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Morquio A Disease Overview

VIMIZIM™ (elosulfase alfa) for the treatment of Morquio A syndrome Please see important safety information, including boxed warning, on slide 54. Morquio A Disease Overview. Morquio A syndrome: key facts. Also referred to as MPS IVA, mucopolysaccharidosis IVA

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Morquio A Disease Overview

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  1. VIMIZIM™ (elosulfase alfa) for the treatment of Morquio A syndromePlease see important safety information, including boxed warning, on slide 54

  2. Morquio A Disease Overview

  3. Morquio A syndrome: key facts • Also referred to as MPS IVA, mucopolysaccharidosis IVA • Autosomal recessive lysosomal storage disorder (LSD) • Limited documented data available for Morquio A incidence worldwide • Incidence varies from 1 in 76,000 live births (Northern Ireland) to 1 in 640,000 live births (Western Australia) • Caused by deficient activity of N-acetyl-galactosamine-6-sulfatase (GALNS), an enzyme that catalyzes the breakdown of two glycosaminoglycans (GAGs), keratan sulfate (KS) and chondroitin-6-sulfate (C6S) • Characterized by progressive accumulation of KS and C6S in tissues • Wide variability in clinical presentation and disease severity • Serious, progressive, life threatening disease Harmatz P., et al. The Morquio A Clinical Assessment Program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013

  4. 11 known enzyme deficiencies classify 7 MPS types that cause 11 different disorders Kakkis, Expert Opinion on Investigational Drugs, 2002 Note that MPS V and VIII are no longer used as designations of disease

  5. GALNS deficiency causes a block in the sequential breakdown of glycosaminoglycans N-acetylgalactosamine-6-sulfatase (GALNS) Morquio A (MPS IVA) Morquio B (MPS IVB) -D-Galactosidase Neufeld, EF and Muenzer, J. The Mucopolysaccharidoses. Part 16: Chapter 136. In Valle, D, et al. (Eds.), The Online Metabolic & Molecular Bases of Inherited Disease. Germany: The McGraw-Hill Companies; 2001-2006.

  6. GALNS Deficiency leads to GAG accumulation in lysosomes • Deficient GALNS enzyme activity impairs lysosomal degradation of the GAGs keratan sulfate (KS) and chondroitin-6-sulfate (C6S) Lysosomes engorged with undegraded KS • Accumulation of these GAGs in lysosomes leads to cell engorgement and disruption of normal cell function Cell with GAG accumulation in lysosomes • Cellular dysfunction results in the progressive multisystemic morbidities that are the hallmark of this disorder Unaffected cell Bank et al, Mol Genet Metab, 2009 Tomatsu S. et al. Mucopolysaccharidosis type IVA (Morquio A disease):clinical review and current treatment. CurrPharmBiotechnol. 2011

  7. Morquio A is under recognized and challenging to diagnose • Dysostosis multiplex: classic phenotypic appearance • Short thick clavicles • Paddle (oar-shaped) ribs • Rounded iliac wings • Inferior tapered ilia • Dysplastic Capital Femoral Epiphysis (CFE) • Short broad metacarpals • Proximally pointed metacarpals • Hypoplasticcarpal bones • Anterior vertebral beaking • Posterior vertebral scalloping • Platyspondyly • Broadened ribs Radiographic imaging is a key component of diagnosing Morquio A however, findings vary and may be subtle. Solanki, G. et al, Spinal involvement in mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome): presentation, diagnosis and management J Inherit MetabDis January 2013

  8. Molecular heterogeneity leads to phenotypic variability • Over 185 mutations in the GALNS gene give rise to wide genotypic and phenotypic heterogeneity • No pre-dominant mutation • Most common allele <9% Ages 18, 34, 54, 33, 7 Tomatsu S. et al. Mucopolysaccharidosis type IVA (Morquio A disease): clinical review and current treatment. CurrPharmBiotechnol. 2011

  9. A Debilitating, Multisystemic Disorder Clinical signs and symptoms: • Skeletal dysplasia • Joint laxity • Short stature • Cervical spine instability • Spinal cord compression • Impaired endurance • Respiratory disease • Hearing loss • Corneal clouding • Heart valvular disease • Dental abnormalities • Normal intelligence Harmatz P., et al. The Morquio A Clinical Assessment Program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013

  10. Life Expectancy is Reduced Distribution of Age in Morquio A Population • Most patients usually do not survive beyond 30s • Major causes of mortality: • Pulmonary complications • Cervical instability and myelopathy • Cardiac complications • Complications associated with surgery and general anesthesia US Population Age Distribution – 2010 Census Age (Years) Harmatz P., et al. The Morquio A Clinical Assessment Program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013. US Census 2010

  11. Musculoskeletal Manifestations • Skeletal dysplasia/Dysostosis multiplex • Spinal abnormalities • Pectuscarinatum (pigeon chest) • Hip dysplasia • Genuvalgum (knock knees) • Growth retardation • Joint laxity and degeneration • Frequent surgeries • Complicated • Long recovery • Increased caregiver burden Images courtesy of Christina Lampe, MD and Ralph Lachman, MD Harmatz P., et al. The Morquio A Clinical Assessment Program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013

  12. Joint abnormalities are common in Morquio A patients • Joint instability • floppy wrists with weak grip and loss of fine motor skills • exacerbates knee valgus and gait abnormalities • Subluxation of the hip and the atlantoaxial joint • Joint degeneration due to bone defects, cartilage deterioration and altered mechanics • Joint pain Harmatz P., et al. The Morquio A Clinical Assessment Program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013

  13. Abnormal gait results from bone and joint defects • A study of 9 children with Morquio (subtype not specified) with no previous lower extremity surgery revealed a consistent gait pattern: • Slower walking speed, reduced cadence and reduced stride length vs normal • Trunk, pelvis, hip: increased forward tilt of trunk and pelvis, increased hip flexion • Knee: increased knee flexion, genuvalgus, and external tibial torsion; dynamic knee varus-valgus joint laxity • Joint moments and power: reduced hip and ankle joint moments, reduced power generation Dhawale, A., et al. Gait pattern and lower extremity alignment in children with Morquio syndrome. Journal of Pediatrics Orthopaedics B; Vol.22 No. 1 January 2013

  14. Non-skeletal involvement is common n = 325 subjects (mean age = 14.5 years) Harmatz P., et al. The Morquio A Clinical Assessment Program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013

  15. Respiratory Function Is Severely Limited Mean MVV Mean FVC n=195 n=66 n=261 n=178 n=59 n=237 • Mean FVC = 1.2 ±0.9 L (n = 261 subjects) • FVC in unaffected population = 3.5 – 4 L • Mean MVV = 34.8 ±25.5 L/min (n= 237 subjects) • MVV in unaffected population = 140 – 150 L/min Harmatz P., et al. The Morquio A Clinical Assessment Program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013 15

  16. Respiratory System Manifestations GAG deposits Narrow, tortuous trachea Pigeon chest Narrow trachea • Upper airway obstruction • Narrow/torturous trachea and bronchi • Excessive and thickened secretions • Restricted thoracic space due to skeletal deformities and muscular weakness • Recurrent pulmonary infections • Respiratory failure and early death Hendriksz et al, J Inherit Metab Dis, 2012; Tomatsu et al, Curr Pharm Biotechnol, 2011; Walker et al, Thorax, 2003; Pelley et al, Respir Care, 2007 ; Semenza and Pyeritz, Medicine (Baltimore), 1998; Buhain et al, Chest, 1975; Pritzker et al, Am J Med, 1980.

  17. Cardiac Involvement is Common Incidence Rate Regurgitation by age group: Pediatric Adult Stenosis by age group: Pediatric Adult Pediatric n=256 subjects Adult n=69 subjects Harmatz P., et al. The Morquio A Clinical Assessment Program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013

  18. Cardiac Manifestations • Valvular heart disease • Myocardial hypertrophy • Cardiomegaly • Develop slowly over many years Ireland and Rolands, Br Heart J, 1981 Autopsy specimen of Morquio A patient shows thickening of mitral valve cusps, tricuspid valve cusps, and chordae Hendriksz et al, J Inherit Metab Dis, 2012; John et al, Arch Dis Child, 1990; Wipperman et al, Eur J Pediatr, 1995; Mohan et al, Acta Paediatr, 2002; Ireland and Rolands, Br Heart J, 1981. Ireland and Rolands, Br Heart J, 1981.

  19. Patients Typically Require Surgery • >70% of 325 Morquio A patients required at least one surgical procedure n = 325 subjects (mean age= 14.5 years) Harmatz P., et al. The Morquio A Clinical Assessment Program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013.

  20. Airway and anesthetic management for Morquio A patients is challenging • Morquio A patients are at high risk of anesthesia-related morbidity and mortality due to: • Cervical instability and myelopathy • Compromised respiratory function • Upper and lower airway obstruction • Restrictive lung disease • Cardiac abnormalities • Any elective surgery requires: • Thorough pre-operative ENT, pulmonary and cardiac evaluations • Pre-operative radiological assessment of the cervical spine • Skilled personnel in airway management • Spectrum of airway management equipment Morquio A patients should be managed by experienced anesthesiologists at centers familiar with MPS disorders. • Theroux et al, PaediatrAnaesth, 2012; Solanki et al, J Inherit MetabDis, 2013; Walker et al, J Inherit MetabDis, 2013; • McLaughlin et al, BMC Anesthesiol, 2010; Morgan et al, PaediatrAnaesth, 2002; Shinhar et al, Arch Otolaryngol Head Neck Surg, 2004; • Belani et al, J PedSurg, 1993; Walker et al, Anaesthesia, 1994

  21. MultisystemicMorbidities Impact Ambulation Case Illustration: 3 Minute Stair Climb Test (3MSCT)

  22. Endurance (6MWT) is Severely Impaired in Morquio A Patients 6MWT Distance in Untreated Morquio A Patients and Age-matched Healthy Controls • The 6 Minute Walk Test (6MWT) evaluates the global and integrated responses and functional reserves of cardiovascular, pulmonary and musculoskeletal systems • Comparing 12-18 year olds with and without Morquio A, those with Morquio A exhibit up to 74% less endurance as demonstrated by 6MWT 687.7 vs. 181.2 meters • Reduced endurance progresses over time for individuals with Morquio A aAdapted from Geiger et al, study provides reference values for 6MWT based on and limited to demographics for 528 healthy children and adolescents ages 3 to 18. bBaselinedata for MorCAP, a multicenter, multinational, cross sectional longitudinal study of 325 patients with Morquio A. Harmatz P., et al. The Morquio A Clinical Assessment Program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013. 22

  23. LimitedMobility • Reduced Activities of Daily Living • Chronic Pain and Fatigue Reduced Endurance is Attributed to Multisystemic Complications of Morquio A Decreased Quality of Life Harmatz P., et al. The Morquio A Clinical Assessment Program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013. Hendriksz et al,Clinical overview and treatment options for non-skeletal manifestations of mucopolysaccharidosis type IVA. J Inherit Metab Dis, 2012 23

  24. VIMIZIM (elosulfase alfa) Clinical Trial Results

  25. VIMIZIM (elosulfase alfa) is a weekly IV infusion indicated for patients with Morquio A (MPS IVA) Life-threatening anaphylactic reactions have occurred in some patients during VIMIZIM™ (elosulfase alfa) infusions. Anaphylaxis, presenting as cough, erythema, throat tightness, urticaria, flushing, cyanosis, hypotension, rash, dyspnea, chest discomfort, and gastrointestinal symptoms (eg, nausea, abdominal pain, retching, and vomiting) in conjunction with urticaria, have been reported to occur during VIMIZIM infusions, regardless of duration of the course of treatment. Closely observe patients during and after VIMIZIM administration and be prepared to manage anaphylaxis. Inform patients of the signs and symptoms of anaphylaxis and have them seek immediate medical care should symptoms occur. Patients with acute respiratory illness may be at risk of serious acute exacerbation of their respiratory compromise due to hypersensitivity reactions, and require additional monitoring. Please see Important Safety Information, including boxed warning, on slide 54.

  26. BioMarin Clinical Program for Morquio A

  27. VIMIZIM™ (elosulfase alfa) replaces deficient GALNS • The goal of ERT in Morquio A is to reduce GAG accumulation in order to restore cellular function.28 At a cellular level, GAGs accumulate in the lysosomes and occupy an increasingly greater area of the cytoplasm which disrupts normal cell function and activates secondary pathogenic cascades.28 VIMIZIM™ (elosulfase alfa) is an exogenous recombinant human enzyme that replaces deficient GALNS.4,19 Within the lysosome, VIMIZIM increases catabolism of GAGs (KS and C6S)—restoring cell function.28,29 Please see Important Safety Information, including boxed warning, on slide 54.

  28. VIMIZIM (elosulfase alfa) Tissue Distribution Elosulfase alfa distributes to target tissues of the disease after IV administration in mice Chondrocytes Nucleus Labeled Elosulfase alfa Dvorak-Ewell et al, PLoS 2010. Please see Important Safety Information, including boxed warning, on slide 54.

  29. VIMIZIM (elosulfase alfa) Pharmacological Activity KS Lysosomes Co-localization Extracellular KS Intracellular KS Nucleus • Elosulfase alfa clears intracellular GAGs (KS) in MPS IVA chondrocytes • Restores normal chondrocyte enzymatic function Untreated 10 nMelosulfase alfa Dvorak-Ewell et al, PLoS 2010. Please see Important Safety Information, including boxed warning, on slide 54.

  30. Morquio A Clinical Development Program:The Largest Clinical Study program for any MPS disorder • Designed to capture the immense heterogeneity and range of progression • VIMIZIM (elosulfase alfa) has been widely studied in 6 clinical trials totaling 235+ patients treated. • The pivotal phase III trial of VIMIZIM, MOR-004, is the largest prospective trial to evaluate the efficacy and safety of ERT in any MPS disease Please see Important Safety Information, including boxed warning, on slide 54.

  31. VIMIZIM (elosulfase alfa) clinical study summary Please see Important Safety Information, including boxed warning, on slide 54.

  32. VIMIZIM (elosulfase alfa) Phase 3, randomized, double- blind, placebo controlled study

  33. Phase 3 Pivotal Trial (MOR-004) Overview The safety and efficacy of VIMIZIM (elosulfase alfa) were assessed in a 24 week, randomized, double-blind, placebo-controlled clinical trial of 176 patients with Morquio A. Primary endpoint • Evaluate VIMIZIM (elosulfase alfa) compared to placebo to improve endurance, as measured by 6MWT Secondary endpoints • Evaluate VIMIZIM (elosulfase alfa) compared to placebo as measured by number of stairs climbed per minute in 3MSCT • Evaluate VIMIZIM compared to placebo, as measured by reduced uKS levels Tertiary endpoints • To determine the pharmacodynamic parameters of VIMIZIM administered intravenously • To evaluate the ability of VIMIZIM compared to placebo to improve respiratory function Exploratory endpoints • Selected to evaluate growth, activities of daily living, and other disease symptoms Please see Important Safety Information, including boxed warning, on slide 54.

  34. Phase 3 - MOR-004 Study Sites • 177 individuals enrolled at 33 sites in 17 countries Please see Important Safety Information, including boxed warning, on slide 54.

  35. Phase 3 Trial Design Randomized (N=177) Screened (N=204) 1 excluded before treatment due to unconfirmed diagnosisof Morquio A syndrome • Dosecompliance exceeded 98% ITT Population (N=176) VIMIZIM (elosulfasealfa) 2.0 mg/kg/qow (n=59) VIMIZIM (elosulfasealfa)2.0 mg/kg/week (n=58) Placebo (n=59) 1 (1.7%) discontinued Reason: Patient withdrawal of consent Please see Important Safety Information, including boxed warning, on slide 54.

  36. Phase 3 Baseline Demographics • Patients ranged from 5 to 57 years. • The majority of the patients (82%) presented with a medical history of musculoskeletal conditions, including • knee deformity (52%) • kyphosis (31%) • hip dysplasia (22%) • prior spinal fusion surgery (22%) • arthralgia (20%) • At baseline, all enrolled patients could walk more than 30 meters (m) but less than 325 m in six minutes. Please see Important Safety Information, including boxed warning, on slide 54. aStratificationfactor.

  37. Phase 3 Baseline Characteristics aStratification factor.bWalking aids used in 6MWT include crutches, walker/walking frame and cane/walking stick. Please see Important Safety Information, including boxed warning, on slide 54.

  38. Primary Endpoint Results:VIMIZIM (elosulfase alfa) significantly improved endurance as measured in the 6MWT • 175 of 176 (99.4%) completed the 24-week study in the Intent-to-Treat group • Compared with placebo, VIMIZIM™ (elosulfase alfa) 2 mg/kg/wk demonstrated a statistically significant improvement in 6MWT distance in only 24 weeks (P=0.0174) • Patients walked farther at Week 24 than at baseline, with a mean 23.9% improvement over baseline in the 6MWT • Patients who continued receiving VIMIZIM through the extension trial stabilized walking ability after 72 weeks in extension study Please see Important Safety Information, including boxed warning, on slide 54. • ANCOVA model for 24 Week 6MWT change from baseline adjusting forage (5–11, 12–18, ≥19 yrs) and BL6MWT (≤200 m and >200 m)

  39. Responder Analysis of the 6MWT Cumulative Distribution for Change from Baseline to Week 24(ITT Population) In cumulative distribution function analysis of the 6MWT change from baseline to Week 24, patients treated with VIMIZIM (elosulfase alfa) 2 mg/kg/wk showed clear separation from placebo across all levels of response Please see Important Safety Information, including boxed warning, on slide 54.

  40. 6MWT – a validated measure of endurance • The 6MWT is validated measure of endurance by the American Thoracic Society • The 6MWT evaluates the global and integrated responses and functional reserves of cardiovascular, pulmonary and musculoskeletal systems • Congenital effects of Morquio A lead to intrinsically reduced endurance as compared to the unaffected population; therefore for patients with Morquio A, even small changes in distance on the 6MWT can be clinically significant. Please see Important Safety Information, including boxed warning, on slide 54.

  41. VIMIZIM (elosulfase alfa) Phase 3 Secondary Endpoints at Week 24 aModel-based mean of VIMIZIM minus Placebo, adjusted for baseline. • There was no change from baseline in 3MSCT at week 24 compared to placebo • Reduction in uKS levels from baseline, a measure of pharmacodynamic effect, was greater in the VIMIZIM (elosulfasealfa) treatment groups compared to placebo. The relationship between uKS and other measures of clinical response has not been established. Please see Important Safety Information, including boxed warning, on slide 54.

  42. VIMIZIM (elosulfasealfa) Tertiary Endpoints and Week 24Maximum Voluntary Ventilation - MVV • At Week 24, patients administered VIMIZIM™ (elosulfase alfa) 2 mg/kg/wk trended toward improvement in MVV percent change from baseline vs placebo Respiratory Function Test MVVLS Mean % Change from Baseline at Week 24 (ITT Population) Please see Important Safety Information, including boxed warning, on slide 54.

  43. VIMIZIM(elosulfasealfa) Tertiary Endpoints and Week 24Forced Vital Capacity- FVC • At Week 24, patients administered VIMIZIM™ (elosulfase alfa) 2 mg/kg/wk and 2 mg/kg/qow showed a trend toward improvement in FVC percent change from baseline vs placebo Respiratory Function Test FVCLS Mean % Change from Baseline at Week 24 (ITT Population)

  44. VIMIZIM (elosulfase alfa) Week 24Summary of Efficacy Endpoints Please see Important Safety Information, including boxed warning, on slide 54.

  45. Additional Analyses Related to Activities of Daily Living (MPS HAQ) – ITT Population • Of the 52 HAQ questions, responses to 36 questions favored weekly treatment, 12 favored placebo and 4 showed no difference Please see Important Safety Information, including boxed warning, on slide 54.

  46. Clinical Efficacy Conclusions • Pivotal Phase 3 study met primary endpoint of significant improvement from baseline in 6MWT distance at Week 24 for VIMZIM (elosulfase alfa) 2.0 mg/kg/week compared to placebo (P=0.0174) • Totality of data including sub-group analysis and majority of exploratory endpoints directionally consistent with primary endpoint, supporting effectiveness of weekly dosing regimen • VIMIZIM was efficacious across full spectrum of age, disease severity, and clinical manifestations in diverse patient population • Long-term continuous treatment with VIMIZIM generally maintained or improved efficacy measures • Magnitude of observed effect is substantial in a disease characterized by progressive decline in mobility and endurance, resulting ultimately in need for life-long assistance with activities of daily living Please see Important Safety Information, including boxed warning, on slide 54.

  47. VIMIZIM (elosulfasealfa) Tertiary Endpoints and Week 24Summary of Efficacy Endpoints • Other efficacy endpoints that did not show clinically significant changes during MOR-004: • Cardiac EKGs/ECHOs • Lower extremity bone length • Inflammatoryand bone and cartilage metabolism markers • Growth • Corneal clouding • Hearing Please see Important Safety Information, including boxed warning, on slide 54.

  48. VIMIZIM™(elosulfase alfa) safety and tolerability • Adverse reactions were collected from 176 patients ages 5 to 57 who were enrolled in the 24-week, phase 3 pivotal study. The most common adverse reactions (≥10%) were pyrexia, vomiting, headache, nausea, abdominal pain, chills, and fatigue. • Acute reactions requiring intervention were managed by • Temporarily interrupting or slowing the infusion • Administering additional antihistamines, antipyretics, or corticosteroids 28 aSafetyand effectiveness in pediatric patients <5 years of age has not been established and is currently being evaluated. Please see Important Safety Information, including boxed warning, on slide 54.

  49. VIMIZIM™ (elosulfase alfa) safety and tolerability (cont’d) • Hypersensitivity reactions, including anaphylaxis, were reported in patients treated with VIMIZIM™ (elosulfase alfa) in six clinical trials; the risks and benefits of re-administering VIMIZIM following a severe reaction should be considered • 44 of 235 (18.7%) patients experienced hypersensitivity reactions • Frequent symptoms of hypersensitivity reactions (occurring in more than 2 patients) included anaphylactic reactions, urticaria, peripheral edema, cough, dyspnea, and flushing • Hypersensitivity reactions have occurred as early as 30 minutes from the start of infusion but as late as 6 days after infusion2 • 18 of 235 (7.7%) patients experienced signs and symptoms consistent with anaphylaxis (see boxed warning) • Cases of anaphylaxis have occurred as early as 30 minutes from the start of infusion and up to three hours after infusion; anaphylaxis occurred as late into treatment as the 47th infusion Please see Important Safety Information, including boxed warning, on slide 54.

  50. Serious adverse reactions associated with VIMIZIM™ (elosulfase alfa) are manageable with appropriate medical support • Due to the potential for anaphylaxis, appropriate medical support should be readily available when VIMIZIM™ (elosulfase alfa) is administered; inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs and symptoms occur • Patients with acute febrile or respiratory illness at the time of VIMIZIM infusion may be at a higher risk of life-threatening complications from hypersensitivity reactions; careful consideration should be given to the patient’s clinical status prior to administration of VIMIZIM and consider delaying the VIMIZIM infusion • Management of hypersensitivity reactions should be based on the severity of the reaction and include slowing or temporary interruption of the infusion and/or administration of additional antihistamines, antipyretics, and/or corticosteroids for mild reactions • If severe hypersensitivity reactions occur, immediately stop the infusion of VIMIZIM and initiate appropriate treatment; because of the potential for hypersensitivity, administer antihistamines with or without antipyretics prior to the infusion • The risks and benefits of re-administering VIMIZIM following a severe reaction should be considered Please see Important Safety Information, including boxed warning, on slide 54.

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