1. REPORT INTRODUCTION 1.1 Objective of the Study 8 1.2 Secondary Research 8 1.3 Scope of the report: 8 2. DISEASE OVERVIEW 9 2.1 Introduction 9 2.2 Classification of Niemann-Pick Disease 10 2.2.1 Niemann-Pick disease type A 10 2.2.2 Niemann-Pick disease type B 10 2.2.3 Niemann-Pick disease type C 10 2.3 Classification of NPC 10 2.4 Signs and Symptoms 12 2.5 Causes 14 2.5.1 NPC1 and NPC2 proteins 14 2.6 Pathogenesis 15 2.6.1 Molecular Pathogenesis 15 2.6.2 NPC1 15 2.6.3 NPC2 16 2.7 Pathophysiology 17 2.7.1 Cell Death and Oxidative Damage in NPC 18 2.7.2 Increase in Mitochondrial Cholesterol and Dysfunction in NPC Disease 20 2.7.3 Peroxisomes Alterations in NPC Disease 20 2.7.4 Intracellular Accumulation of Vitamin E in NPC Disease 21 2.7.5 Glycosphingolipid Accumulation in NPC Disease 22 2.7.6 Other Sources of Reactive Species in Oxidative Damage in NPC 23 2.8 Diagnosis 24 2.8.1 Biochemical Testing: 25 2.8.2 Histology: 25 2.8.3 Molecular Genetic Testing: 25 2.8.4 Testing Strategy 27 2.8.5 Biomarkers: 27 2.8.5.1 Oxysterols (cholesterol oxidation products) 27 2.8.5.2 Lyso-sphingolipids 28 2.8.5.3 Bile acids 28 2.8.6 The Filipin test 28 2.8.7 Brain imaging 29 2.8.8 Differential Diagnosis 29 2.8.8.1 Neonatal and infantile presentations 29 2.8.8.2 Childhood presentations 29 2.8.8.3 Adolescent and adult presentations 30 2.9 Diagnosis Algorithm 33 2.10 Treatment 34 2.10.1 Symptomatic therapy 35 2.10.2 Evaluations Following Initial Diagnosis 37 2.10.3 Treatment of Manifestations 37 2.10.4 Prevention of Secondary Complications 37 2.10.5 Surveillance 38 2.10.6 Agents/Circumstances to Avoid 38 2.10.7 Evaluation of Relatives at Risk 38 2.10.8 Therapies Under Investigation 38 2.10.9 Other 39 2.11 Genetic Counselling 39 2.12 Treatment Algorithm 40 3. PIPELINE THERAPEUTICS AT A GLANCE 41 3.1 Products Under Development by Technology 41 4. COMPARATIVE ANALYSIS 42 4.1 Number of Products in NPC 42 5. LATE PHASE PRODUCTS (PHASE III) 43 5.1 Comparative Analysis 43 5.2 Arimoclomol: Orphazyme 43 5.2.1 Product Description 43 5.2.2 Research and Development 44 5.2.2.1 Clinical Studies 44 5.2.2.1.1 Phase II/III 44 5.2.2.1.2 Results of Analysis 44 5.2.2.2 Observational Study 46 5.2.2.3 Results of Analysis 46 5.2.3 Product Development Activities 46 5.2.3.1 Agreement 46 5.2.3.2 Designation 47 5.3 Trappsol Cyclo: CTD Holdings 48 5.3.1 Product Description 48 5.3.2 Research and Development 48 5.3.2.1 Clinical Studies 48 5.3.2.1.1 Phase II/III 48 5.3.2.1.2 Results of Analysis 48 5.3.3 Product Development Activities 50 5.3.3.1 Designation 50 5.3.3.2 Clinical Trial Application Approval 51 5.3.3.3 Compassionate Use 51 5.4 Adrabetadex: Mallinckrodt Pharmaceuticals 52 5.4.1 Product Description 52 5.4.2 Research and Development 53 5.4.2.1 Clinical Studies 53 5.4.2.1.1 Phase IIb/III 53 5.4.2.1.2 Results of Analysis 54 5.4.3 Product Development Activities 54 5.4.3.1 FDA Type A Meeting 54 5.4.3.2 Agreement 54 5.4.3.3 Funding 55 5.4.3.4 Designation 55 5.4.3.5 Patent 56 6. MID PHASE PRODUCTS (PHASE II) 57 6.1 Comparative Analysis 57 6.2 IB1001: IntraBio 57 6.2.1 Product Description 57 6.2.2 Research and Development 57 6.2.2.1 Clinical Studies 57 6.2.2.1.1 Phase II 58 6.2.3 Product Development Activities 58 6.2.3.1 Designation 58 7. PRE-CLINICAL AND DISCOVERY STAGE PRODUCTS 60 7.1 Comparative Analysis 60 7.2 Ursodeoxycholic acid: IntraBio 60 7.2.1 Product Description 60 7.2.2 Research and Development 61 7.2.2.1 Observational Study 61 7.2.3 Product Development Activities 61 7.2.3.1 Designation 61 7.3 PERL101: Perlara 62 7.3.1 Product Description 62 7.3.2 Research and Development 62 7.3.2.1 Preclinical Studies 62 7.3.3 Product Development Activities 62 7.3.3.1 Technology 62 7.3.3.2 Collaboration 62 7.4 Bryostatin-1: Neurotrope BioScience 63 7.4.1 Product Description 63 7.4.1.1 Agreement 64 7.5 Exosomes: Evox Therapeutics 65 7.5.1 Product Description 65 7.5.2 Product Development Activities 65 7.5.2.1 Funding 65 7.5.2.2 Financing 65 7.5.2.3 Technology 65 7.5.2.4 Patent 66 7.6 Gene therapy for NPC: Amicus Therapeutics 67 7.6.1 Product Description 67 7.6.2 Product Development Activities 67 7.6.2.1 Agreement 67 7.7 Cyclodextrins: Okklo Life Sciences 68 7.7.1 Product Description 68 7.7.2 Product Development Activities 68 7.7.2.1 Technology 68 7.7.2.2 Agreement 68 8. THERAPEUTIC ASSESSMENT 70 8.1 Assessment by Stage and Product Type 70 8.2 Assessment by Route of Administration 70 8.3 Assessment by Stage and Route of Administration 71 8.4 Assessment by Molecule Type 72 8.5 Assessment by Stage and Molecule Type 72 9. APPROVAL TIMELINES 74 9.1 Approval Timelines for Clinical Products 74 10. ANALYST INSIGHTS 75

FIG. 1 Oxidative stress as a pathogenic mechanism in Niemann-Pick C disease 19 FIG. 2 Diagnosis Algorithm of Niemann-Pick C disease 33 FIG. 3 Treatment Algorithm, by Disease Type 40 FIG. 4 Total Number of Products in NPC 42 FIG. 5 Late Stage Products (Phase III) 43 FIG. 6 Mid Stage Products (Phase II) 57 FIG. 7 Pre-clinical and Discovery Stage Products 60 FIG. 8 Assessment by Stage and Product Type 70 FIG. 9 Assessment by Route of Administration 70 FIG. 10 Assessment by Stage and Route of Administration 71 FIG. 11 Assessment by Molecule Type 72 FIG. 12 Assessment by Stage and Molecule Type 72 FIG. 13 Approval Timelines for Clinical Products 74Table 1: Clinical signs and symptoms in NP-C, by age of onset 13 Table 2: NPC1 Variants 16 Table 3: NPC2 Pathogenic Variants 17 Table 4: Molecular Genetic Testing Used in Niemann-Pick Disease Type C 27 Table 5: Clinical Severity assessment 31 Table 6: Multidisciplinary assessments of patients with NPC 34 Table 7: Recommended assessments 35 Table 8: Total Number of Products in NPC 42 Table 9: Late Stage Products (Phase III) 43 Table 10: Full Data Set Results of the trial 45 Table 11: Clinical Trial Description: Arimoclomol 46 Table 12: General Description: Arimoclomol 47 Table 13: Clinical Trial Description: Trappsol Cyclo 50 Table 14: General Description: Trappsol Cyclo 52 Table 15: Clinical Trial Description: VTS-270 54 Table 16: Patent Details: VTS-270 56 Table 17: General Description: Adrabetadex 56 Table 18: Mid Stage Products (Phase II) 57 Table 19: Clinical Trial Description: IB1001 58 Table 20: General Description: IB1001 58 Table 21: Pre-clinical and Discovery Stage Products 60 Table 22: General Description: Ursodeoxycholic Acid 61 Table 23: General Description: PERL101 63 Table 24: General Description: Bryostatin-1 64 Table 25: General Description: Exosomes 66 Table 26: General Description: Gene therapy for NPC 67 Table 27: General Description: Cyclodextrins 69 Table 28: Assessment by Stage and Product Type 70 Table 29: Assessment by Route of Administration 71 Table 30: Assessment by Stage and Route of Administration 71 Table 31: Assessment by Molecule Type 72 Table 32: Assessment by Stage and Molecule Type 73 Table 33: Approval Timelines for Clinical Products 74

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