Contents

12.1 Introduction and Overview 240

12.2 Biochemistry and Genetics of Recombinant a-L-Iduronidase 242

12.2.1 Enzyme Composition, Synthesis, and Biochemical Action 242

12.2.1.1 Protein and Gene Sequence and Structure 242

12.2.1.2 N-Linked Carbohydrate Structure 243

12.2.1.3 Intracellular Trafficking and Uptake Via M6PR 244

12.2.1.4 Biochemical Function in GAG Metabolism 245

12.3 Clinical Deficiency of a-L-Iduronidase and MPS 1 245

12.3.1 Clinical Characteristics of MPS I 245

12.3.1.1 Pathophysiology of MPS I 246

12.3.1.2 Manifestations of the Spectrum of MPS I Disease 246

12.3.2 Molecular Genetics and Mutations 247

12.3.2.1 Mutations in a-L-Iduronidase in MPS I 247

12.3.2.2 Polymorphisms 247

12.4 Early Development of ERT 247

12.4.1 Discovery of Correction: In Vitro Uptake and Treatment of MPS I 247

12.4.2 Rationale for Enzyme Therapy in MPS I 248

12.4.3 Early Production of rhIDU 248

12.4.4 Studies of ERT in Canine MPS I 249

12.5 Manufacturing of Aldurazyme for the Commercial Market 250

12.5.1 Cell Culture and Perfusion Process 250

12.5.2 Purification of Highly Purified High-Uptake rhIDU 250

12.6 Quality Control System and Assays 251

12.6.1 Purity and Safety 252

12.6.2 Characterization of Protein and Carbohydrate 252

12.6.3 Activity and Potency 252

12.7 Clinical Development of Aldurazyme 252

12.7.1 Phase 1 Open-Label Study in Ten MPS I Patients 253

12.7.1.1 Study Objectives and Design 253

12.7.1.2 Study Results in Reducing Lysosomal Storage 254

12.7.1.3 Study Results in the Clinical Manifestations 254

12.7.1.4 Safety 254

12.7.2 Phase-3 Study of Aldurazyme 254

12.7.2.1 Study Objectives and Design 254

12.7.2.2 Study Results in the Primary Endpoints 255

12.7.2.3. Reductions in Measures of Storage 255

12.7.2.4 Study Results in Other Endpoints 255

12.7.2.5 Safety 256

12.8 Regulatory Approval 256

12.8.1 Regulatory Strategies and Challenges with Surrogate Endpoints 256

12.8.2 Use of Clinical Endpoints in a Novel Disease Target 257

12.8.3 Advisory Committee Preparation and Execution 258

12.9 Conclusions 258

Acknowledgements 259

References 259

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