Niemann Pick Type C Disease - Pipeline Analysis 2019

About the Report

About the Report

Niemann Pick Type-C is a rare disorder that mostly affects the children. The genetic mutation leads to accumulation of cholesterol in spleen, liver and lungs followed by several other symptoms such as ataxia, dystonia, vertical supranuclear gaze palsy among others. The lack of medication can worsen the condition of the patient. diagnosis is another factor that contributes to the deterioration of the patient's health. Biomarker assessment is considered as a first line of test for NPC. The biochemical testing demonstrating abnormal intracellular cholesterol homeostasis in cultured fibroblasts is the mainstay of diagnosis and may be supported by ultrastructural changes on skin or rectal biopsy. The molecular genetic testing is also utilized primarily for the confirmation of diagnosis in individuals with variant biochemical findings. The individuals suffering from NPC are monitored regularly for cognitive function. Patients undergo several tests in order to confirm if the subject is suffering from NPC.

A main goal is to develop treatments in order to minimize both general symptoms and neurodegeneration due to the lack of approved therapies. The mainstay of therapy is symptomatic management employing disease modifying agent(s). Miglustat (Zavesca) by Johnson and Johnson (Actelion Pharmaceuticals) is the first and only specific drug approved for this disease in Europe [2009], Canada [2010] and Japan [2012]; its objective is based on alleviating disease symptoms while attenuating neurodegeneration. In the US, the FDA declined to approve this drug in 2010 and called for more data. Currently, there is no therapy approved in US for the treatment of same.

Currently, various companies are working in this area contributing towards a strong pipeline of 10 active products for the treatment of this rare indication. The key players involved in the development of the therapeutics for the treatment of NPC include Orphazyme (Arimoclomol); CTD Holdings (Trappsol Cyclo); Mallinckrodt Pharmaceuticals (Adrabetadex); IntraBio (IB1001; Ursodeoxycholic Acid); Perlara (PERL101); Neurotrope Biosciences (Bryostatin-1); Evox Therapeutics (Exosomes); Okklo LifeSciences (Cyclodextrins); and Amicus Therapeutics (Gene Therapy). Cyclodextrins and small molecules are the major type of molecules that are being used for the development of drugs. Two of three phase III drugs are cyclodextrins or modified cyclodextrin formulations as it reduces lysosomal cholesterol accumulation in liver and other organs. These drugs can be administered orally, intravenously or lumbar intrathecally. These drugs are anticipated to launch in between year 2021 to 2024. Approximately four drugs are presently in preclinical stage of development. Gene therapy is another novel therapy that is being worked upon, though in initial stage of discovery development. The development and launch of these therapies are expected to lead to the better treatment and longer life span of the individuals with Niemann Pick Type C.



Amicus Therapeutics

CTD Holdings

Evox Therapeutics


Mallinckrodt Pharmaceuticals

Neurotrope BioScience

Okklo Life Sciences



Table of Contents

Table of Contents


1.1 Objective of the Study 8

1.2 Secondary Research 8

1.3 Scope of the report: 8


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 Oxysterols (cholesterol oxidation products) 27 Lyso-sphingolipids 28 Bile acids 28

2.8.6 The Filipin test 28

2.8.7 Brain imaging 29

2.8.8 Differential Diagnosis 29 Neonatal and infantile presentations 29 Childhood presentations 29 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


3.1 Products Under Development by Technology 41


4.1 Number of Products in NPC 42


5.1 Comparative Analysis 43

5.2 Arimoclomol: Orphazyme 43

5.2.1 Product Description 43

5.2.2 Research and Development 44 Clinical Studies 44 Phase II/III 44 Results of Analysis 44 Observational Study 46 Results of Analysis 46

5.2.3 Product Development Activities 46 Agreement 46 Designation 47

5.3 Trappsol Cyclo: CTD Holdings 48

5.3.1 Product Description 48

5.3.2 Research and Development 48 Clinical Studies 48 Phase II/III 48 Results of Analysis 48

5.3.3 Product Development Activities 50 Designation 50 Clinical Trial Application Approval 51 Compassionate Use 51

5.4 Adrabetadex: Mallinckrodt Pharmaceuticals 52

5.4.1 Product Description 52

5.4.2 Research and Development 53 Clinical Studies 53 Phase IIb/III 53 Results of Analysis 54

5.4.3 Product Development Activities 54 FDA Type A Meeting 54 Agreement 54 Funding 55 Designation 55 Patent 56


6.1 Comparative Analysis 57

6.2 IB1001: IntraBio 57

6.2.1 Product Description 57

6.2.2 Research and Development 57 Clinical Studies 57 Phase II 58

6.2.3 Product Development Activities 58 Designation 58


7.1 Comparative Analysis 60

7.2 Ursodeoxycholic acid: IntraBio 60

7.2.1 Product Description 60

7.2.2 Research and Development 61 Observational Study 61

7.2.3 Product Development Activities 61 Designation 61

7.3 PERL101: Perlara 62

7.3.1 Product Description 62

7.3.2 Research and Development 62 Preclinical Studies 62

7.3.3 Product Development Activities 62 Technology 62 Collaboration 62

7.4 Bryostatin-1: Neurotrope BioScience 63

7.4.1 Product Description 63 Agreement 64

7.5 Exosomes: Evox Therapeutics 65

7.5.1 Product Description 65

7.5.2 Product Development Activities 65 Funding 65 Financing 65 Technology 65 Patent 66

7.6 Gene therapy for NPC: Amicus Therapeutics 67

7.6.1 Product Description 67

7.6.2 Product Development Activities 67 Agreement 67

7.7 Cyclodextrins: Okklo Life Sciences 68

7.7.1 Product Description 68

7.7.2 Product Development Activities 68 Technology 68 Agreement 68


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


9.1 Approval Timelines for Clinical Products 74


List of Figure

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 74

List of Table

Table 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

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