1. REPORT INTRODUCTION 1.1 Objective of the Study 10 1.2 Secondary Research 10 1.3 Scope of the report: 10 2. DISEASE OVERVIEW 11 2.1 Introduction 11 2.2 Etiology 12 2.3 Classification 13 2.4 Signs and Symptoms 14 2.4.1 The early and progressive clinical symptoms include: 14 2.5 Pathogenesis 15 2.5.1 Metabolic Defect 15 2.5.2 The Molecular Basis 17 2.5.3 Genotype/Phenotype Correlation 20 2.6 Diagnosis 21 2.6.1 Biochemical Diagnosis: 21 2.6.1.1 Measurement of a-Gal Activity in Cultivated Fibroblasts, Plasma, or Leukocytes 21 2.6.1.2 Measurement of α-Gal A Activity in Blood Spot Filter Paper 22 2.6.1.3 GL-3 Levels 22 2.6.2 Molecular Diagnosis 22 2.6.3 Molecular Analysis 23 2.7 Treatment 25 2.7.1 Clinical management of pediatric patients 25 2.7.2 Management of Fabry related pain in pediatric patients 26 2.7.2.1 Trigger management 26 2.7.2.2 Symptomatic therapy 26 2.7.2.3 Management of neuropathic pain 26 2.7.2.4 Management of psychological disturbances 27 2.7.3 Treatment Algorithm for the management of neuropathic pain in paediatric Fabry Disease patients 28 2.7.3.1 Enzyme replacement therapy 29 2.7.3.2 Recommendations for ERT initiation 30 2.7.4 Management in adults 31 2.7.4.1 Available Enzyme Replacement therapies 32 2.7.4.2 Initiation of enzyme replacement therapy 32 2.7.4.3 Expert panel recommendations for initiation of enzyme replacement therapy in adult patients with Fabry Disease 32 2.7.4.4 Adjunctive therapies 34 2.7.4.5 Non-ERT approaches for patients with specific mutations 36 2.7.5 Monitoring of adult patients with Fabry Disease 36 3. PRODUCTS UNDER DEVELOPMENT BY TECHNOLOGY 39 4. PRODUCTS UNDER DEVELOPMENT BY DESIGNATION 40 4.1 Comparative Analysis 40 5. TOTAL NUMBER OF MARKETED AND EMERGING PRODUCTS 41 5.1 Comparative Analysis 41 6. MARKETED PRODUCTS 42 6.1 Galafold: Amicus Therapeutics 42 6.1.1 Product Description 42 6.1.1.1 Dosage and Administration: 42 6.1.2 Regulatory Milestones 43 6.1.2.1 Approval 43 6.1.3 Research and Development 43 6.1.3.1 Clinical Studies 43 6.1.3.1.1 Clinical Studies 43 6.1.3.1.2 Results of Analysis 44 6.1.4 Product Development Activities 46 6.1.4.1 Positive Recommendation 46 6.1.4.2 Designation 46 6.1.4.3 Patents 46 6.1.4.4 Licensing 47 6.1.4.4.1 GlaxoSmithKline 47 6.1.4.4.2 Mt. Sinai School of Medicine 47 6.2 Replagal: Shire 49 6.2.1 Product Description 49 6.2.1.1 Dosage and Administration: 49 6.2.2 Regulatory Milestones 49 6.2.2.1 Approval 49 6.2.3 Research and Development 49 6.2.3.1 Clinical Studies 49 6.2.4 Product Development Activities 51 6.2.4.1 BLA Withdrawn 51 6.2.4.2 Business Expansion 51 6.2.4.3 Acquisition 51 6.2.4.4 Designation 51 6.3 Fabrazyme: Sanofi Genzyme 52 6.3.1 Product Description 52 6.3.1.1 Dosage and Administration: 53 6.3.2 Regulatory Milestones 53 6.3.2.1 Approval 53 6.3.3 Research and Development 53 6.3.3.1 Clinical Studies 53 6.3.4 Product Development Activities 56 6.3.4.1 Designation 56 7. PIPELINE THERAPEUTICS AT A GLANCE 57 7.1 General Overview 57 8. COMPARATIVE ANALYSIS 58 8.1 General Overview 58 9. LATE PHASE PRODUCTS (PHASE III) 59 9.1 Comparative Analysis 59 9.2 Lucerastat: Idorsia Pharmaceuticals 59 9.2.1 Product Description 59 9.2.2 Research and Development 60 9.2.2.1 Clinical Studies 60 9.2.2.1.1 Phase III 60 9.2.2.1.2 Phase I 60 9.2.2.1.3 Results of Analysis 60 9.2.2.1.4 Results of Analysis II 61 9.2.3 Product Development Activities 62 9.2.3.1 Designation 62 9.2.3.2 Spin Off 62 9.3 Pegunigalsidase alfa: Protalix Biotherapeutics 63 9.3.1 Product Description 63 9.3.2 Research and Development 63 9.3.2.1 Clinical Studies 63 9.3.2.1.1 Phase III 63 9.3.2.1.2 Results of Analysis 64 9.3.2.1.3 Results of Analysis II 65 9.3.3 Product Development Activities 66 9.3.3.1 Designation 66 9.3.3.2 Agreement 66 9.3.3.3 Patent 67 9.3.3.4 Technology 67 10. MID PHASE PRODUCTS (PHASE II) 69 10.1 Comparative Analysis 69 10.2 Venglustat: Sanofi Genzyme 69 10.2.1 Product Description 69 10.2.2 Research and Development 70 10.2.2.1 Clinical Studies 70 10.2.2.1.1 Phase II 70 10.2.3 Product Development Activities 70 10.2.3.1 Designation 70 11. EARLY STAGE PRODUCTS (PHASE I) 72 11.1 Comparative Analysis 72 11.2 Apabetalone: Resverlogix Corp 72 11.2.1 Product Description 72 11.2.2 Research and Development 73 11.2.2.1 Clinical Studies 73 11.2.2.1.1 Phase II 73 11.3 Moss-aGal: Greenovation Biotech 74 11.3.1 Product Description 74 11.3.2 Research and Development 75 11.3.2.1 Clinical Studies 75 11.3.2.1.1 Phase I 75 11.3.2.1.2 Results of Analysis 75 11.3.3 Product Development Activities 76 11.3.3.1 Technology 76 12. PRE-CLINICAL STAGE PRODUCTS 77 12.1 Comparative Analysis 77 12.2 Fabry Gene Therapy: Amicus Therapeutics 77 12.2.1 Product Description 77 12.2.2 Product Development Activities 78 12.2.2.1 Agreement 78 12.3 FTL190: Freeline 79 12.3.1 Product Description 79 12.3.2 Research and Development 79 12.3.2.1 Pre-clinical Studies 79 12.3.3 Product Development Activities 80 12.3.3.1 Financing 80 12.4 mRNA-3630: Moderna 81 12.4.1 Product Description 81 12.5 PGN005 (α-galactosidase): Pharming 81 12.5.1 Product Description 81 12.6 ST-920: Sangamo Therapeutics 82 12.6.1 Product Description 82 12.6.2 Research and Development 82 12.6.2.1 Pre-clinical Studies 82 12.6.3 Product Development Activities 82 12.6.3.1 IND Acceptance 82 13. THERAPEUTIC ASSESSMENT 84 13.1 Assessment by Stage and Product Type 84 13.2 Assessment by Route of Administration 85 13.3 Assessment by Stage and Route of Administration 86 13.4 Assessment by Molecule Type 87 13.5 Assessment by Stage and Molecule Type 88 14. APPROVAL TIMELINES 89 14.1 Approval Timeline for Clinical Products 89 15. ANALYST INSIGHTS 90 16. INACTIVE PRODUCTS 91 16.1 Comparative Analysis 91 16.2 Small Molecule Inhibitor: Evotec 91 16.2.1 Product Description 91 16.2.2 Product Development Activities 91 16.2.2.1 Collaboration 91

Figure 1: Typical Signs and Symptoms of Fabry Disease according to age 14 Figure 2: Some key mutations associated with the classic or later-onset Fabry Disease phenotype, GLA variants of unclear significance (VUS), and benign variants 17 Figure 3: α-galactosidase A gene mutations 18 Figure 4: Fabry disease X-linked Inheritance Pattern 19 Figure 5: Treatment Algorithm for the management of neuropathic pain in paediatric Fabry Disease patients 28 Figure 6: Products under development by Designation 40 Figure 7: Total Number of Marketed and Emerging Products 41 Figure 8: Total Number of Products in Fabry Disease 58 Figure 9: Late Stage Products (Phase III) 59 Figure 10: Mid Stage Products (Phase II) 69 Figure 11: Early Stage Products (Phase I) 72 Figure 12: Pre-clinical Stage Products 77 Figure 13: Assessment by Stage and Product Type 84 Figure 14: Assessment by Route of Administration 85 Figure 15: Assessment by Stage and Route of Administration 86 Figure 16: Assessment by Molecule Type 87 Figure 17: Assessment by Stage and Molecule Type 88 Figure 18: Approval Timelines for Clinical Products 89 Figure 19: Inactive Products 91Table 1: Criteria for Phenotype Classification 13 Table 2: Clinical evaluation and monitoring of pediatric patients with Fabry Disease 23 Table 3: Clinical evaluation and monitoring of adult patients with Fabry Disease 24 Table 4: Recommendations for initiation of ERT in pediatric patients with FD 31 Table 5: Recommendations for initiation of ERT in adult male and female patients with classic or later-onset mutations, or GLA VUS. 32 Table 6: Adjunctive support for the management of adult patients with Fabry Disease 35 Table 7: Recommended assessments and schedule for monitoring organ involvement in adult patients with Fabry Disease 37 Table 8: Products under development by Technology 39 Table 9: Products under development by Designation 40 Table 10: Total Number of Marketed and Emerging Products 41 Table 11: Marketed Products 42 Table 12: Clinical Trial Description: Migalastat 45 Table 13: General Description: Migalastat 48 Table 14: Clinical Trial Description: Replagal 51 Table 15: General Description: Replagal 52 Table 16: Reduction of GL-3 Inclusions to Normal or Near Normal Levels (0 Score) in the Capillary Endothelium of the Kidney, Heart, and Skin 54 Table 17: Clinical Trial Description: Fabrazyme 55 Table 18: General Description: Fabrazyme 56 Table 19: Total Number of Products in Fabry Disease 58 Table 20: Late Stage Products (Phase III) 59 Table 21: Clinical Trial Description: Lucerastat 61 Table 22: General Description: Lucerastat 62 Table 23: Clinical Trial Description: Pegunigalsidase alfa 66 Table 24: General Description: Pegunigalsidase alfa 68 Table 25: Mid Stage Products (Phase II) 69 Table 26: Clinical Trial Description: Venglustat 70 Table 27: General Description: Venglustat 70 Table 28: Early Stage Products (Phase I) 72 Table 29: Clinical Trial Description: Apabetalone 73 Table 30: General Description: Apabetalone 74 Table 31: Clinical Trial Description: Moss-aGal 75 Table 32: General Description: Moss-aGal 76 Table 33: Pre-clinical Stage Products 77 Table 34: General Description: Fabry Gene Therapy 78 Table 35: General Description: FTL190 80 Table 36: General Description: mRNA-3630 81 Table 37: General Description: PGN005 81 Table 38: General Description: ST-920 83 Table 39: Assessment by Stage and Product Type 84 Table 40: Assessment by Route of Administration 85 Table 41: Assessment by Stage and Route of Administration 86 Table 42: Assessment by Molecule Type 87 Table 43: Assessment by Stage and Molecule Type 88 Table 44: Approval Timelines for Clinical Products 89 Table 45: Inactive Products 91 Table 46: General Description: Small Molecule Inhibitor 92

Amicus Therapeutics Evotec Freeline Greenovation Biotech Idorsia Pharmaceuticals Moderna Pharming Protalix Biotherapeutics Resverlogix Corp Sangamo Therapeutics Sanofi Genzyme Shire