1. REPORT INTRODUCTION 1.1 Objective of the Study 9 1.2 Secondary Research 9 1.3 Scope of the report: 9 2. DISEASE OVERVIEW 10 2.1 Introduction 10 2.2 Classification of Niemann-Pick Disease 11 2.2.1 Niemann-Pick disease type A 11 2.2.2 Niemann-Pick disease type B 11 2.2.3 Niemann-Pick disease type C 11 2.3 Classification of NPC 11 2.4 Signs and Symptoms 13 2.5 Causes 15 2.5.1 NPC1 and NPC2 proteins 15 2.6 Pathogenesis 16 2.6.1 Molecular Pathogenesis 16 2.6.2 NPC1 16 2.6.3 NPC2 17 2.7 Pathophysiology 18 2.7.1 Cell Death and Oxidative Damage in NPC 19 2.7.2 Increase in Mitochondrial Cholesterol and Dysfunction in NPC Disease 21 2.7.3 Peroxisomes Alterations in NPC Disease 21 2.7.4 Intracellular Accumulation of Vitamin E in NPC Disease 22 2.7.5 Glycosphingolipid Accumulation in NPC Disease 23 2.7.6 Other Sources of Reactive Species in Oxidative Damage in NPC 24 2.8 Diagnosis 25 2.8.1 Biochemical Testing: 26 2.8.2 Molecular Genetic Testing: 26 2.8.3 Testing Strategy 28 2.8.4 Biomarkers 28 2.8.4.1 Oxysterols (cholesterol oxidation products) 29 2.8.4.2 Lyso-sphingolipids 29 2.8.4.3 Bile acids 29 2.8.5 The Filipin test 29 2.8.6 Brain imaging 30 2.8.7 Differential Diagnosis 30 2.8.7.1 Neonatal and infantile presentations 30 2.8.7.2 Childhood presentations 30 2.8.7.3 Adolescent and adult presentations 31 2.9 Diagnosis Algorithm 34 2.10 Treatment 35 2.10.1 Symptomatic therapy 36 2.10.2 Evaluations Following Initial Diagnosis 38 2.10.3 Treatment of Manifestations 38 2.10.4 Prevention of Secondary Complications 38 2.10.5 Surveillance 39 2.10.6 Agents/Circumstances to Avoid 39 2.10.7 Evaluation of Relatives at Risk 39 2.10.8 Therapies Under Investigation 39 2.10.9 Other 40 2.11 Genetic Counselling 40 2.12 Treatment Algorithm 41 3. PRODUCTS AND COMPANY CONSIDERED 42 3.1 Products Under Development by Technology 42 3.2 Company Considered in the Study 42 4. PRODUCTS UNDER DEVELOPMENT BY DESIGNATION 43 4.1 Products Under Development by Designation 43 5. MARKETED AND EMERGING PRODUCTS 44 5.1 Number of Marketed and Emerging Products 44 5.2 Marketed Product 44 5.2.1 Zavesca: Johnson & Johnson 44 5.2.1.1 Product Description 44 5.2.1 Regulatory Milestones 46 5.2.1.1 Approval 46 5.2.2 Research and Development 46 5.2.2.1 Clinical Studies 46 5.2.2.1.1 Phase II 46 5.2.2.1.2 Results of Analysis 46 5.2.3 Product Development Activities 48 5.2.3.1 Acquisition 48 5.2.3.2 Designation 48 6. PIPELINE THERAPEUTICS AT A GLANCE 49 6.1 Pipeline Therapeutics at a Glance 49 7. COMPARATIVE ANALYSIS 50 7.1 Number of Products in NPC 50 8. LATE PHASE PRODUCTS (PHASE III) 51 8.1 Comparative Analysis 51 8.2 Arimoclomol: Orphazyme 51 8.2.1 Product Description 51 8.2.2 Research and Development 52 8.2.2.1 Clinical Studies 52 8.2.2.1.1 Phase II/III 52 8.2.2.1.2 Results of Analysis 52 8.2.2.2 Observational Study 54 8.2.2.2.1 Results of Analysis 54 8.2.3 Product Development Activities 54 8.2.3.1 Agreement 54 8.2.3.2 Designation 55 8.3 Trappsol Cyclo: CTD Holdings 56 8.3.1 Product Description 56 8.3.2 Research and Development 56 8.3.2.1 Clinical Studies 56 8.3.2.1.1 Phase II/III 56 8.3.2.1.2 Results of Analysis 56 8.3.3 Product Development Activities 58 8.3.3.1 Designation 58 8.3.3.2 Clinical Trial Application Approval 59 8.3.3.3 Compassionate Use 59 8.4 Adrabetadex: Mallinckrodt Pharmaceuticals 60 8.4.1 Product Description 60 8.4.2 Research and Development 61 8.4.2.1 Clinical Studies 61 8.4.2.1.1 Phase IIb/III 61 8.4.2.1.2 Results of Analysis 62 8.4.3 Product Development Activities 62 8.4.3.1 FDA Type A Meeting 62 8.4.3.2 Agreement 62 8.4.3.3 Funding 63 8.4.3.4 Designation 63 8.4.3.5 Patent 64 9. MID PHASE PRODUCTS (PHASE II) 65 9.1 Comparative Analysis 65 9.2 IB1001: IntraBio 65 9.2.1 Product Description 65 9.2.2 Research and Development 65 9.2.2.1 Clinical Studies 65 9.2.2.1.1 Phase II 66 9.2.3 Product Development Activities 66 9.2.3.1 Designation 66 10. PRE-CLINICAL AND DISCOVERY STAGE PRODUCTS 68 10.1 Comparative Analysis 68 10.2 Ursodeoxycholic acid: IntraBio 68 10.2.1 Product Description 68 10.2.2 Research and Development 69 10.2.2.1 Observational Study 69 10.2.3 Product Development Activities 69 10.2.3.1 Designation 69 10.3 PERL101: Perlara 70 10.3.1 Product Description 70 10.3.2 Research and Development 70 10.3.2.1 Preclinical Studies 70 10.3.3 Product Development Activities 70 10.3.3.1 Technology 70 10.3.3.2 Collaboration 70 10.4 Bryostatin-1: Neurotrope BioScience 71 10.4.1 Product Description 71 10.4.1.1 Agreement 72 10.5 Exosomes: Evox Therapeutics 73 10.5.1 Product Description 73 10.5.2 Product Development Activities 73 10.5.2.1 Funding 73 10.5.2.2 Financing 73 10.5.2.3 Technology 73 10.5.2.4 Patent 74 10.6 Gene therapy for NPC: Amicus Therapeutics 75 10.6.1 Product Description 75 10.6.2 Product Development Activities 75 10.6.2.1 Agreement 75 10.7 Cyclodextrins: Okklo Life Sciences 76 10.7.1 Product Description 76 10.7.2 Product Development Activities 76 10.7.2.1 Technology 76 10.7.2.2 Agreement 76 11. THERAPEUTIC ASSESSMENT 78 11.1 Assessment by Stage and Product Type 78 11.2 Assessment by Route of Administration 78 11.3 Assessment by Stage and Route of Administration 79 11.4 Assessment by Molecule Type 80 11.5 Assessment by Stage and Molecule Type 80 12. APPROVAL TIMELINES 82 12.1 Approval Timelines for Clinical Products 82 13. ANALYST INSIGHTS 83

Figure 1: Oxidative stress as a pathogenic mechanism in Niemann-Pick C disease 20 Figure 1: Diagnosis Algorithm of Niemann-Pick C disease 34 Figure 1: Treatment Algorithm, by Disease Type 41 Figure 2: Products Under Development by Technology 42 Figure 3: Company Consolidations 42 Figure 4: Products Under Development by Designation 43 Figure 5: Total Number of Marketed and Emerging Products 44 Figure 6: Total Number of Products in NPC 50 Figure 7: Late Stage Products (Phase III) 51 Figure 8: Mid Stage Products (Phase II) 65 Figure 9: Pre-clinical and Discovery Stage Products 68 Figure 10: Assessment by Stage and Product Type 79 Figure 11: Assessment by Route of Administration 79 Figure 12: Assessment by Stage and Route of Administration 80 Figure 13: Assessment by Molecule Type 81 Figure 14: Assessment by Stage and Molecule Type 81 Figure 15: Approval Timelines for Clinical Products 83Table 1: Clinical signs and symptoms in NP-C, by age of onset 14 Table 2: NPC1 Variants 17 Table 3: NPC2 Pathogenic Variants 18 Table 4: Molecular Genetic Testing Used in Niemann-Pick Disease Type C 28 Table 5: Clinical Severity Assessment 32 Table 6: Multidisciplinary assessments of patients with NPC 35 Table 7: Recommended assessments 36 Table 8: Total Number of Marketed and Emerging Products 44 Table 9: Dosing in Patients Under 12 Years 45 Table 10: Clinical Trial Description: Miglustat 48 Table 11: General Description: Miglustat 48 Table 12: Total Number of Products in NPC 50 Table 13: Late Stage Products (Phase III) 51 Table 14: Full Data Set Results of the trial 53 Table 15: Clinical Trial Description: Arimoclomol 54 Table 16: General Description: Arimoclomol 55 Table 17: Clinical Trial Description: Trappsol Cyclo 58 Table 18: General Description: Trappsol Cyclo 60 Table 19: Clinical Trial Description: VTS-270 62 Table 20: Patent Details: VTS-270 64 Table 21: General Description: Adrabetadex 64 Table 22: Mid Stage Products (Phase II) 65 Table 23: Clinical Trial Description: IB1001 66 Table 24: General Description: IB1001 66 Table 25: Pre-clinical and Discovery Stage Products 68 Table 26: General Description: Ursodeoxycholic Acid 69 Table 27: General Description: PERL101 71 Table 28: General Description: Bryostatin-1 72 Table 29: General Description: Exosomes 75 Table 30: General Description: Gene therapy for NPC 76 Table 31: General Description: Cyclodextrins 78 Table 32: Assessment by Stage and Product Type 79 Table 33: Assessment by Route of Administration 80 Table 34: Assessment by Stage and Route of Administration 80 Table 35: Assessment by Molecule Type 81 Table 36: Assessment by Stage and Molecule Type 82 Table 37: Approval Timelines for Clinical Products 83 1.

Amicus Therapeutics CTD Holdings Evox Therapeutics IntraBio Johnson & Johnson Mallinckrodt Pharmaceuticals Neurotrope BioScience Okklo Life Sciences Orphazyme Perlara