biomarin team masters project public presentation
TRANSCRIPT
August 2008
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.
BioMarin at a Glance Proven Business Strategy Targeting Genetic and Metabolic DisordersThree 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
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
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
-glucosidase (GAA) for Pompe Disease
SMT C1100 Utrophin upregulator for Duchenne Muscular Dystrophy
Kuvan® and PEG-PAL for PKU:Leveraging a Proven Development Strategy
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
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
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
Kuvan Launch Update
Launch on track and progressing according to planResponse 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
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)
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
PEG-PAL Clinical Program Overview
PAL-001 PAL-002*
Weekly fixed dose for at least 8 weeks
Long-term extensionin which dose and frequency of administration may be changed
Dose adjustmentfor 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
PEG-PAL for PKUEffective in weekly dosing in PKU mice
0.00
0.50
1.00
1.50
2.00
-10 100
Ph
e L
evel
s (m
M)
Days
Dose 1
Dose 8
Dose 9
Dose 1
9Follow-up Dosing
Vehicle Control
PEG-PAL treated
Initial Dosing No Dosing
Phe measured 3 and 7 days post injection throughout study
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
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
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
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 yrsPKU 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)
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
Preclinical Product Pipeline:Multiple Opportunities for Continued Growth
Cystic Fibrosis Technology licensed from University of California, San FranciscoLicensed 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
IgA Nephropathy, a Rare and Life-Threatening Kidney DiseaseIgA 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
Morquio Type A - MPS IVAA 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
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
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 -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 -glucosidase (GAA) for Pompe Disease
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
Duchenne Muscular Dystrophy (DMD) ProgramDuchenne 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
Commercial Product Portfolio:Building a Meaningful Revenue Base
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*
Naglazyme® for MPS VI – Increasing SalesCommercialized by BioMarin in the U.S., E.U. and Latin America
* Per BioMarin press release issued August 5, 2008
$130 M – $140 M*
$ inmillions
U.S. approval: - May 05
E.U. approval:- Jan. 06
0
5
10
15
20
25
30
35
40
Q205Q305Q405Q106Q206Q306Q406Q107Q207Q307Q407Q108Q2080
20
40
60
80
100
120
140
$ in
milli
ons
2005 2006 2007 2008E
Global Commercial Development – April 2008
Countries with Naglazyme Sales since Launch
ALGERIAARGENTINAAUSTRIABRAZILCANADACHILECOLOMBIACROATIAFRANCEGERMANYGREECEIRELANDITALYJAPANJORDANNETHERLANDSNORWAYPORTUGALQATARSAUDI ARABIASLOVAKIASPAINSWEDENSWITZERLANDTAIWANTURKEYUNITED ARAB EMIRATESUNITED KINGDOMUNITED STATESTotal = 29 Countries
BioMarin Direct Presence 24
Distribution Partner in Place 24
Named Patient Sales - No Distributor 3
Markets Being Assessed 5
Total Countries 56
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
$ in
mil
lio
ns
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
$ i
n m
illi
on
s2003 2004 2005 2006 2007
($18.7) ($3.0)
$11.8
$19.3
$30.5
Revenue to BioMarin in 2008: $72 million to $80 million*
2005 - 2008: Improving Financial Profile
2005 2006 2007 2008E*-80
-60
-40
-20
0
20
40
Net
Pro
fit/L
oss
($M
illio
ns)
(74.3) (28.5) (15.8)
30–42
* Per BioMarin press release issued August 5, 2008
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
Moving ForwardContinued 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
THANK YOU