Halozyme Therapeutics

ANALYST AND INVESTOR MEETING

THURSDAY, OCTOBER 15, 2009

New York
Safe Harbor

The Private Securities Litigation Reform Act of 1995

provides a "safe
safe harbor"
harbor for forward-looking
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-looking
forward looking
statements could be affected by the risks and uncertainties
of the Company's business. Such risks inherent to the
Company’s
Company s business will be described in the Company’s
Company s
filings, when they occur, with the Securities and Exchange
Commission, as well as in its press releases. The
Company's
Company 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 and
Introduction d St
Strategic
t i Review
R i

Robert J. Little
Vice President,
President Chief Commercial Officer
Leveraging the Technology Across Multiple Partners

Gregory II. Frost

Frost, Ph
Ph.D.
D
Vice President, Chief Scientific Officer
Discovery and Early Development Pipeline Update

Douglas B. Muchmore, M.D.

Vice President, Endocrinology Clinical Development
Ultrafast Insulin-PH20 Program – Where We Are Going

3
Introduction & Strategic Review

Jonathan E. Lim, M.D.

President & 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
million, plus
royalties; near term launches underway (Hylenex) and anticipated
(Enhanze GAMMAGARD, Roche)
– Proprietary
p ypprograms
g in clinical development
p that could g
generate high
g
value partnerships (e.g., Phase 2 Ultrafast Insulin-PH20 Program)
– Investment in high value but low-cost development activities that
advance programs
g to next value inflection point
• Innovative biotech company with strong biologics capabilities that can help
drive long-term growth
– Scientific focus and expertise in the extracellular matrix (the “Matrix”)
Matrix )
– Expertise in maximizing value from multifunctional Matrix platforms
(rHuPH20, HTI-501, rHuMMP1ts)
– C
Culture
lt off excellence:
ll E
Exceptional
ti l tteam with
ith extensive
t i bibiologics
l i
experience and ability to produce complex recombinant proteins
5
 Strong patent
protection and
lif
lifecycle
l
extension
Validation Diversified,
through robust
existing pipeline/
or Partnerss

partnerships portfolio

Novel M
Matrix Thera
Toolbox fo

Halozyme’s
Technology
Increased
De-risked Foundation footprint in high
biological
g growth
g
Biologics T

rapeutics
programs biologics
market
B

Differentiated
Expedited
biologics with
regulatory
best-in-class
pathway
potential

Differentiated Products
6
Existing Alliances Drive Significant Value

Enhanze Technology with Roche (up to 13 biologic targets)

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

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

Nearly $100 million of alliance related cash received to date

7
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
biotechnology products for patients

9
Halozyme’s Robust Pipeline of Multifunctional
Platforms Targeting the Matrix

Matrix Targets Matrix Biologics

PH20 PEGPH20 PH20 PH20 SC

Hyaluronan Depot Intravesical

rHuCAT-L
Collagen
g rHuMMP1ts

Other Matrix
Other modifying
y g
agents

Discovery Preclinical Phase 1 Phase 2 Phase 3 Commercial

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

Analog-PH20
Phase 2
Roche
g
Biologic#1
Hylenex
Phase 1
for drugs
Phase 4

Roche Biologics
rHuPH20 #2 & #3
Enzyme Phase 1

Hylenex
f fluids
for fl id
Launched
Enhanze
IgG
Insulin-
Phase 3
PH20
Phase 2

Fluids and small molecules Peptides Large molecules 11

Culture of Excellence: “The Halo Edge”
• Attracting
Att ti world
ld class
l bi h
biopharma t l t to
talent t key
k positions
iti
– H. Michael Shepard, Ph.D., VP of Discovery Research (Receptor
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 initiatives
– Offer acceptance rate was 87% last year; 60% of new employees
came from internal referrals
– Voluntary turnover remains less than 5% (vs. 10.5% industry
average; Radford) 12
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
Generate value for
patients and shareholders
Value creation
• Grow partnership and
own product revenue
Develop pipeline of
• Other Matrix drugs
proprietary programs
• Other promising
innovations
• Analog-PH20
• Insulin-PH20
Insulin PH20
Build
B ild revenue
• PEGPH20
generating engine
• PH20 Depot
• HTI-501
• Roche Enhanze
• rHuMMP1ts
programs
p g
• Enhanze
GammaGard
• Hylenex

Time

Capabilities • PH20 drug delivery • PH20 drug development • Commercialization in core TA’s
• Protein engineering • Other Matrix drug alone or with partners
development • Delivery or development of
other promising breakthroughs
14
HALO Pursuing Multi-Billion Dollar Franchise
Opportunities Targeting the Matrix

Drug delivery revenue Proprietary pipeline targeting

generating engine the Matrix
• Enhanze Technology with • Ultrafast Insulin-PH20 (diabetes)
Roche (up to 13 biologic targets) • PEGPH20 (NME, solid tumors)
• Enhanze Technology with • Chemophase (bladder cancer)
Baxter BioScience
• HTI-501 (NME, dermatology)
(GAMMAGARD)
• HYLENEX with Baxter
Medication delivery

15
 Commercial Opportunities –
Leveraging the Technology Across Multiple
Partners

Robert J. Little
Vice President, Chief Commercial Officer

16
Leveraging the rHuPH20 Technology
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’s

proprietary pipeline

17
Enhanze Technology:
For Partners with Injectable Biologics and Drugs
Value proposition
• Deliver more drug to intended targets
Increased • Allow drugs to work faster
efficacy • Increased volume of drug at each injection

• Change route of administration (IV to SC)

Convenience
and j
• Reduce adverse injection site reactions
compliance • Decrease pain and tissue distortion upon injection

• Provide competitive differentiation and reduce COGS

Economic • Enable cost-effective self-administration of physician
benefits delivered drugs
• Extend lifecycle of products coming off patent

18
Enhanze Technology Platform De-Risked Through
Progress of Roche and Baxter Collaborations

• Preclinical Safety – high dose chronic and reproductive tox

completed 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
Phase 3, other clinical studies underway
• Manufacturing – two API manufacturing sites established, 2nd
generation
ti cellll liline and
d scale-up
l completed
l t d
• Commercial – reimbursement and pricing research with
partners completed

19
Three Partnered Programs Based on
Halozyme’s
Halozyme s Drug Delivery Technology

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

1.
2. Enhanze Technology with Baxter BioScience
((GAMMAGARD))
3. HYLENEX with Baxter Medication Delivery
20
Roche Enhanze Technology Alliance
Moving Forward

• Three targets in Phase 1 clinical trials

trials, including third
target which began in September 2009

• Exercised exclusive global rights to a fourth biologic

target in December 2008 and fifth target in June 2009

• Initiation of additional Roche clinical trial plus milestone

possible in 2009

• Clinical progress also expected in 2010

21
 Recent Public Disclosures Reflect Strong
Momentum of Roche-Halo
Roche Halo Progress

• 4th exclusive biologic

target elected
$612M partnership signed, • 1st Phase 1 (n=70, mid-09 5th exclusive 3rd Phase
3 exclusive biologic completion) biologic 1 begins
targets elected • Annual maintenance fees target elected (Sep09)
(Dec06) (Dec08) (Jun09)

YE06 YE07 YE08 YE09

CMC, including manufacturing scale-up, nonclinical, 2nd Phase 1 Additional Roche

toxicology, and other development activities for product (n=48, mid-09 clinical trial plus
candidates formulated with PH20 ((not disclosed)) completion)
p ) milestone p possible
(Jan09) (2H09)
Baxter BioScience - Enhanze GAMMAGARD
Addressable IgG Market Forecast at $8-$9
$8 $9 Billion

Market Size Reflects The Broad Clinical Applications Of IgG

Source: Baxter 23
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
dosing at multiple injection sites
• Phase 1/2a trial showed SC bioavailability equal to 92% of IV administration
with dosing of up to 61
61.2
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
2009, ahead of plan
• Final clinical study reports planned in 1H11
• Pre-launch activities initiated with pphysician,
y p
patient and p
payer
y research
underway
• SC GAMMAGARD offers convenient, once monthly, self-administration in a
g SC injection
single j site; could become g
gold standard in large
g ggrowing
g market

24
HYLENEX –
Franchise Potential Could be Worth up to $500M

• $200M U.S. market opportunity in Addressable U.S. ED Visits (M)

pediatric hydration alone
4.0
• 2.4M ED (emergency
department) visits potentially
addressable by HYLENEX 1.6

• Potential for $500M franchise 2.4

– Adult hydration
– Ex
Ex-U.S.
U.S. markets
– Delivery of small molecule
drugs (e.g., pain, infection)
• Paradigm shift in ED medical
practice means slow, gradual ED pediatric Successful Total IV
uptake and acceptance visits for ORT procedures
dehydration (incl. ORT
only failures)

Source: Baxter
ORT: Oral rehydration therapy
25
HYLENEX – Clinically Meaningful Rehydration
Demonstrated in INFUSE Peds 1 Study

Allen, C.H., et al, Recombinant Human Hyaluronidase-Enabled Subcutaneous

Pediatric Rehydration, Pediatrics, 2009;124;e859-e868. 26
HYLENEX – Favorably Perceived By 9 out of 10
Healthcare Providers and Patients

Allen, C.H., et al, Recombinant Human Hyaluronidase-Enabled Subcutaneous Pediatric

Rehydration, Pediatrics, 2009;124;e859-e868. 27
HYLENEX – Encouraging Interim Results at ACEP
from INFUSE PEDS 2 Study

28
HYLENEX – Fully Resourced Launch in
Pediatric Hydration Underway

• Product launched for pediatric hydration at ACEP in Boston

on Oct 5th
• Two sales forces - dedicated HYLENEX specialty team and
existing Baxter IV team supported by formulary specialists in
place
l
• 90% acceptance rate onto target formularies, even prior to
published data
• Full team of clinical and scientific medical science liaisons
established
• Large
L advocacy
d program with
ith multiple
lti l speaker
k programs
have been underway for several months
• Leadingg national and regional
g KOLs on board

29
HYLENEX –
An Emerging Strong Value Proposition

• Enables rehydration
y with less stress for p
parents and children
• Makes infusion simple and efficient
• Facilitates clinically meaningful hydration
• Potentially benefits over 2 million pediatric patients each year in
the U.S. alone
• P
Perceived
i d ffavorably
bl bby 9/10 h
healthcare
lth providers
id compared
d tto IV
• Additional post-marketing clinical data being developed
• Building a new standard of care for rehydration
rehydration, paradigm shift
• HYLENEX safe and well tolerated in clinical experience

30
Strong Alliances Generate Non-dilutive
Cash 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

31
Discovery and Early Development
Pi li Update
Pipeline U d t

Gregory I. Frost, Ph.D.

Vice President , Chief Scientific Officer

32
 ECM: Breaking it Down
5 classes of macromolecules

1. Collagens
2. Elastic fibers 3. Hyaluronan
4. Proteoglycans
5. Adhesive glycoproteins

33
 rHuPH20 SC
Preclinical
through
Commercial
rHuMMP1ts
Conditional rHuPH20-
Collagenase Intravesical
Phase 2
Discovery
Research

Matrix
Biologics
rHuCAT-L
Conditional PEGPH20
P t i
Proteinase
Phase 1
Preclinical

PH20 Depot
Preclinical

34
 How Halozyme is Targeting the Matrix Environment

Delivery ECM Disease

Current Candidate Mechanism

Matrix Targets Enzymes of Action Potential Applications
COLLAGENS rHuCAT-L Focal Proteolysis Cellulite
Dupuytren’s Contracture
rHuMMP1ts Fib
Fibrosis
i
Keloids/Scarring
Transient Focal SC administration:
rHuPH20 Hydrolysis Fluids, Peptides and Biologics
Chemotherapy Delivery

HYALURONAN PH20 Depot Prolonged Focal Postsurgical Edema,

Hydrolysis Benign Prostatic Hypertrophy (BPH)
Chemonucleolysis
PEGPH20 Prolonged Systemic Solid Tumors
Hydrolysis
35
Matrix Target: Collagen

Type I Collagen - Abundant in skin, tendon,

ligament bone
ligament, bone, cornea – 88
88-99%
99% of total collagen

36
Fibrous Septae:
A Potential Target for Enzymatic Contouring?

Potential
P t ti l Approaches
A h Challenge:
Ch ll
1) Surgical subscision Temporal spatial
2) Enzymatic subscision control of enzyme activity

37
Enzymatic Subscision: Focal Digestion of
Fibrous Septae with Collagenolytic Enzymes

Dimple

TARGET

Fibrous
fibrous septae
Septaecreate dimples

38
rHuCathepsin-L (rHuCAT-L) is a Recombinant
Human Lysosomal Cysteine Endopeptidase
• Cathepsin-L: an enzyme naturally
regulated by an acidic cellular
environment
• Active at acidic pH but rapidly
inactivated at p
physiological
y g p
pH in
the extracellular space
• Very efficient ‘collagenase’ at pH
5 0 (~pH
5.0 ( pH of lidocaine)

ollagen
Type I Co
pH 5.0
T

Enzyme ‘On’ Enzyme ‘Off’

 Concept:
Temporal Spatial Control of
Dimple Collagenolytic Activity

1- rHuCAT-L enzyme injected in an active state

formulated in artificial lysosomal buffer

2- Enzyme cleaves fibrous septae

3 Body
3- Body’ss natural pH in the Matrix
inactivates rHuCAT-L as it diffuses
Adipocytes away from injection site

4- Dimple relieved as septae lysed

Fibrous Septae
fibrous septae
create dimples 40
rHuCAT-L Treatment Leads to pH Conditional
Release of Collagen Fragments In Vivo
Rodent perfusion model Porcine model

CATL
C Buffer
B ff Collagenase
C ll
4.0
pH 5 pH 5 pH 7.5
pH 7.4
3.5

grosss
pH 5 0
pH 5.0
3.0

pH 7.4 + CATL
2.5
proline

pH 5.0 + CATL
2.0

Trichrome
e
Hydroxyp
(ug/mL)

1.5

1.0

05
0.5

0.0
septae lysis septae septae lysis
0 min 8 min 16 min
control

41
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
• Final pharmacology and secondary indication
evaluation
• IND filing

42
Second Collagenase Program: rHuMMP1ts
(Temperature Specific MMP1 Analog)
MMP1 (Matrix Metalloproteinase 1)
• Prototypical
yp interstitial human collagenase
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?

ollagen Type I/III
Collagen Type I/III

BacterialControl 
Collagenase rHuMMP1
(positive control)
(Dermis H&E)

Co
In situ collagen release In situ collagen release
43
by MMP1 43
By High Throughput Single AA Mutagenesis,
Temperature Specific MMP1 Analogs Identified
structed

Product Concept:
NA’s Cons

• 199 amino acid (AA) protein Inject enzyme at room temperature.

• All potential single amino Digestion of target until body
acid substitutions screened temperature warms enzyme to
• 8 strong hits identified
2985 cDN

i
inactivate
ti t

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

44
Value of New Matrix Platforms

•Appositive extension of Halozyme’s

y expertise
p in Matrix
enzymes, 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
beyond HA and hyaluronidase

45
Matrix Target: Hyaluronan in the Tumor Microenvironment
• 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
y angiogenesis)
g g )

VESSELS
TUMOR CELLS
STROMA

PEGPH20
Example: Stromal Matrix Occupies Most of the
Pancreatic Cancer Microenvironment
Duct TxN0M0 Duct T3N0M0 Duct T3N0M0 Normal

40x

200x

Blue BROWN HA(+)

HA(
HA(+++)
)
(Tumor Cells) (HA rich Stroma)

* Representative images of HA/ Hematoxylin on pancreatic tumor tissue 47

PEGPH20: Background

Section from Metastatic Breast Cancer

• The Matrix comprises the majority of

tumor volume in many tumors
Tumor Matrix
• The functions of the Matrix
– Support
pp structure for the cancer
– Storage for growth factors and
cytokines
– Altered composition during growth
Tumor Matrix and tissue remodeling

• Halozyme’s PEGPH20 degrades Matrix

by removing the hyaluronan component
Nest of of the Matrix
Malignant Cells
• Enhances malignant cell vulnerability to
– Chemotherapy
– Biotherapeutics
– Immune system
48
Hyaluronan Overproduction is
Common in Malignancy

87% HA High

All HA overexpressing 
46% HA High
46% HA High tumors tested in
tumors tested in 
xenograft models respond
to PEGPH20 and enhance 
activity of chemotherapeutic

49
PEGPH20 – HA Degradation May Represent
A Novel Mechanism for Cancer Treatment

• HA
HA-rich
rich halos found
on many types of
TUMOR aggressive tumors
Halo CELL (breast prostate,
(breast, prostate
pancreatic)

• PEGPH20 collapsesp
+ Enzyme=Halo degraded PEGPH20 HA dependent
HA
pericellular halos on
tumor cells
TUMOR
CELL • Modulates resistance
to chemotherapy

50
Removal of Hyaluronan from the Tumor Matrix
Alters Tissue Structure
PC3 Xenografts (H&E) PC3 Xenografts
X ft (H&E)

PEGPH20
i.v 8hrs
TUMOR
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)
1.2
1.1
umor IFP

1.0 + API Buffer

0.9
0.8 >80% reduction in
malized Tu

0.7
0 7 tumor IFP within
0.6 1st hour
Dosed

0.5
Norm

0.4
D

0.3 + PEGPH20
0.2
0.1
0.0
-20 0 20 40 60 80 100 120

Time after injection (min)

* 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) 52
 Combinations of PEGPH20 with Docetaxel or Liposomal
Doxorubicin Demonstrates Significantly Improved Anti-
Tumor Activity 3000
3000

2500
2500 Vehicle
Vehicle
Tumor Volume (mm3)

mm 3 )
PEGPH20 2000
2000 15 mg/kg

Tumor Volume (m
PEG PH20
PEG-PH20

1500 Taxotere 1500

10 mg/kg Doxil
(0/6)
1000 1000

PEGPH20
T

(4/7) Doxil + PEG-PH20

500 + Tax 500
D+P P P D+P P P D+P
0
-2 0 234 6 7 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 0
0 3 567 9 10 12 1415 18 21 24 27 30 33 36
Time (days) Time (Days)
T+P P T+P P

Tumor IFP Drug Accumulation

Stromal Matrix 15 mg/kg PEGPH20
60
Pre-dose
Pre dose Post-dose
Post dose
g)
umor IFP (mmHg

50

40

30

20

10
Tu

0
0 120
PEGPH20 enzyme removes
Time (minutes)
matrix substrate in tumor
53
PEGPH20 + Gemcitabine Shows Activity

D18-Data
(1 Round of Rx)
(%TGI=21% at
BXPC-3 Tumor Line D18)
• HALO++ w/Aggrecan

Tumor Tissue
• HA Stroma+ / Tumor (%TGI=62% at D18)

Cells+

Superior Effect of D28-Data

(2 Rounds of Rx)
PEGPH20+Gemcitabine
vs. Gemcitabine

54
PEGPH20 + Erlotinib Shows Activity

D18-Data
(1 Round of Rx)
BXPC-3 Tumor Line (%TGI=27% at D18)

• HALO++ w/Aggrecan

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

Superior Effect of D28-Data

(2 Rounds of Rx)
PEGPH20 + Erlotinib
vs. Erlotinib
E l ti ib

55
PEGPH20 Program - Phase 1 Clinical Trial

• Multicenter, open-label, dose evaluation trial of IV administered

PEGPH20 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 activity
• Study will guide PEGPH20 dose selection for future clinical trials
– Phase 1b/2 combination studies
– Phase 2 single agent studies

56
PEGPH20 Program Summary

• Hyaluronan is a major component of the tumor matrix

(e.g., 87% of pancreatic cancer)

• PEGPH20 disrupts p tumor matrix to enhance cancer cell

sensitivity 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
yp p y ((BPH))

• Affects 50% of men by age 50

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
g intervention  $2.3 billion p
per yyear

• 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

Epithelial & Stromal Proliferation

37x  Stromal Proliferation Rate

HA
BPH Overproduction
9x  Epithelial Proliferation Rate

Proliferative Stromal Disease

60
Removal of Prostate Stromal HA Represents
a Novel Mechanism of Action for BPH
Apoptosis of stromal cells following HA removal in rat BPH model
TE 18d
Non- PEGPH20 TE 12d TE 14d TE 16d
TE 7d TE 18d PEGPH20
treated 12d PEGPH20 5d PEGPH20 7d PEGPH20 9d
11d
Apoptotic
cells/section 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
Mean ± SD

P-Value - - 0.006 0.001 0.001 0.010

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

Prostatic Weight (g) TE 3wk
Group P Value % Inhibition
Mean ± SD

Control 1.33 ± 0.23 - -

PEGPH20 Alone
PEGPH20 (2wk) 1.08 ± 0.21 0.038 18.8

Finasteride (2wk) 1.00 ± 0.19 0.007 25.2

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

61
Next Steps

• Examine dosing g schemes,, compounds

p ((PEGPH20,,
PH20 depot) and routes of delivery to optimize
therapeutic effect with minimal dosing frequency
alone and in combination with standard of care
• Evaluate Hyaluronan targeting compounds in
canine models of BPH
• Relevant safety testing
• Clinical evaluation

62
Halozyme’s Unique Scientific Core:
The Extracellular Matrix

our science begins…

63
 Ultrafast Insulin-PH20 Program –
Where We are Going

D
Douglas
l B.B M
Muchmore,
h MD
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 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
p this goal
g

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

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

Suboptimal glycemic control

• Inability to control post meal blood sugar impedes diabetes
management
– >50% of A1C elevation is due to postprandial hyperglycemic
excursions for p patients with A1C < 8.4%1
• <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
form, can be fatal

Weight gain
• Intensive insulin therapy and hypoglycemia associated with weight gain

1 Monnier et al. Diabetes Care (2003) 26:881-85

2 IMS Data, 2008 GFK Roper Patient Survey, N = 2,000 (projectable) 67
Rise of Multiple Daily Injections in Type 2 DM
Rapid
p Acting
g Analog
g Insulin Market ~$3B and Growing
g

Intensive Conventional
100

83 80
80
72
69 66%
60

40 34%
28 31
20
20 17

0
2000 2002 2004 2006 2008

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

Source: Roper Starch, 2008 68

Growing Percentage of Type 2 Patients
Treated with Insulin Analogs

Rapid Analog Use in Type 2 Diabetes:

% of Insulin Users
35
29.5%
30 25 4
25.4
23.1
25
19.3
17.9
20
15
10
5
0
2004 2005 2006 2007 2008

Source: Roper Starch Data (U.S. only) 69

Halo’s Ultrafast Insulin-PH20 Products Better
Mimic Physiologic Insulin Response - Phase 1 Data
PK of Insulin Lispro and Regular Insulin with and without PH20
1500 250
ol/L)

Mea
an (± SEM) Imm
e Insulin (pmo

1250
Lispro+rHuPH20 200

1000
mmunoreactive

munoreactive Insulin (U/mL

150
Regular Insulin+PH20
750

100
Mean (± SEM) Im

500 Lispro

50
250 Regular Insulin

L)
M

0 0

0 60 120 180 240 300 360

Time (min)

• 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 70

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 +/-
/ 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
post-meal
meal (12 oz.
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,
EASD Vienna
Vienna, Oct 2009

* FBS: Fasting blood sugar 71

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

“Fast In”: Exposure in first hour

5000
ve Insuliin

increased 50% (p
(p=.0002)*
.0002)
U  SEM))
malized

4000
Lispro (N=22)
noreactiv

3000 Lispro + PH20 (N=37)

ol*kg/L*U
ose Norm

2000 “Fast Out”: Exposure after two hours

reduced approximately
pp y 45% (p(p=.027))
Immun
(pmo
Do

1000

0 60 120 180 240 300 360 420 480

Time (minutes)

Faster, greater insulin absorption with greater and earlier peak exposure achieved: Cmax
increased by 41%, p=.0007; Tmax from 49  30 mins, p<.0001 72
PH20 Changes Lispro PK Profile and Leads to
Significant Reduction in Post
Post-Meal
Meal Hyperglycemia
220
EM

200
se  SE

180 Lispro
Lispro + PH20
(mg/dL)
Blood Glucos

160
140 ACE Goal

120
100
80
0 60 120 180 240
Time from injection (minutes)

Glycemic response was measured using 60gm CHO liquid test meal; Mean insulin dose = 5.7 U/subject.
73
Phase 2 Regular Insulin-PH20 Data Confirm in
T1DM the PK Effects Observed in Phase 1 Study

5000
ve Insulin
n

Regular
R l IInsulin
li (N
(N=19)
19)
(pmol*kg/L*U  SEM)
se Normalized

4000 Regular Insulin+PH20 (N=34)

noreactiv

3000

2000
Dos
Immun

1000

0 60 120 180 240 300 360 420 480

Time (minutes)

74
PH20 Changes Regular Insulin PK Profile and
Leads to Significant Reduction in Post
Post-Meal
Meal
Hyperglycemia
220 Regular Insulin
se  SEM
M

200 Regular Insulin+PH20

180
L)
(mg/dL
d Glucos

160
140 ACE Goal
120
Blood

100
80
0 60 120 180 240
Time from injection (minutes)

Glycemic response was measured using 60gm CHO liquid test meal; Mean insulin dose = 6.2 U/subject.
75
PK and Glycemic Responses to Test Meal for
Regular Insulin
Insulin-PH20
PH20 versus Lispro Alone

220
5000
ve Insulin

se  SEM
200 Regular Insulin+PH20
malized

4000 Regular Insulin+PH20 (N=34)

Lispro
(pmol*kg//L*U)

Lispro (N=22) 180

L)
mmunoreactiv

(mg/dL
3000

Bllood Glucos
Dose Norm

160
ACE
2000 140
Goal
1000 120
Im

100
0
80
0 60 120 180 240 300 360 420 480 0 60 120 180 240
Time (minutes) Time from injection (minutes)

Glycemic response was measured using 60gm CHO liquid test meal
Mean insulin dose = 5.7
5 7 U/subject for Lispro and 6
6.2
2 U for Insulin
Insulin-PH20
PH20

76
PK and Glycemic Excursion Improvements of
Lispro-PH20
Lispro PH20 vs. Lispro Alone are Similar to
Lispro Alone Improvements vs. Regular Insulin Alone

5000
220
Lispro
e Insulin

ood Glucose  SEM

(pmol*kg/L*U  SEM)

4000
200 Lispro+PH20
alized

Lispro+PH20 (N=37)
Lispro (N=22)
(N 22) 180 Regular Insulin
Immunoreactive
Dose Norma

3000

(m g/dL)
Regular Insulin (N=19)
160
2000 ACE
140
Goal
1000 120

Blo
100
0
80
0 60 120 180 240 300 360 420 480 0 60 120 180 240
Time (minutes)
Time from injection (minutes)

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
previous findings from Phase 1
• Lispro-PH20 and Insulin-PH20 accelerate insulin absorption
comparedd tto the
th respective
ti iinsulin
li products
d t alone,
l yielding
i ldi 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 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

concentration
– Data to be presented at International Diabetes Federation
(Montreal October 18-22) and Diabetes Technology
(Montreal,
Society (San Francisco, November 5-7)

• IIntra-subject
t bj t PK/GD variability
i bilit study
t d completed
l t d tto clarify
l if d 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
Phase 1 euglycemic
l i glucose
l clamp
l study
t d comparingi 3 marketed
k t d ffastt
acting analog insulins +/- PH20 (first subject dosing performed)
– Phase 2 standard meal study in T2DM patients (enrollment completed)
• Phase
Ph 3 Enabling
E bli studies:
t di
– 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)
– Phase 2 3x/day treatment study comparing Analog-PH20 to analog alone
(2010)
• Pivotal 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
candidate (Analog-PH20 and/or regular Insulin-PH20)

80
Ultrafast Insulin-PH20 Goal – Potential Benefits
vs. Standard of Care Analogs

Better glycemic control

• Faster,
Faster higher insulin concentrations and peak exposure (i
(i.e.,
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
p is ideal for insulin p
pump
p applications
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
self medicating snacking,
snacking especially in Type 2 patients

81
Key Takeaways and Closing Comments

Jonathan E. Lim, M.D.

President & Chief Executive Officer

82
Balanced Growth Strategy –
Multiple
p Programs
g Movingg Forward

Business Development Proprietary Pipeline

• Roche has entered the clinic • Ultrafast Insulin-PH20

Insulin PH20
with three biologic compounds
– Two scientific presentations for Halo
• Baxter BioScience in Phase 3 insulins in 4Q09
pivotal with GAMMAGARD
– Three additional trials underway
• Baxter Medication Delivery with results likely mid-2010
launching HYLENEX for
pediatric hydration – Phase 2 Analog-PH20
g 3x/dayy
treatment study expected to begin
• Seeking additional business 3Q10
development deals to leverage
the technology and generate • PEGPH20 Phase 1 continues
non-dilutive cash • HTI-501 and other dermatology
candidates in preclinical phase
• Pi
Pipeline
li h has significant
i ifi t partnership
t hi
value
83
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
Phase 2 treatment
t t t studies
t di provide
id significant
i ifi tddata
t off iinterest
t t tto
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
Initiated Phase 1
1, 1Q09
• Initiated Insulin-PH20 Phase 2 3x/day treatment study, 2Q09
• Presented Analog-PH20 Phase 2 interim data at ADA
ADA, 2Q09
• $4.25 million payment from Roche for fifth exclusive target, 2Q09
• Completion
p of p
patient enrollment for Phase 3 GAMMAGARD-PH20 byy
Baxter, 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
Present
t Analog-PH20
A l PH20 andd Insulin-PH20
I li PH20 variability
i bilit ddata,
t 4Q09
• Initiation of additional Roche clinical trial plus milestone possible
85
Potential Milestones for 2010
• Presentation
P t ti off PEGPH20 preclinical
li i l ddata,
t 2Q10
• Presentation of Analog-PH20 and Insulin-PH20 Phase 1 and 2
studies at ADA,
ADA 2Q10
• Initiation of Analog-PH20 Phase 2 3x/day treatment study, 3Q10
• Completion of PEGPH20 Phase 1 clinical trial
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
• Additional guidance for proprietary programs to be provided in 2010
86
What is Halozyme?

An innovative biotech company with strong biologics

capabilities and multi-functional
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
Other M
Matrix
t i platforms
l tf th
thatt can generate
t ffuture
t value
l (HTI
(HTI-501,
501
tsMMP)
• Ability
y to p
produce complex
p recombinant p
proteins
• Attracting top level biopharma talent

87
HALO’s Unique Investment Thesis

• Existing and potential drug delivery partnerships (Enhanze

Technology, 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 June

88