Morquio A Disease Overview

Slide 1

VIMIZIM (elosulfase alfa) for the treatment of Morquio A syndrome

Please see important safety information, including boxed warning, on slide 54NOTES:

To date, there has been significant unmet medical need for individuals with Morquio A. [Tomatsu 2011; Northover 1996] Now, with the availability of VIMIZIM (elosulfase alfa), clinicians can address the cause of Morquio A by providing therapeutic intervention that address the underlying enzyme deficiency. [VIMIZIM PI]

REFERENCES:

Vimizim PI/p 2/section 11Morquio A Disease Overview 2No references needed.2Morquio 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 worldwideIncidence 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 tissuesWide variability in clinical presentation and disease severitySerious, progressive, life threatening disease3Harmatz P., et al. The Morquio A Clinical Assessment Program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013NOTES:

While initial signs of Morquio A are typically musculoskeletal complications, progressive systemic manifestations can lead to potentially severe cardiovascular, pulmonary, neurologic, rheumatologic, ophthalmologic, ENT, hepatic, abdominal, and dental consequences. [Tomatsu 2011; Montano 2007; Semenza 1988; Harmatz 2013; Hendrickz 2013; Ireland 1981; John 1990; Pelley 2007; Pritzker 1980; Gulati 1996; Holzgreve 1981; Danes 1973; Leslie 2005; Couprie 2010; Cahane 1990; Kinirons 1990]

The majority of patients with Morquio A do not survive past the second or third decade of life, with frequent causes of death including respiratory failure, and cardiovascular disease. [Tomatsu 2011; Harmatz 2013; Semenza 1988]

REFERENCES:

Bullet 1: Harmatz 2013/p 1/col 1/para 1/col 2/para 1

Bullet 2: Harmatz 2013/p 1/col 1/para 1

Bullet 3: Tomatsu 2005/p 500/col 2/para 1

Bullet 4: Harmatz 2013/p 1/col 2/para 1/p 2/col 1/para 1



Bullet 7: Harmatz 2013/p 1/abstract311 known enzyme deficiencies classify 7 MPS types that cause 11 different disorders4MPS Type Common NameEnzyme DeficiencyMPS IHurler, Hurler Scheie, Scheie-L-iduronidase MPS IIHunterIduronate sulfatase MPS III AMPS III BMPS III CMPS III DSanfilippo ASanfilippo BSanfilippo CSanfilippo DHeparan N-sulfatase-N-acetylglucosaminidaseAcetyl CoA:-glucosaminide acetyltransferaseN-acetylglucosamine-6-sulfataseMPS IV AMPS IV BMorquio AMorquio BN-acetyl-galactosamine-6-sulfatase (GALNS) -galactosidase

MPS VIMaroteaux-Lamy N-acetylgalactosamine 4-sulfatase (arylsulfatase B)

MPS VIISly -glucuronidase

MPS IXHyaluronidase Deficiency Hyaluronidase

Note that MPS V and VIII are no longer used as designations of disease Kakkis, Expert Opinion on Investigational Drugs, 2002NOTES:

Morquio A is one of more than 40 identified LSDs, which collectively occur in approximately 1 in 5000 live births. [Wilcox 2004; Fisher 2004] A subset of LSDs are the MPS disorders, each of which is caused by a deficiency in an enzyme(s) that degrades GAGs. [Wilcox 2004; Heese 2008]

In Morquio A specifically, the underlying cause of the disease is an inherited deficiency in the GALNS enzyme. [Tomatsu 2011] This deficiency results in multiple metabolic pathologies, including, most notably, the accumulation of the GAG substrates KS and C6S in lyosomes throughout the body. [Tomatsu 2011]

While each MPS disease is distinct, many share similar presenting signs and symptoms, making differential diagnosis a challenge, even for those practices with deep clinical experience in these conditions. A key difference in Morquio A, however, is that affected individuals do not experience intellectual impairment and have normal IQs. [Northover 1996; Tomatsu 2011]

REFERENCES:

Entire page: Kakkis, Expert Opinion on Investigational Drugs, 2002/p 676/table 1

4GALNS deficiency causes a block in the sequential breakdown of glycosaminoglycans

Morquio B (MPS IVB)Morquio A (MPS IVA)-D-GalactosidaseN-acetylgalactosamine-6-sulfatase (GALNS)5Neufeld, 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.NOTES:

The precise etiology of Morquio A syndrome is known, and deficient GALNS activity has been identified as the basis for the destructive morbidities and mortality associated with Morquio A. [Northover 1996; Tomatsu 2011] Replacement of GALNS enzyme activity can only be used as a therapy for MPS IVA and not for other MPS conditions, including Morquio B (MPS IVB).

REFERENCES:

Neufield 2011 p. 12, fig. 136-4, p. 13, para 1Neufeld, 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.

5GALNS Deficiency leads to GAG accumulation in lysosomesUnaffected cell

Cell with GAG accumulation in lysosomes

Lysosomes engorged with undegraded KSDeficient GALNS enzyme activity impairs lysosomal degradation of the GAGs keratan sulfate (KS) and chondroitin-6-sulfate (C6S)Accumulation of these GAGs in lysosomes leads to cell engorgement and disruption of normal cell functionCellular dysfunction results in the progressive multisystemic morbidities that are the hallmark of this disorder

6Bank et al, Mol Genet Metab, 2009Tomatsu S. et al. Mucopolysaccharidosis type IVA (Morquio A disease):clinical review and current treatment. Curr Pharm Biotechnol. 2011NOTES:

Deficient GALNS activity results in a cascade of metabolic pathologies [Tomatsu 2011; Northover 1996], including increased accumulation of GAG species, including KS and C6S, across multiple organs [Northover 1996; Montano 2007], disruption of the extracellular matrix, affecting multiple organ systems [Bank 2009], and intrinsic collagen derangement, affecting cardiovascular and pulmonary function [Bank 2009; Barry 2006; Dvorak-Ewell 2010; DeFranceschi 2007]. Other pathogenic effects (eg, modulation of collagen gene expression) are currently being characterized through evolving clinical understanding. [Dvorak-Ewell 2010]

REFERENCES:

Headline: Northover 1996, p. 357, para 1; Tomatsu 2011 p. 931, col 2, para 1

First statement: Harmatz 2013 p. 1, col 2, para 1; Tomatsu 2011 p. 931, col 1, para 1, col 2, para 1; Northover 1996 p. 357, para 1

Second statement: Tomatsu 2011 p. 931, col 1, para 1, col 2, para 1

Third statement: Tomatsu 2011 p. 931, col 1, para 1, col 2, para 1, p. 934, col 1, para 1, p. 935, fig. 3; Harmatz 2013, p. 3, col 2, para 2;Bank 2009, p. 3, col 2, para 3, p. 4, col 1, para 1,2; Montano 2007, p. 166, col 1, para 1; Barry 2006, p. 841, col 2, para 2; Dvorak-Ewell 2010, p. 1, col 2, para 1+2; De Franceschi 2007, p 1, col 1, para 1, col 2, para 1Yeung 2009 p. 73, col 1, para 1Coutinho 2012 p. 1, col 1, para 1, p. 2, table 2Hendriksz 2013 p. 2, col 1, para 1,3

67Morquio A is under recognized and challenging to diagnoseDysostosis multiplex: classic phenotypic appearance

Short thick claviclesPaddle (oar-shaped) ribs

Anterior vertebral beaking Posterior vertebral scalloping Platyspondyly Broadened ribs

Rounded iliac wingsInferior tapered iliaDysplastic Capital Femoral Epiphysis (CFE)

Short broad metacarpalsProximally pointed metacarpalsHypoplastic carpal bonesSolanki, G. et al, Spinal involvement in mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome):presentation, diagnosis and management J Inherit Metab Dis January 2013 Radiographic imaging is a key component of diagnosing Morquio A however, findings vary and may be subtle. NOTES:

Differential diagnosis of Morquio A can be challenging, even in practices with experience in MPS disorders and other rare conditions; however, as Morquio A is both progressive and potentially life-threatening, early diagnosis enables timely disease-specific intervention, which can help prevent complications and provide clinicians with the ability to appropriately and effectively coordinate care across specialties throughout a patients life. [Tomatsu 2011; Solanki 2013] On average, time to diagnosis from initial disease manifestation is over 2 years. [Montano 2007]

Once Morquio A is suspected, clinical, radiological, and laboratory diagnostic tools can be utilized together to confirm a diagnosis of Morquio A. [Montano 2007; Palandurkar 2011]

Radiographic findings are critical to identifying patients with Morquio A. In fact, over 70% of Morquio A patients manifest with unusual skeletal features within the first few years of life. [Montano 2007] Radiographic findings are also critical to helping distinguish Morquio A from non-dysostosis multiplex skeletal dysplasias including other MPS disorders, spondyloepiphyseal dysplasia congenita, multiple epiphyseal dysplasia, and brachyolmia. [Wood 2013]

7Molecular heterogeneity leads to phenotypic variability Over 185 mutations in the GALNS gene give rise to wide genotypic and phenotypic heterogeneity No pre-dominant mutationMost common allele 70% of 325 Morquio A patients required at least one surgical procedure 19Patients Typically Require SurgeryHarmatz P., et al. The Morquio A Clinical Assessment Program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013. n = 325 subjects (mean age= 14.5 years) Harmatz et al. Mol Genet Metab, 2013; 109:54-61

19Airway and anesthetic management for Morquio A patients is challengingMorquio A patients are at high risk of anesthesia-related morbidity and mortality due to:Cervical instability and myelopathyCompromised respiratory functionUpper and lower airway obstructionRestrictive lung diseaseCardiac abnormalitiesAny elective surgery requires:Thorough pre-operative ENT, pulmonary and cardiac evaluationsPre-operative radiological assessment of the cervical spine Skilled personnel in airway managementSpectrum of airway management equipment 20Theroux et al, Paediatr Anaesth, 2012; Solanki et al, J Inherit Metab Dis, 2013; Walker et al, J Inherit Metab Dis, 2013; McLaughlin et al, BMC Anesthesiol, 2010; Morgan et al, Paediatr Anaesth, 2002; Shinhar et al, Arch Otolaryngol Head Neck Surg, 2004; Belani et al, J Ped Surg, 1993; Walker et al, Anaesthesia, 1994 Morquio A patients should be managed by experienced anesthesiologists at centers familiar with MPS disorders.NOTES:

Morquio A patients suffer from multiple factors that can dramatically increase surgical risk and the need for monitoring, including reduced respiratory capacity, impaired cardiovascular function, skeletal morphology, cervical spinal instability, and complex airway structure. [Theroux 2012; Bartz 1999] These factors complicate surgical and anesthetic care, require preplanning, and necessitate disease-specific techniques to increase optimal outcomes. [Theroux 2012; Bartz 1999]

Specialized perioperative procedures during anesthesia, such as intubation and extubation, are essential to successful surgical interventions. [Theroux 2012; Bartz 1999] An integrated surgical team consisting of MPS specialists is critical for positive, durable outcomes.

REFERENCES:

Theroux et al, Paediatr Anaesth, 2012; Solanki et al, J Inherit Metab Dis, 2013; Walker et al, J Inherit Metab Dis, 2013; McLaughlin et al, BMC Anesthesiol, 2010; Morgan et al, Paediatr Anaesth, 2002; Shinhar et al, Arch Otolaryngol Head Neck Surg, 2004; Belani et al, J Ped Surg, 1993; Walker et al, Anaesthesia, 1994 20Case Illustration: 3 Minute Stair Climb Test (3MSCT)Multisystemic Morbidities Impact Ambulation21

NOTES:

This video illustrates the dramatic functional deficits individuals with Morquio A face in their day-to-day lives. These deficitsand their impact on endurancemay be directly linked to the progressive, multisystemic effects of the disease. [Harmatz 2013]

REFERENCES:

No references needed.21

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.bBaseline data for MorCAP, a multicenter, multinational, cross sectional longitudinal study of 325 patients with Morquio A.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 A6MWT Distance in Untreated Morquio A Patients and Age-matched Healthy ControlsEndurance (6MWT) is Severely Impaired in Morquio A Patients22Harmatz P., et al. The Morquio A Clinical Assessment Program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013. NOTES:

The 6MWT has been used as a predictor of morbidity and mortality in multiple indications, including COPD, heart failure, cystic fibrosis, fibromyalgia, and others. [ATS Paper] Significant change in the 6MWT reflects improvement or decline in the functional status of the cardiac, respiratory, and musculoskeletal systems, and a change in disease progression. [ATS Paper]

The 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. [ATS Paper; MacDonald 2010] Compared to the unaffected population (where 6MWT distance improves with age), patients with Morquio A face the effects of progressive multiorgan involvement leading to sharply reduced endurance before the age of 18. [Tomatsu 2011; Harmatz 2013; Geiger 2006]

REFERENCES:

Headline: Ulrich 2013/p. 3/Figure 1; Tomatsu 2011 p. 934, col 1, para 1, p. 935, Fig 3; Harmatz 2013 p. 3, col 1, para 2, p. 5, col 1, para 3, col 2, para 1, p. 6, table 3, Supplementary table;Harmatz 2013 p. 3, col 1, para 4

Bullet 1: Harmatz 2013 p. 3, col 1, para 4, col 2, paras 1-3

Bullet 2: Harmatz 2013 p. 3, col 1, para 4

Bullet 3: Harmatz 2013 p. 3, col 1, para 4

Graph: Ulrich 2013/p. 3/Figure 1; Harmatz 2013 p. 3, col 1, para 2, p. 5, col 1, para 3, col 2, para 1, p. 6, table 3, Supplementary table;Harmatz 2013 p. 3, col 1, para 4

2223Reduced Endurance is Attributed to Multisystemic Complications of Morquio ADecreased Quality of LifeLimitedMobility

Reduced Activities of Daily LivingChronic Pain and Fatigue

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, 2012NOTES:

Clinical decline in endurance as seen in the 6MWT demonstrates how multisystemic pathologies associated with Morquio A may contribute to reduction in patient function. [MorCAP 2013 data to come] In this patient population, reduced endurance or mobility can be caused by any of the systemic complications of Morquio A, including cardiac disease (valve thickening, regurgitation, or stenosis), respiratory disease (airway obstruction or restrictive disease), musculoskeletal disease (joint pain, muscle weakness, or abnormal gait), and/or spinal cord compression. [Tomatsu 2011; Montano 2007; Semenza 1988; Harmatz 2013; Hendrickz 2013; Ireland 1981; John 1990; Pelley 2007; Pritzker 1980; Gulati 1996; Holzgreve 1981; Danes 1973; Leslie 2005; Couprie 2010; Cahane 1990; Kinirons 1990]

REFERENCES:

Headline: Harmatz 2013 p. 2, col 2, para 6, p. 3, col 2, para 2,3, p. 6, col 1, para 2, col 2, para 1+ 3

Cardiac Complications: Harmatz 2013, p. 6, col 2, para 1+2

Musculoskeletal Complications: Harmatz 2013 p. 2, col 1, para 3, col 2, para 6

Respiratory Complications: Harmatz 2013 p. 6, col 1, para 2/col 2, para 1

Reduced Endurance- Reduced Activities of daily living: ATS paper p. 112, col 1, para 2; Harmatz 2013/p3/c 1, para 4, col 2, para 1,3 Reduced Endurance- Limited mobility: Harmatz 2013 p. 3, col 1, para 4, col 2, para 1,3

23VIMIZIM (elosulfase alfa)Clinical Trial ResultsNOTES:

VIMIZIM (elosulfase alfa) is the only ERT approved for the treatment of Morquio A. [VIMIZIM PI]

REFERENCES:

No references needed.2425Please see Important Safety Information, including boxed warning, on slide 54.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.REFERENCES:

VIMIZIM PI p. 2, black box25BioMarin Clinical Program for Morquio A26No references needed.2627VIMIZIM (elosulfase alfa) replaces deficient GALNSThe goal of ERT in Morquio A is to reduce GAG accumulation in order to restore cellular function.28At 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.28VIMIZIM (elosulfase alfa) is an exogenous recombinant human enzyme that replaces deficient GALNS.4,19Within 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.NOTES:

Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome) is characterized by the absence or marked reduction in N-acetylgalactosamine-6 sulfatase activity. The sulfatase activity deficiency results in the accumulation of the GAG substrates, KS and C6S, in the lysosomal compartment of cells throughout the body. The accumulation leads to widespread cellular, tissue, and organ dysfunction. [VIMIZIM PI]

VIMIZIM is intended to provide the exogenous enzyme N-acetylgalactosamine-6-sulfatase that will be taken up into the lysosomes and increase the catabolism of the GAGs KS and C6S. [VIMIZIM PI] Elosulfase alfa uptake by cells into lysosomes is mediated by the binding of mannose-6-phosphate-terminated oligosaccharide chains of elosulfase alfa to mannose-6-phosphate receptors. [VIMIZIM PI]

REFERENCES:

Headline: VIMIZIM PI p. 8, section 12.1, para 1

Subhead: VIMIZIM PI p. 8, section 12.1, para 1

Description 1: Coutinho 2012 p. 1, col 2, para 2; Hendriksz 2013 p. 2, col 1, para 1

Description 2: VIMIZIM PI p 8, section 12.1, para 1

Description 3: VIMIZIM PI p 8, section 12.1, para 1; Wood 2013 p. 2, col 1, para 2

27VIMIZIM (elosulfase alfa) Tissue DistributionElosulfase alfa distributes to target tissues of the disease after IV administration in miceChondrocytes

Nucleus Labeled Elosulfase alfa28Dvorak-Ewell et al, PLoS 2010.


Repeat injections of elosulfase alfa in mice demonstrates biodistribution specifically to the growth plate and articular cartilage; product diffuses through the avascular cartilage to reach target cells. [Dvorak-Ewell 2010/p6/col2/para 1, para2/lines1-2]

Notably, in nucleus labeled elosulfase alfa, fluorescence was present throughout the growth plate with the highest abundance at the cartilage/bone interface, in resting and hypertrophic chondrocytes. [Dvorak-Ewell 2010/p6/col2/para2/lines3-7]

Such biodistribution may be a reflection of the proximity of these cells to the vasculature present in the neighboring bone. In favor of this hypothesis is the finding of significant enzyme delivery in the well-vascularized bone marrow. [Dvorak-Ewell 2010/p6/col2/para2/lines6-10]

REFERENCES:

Dvorak-Ewell 2010 p. 8, fig. 6 Dvorak-Ewell et al, PLoS, 2010.

28VIMIZIM (elosulfase alfa) Pharmacological ActivityElosulfase alfa clears intracellular GAGs (KS) in MPS IVA chondrocytesRestores normal chondrocyte enzymatic function

KSLysosomesCo-localizationExtracellular KSIntracellular KSNucleusUntreated10 nM elosulfase alfa29Dvorak-Ewell et al, PLoS 2010.


Pharmacological activity in long-term MPS IVA chrondocyte cultures showed significantly reduced accumulation of KS when cultured with 10 nM rhGALNS in cells and restored chondrocyte enzymatic function to normal physiologic levels. [Dvorak-Ewell 2010/p3/col2/para3] This observation supports that rhGALNS acts in the lysosomal compartment, as the therapeutic enzyme is inactive at extracellular pH and cannot degrade KS without participation of other lysosomal enzymes. [Dvorak-Ewell2010/p3/col2/para4/lines15-19] Nevertheless, extracellular KS may also be affected, secondary to amelioration in KS turnover and trafficking defects, in response to lysosomal clearance by rhGALNS. [Dvorak-Ewell/p3/col2/para4/lines18-20]

REFERENCES:

Photos: Dvorak-Ewell 2010 p. 6, fig. 4

Bullet 1: Dvorak-Ewell 2010 p. 6, col 2, para 1

Bullet 2: Dvorak-Ewell 2010 p. 7, col 2, para 1Dvorak-Ewell et al, PLoS 2010.

29Morquio A Clinical Development Program:The Largest Clinical Study program for any MPS disorder 30Designed to capture the immense heterogeneity and range of progressionVIMIZIM (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 diseasePlease see Important Safety Information, including boxed warning, on slide 54.NOTES:

Six clinical trials involving a total of 325 patients with Morquio A have been performed in order to characterize the efficacy, safety, and tolerability of VIMIZIM (elosulfase alfa).

These trials confirmed the utility of VIMIZIM in all patients with Morquio A, and showed significantly improved endurance as demonstrated by the 6MWT (P=0.0174), as well as an acceptable safety and tolerability profile. [VIMIZIM PI]

30VIMIZIM (elosulfase alfa) clinical study summaryMOR-002Phase 1/2, multicenter, open-label dose-escalation study to evaluate the safety, tolerability and efficacy of VIMIZIM in patients with Morquio A (n=20) Initiated October 2008 MOR-100Multicenter, open-label extension study enrolling patients from MOR-002 to evaluate the long term safety and efficacy of VIMIZIM in patients with Morquio A (n=17)MOR-004Phase 3, randomized, double-blind, placebo-controlled, multinational clinical study to evaluate the efficacy and safety of VIMIZIM 2mg/kg/wk and 2mg/kg/qow in patients with Morquio A. (n=176)Initiated January 2011MOR-005Multinational, multicenter extension study to evaluate the long-term efficacy and safety of VIMIZIM in patients with Morquio A. (n=173)MOR-006Phase 2 open-label multinational clinical study to evaluate the safety and efficacy of VIMIZIM in Morquio A patients with limited ambulation (n=13)MOR-007Phase 2 open-label multinational clinical study to evaluate the safety and efficacy of VIMIZIM in pediatric patients less than 5 years of age with Morquio A (n=15)MOR-008Phase 2, randomized, double-blind pilot study of safety and physiological effects of 2 doses of VIMIZIM in patients with Morquio A (n=25)31Please see Important Safety Information, including boxed warning, on slide 54.NOTES:

VIMIZIM is the most extensively studied ERT for MPS diseases. MOR-004 is to date the largest prospective trial to evaluate the efficacy and safety of ERT in any MPS disease. [VIMIZIM PI] MOR-005 was an extension study to evaluate the long-term efficacy and safety of VIMIZIM in patients with Morquio A. As of February 2014, MOR-100, MOR-005, MOR-006, MOR-007 and MOR-008 are currently ongoing.

31VIMIZIM (elosulfase alfa) Phase 3, randomized, double- blind, placebo controlled study32No references needed32Phase 3 Pivotal Trial (MOR-004) OverviewThe safety and efficacy of VIMIZIM (elosulfase alfa) were assessed in a 24 week, randomized, double-blind, placebo-controlled clinical trial of 176patients with Morquio A.

Primary endpointEvaluate VIMIZIM (elosulfase alfa) compared to placebo to improve endurance, as measured by 6MWT

Secondary endpointsEvaluate VIMIZIM (elosulfase alfa) compared to placebo as measured by number of stairs climbed per minute in 3MSCTEvaluate VIMIZIM compared to placebo, as measured by reduced uKS levels

Tertiary endpointsTo determine the pharmacodynamic parameters of VIMIZIM administered intravenouslyTo 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

33Please see Important Safety Information, including boxed warning, on slide 54.NOTES:

The pivotal VIMIZIM phase 3 trial, MOR-004, is to date the largest prospective trial to evaluate the efficacy and safety of ERT in any MPS disease. [VIMIZIM PI] Improvement in patients endurance was assessed by the 6MWT. This test is validated as a measure of endurance in the clinical setting, assessing the functional reserves of the cardiovascular, pulmonary, or musculoskeletal systems. [American Thoracic Society 2002]

Secondary and tertiary endpoints helped further elucidate additional data regarding respiratory function and activities of daily living, as well as pharmacodynamics. [Data on file]

REFERENCES:

Bullet 1: VIMIZIM PI p. 9, section 14, para 1

Primary endpoint: VIMIZIM PI p. 9, section 14, para 3;MOR-004 p. 66, para 2, p. 67, para 1

Secondary endpoint: VIMIZIM PI p. 9, section 14, para 3;MOR-004 p. 66, para 2; p. 67, para 2,3

Tertiary endpoints: MOR-004 p. 67, para 4-10

Phase 3 - MOR-004 Study Sites 177 individuals enrolled at 33 sites in 17 countries34Please see Important Safety Information, including boxed warning, on slide 54.Source for countries: MOR 004 CSR Section 8.7.7.1.9 ; also Table 5.1 (Argentina)

Dose compliance exceeded 98%Screened (N=204)Randomized (N=177)ITT Population (N=176)1 excluded before treatment due to unconfirmed diagnosisof Morquio A syndromePlacebo(n=59)VIMIZIM (elosulfase alfa) 2.0 mg/kg/qow(n=59)VIMIZIM (elosulfase alfa)2.0 mg/kg/week(n=58)1 (1.7%) discontinuedReason: Patient withdrawal of consentPhase 3 Trial Design35Please see Important Safety Information, including boxed warning, on slide 54.NOTES:

High data quality through the study including consistency of duplicate 6MWT assessments, high intraclass correlation coefficients across visits/treatments, dosing compliance exceeding 98%, few missing data points, and 99% completed the study. [Data on File, BioMarin Pharmaceutical Inc.]

REFERENCES:MOR-004 p. 68, section 8.1, p. 124, Fig. 9.1.1Phase 3 Baseline DemographicsPlacebon=59VIMIZIM(elosulfase alfa)2.0 mg/kg/qown=59VIMIZIM (elosulfase alfa)2.0 mg/kg/weekn=58Age at Enrollment (years) Mean (SD)15 (11)15 (11)13 (8)Age Group (years)a, n (%) 51130 (50.8)31 (52.5)32 (55.2) 121815 (25.4)16 (27.1)16 (27.6) 1914 (23.7)12 (20.3)10 (17.2)Sex, n (%) Female32 (54.2)25 (42.4)32 (55.2)Race, n (%) Asian11 (18.6)15 (25.4)14 (24.1) Black or African American02 (3.4)2 (3.4) White44 (74.6)35 (59.3)36 (62.1) Other4 (6.8)7 (11.9)6 (10.3)Ethnicity, n (%) Hispanic or Latino13 (22.0)16 (27.1)9 (15.5)aStratification factor.Patients ranged from 5 to 57years. 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 30meters (m) but less than 325m in six minutes.


MOR-004 baseline demographics represent the heterogeneity of the Morquio A patient population. There were no meaningful imbalances between treatment groups in baseline demographics or other characteristics. [Data on file, BioMarin Pharmaceutical Inc.]

REFERENCES:

Table: MOR-004 p. 130, Table 10.2.1

Bullet 1: MOR-004 p. 130, Table 10.2.1

Bullet 2: MOR-004 p. 135, Table 10.2.4

Bullet 3: MOR-004 p. 130, para 1, p. 131, para 136Placebon=59Elosulfase alfa2.0 mg/kg/qown=59Elosulfase alfa2.0 mg/kg/weekn=586-Minute Walk Test (meters) Mean (SD)212 (70)206 (81)204 (76)3-Minute Stair Climb Test (stairs/min) Mean (SD)30 (14)27 (16)30 (16)Normalized Urine KS (g/mg) Mean (SD)26 (15)29 (21)27 (14)Walk Categorya, n (%) 200m23 (39.0)24 (40.7)23 (39.7) >200m36 (61.0)35 (59.3)35 (60.3)Walking Aids Usedb11 (18.6)16 (27.1)9 (15.5)Phase 3 Baseline CharacteristicsaStratification factor.bWalking aids used in 6MWT include crutches, walker/walking frame and cane/walking stick.37Please see Important Safety Information, including boxed warning, on slide 54.NOTES:

A physical examination and endurance tests (6MWT and 3MSCT, in duplicate) were performed at screening and/or baseline, Week 12, and Week 24 (or within 1 week of the early termination visit [ETV]). Urine samples for urine KS and creatinine and blood samples for immunogenicity testing were collected at baseline, Weeks 2 and 4, and every 4 weeks thereafter (or within 1 week of the ETV). Respiratory function was also evaluated at baseline, Week 24, and within 1 week of early withdrawal from the study. [VIMIZIM PI; Data on file, BioMarin Pharmaceutical Inc.]

Medical history findings were similarly distributed across treatment groups and reflected the serious morbidities that Morquio A patients experience. [VIMIZIM PI; Data on file, BioMarin Pharmaceutical Inc.]

REFERENCES:

MOR-004 p. 132, Table 10.2.23738Primary Endpoint Results:VIMIZIM (elosulfase alfa) significantly improved endurance as measured in the 6MWTANCOVA model for 24 Week 6MWT change from baseline adjusting for age (511, 1218, 19 yrs) and BL6MWT (200m and >200 m)175 of 176 (99.4%) completed the 24-week study in the Intent-to-Treat groupCompared 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 6MWTPatients who continued receiving VIMIZIM through the extension trial stabilized walking ability after 72 weeks in extension studyPlease see Important Safety Information, including boxed warning, on slide 54.

NOTES:

Compared to patients taking a placebo, patients administered once-weekly VIMIZIM in MOR-004 demonstrated a 22.5-meter (P=0.0174) improvement in the 6MWT in only 24 weeks of 2 mg/kg/wk dosing. [VIMIZIM PI] However, when VIMIZIM was administered 2 mg/kg/qow, the results were similar to patients taking a placebo, with no statistically significant change observed in walk distance. [VIMIZIM PI]

REFERENCES:

Headline: VIMIZIM PI p. 9, section 14, para 3, p. 10, section 14, para 1, table 3

Bullet 1: VIMIZIM PI p. 10, table 3

Bullet 2: VIMIZIM PI p. 9, section 14, para 3, p. 10, section 14, table 3

Bullet 3: BioMarin data on file

Bullet 4: VIMIZIM PI p. 10, para 2

Graph: VIMIZIM PI p. 10, section 14, table 3

38

Cumulative Distribution for Change from Baseline to Week 24(ITT Population)Responder Analysis of the 6MWTIn 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


In the 6MWT, those patients with the greatest disability at screening (ability to walk < 200 m) achieved a significant difference of 40.38 meters at Week 24 when receiving VIMIZIM 2 mg/kg/wk. [Briefing Book CSR SubgroupsTable]

Source: BioMarin Briefing Doc Figure 6.5.3.4MOR-004 p. 147, Figure 10.4.1.1.3.26MWT 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.

40Please see Important Safety Information, including boxed warning, on slide 54.

NOTES:

The 6MWT is not merely a measure of distance walked; in fact, it has been used as a predictor of morbidity and mortality in multiple indications besides MPS diseases, including COPD, heart failure, cystic fibrosis, fibromyalgia, and others. [ATS paper]

REFERENCES:

Headline: ATS 2002 p. 111, col 2, para 3

Bullet 1: ATS 2002 p. 111, col 2, para 3

Bullet 2: ATS 2002 p. 111, col 2, para 3

Bullet 3: MacDonald 2010/p 124/c 2/para 3/p 125/c 1/para 1

40VIMIZIM (elosulfase alfa) Phase 3 Secondary Endpoints at Week 24VIMIZIM (elosulfase alfa) QW vs. Placeboa 3MSCTMean (stairs/min)1.195% CI(-2.1, 4.4)p-value0.494 uKSMean (%)-40.795% CI(-49.0, -32.4)p-value

Documents

Morquio A Disease Overview