-Data(2 Rounds of Rx)

vs. Gemcitabine

54

PEGPH20 + Erlotinib Shows Activity

(%TGI=27% at D18)

D18-Data(1 Round of Rx)BXPC-3 Tumor Line

• HALO++ w/Aggrecan

(%TGI=63% at D18)Tumor Tissue• HA Stroma+ / Tumor

Cells+

D28-Data(2 Rounds of Rx)

Superior Effect of PEGPH20 + Erlotinib

E l ti ibvs. Erlotinib

55

PEGPH20 Program - Phase 1 Clinical Trial

• Multicenter, open-label, dose evaluation trial of IV administered PEGPH20 in advanced cancer patients began 1Q09PEGPH20 in advanced cancer patients began 1Q09

• Safety and tolerability, PK, and PD data from oncology patients anticipated 2H10

• Determine maximum tolerated dose & dose-limiting toxicities

• Observe patients for evidence of antitumor activityObserve patients for evidence of antitumor activity

• Study will guide PEGPH20 dose selection for future clinical trials

Phase 1b/2 combination studies– Phase 1b/2 combination studies

– Phase 2 single agent studies

56

PEGPH20 Program Summary

• Hyaluronan is a major component of the tumor matrixHyaluronan is a major component of the tumor matrix (e.g., 87% of pancreatic cancer)

• PEGPH20 disrupts tumor matrix to enhance cancer cell psensitivity to chemotherapeutics

• Clinical Phase 1 trial currently underway

• Complete Phase 1b planned to test combinations with chemotherapy

57

Stromal Matrix Target: Hyaluronan in Benign Prostatic Hypertrophy (BPH)yp p y ( )

• Affects 50% of men by age 50 75% by age 80• Affects 50% of men by age 50, 75% by age 80

• 40-50% of patients, BPH clinically significant

• Health care costs > $4.8 billion annually (2004)– Non-surgical intervention $2.5 billion per year– Surgical intervention $2.3 billion per yearg p y

• Most BPH involves smooth muscle proliferation and overproduction of HA, leading to increased prostate size

58

HA Distribution in BPH

Basal Cells

Epithelial Cells

Fibroblasts

Smooth Muscle Cells

59

BPH Pathogenesis

Prostate Transitional Zone Growth Due to Prostate Transitional Zone Growth Due to Epithelial & Stromal ProliferationEpithelial & Stromal ProliferationEpithelial & Stromal ProliferationEpithelial & Stromal Proliferation

37x Stromal Proliferation Rate HABPH

9x Epithelial Proliferation Rate

37x Stromal Proliferation Rate HA Overproduction

Proliferative Stromal Disease

60

Removal of Prostate Stromal HA Represents a Novel Mechanism of Action for BPHa Novel Mechanism of Action for BPH

Non- PEGPH20 TE 7d TE 18d TE 12d TE 14d TE 16d TE 18d PEGPH20

Apoptosis of stromal cells following HA removal in rat BPH model

treated 12d TE 7d TE 18d PEGPH20 5d PEGPH20 7d PEGPH20 9d PEGPH20 11d

Apoptotic cells/sectionMean ± SD

0 0.8 ± 1.79 4.6 ± 2.51 1.75 ± 1.71 25.6 ± 20.16 36.8 ± 21.99 13.4 ± 5.73 7.8 ± 2.71

P-Value - - 0.006 0.001 0.001 0.010

Prostatic weights of BPH rats treated with PEGPH20 and/or Finasteride

Group Prostatic Weight (g)Mean ± SD P Value % Inhibition

Control 1.33 ± 0.23 - -

TE 3wk

PEGPH20 (2wk) 1.08 ± 0.21 0.038 18.8

Finasteride (2wk) 1.00 ± 0.19 0.007 25.2

PEGPH20 Alone

61

PEGPH20+Finasteride (2wk) 0.79 ± 0.17 < 0.0001 41 PEGPH20 + Finasteride

Next Steps

• Examine dosing schemes, compounds (PEGPH20, g , p ( ,PH20 depot) and routes of delivery to optimize therapeutic effect with minimal dosing frequency alone and in combination with standard of carealone and in combination with standard of care

• Evaluate Hyaluronan targeting compounds in canine models of BPHcanine models of BPH

• Relevant safety testing

• Clinical evaluationClinical evaluation

62

Halozyme’s Unique Scientific Core: The Extracellular MatrixThe Extracellular Matrix

our science begins…our science begins…

63

Ultrafast Insulin-PH20 Program –Ultrafast Insulin-PH20 Program –

D l B M h M DD l B M h M D

Where We are GoingWhere We are Going

Douglas B. Muchmore, M.D.

Vice President, Endocrinology Clinical Development

Douglas B. Muchmore, M.D.

Vice President, Endocrinology Clinical Development

64

Halozyme’s Ultrafast Insulin-PH20 Program

• Goal - To develop best-in-class rapid-acting insulin products that surpass current standards of care

• Proprietary insulin formulations of novel PH20 permeation enhancing excipient with

– Fast acting analog insulin (Humalog, Novolog, Apidra) “Analog-PH20”

– Short acting regular human insulin (Humulin R) “Insulin-PH20”

• Currently in Phase 2, targeting commercialization by 2014, depending on most attractive product candidate (Analog-PH20 vs. Regular Insulin-PH20)

65

Goal of Insulin Therapy – Replicate Normal Physiologic Insulin ResponsePhysiologic Insulin Response

• Role of fast acting insulin is to replicate normal insulin release response to meal• Current meal time insulin alternatives are still too slow to accomplish this goal

66Source: Am Fam Physician. 2004 Aug 1;70(3):489-500

p g

Failure to Match Physiologic Insulin Leads to Unmet Needs and Risk of Adverse OutcomesUnmet Needs and Risk of Adverse Outcomes

Suboptimal glycemic controlInability to control post meal blood sugar impedes diabetes• Inability to control post meal blood sugar impedes diabetes management– >50% of A1C elevation is due to postprandial hyperglycemic

excursions for patients with A1C < 8.4%1p• <30% of all insulin patients meet ADA A1C goal of <7%2

Hypoglycemia still a problem with current products

• 72% of T1DM and 54% of T2DM patients on insulin reported hypoglycemia in the past 3 months2

– In mild form, significant quality of life impact– In severe form can be fatal– In severe form, can be fatal

Weight gain

• Intensive insulin therapy and hypoglycemia associated with weight gain

671 Monnier et al. Diabetes Care (2003) 26:881-852 IMS Data, 2008 GFK Roper Patient Survey, N = 2,000 (projectable)

Intensive insulin therapy and hypoglycemia associated with weight gain

Rise of Multiple Daily Injections in Type 2 DMRapid Acting Analog Insulin Market ~$3B and Growingp g g g

100Intensive Conventional

66%69728083

80

34%40

60

34%312820

1720

40

02000 2002 2004 2006 2008

68Source: Roper Starch, 2008

Definitions: Conventional = 1 – 2 injections/d; Intensive = 3 or more

Growing Percentage of Type 2 Patients Treated with Insulin Analogs

Rapid Analog Use in Type 2 Diabetes:

Treated with Insulin Analogs

% of Insulin Users

25 429.5%

3035

17.9 19.3

25.4 23.1

202530

1015

05

2004 2005 2006 2007 2008

69

2004 2005 2006 2007 2008

Source: Roper Starch Data (U.S. only)

Halo’s Ultrafast Insulin-PH20 Products Better Mimic Physiologic Insulin Response - Phase 1 DataMimic Physiologic Insulin Response Phase 1 Data

PK of Insulin Lispro and Regular Insulin with and without PH20

1500 250

ol/L

) Mea

1000

1250200

e In

sulin

(pm

o an (± SEM) Im

m

Lispro+rHuPH20

500

750

100

150

mm

unor

eact

ive m

unoreactive

Regular Insulin+PH20

250

500

50

Mea

n (±

SEM

) Im Insulin ( U

/mL

Lispro

Regular Insulin

0 60 120 180 240 300 360

0 0

Time (min)

ML)

70

• PH20 Co-formulation With Humalog Reduced Median Tmax By 54% (p=0.0006)• Co-formulation With Humulin Reduced Median Tmax By 64% (p=0.0002)

Vaughn et al. Diabetes Technology and Ther. (2009) 11:345-352

Phase 2 Meal Study in Type 1 Diabetes

4-way crossover standardized test meal study in type 1 diabetes• Objective: compare PK and glucose profiles in response to regular

insulin +/- PH20 and insulin lispro +/- PH20insulin / PH20 and insulin lispro / PH20• Primary endpoint: PK AUC0-60

• Secondary endpoints: Multiple PK parameters, glycemic excursion

Study design• Stabilize FBS* with glucose/insulin infusion

Up to 3 dose finding visits to optimize post meal (12 oz Ensure = 60• Up to 3 dose finding visits to optimize post-meal (12 oz. Ensure = 60 gm CHO) glycemic response to Lispro + PH20

• Using “optimized” dose, repeat test meal with Lispro alone• Repeat using regular Insulin-PH20 and regular insulin alone

Interim data at ADA, New Orleans, June 2009; final data presented at EASD Vienna Oct 2009

71* FBS: Fasting blood sugar

at EASD, Vienna, Oct 2009

Phase 2 Lispro-PH20 Data Confirm in T1DM the PK Effects Observed in Phase 1 StudyPK Effects Observed in Phase 1 Study

5000in )“Fast In”: Exposure in first hour increased 50% (p=.0002)*

3000

4000Lispro (N=22)Lispro + PH20 (N=37)m

aliz

edve

Insu

liU

SEM

) increased 50% (p .0002)

2000

3000 Lispro + PH20 (N=37)

ose

Nor

mno

reac

tivol

*kg/

L*U

“Fast Out”: Exposure after two hours reduced approximately 45% (p=.027)

0

1000Do

Imm

un(p

mo pp y (p )

0 60 120 180 240 300 360 420 480Time (minutes)

72Faster, greater insulin absorption with greater and earlier peak exposure achieved: Cmax increased by 41%, p=.0007; Tmax from 49 30 mins, p<.0001

PH20 Changes Lispro PK Profile and Leads to Significant Reduction in Post-Meal HyperglycemiaSignificant Reduction in Post Meal Hyperglycemia

200

220

EM

160

180

200

Lispro + PH20Lispro

se

SEL)

120

140

160

Glu

cos

(mg/

d

ACE Goal

80

100

120

Blo

od

0 60 120 180 24080

Time from injection (minutes)

73

Glycemic response was measured using 60gm CHO liquid test meal; Mean insulin dose = 5.7 U/subject.

Phase 2 Regular Insulin-PH20 Data Confirm in T1DM the PK Effects Observed in Phase 1 Study

5000R l I li (N 19)n

T1DM the PK Effects Observed in Phase 1 Study

3000

4000

5000Regular Insulin (N=19)Regular Insulin+PH20 (N=34)

aliz

edve

Insu

lin

SEM

)

2000

3000

se N

orm

nore

activ

l*kg

/L*U

0

1000Dos

Imm

un(p

mo

0 60 120 180 240 300 360 420 480Time (minutes)

74

PH20 Changes Regular Insulin PK Profile and Leads to Significant Reduction in Post-MealLeads to Significant Reduction in Post Meal Hyperglycemia

220 Regular Insulin

M

180

200 Regular Insulin+PH20

se

SEM

L)

120

140

160

d G

luco

s(m

g/dL

ACE Goal

80

100

120

Blo

od

0 60 120 180 240Time from injection (minutes)

75

Glycemic response was measured using 60gm CHO liquid test meal; Mean insulin dose = 6.2 U/subject.

PK and Glycemic Responses to Test Meal for Regular Insulin-PH20 versus Lispro AloneRegular Insulin PH20 versus Lispro Alone

180

200

220

LisproRegular Insulin+PH20

se

SEM

L)3000

4000

5000

Lispro (N=22)Regular Insulin+PH20 (N=34)

mal

ized

ve In

sulin

/L*U

)

100

120

140

160

lood

Glu

cos

(mg/

dL ACEGoal

1000

2000

3000

Dos

e N

orm

mm

unor

eact

iv(p

mol

*kg/

0 60 120 180 24080

100

Time from injection (minutes)B

l0 60 120 180 240 300 360 420 480

0

Time (minutes)

Im

Glycemic response was measured using 60gm CHO liquid test mealMean insulin dose = 5 7 U/subject for Lispro and 6 2 U for Insulin-PH20

76

Mean insulin dose = 5.7 U/subject for Lispro and 6.2 U for Insulin PH20

PK and Glycemic Excursion Improvements of Lispro-PH20 vs. Lispro Alone are Similar toLispro PH20 vs. Lispro Alone are Similar toLispro Alone Improvements vs. Regular Insulin Alone

3000

4000

5000

Lispro (N=22)Lispro+PH20 (N=37)

aliz

ede

Insu

lin

SEM

)

180

200

220

Lispro+PH20Lispro

Regular Insulin SE

M

1000

2000

3000 Lispro (N 22)Regular Insulin (N=19)

Dos

e N

orm

aIm

mun

orea

ctiv

e(p

mol

*kg/

L*U

120

140

160

180 Regular Insulin

ood

Glu

cose

(m

g/dL

)

ACEGoal

0 60 120 180 240 300 360 420 480

0

Time (minutes)0 60 120 180 240

80

100

Time from injection (minutes)B

lo

77

Phase 2 Type 1 Diabetes Meal Study Conclusions

• Lispro-PH20 and Insulin-PH20 are well tolerated

• PK results for these preparations confirm in Type 1 patients• PK results for these preparations confirm in Type 1 patients previous findings from Phase 1

• Lispro-PH20 and Insulin-PH20 accelerate insulin absorption d t th ti i li d t l i ldicompared to the respective insulin products alone, yielding more

physiologic mealtime insulin PK profiles

• Greater and earlier peak Lispro-PH20 and Insulin-PH20 exposure and reduced late exposure compared to respective insulin products alone

• These changes in PK profiles lead to significant reductions inThese changes in PK profiles lead to significant reductions in postprandial hyperglycemia and are meaningful relative to achieving treatment targets

78

Upcoming Ultrafast Insulin-PH20 Data Presentations During 4Q09

• PH20 dose response study to determine optimal PH20

Data Presentations During 4Q09

PH20 dose response study to determine optimal PH20 concentration– Data to be presented at International Diabetes Federation

(Montreal October 18-22) and Diabetes Technology(Montreal, October 18-22) and Diabetes Technology Society (San Francisco, November 5-7)

I t bj t PK/GD i bilit t d l t d t l if d• Intra-subject PK/GD variability study completed to clarify dose reproducibility – Data to be presented at Diabetes Technology Society

79

Efficient Development Strategy to Maximize Program Value

• Additional clinical studies to further characterize Ultrafast Insulin-PH20 value proposition prior to starting pivotal studies

Ph 1 l i l l t d i 3 k t d f t

Maximize Program Value

– Phase 1 euglycemic glucose clamp study comparing 3 marketed fast acting analog insulins +/- PH20 (first subject dosing performed)

– Phase 2 standard meal study in T2DM patients (enrollment completed)Ph 3 E bli t di• Phase 3 Enabling studies: – Phase 2 3x/day treatment study in T1DM patients comparing

regular Insulin-PH20 to lispro in a 3 month x 3 month crossover design (initiated 2Q09)(initiated 2Q09)

– Phase 2 3x/day treatment study comparing Analog-PH20 to analog alone (2010)

• Pivotal Phase 3 trials in T1DM and T2DM patients comparing PH20 productPivotal Phase 3 trials in T1DM and T2DM patients comparing PH20 product candidate to analog insulin following Phase 2 trials and program review with regulatory authorities

• Halo prepared to partner or proceed to Phase 3 with most attractive product

80

Halo prepared to partner or proceed to Phase 3 with most attractive product candidate (Analog-PH20 and/or regular Insulin-PH20)

Ultrafast Insulin-PH20 Goal – Potential Benefits vs. Standard of Care Analogsvs. Standard of Care Analogs

Better glycemic control • Faster higher insulin concentrations and peak exposure (i e fast in)• Faster, higher insulin concentrations and peak exposure (i.e., fast in)

results in early glucose lowering effects and reduced post-meal hyperglycemia, which may lead to better A1C control

• Fast in, fast out profile is ideal for insulin pump applications, p p p pp

Less hypoglycemia• Reduced late post-meal exposure (i.e., fast out) may result in fewer

hypoglycemic events• Lowering insulin dose requirements with PH20 to match glycemic control

of analogs may further reduce hypoglycemia

Less weight gain• Fewer hypoglycemic events and lower insulin doses could result in less

self-medicating snacking especially in Type 2 patients

81

self medicating snacking, especially in Type 2 patients

Key Takeaways and Closing CommentsKey Takeaways and Closing Comments

Jonathan E. Lim, M.D.Jonathan E. Lim, M.D.

President & Chief Executive OfficerPresident & Chief Executive Officer

82

Balanced Growth Strategy –Multiple Programs Moving Forwardp g g

Business Development Proprietary Pipeline

• Roche has entered the clinic Ultrafast Insulin PH20• Roche has entered the clinic with three biologic compounds

• Baxter BioScience in Phase 3 pivotal with GAMMAGARD

• Ultrafast Insulin-PH20

– Two scientific presentations for Halo insulins in 4Q09

pivotal with GAMMAGARD

• Baxter Medication Delivery launching HYLENEX for pediatric hydration

– Three additional trials underway with results likely mid-2010

– Phase 2 Analog-PH20 3x/day pediatric hydration

• Seeking additional business development deals to leverage the technology and generate

g ytreatment study expected to begin 3Q10

• PEGPH20 Phase 1 continuesthe technology and generate non-dilutive cash • HTI-501 and other dermatology

candidates in preclinical phase

Pi li h i ifi t t hi

83

• Pipeline has significant partnership value

Licensing Strategy for Insulin Program

• Goal is to develop best-in-class ultrafast prandial insulin with unique value relative to current standard of care

• Having conversations with multiple players in the diabetes marketplace

Ph 2 t t t t di id i ifi t d t f i t t t• Phase 2 treatment studies provide significant data of interest to potential partners

– Regular Insulin-PH20 3x/day treatment study data available in mid-2010

– Analog-PH20 3x/day treatment study data available in mid-2011

• Additional high value, low cost clinical pharmacology studies that produce favorable results enhance the value of the program

84

Milestones for 2009

• $5.5 million payment from Baxter for HYLENEX, 1Q09

• Phase 1 underway for second Roche exclusive target, 1Q09

• I iti t d PEGPH20 Ph 1 1Q09• Initiated PEGPH20 Phase 1, 1Q09

• Initiated Insulin-PH20 Phase 2 3x/day treatment study, 2Q09

• Presented Analog-PH20 Phase 2 interim data at ADA 2Q09Presented Analog-PH20 Phase 2 interim data at ADA, 2Q09

• $4.25 million payment from Roche for fifth exclusive target, 2Q09

• Completion of patient enrollment for Phase 3 GAMMAGARD-PH20 by p p yBaxter, 3Q09

• Phase 1 underway for third Roche exclusive target, 3Q09

• Presented Insulin-PH20 Phase 2 data at EASD, 4Q09

• HYLENEX launched in pediatric hydration by Baxter, 4Q09

P t A l PH20 d I li PH20 i bilit d t 4Q09

85

• Present Analog-PH20 and Insulin-PH20 variability data, 4Q09

• Initiation of additional Roche clinical trial plus milestone possible

Potential Milestones for 2010

P t ti f PEGPH20 li i l d t 2Q10• Presentation of PEGPH20 preclinical data, 2Q10

• Presentation of Analog-PH20 and Insulin-PH20 Phase 1 and 2 studies at ADA 2Q10studies at ADA, 2Q10

• Initiation of Analog-PH20 Phase 2 3x/day treatment study, 3Q10

• Completion of PEGPH20 Phase 1 clinical trial 2H10• Completion of PEGPH20 Phase 1 clinical trial, 2H10

• Initiation of PEGPH20 Phase 1b chemotherapy combination clinical trial, 2H10

• Completion of Phase 3 GAMMAGARD clinical trial by Baxter in PID, 4Q10

• Initiation of additional Roche clinical trial(s) plus milestone(s) possible

• Additional licensing deal(s) possible

86

• Additional guidance for proprietary programs to be provided in 2010

What is Halozyme?

An innovative biotech company with strong biologics capabilities and multi-functional Matrix platformscapabilities and multi functional Matrix platforms

• Commercial, partnered and clinical stage assets (Roche, BAX, Insulin, PEGPH20)

• Enabling biologics delivery platform (rHuPH20) for lifecycle management with strong proof of concept

Oth M t i l tf th t t f t l (HTI 501• Other Matrix platforms that can generate future value (HTI-501, tsMMP)

• Ability to produce complex recombinant proteinsy p p p

• Attracting top level biopharma talent

87

HALO’s Unique Investment Thesis

• Existing and potential drug delivery partnerships (EnhanzeTechnology, HYLENEX) may provide non-dilutive cash to fund proprietary pipeline opportunities and drive near-term value

• Multifunctional enzymes targeting the Matrix (PH20, PEGPH20, HTI-501), with broad potential and patient benefits across variety of therapeutic uses, drives long-term value

• Strong financial position to execute plan and drive towards key value inflection points: $89M cash at end of 2Q09, includes $40M equity offering in Juneequity offering in June

88