2. Safe Harbor Statement
This non-confidential presentation contains ‘forward-looking statements’
about the business prospects of BioMarin Pharmaceutical Inc., including
potential future products in different areas of therapeutic research and
development. Results may differ materially depending on the progress of
BioMarin’s product programs, actions of regulatory authorities, availability of
capital, future actions in the pharmaceutical market and developments by
competitors, and those factors detailed in BioMarin’s filings with the
Securities and Exchange Commission such as 10-Q, 10-K and 8-K reports.
3. BioMarin at a Glance
Proven Business Strategy Targeting Genetic and Metabolic Disorders
Three approved products on the market
• Total 2008 revenue projected: $288 M–$326 M*
• Naglazyme® for MPS VI (2008 projected revenue: $130M–$140M*)
• Aldurazyme® for MPS I (2008 projected total revenue: $135M–
$145M with net revenue to BioMarin: $72M–$80M*)
• Kuvan® for PKU—(2008 projected revenue: $45M–$65M*)
Multiple new product opportunities
• PEG-PAL for PKU—Phase 1 initiated in Q208
• 6R-BH4 for cardiovascular indications in Phase 2
• New IND candidates in development
Strong financials
• Projected 2008 net income: $30M–$42M (GAAP)*,
$54M–$69 M (non-GAAP)*
• Cash available to fund development: Approx. $576M*
* Financial information per BioMarin press release issued August 5, 2008
4. Time in Years (From IND Filing to Approval)
Record Time to Approval
Average Pharmaceutical Time to Approval 10 Years
0 5 10
5.25 Years
3.25 Years
5.00 Years
5. BioMarin’s Product Pipeline
PRECLINICAL TESTING PHASE 1 PHASE 2 PHASE 3 BLA/NDA/MAA COMMERCIALIZATION
Kuvan®
for PKU
Aldurazyme® for MPS I
Naglazyme®
for MPS VI
6R-BH4 for CV Indications and Sickle Cell Disease
PEG-PAL for PKU
BMN-110
BMN-185
BMN-103
IgA Protease for IgA Nephropathy
GALNS for MPS IVA
BMN-180
BMN-111
α-glucosidase (GAA) for Pompe Disease
SMT C1100 Utrophin upregulator for Duchenne Muscular
Dystrophy
7. About PKU (phenylketonuria)
One of the Most Commonly Inherited Metabolic Disorders: 1:10,000-15,000 births
Genetic disease that blocks phenylalanine metabolism
Characterized by high blood phenylalanine (Phe) levels
• Insufficient quantity of phenylalanine hydroxylase
(PAH), the enzyme needed to break down Phe
• Phe is found in most protein-containing foods
Sustained high Phe levels cause serious brain disease
Diagnosed via newborn screening
Transverse T2-weighted scans through lateral ventricles on PKU patient
(a) immediately before and (b) 3 months after strict dietary restriction
8. Potential to Address the Entire Spectrum of PKU
~50,000 pts.
in the developed world
Kuvan®
(sapropterin dihydrochloride)
• Oral, small molecule (6R-BH4)
• For BH4-responsive patients
(~15,000–25,000 individuals)
• FDA Approval—
December 13, 2007
PEG-PAL
(phenylalanine ammonia lyase)
• Enzyme substitution therapy
• For patients who do not respond
adequately to Kuvan or wish to
reduce blood Phe levels beyond
what is possible with Kuvan
• Phase 1 study in PKU
patients – initiated Q208
9. Kuvan: Immediately Addressable U.S. PKU Patient
Population
* Patients under 40 years of age diagnosed by newborn screening
** As reported on August 5, 2008
Does not include patients with PKU not diagnosed at birth and now in institutions
Average dose: ~18mg/kg/day**
Average patient weight: ~50kg**
Expected average compliance: 80%
Average price: ~$76K / year
Total U.S. PKU
population
~13K patients*
In-clinic
~7,400 patients
Expected response rate
~40%-60%
~2,960-4,400 patients
10. Kuvan Launch Update
Launch on track and progressing according to plan
Response rate
• Response rate higher vs. clinical trials - higher average dose, longer trial period, relaxed
definition of “response”
Compliance rate
• Compliance with diet not necessary to initiate Kuvan therapy (consistent with label)
• Observed compliance rate with Kuvan between 88% and 100% (6 months into product
launch)
• Long-term compliance should be driven by positive qualitative benefits – increased
ability to concentrate, better grades in school, feeling better overall
Post-marketing commitments – strengthening clinical profile
• PKU registry program – start in September 2008
• 2-year extension study for pivotal study patients
• Single-dose QT cardiovascular study in healthy volunteers
• 7-year open-label study (~50 patients ≤8 years) to assess neurocognitive development
and to provide safety, efficacy and pharmacokinetic data in PKU patients ≤4 years
11. Kuvan Long-Term Potential
Of the 49 U.S. patients in the extension study, 36 (73%) have continued onto
commercial therapy and all 36 patients have remained on Kuvan as of June 30,
2008 – majority of these patients have been on therapy for over two years
As of June 30, 2008, of all the commercial patients on Kuvan for 90 days or more,
88% remain on therapy and are current with refills
Market expansion beyond immediately addressable population
• Out of clinic patients
• BioMarin began working with clinics to reach out to patients lost to follow-up in
summer 2008 – provide resources and support for targeted patient outreach
programs
• Hyperphe and institutionalized patients (not included in current market assumptions)
12. PEG-PAL for PKU
Enzyme substitution therapy for patients who
do not respond adequately to Kuvan or wish
to reduce blood Phe levels beyond what is
possible with Kuvan
Phase I study
• First patient dosed mid-May 2008
• Assess safety and pharmacokinetics of single injections of PEG-PAL in approximately
35 PKU patients in a series of 7 escalating dose cohorts
• Patients in the Phase 1 study will be offered continuation into a Phase 2 study that will
evaluate the safety and efficacy of weekly injections for eight weeks followed by a dose
titration period
• Phase 2 anticipated to start in Q109 – timing does not depend on conclusion of Phase1
trial; need 9 months of monkey tox data
13. PEG-PAL Clinical Program Overview
PAL-001 PAL-002*
Weekly fixed
dose for at
least 8
weeks
Long-term extension
in which dose and
frequency of
administration may be
changed
Dose
adjustment
for at least 8
weeks
Part 1 Part 2
PAL-003*
Each subject
receives 1 dose
only in 7 dose
cohorts, n=5, N=35
*Pending FDA review and approval
14. PEG-PAL for PKU
Effective in weekly dosing in PKU mice
0.00
0.50
1.00
1.50
2.00
-10 100
PheLevels(mM)
Days
D
ose
1
D
ose
8
D
ose
9
D
ose
19
Follow-up Dosing
Vehicle Control
PEG-PAL treated
Initial Dosing No Dosing
Phe measured 3 and 7 days post injection throughout study
15. Summary of BH4 Clinical Studies
Program Results Expected
Sickle Cell Disease Q408
Peripheral Arterial Disease Q109
Pulmonary Arterial Hypertension* Q109
Proteinuria in chronic kidney disease* Q109
Indication-specific studies
Program Results Expected
BH4+Vit.C Study Q109
Coronary Artery Disease* 1H09
Isolated Systolic Hypertension* 2H09
* Investigator-sponsored studies
Mechanistic studies
16. Sickle Cell Disease: Another Genetic Disease
Indication for 6R-BH4
Sickle cell disease (SCD) is a genetic disease affecting red blood cells with
symptoms of endothelial dysfunction
There are 70,000-100,000 SCD patients in the US
• 0.15% of all African Americans (1 in 500 births) and 1 in 1000-1400 Hispanic births
Most patients identified at birth
• Newborn screening in most of the developed world
Existing treatments have some efficacy, but
need for better efficacy/safety profile
• Hydroxyurea is toxic and used in less than 10% of patients
• Hypertransfusion therapy is costly and requires regular blood transfusions and leads
to other complications
17. Sickle Cell Disease Pathophysiology
Most SCD patients have endothelial dysfunction
• Patients have poor vasodilation to signals of poor blood flow
• 30-75% of adult SCD patients have pulmonary arterial hypertension
• Pulmonary arterial hypertension, cell adhesion, and platelet activation can be traced to a
deficiency in nitric oxide (NO)
Vaso-occlusive crises initiate through cell adhesion to blood vessel walls and
blocking of capillaries
• Reduced blood flow due to reduced NO production
• Increased cell adhesion to vessel wall due to reduced NO
Effective in weekly dosing in PKU mice
18. Kuvan Market Exclusivity Irrespective
of Broad Patent Protection
2008 201520112009 2010 2012 2013 2014 20172016 2018
PKU Orphan Drug + Pediatric in the U.S.
7.5 yrs
10 yrs
PKU Orphan Drug Protection in the E.U.
Pediatric NCE Exclusivity in the U.S
5.5 yrs
Data Exclusivity in the E.U.
8–11 yrs
Develop Next Generation Products (e.g. BH4 Prodrug)
19. Intellectual Property for BH4
Orphan Drug Status
- Market exclusivity of 7.5 years in the U.S. and 10 years in the E.U.
50 patents issued / validated
• Use and combination patents
124 additional patent applications in prosecution
• 18 U.S., 106 foreign
• Key method of use patent applications:
• Once daily dosing with KUVAN
• Method of use in various CV indications
Manufacturing process patents
• Formulation patents
• Stable tablet formulation
• Crystal polymorphs
21. Cystic Fibrosis Technology licensed from
University of California, San Francisco
Licensed IP covering compounds demonstrated to improve CFTR protein
functionality
Lead compounds to undergo additional animal testing and optimization
Good strategic fit for BioMarin
• Serious unmet medical need
• Abbreviated development timelines
• High value products
• Relatively low commercial costs
22. IgA Nephropathy, a Rare and Life-Threatening
Kidney Disease
IgA nephropathy (Berger's disease)
• Primary glomerulonephritis characterized by mesangial deposits of IgA complexes
• Over time, deposits damage the kidney, causing 20% of adults with the disorder to
progress to end stage renal disease (ESRD).
• Approximately 800 patients in the U.S. develop ESRD each year caused by IgA
nephropathy out of the 40,000 patients affected by the disorder.
Collaboration with IGAN Biosciences to develop an IgA protease
• IgA proteases have been shown to cleave IgA complexes, the deposition of which
causes IgA nephropathy
Normal glomerulus Green fluorescence showing
IgA deposited in the
mesangium (middle part) of the
glomerulus
23. Morquio Type A - MPS IVA
A Lysosomal Storage Disease Caused By The Inability To
Degrade Keratan Sulfate
Biochemistry
• Deficiency in N-acetylgalactosamine-6-sulfate sulfatase (GALNS)
• Results in inability to degrade keratan sulfate (KS),
• Accumulation of KS in cartilage, connective tissue and
macrophages
• Autosomal recessive disease—many mutations described
Clinical manifestations
• Wide spectrum of severity
• Milder forms: normal lifespan; Severe forms: death in 20s
• Systemic skeletal dysplasia (severe short stature)
• Joint abnormalities
• Cervical spine abnormalities in spinal cord compression
• Respiratory disease (obstructive,restrictive, infections)
• Hearing loss, cataracts and heart valvular disease
• Cognitive development is normal, unlike some other MPS disorders
24. Proposed Clinical Program: Phase 1/2
Open label, within-patient dose escalation, n=12-15
Weekly IV infusions
Establish dose response based on PK and PD parameters
36 weeks divided into three 8 to 12 week dosing intervals:
• Interval 1: sub-therapeutic dose
• Interval 2: dose increased to anticipated therapeutic dose
• Interval 3: 3rd dose if further optimization warranted
• Extension phase will collect long term safety and efficacy data.
Expect study start in Q109
25. Product Recombinant human acid α-glucosidase, GAA
Indication ERT for Pompe Disease, a lysosomal glycogen
storage disorder, GSD type II
Production Novel mutant CHO cell line that secretes high uptake
α-glucosidase
Enzyme Highly phosphorylated like MPS ERT enzymes
Target Tissues Improved uptake and therapy of cardiac & diaphragm
are critical and skeletal muscle is important
Competition Genzyme’s Myozyme®
, low phosphorylated enzyme
Market 5-10,000 patients in developed world
BMN103 α-glucosidase (GAA) for Pompe Disease
26. BMN 103 An Improved GAA Enzyme; May Be
Better Treatment for Pompe Disease
• Novel production system in modified CHO cells
• Secretion of highly phosphorylated GAA enzyme
• 4 fold higher levels of bis-mannose 6-phosphate
• 15 fold more efficient uptake in cells
• Tissue distribution is superior
• Glycogen reduction is superior
• BioMarin is considering options for program
Heart
Myozyme (20 mg/kg) BMN103 (20 mg/kg)Vehicle
27. Duchenne Muscular Dystrophy (DMD) Program
Duchenne muscular dystrophy
• Fatal neuromuscular disorder
• Affects 1 in 3,500 boys with an estimated population of over 40K in the developed world
Exclusive worldwide licensing agreement with Summit for novel preclinical
candidate SMT C1100 and all follow-on molecules
• Small molecule utrophin upregulator
• Promising results in animal models and may have the potential to treat the entire
spectrum of DMD patients
Good strategic fit for BioMarin – genetic disease with no approved treatments
IND-enabling studies underway – plan on entering the clinic in 2009
29. BH4 for non-PKU indications
Phenylketonuria
~ 50,000 pts.
MPS Disorders
MPS VI: ~1,100 pts.
MPS I: ~ 3,000 pts.
Increasing Product Revenue
to Support Expanding Pipeline
* Per BioMarin press release issued August 5, 2008
$86.2 M $130 M – $140 M*
2007 2008 Guidance
$123.7 M
$135 M - $145 M
total revenue*
$72 M - $80M
to BioMarin*2008 guidance:
$45 M - $65 M*
30. Naglazyme®
for MPS VI – Increasing Sales
Commercialized by BioMarin in the U.S., E.U. and Latin America
* Per BioMarin press release issued August 5, 2008
$130 M – $140 M*
$ in
millions
U.S. approval:
- May 05
E.U. approval:
- Jan. 06
0
5
10
15
20
25
30
35
40
Q205Q305Q405Q106Q206Q306Q406Q107Q207Q307Q407Q108Q208
0
20
40
60
80
100
120
140
$inmillions
2005 2006 2007 2008E
31. Global Commercial Development – April 2008
Countries with Naglazyme
Sales since Launch
ALGERIA
ARGENTINA
AUSTRIA
BRAZIL
CANADA
CHILE
COLOMBIA
CROATIA
FRANCE
GERMANY
GREECE
IRELAND
ITALY
JAPAN
JORDAN
NETHERLANDS
NORWAY
PORTUGAL
QATAR
SAUDI ARABIA
SLOVAKIA
SPAIN
SWEDEN
SWITZERLAND
TAIWAN
TURKEY
UNITED ARAB EMIRATES
UNITED KINGDOM
UNITED STATES
Total = 29 Countries
BioMarin Direct Presence 24
Distribution Partner in Place 24
Named Patient Sales - No Distributor 3
Markets Being Assessed 5
Total Countries 56
32. Aldurazyme®
for MPS I – Increasing Sales and
Profits
- Total Revenues by Genzyme - - BMRN share of JV Loss/Profit -
* Per BioMarin press release issued August 5, 2008
0
20
40
60
80
100
120
140
$inmillions
2003 2004 2005 2006 2007 2008E
$11.5
$42.6
$135-$145*
$76.4
$96.3
$123.7
-20
-15
-10
-5
0
5
10
15
20
25
30
35
$inmillions 2003 2004 2005 2006 2007
($18.7) ($3.0)
$11.8
$19.3
$30.5
Revenue to BioMarin in 2008: $72 million to $80 million*
34. KEY MILESTONES
Filed IND for PEG-PAL for PKU Q407
Kuvan®
FDA approval Q407
Kuvan®
launch in the U.S. Q407
Receipt of $15mn milestone payment related to Kuvan®
MAA filing Q407
Initiate Phase 1 trial of PEG-PAL for PKU Q208
Kuvan® approval in Japan Q308
Top-line results from Phase 1 PEG-PAL trial Q408
Results from Phase 2 Sickle Cell Disease trial Q408
Kuvan®
approval by EMEA Q408
Results from Phase 2 PAD trial Q109
Initiate Phase 1/2 trial for ERT for MPS IVA Q109
Initiate Phase 2 trial of PEG-PAL for PKU Q109
Initiate Phase 1 trial for SMT C1100 for Duchenne Muscular Dystrophy H109
35. Moving Forward
Continued focus on commercial products
• Kuvan launch
• Commercialization and geographic expansion of Naglazyme
• Partnership with Genzyme for Aldurazyme
Development of R&D pipeline
• Numerous opportunities in current pipeline
• Actively pursuing in-licensing/acquisition opportunities
Leverage corporate capabilities
• Research and development expertise
• State of the art manufacturing
• Global commercial infrastructure with track record of success
Heading toward full-year profitability
This slide gives an overview of the rAvPAL-PEG program
PAL-001 will be starting this month
Each subject receives 1 dose only in 7 dose cohorts
There will be 7 dose cohorts with 5 patients each, altogether 35 patients
The patients that participated in PAL-001 will be offered to take part in PAL-002
PAL-002 will be conducted in 2 parts
In part 1, each subject will be receiving the same dose for 8 weeks
The doses are corresponding to the PAL-001 cohorts
In part 2, the dose will be adjusted according to phenylalanine level
PAL-003 will be the long-term extension for these same patients where doses may be changed as needed
Primary cause of skeletal pathology in MPSIVA patients is KS accumulation in growth plate chondrocytes and articular chondrocytes.
Both should be the principal target for GALNS delivery.