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  • 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.


  • 1. August 2008
  • 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. Record Time to Approval Time in Years (From IND Filing 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  -glucosidase (GAA) for Pompe Disease SMT C1100 Utrophin upregulator for Duchenne Muscular Dystrophy
  • 6. Kuvan ® and PEG-PAL for PKU: Leveraging a Proven Development Strategy
  • 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
    Phe Levels (mM) Days Dose 1 Dose 8 Dose 9 Dose 19 Follow-up Dosing Initial Dosing No Dosing Phe measured 3 and 7 days post injection throughout study Vehicle Control PEG-PAL treated
  • 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 2015 2011 2009 2010 2012 2013 2014 2017 2016 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
  • 20. Preclinical Product Pipeline: Multiple Opportunities for Continued Growth
  • 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  -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
  • 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
  • 28. Commercial Product Portfolio: Building a Meaningful Revenue Base
  • 29. 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* BH4 for non-PKU indications Phenylketonuria ~ 50,000 pts. MPS Disorders MPS VI: ~1,100 pts. MPS I: ~ 3,000 pts.
  • 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
  • 31. Global Commercial Development – April 2008
  • 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 ($18.7) ($3.0) $11.8 $19.3 $30.5 Revenue to BioMarin in 2008: $72 million to $80 million* $11.5 $42.6 $135-$145* $76.4 $96.3 $123.7
  • 33. 2005 - 2008: Improving Financial Profile * Per BioMarin press release issued August 5, 2008 2005 2006 2007 2008E* -80 -60 -40 -20 0 20 40 Net Profit/Loss ($Millions) (74.3) (28.5) (15.8) 30–42
    • 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
  • 36. THANK YOU