Phase 1/2a Study of 2-Hydroxypropyl-Beta-Cyclodextrin Therapy for Infantile Liver Disease Associated With Niemann-Pick Disease, Type C
Phase: PHASE1
Conditions: Niemann-Pick Disease, Type C
Sponsor: Washington University School of Medicine

 
 
 
Phase 1/2a study of 2-Hydroxypropyl-β-Cyclodextrin Therapy for Infantile Liver Disease Associated 
with Niemann-Pick Disease, type C 
 
 
NCT03471143 
 
11-13-2024 
 
 
 

 
 
 
Phase 1/2a study of 2-Hydroxypropyl-β-Cyclodextrin Therapy for Infantile Liver Disease Associated 
with Niemann-Pick Disease, type C 
 
 
 
Principal Investigators: 
 
 
 
 
 
Barbara Warner, MD 
 
 
 
 
F. Sessions Cole, MD Professor of Newborn Medicine 
 
 
 
 
Director, Division of Newborn Medicine 
 
 
 
 
Professor of Pediatrics 
 
 
 
 
Washington University School of Medicine 
 
 
Patricia Dickson, MD 
Professor of Pediatrics 
Chief, Division of Genetics and Genomic Medicine 
Washington University in St. Louis 
 
 
 
 
 
 
Associate Investigators: 
Forbes D. Porter, MD, PhD 
 
 
 
 
Senior Investigator and Associate Scientific Director  
 
 
 
 
for Translational Research 
 
 
 
 
NICHD, NIH 
 
 
 
 
 
Xuntian Jiang, PhD 
Assistant Professor of Medicine  
Associate Director, Washington University Metabolomics Facility 
Washington University in St Louis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sakil Kulkarni, MD 
 
 
 
 
Assistant Professor of Pediatrics 
 
 
 
 
Division of Pediatric Gastroenterology 
 
 
 
 
Department of Pediatrics 
 
 
 
 
Washington University School of Medicine 
 
 
 
 
 
Marwan Shinawi, MD 
 
 
 
 
Professor of Pediatrics 
 
 
 
 
Division of Genetics and Genomics 
Department of Pediatrics 
 
 
 
 
Washington University School of Medicine 
 
 
 
 
 
Margaret Reynolds, MD 
 
 
 
 
Assistant Professor of Ophthalmology and Visual Sciences 
 
 
 
 
Division of Pediatrics 
 
 
 
 
Washington University School of Medicine 
 
 
 
 
 
 
 
Study type (check all that apply): 
      X       Archived biological specimens/medical information 

 
 
 
                Natural history; definition of phenotype, genotype/phenotype correlation 
                Prospective linkage/gene identification, NOT providing information to participants 
                Prospective linkage/gene identification, providing information to participants  
                Social science; assessments of knowledge, attitudes and behavior 
      X       Drugs or devices 
                Gene transfer 
                Other interventions 
 
  
Estimated Duration of study: Four Years 
 
Subjects:   12 subjects, 0-1 years of age  
 
Ionizing radiation:  Medically indicated  
 
Research participants to be seen at: 
                 NIH only*  
        X      Off-site only 
                 Both NIH* and off-site 
*Includes participants who physically come to the NIH Clinical Center and/or for whom specimens/data 
are analyzed by Clinical Center departments. If participants will be seen at NIH, a Medical Advisory 
Investigator must be indicated on the 1195 form, unless this is a social science project with no clinical 
interventions. 
 
 
 
Collaborative Project:   
 
 
National Institutes of Health  
FWA00005897 
 
 
 
 
 
Washington University 
 
FWA00002284 
 
 
 
 
Identifying words: 
 
 
 
 
 
 
 
 
 
Niemann-Pick Disease, type C1, Neurodegenerative, Lysosomal Storage  
 
 
2-hydroxypropyl-β-cyclodextrin, Phase 1/2a 
 
IND Sponsor:  
Patricia I. Dickson, MD 
 
Protocol version:   11-13-24, Amendment 10 
 
 
 

 
 
 
Table of Contents 
 
1.  
 
Précis 
 
2.  
 
Introduction 
2.1  
 
Niemann-Pick Disease, type C1 
2.2  
 
Liver disease in Niemann-Pick Disease, type C1 
2.3  
 
Investigational Product Description 
2.3.1   
Non-clinical Toxicology Studies   
2.3.1.1  
Acute Toxicity Studies 
2.3.1.2  
Repeat-Dose Toxicity Studies 
2.3.1.3  
Reproductive and Developmental Toxicity Studies 
2.3.1.4  
Genotoxicity and Mutagenicity 
2.3.2   
Previous Human Experience with Intravenous HPBCD 
2.3.3  
Previous Human Experience with Intrathecal HPBCD 
2.4  
 
Study Rationale 
2.5  
 
Route of Administration and Dose Selection Rationale  
        
3.  
 
Study Objectives 
 
4.  
 
Specific Aims 
 
5.  
 
Study Design and Methods 
5.1  
 
Study Overview 
5.2  
 
Subjects 
5.3  
 
Study Size, Duration and Location 
5.4  
 
Eligibility Criteria 
5.4.1   
Inclusion Criteria 
5.4.2   
Exclusion Criteria 
5.5  
 
Prior and Concomitant Medications 
5.6  
 
Dosing and Dose Adjustments 
5.7  
 
Biological Specimens 
5.8  
 
Non-study Drugs 
5.9  
 
Study Drug 
5.10   
Withdrawal of Patients from the Study 
 
6.  
 
Assessments, Procedures, and Testing 
6.1  
 
Medical History and Physical/Neurological Examinations 
6.2  
 
Pulmonary Function Assessment 
6.3.  
 
Liver Function Assessment 
6.4  
 
Abdominal Ultrasound   
6.5  
 
Audiological Evaluation 
6.6  
 
Clinical Laboratory Tests 
6.6.1   
Hematology/Chemistry 
6.6.2   
Urinalysis 
6.7  
 
Research Laboratory Testing 
6.8  
 
Future Research and Other Testing 
6.9  
 
Collaborating Laboratories and Entities 
7.  
 
Human Subjects Protections 
7.1  
 
Institutional Review Board 
7.2  
 
Ethical Conduct of the Study 
7.3  
 
Patient Information and Informed Consent 
7.4  
 
Subject Selection 

 
 
 
7.5  
 
Gender and Ethnic/Racial Background 
7.6  
 
Research Involving Children 
7.7  
 
Subject Withdrawal 
7.8  
 
Adverse Event Assessments 
7.9  
 
Discontinuation or Temporary Suspension of the Study 
7.10   
Potential Benefits and Financial Compensation 
7.11   
Conflicts of Interest 
 
8  
 
Potential Risks and Discomforts 
8.1  
 
Medical Evaluations 
8.2.  
 
Risk of Intravenous Adrabetadex 
8.3  
 
Phlebotomy 
8.4  
 
Audiological Evaluation 
8.5  
 
Sedation 
8.6  
 
Chest X-ray 
8.7  
 
Liver/Spleen Ultrasound 
8.8  
 
Peripherally Inserted Venous Catheter (PICC) and Risks 
 
9.  
 
Study Procedures and Schedule 
9.1  
 
Overview of Study 
9.2  
 
Subject Screening 
9.3  
 
Outline of Protocol Admissions and Testing     
9.4  
 
Baseline Admissions 
9.5  
 
First Two IV Drug Administrations 
9.6  
 
Doses 3-12 
9.7  
 
Final Evaluation 
9.8  
 
Phase 1: Post-dose Safety Evaluation 
9.9  
 
Phase 2: Open-Label extension (Doses 13-18) 
9.10 
 
Phase 2: Post-dose Safety Evaluation 
9.11 
 
Adrabetadex dose 
 
10.  
 
Statistical Analysis Plan 
 
11.  
 
Adverse Events, Protocol Deviations, and Data Safety Monitoring 
11.1   
Definitions 
11.2   
Adverse Event Classification 
11.3   
Severity of an Adverse Event 
11.4   
Monitoring of Adverse Event Data 
11.4.1   
Review of Safety and Tolerability 
11.4.2   
Review of Respiratory Compromise 
11.4.3   
Review of High Frequency Hearing Loss 
11.5   
Data Safety Monitoring Board 
11.6   
Documentation of Adverse Events 
11.7   
Notification about Serious Adverse Events and Serious Unexpected Adverse Reactions 
11.7.1   
Investigator Reporting 
11.7.2   
Adverse Events Exempt from IRB Reporting 
11.8   
Protocol Deviations 
 
12.  
 
Investigational Product 
12.1   
Identify of the Investigational Product 
12.2   
Storage of the Investigational Product 
12.3   
Investigational Product Accountability 
 

 
 
 
13.  
 
Study Administration 
13.1   
Data Handling and Recordkeeping 
13.1.1   
Electronic Data 
13.1.2   
Case Report Form Completion 
13.1.3   
Retention of Study Records 
13.2   
Confidentiality 
13.3   
Publication Policy 
13.4   
Direct Access to Source Data 
13.5   
Protocol Amendments 
 
14.  
 
References 
 

 
 
 
 
Abbreviations 
Abbreviations 
Description of Abbreviations 
24-OHC 
24-(S) hydroxycholesterol 
27-OHC 
27-hydroxycholesterol 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
activated Partial Thromboplastin Time 
AST 
Aspartate aminotransferase 
AUA 
American Urological Association 
AUC 
Area under the curve 
AUC0-t 
Area under the plasma or CSF concentration-time curve from zero (0) hours to 
time (t) 
Caregiver-CGIC 
Caregiver-Clinical Global Impression of Change 
CFR 
Code of Federal Regulations 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration equation  
Clinician-CGIC 
Clinician-Clinical Global Impression of Change 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
CSF 
Cerebrospinal fluid 
CSS 
Clinical Severity Score 
CT 
Cholestane-3β,5α,6β-triol 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid 
DPOAE 
Distortion Product Otoacoustic Emission(s) 
DSC 
Dose Selection Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GCA 
Glycine-conjugated trihydroxycholanic acid or Glycine Conjugated Acids 
GLP 
Good Laboratory Practice 
GRAS 
Generally regarded as safe 
HPBCD 
2-hydroxypropyl-β-cyclodextrin 
hsCRP 
C-Reactive Protein High Sensitivity 
IC 
Intracisternal 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICV 
Intracerebroventricularly 
IEC 
Independent Ethics Committee 
iIND 
Investigator Sponsored Investigational New Drug Application 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IT 
Intrathecal 
IUD 
Intrauterine device 
IV 
Intravenous 

 
 
 
Abbreviations 
Description of Abbreviations 
LE/LY 
Late endosomal/lysosomal 
LGAL3 
Galectin 3 
Lipid-509 
LysoSM-509 
LP 
Lumbar puncture 
LSOs 
Lysosomal storage organelles 
mITT 
Modified intent-to-treat 
NCI 
National Cancer Institute 
NfL 
Neurofilament light chain 
NICHD 
National Institute of Child Health and Human Development 
NIH 
National Institutes of Health 
NOAEL 
No observable adverse effect level 
NPC 
Niemann-Pick disease, type C 
NPC/Npc1 and NPC2 
Genes that, when mutated, cause NPC phenotypes 
NPC1 
Niemann-Pick disease, type C1 phenotype 
NPC1 
Niemann-Pick disease, type C1 cat phenotype 
Npc1 or Npc1-/- 
Niemann-Pick disease, type C1 mouse phenotype 
OAE 
Otoacoustic emissions 
PPCS 
N-palmitoyl-O-phosphocholineserine 
PT 
Prothrombin time 
PTA 
Pure Tone Audiometry 
QoL 
Quality of life 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SCr 
Serum creatinine 
SD 
Standard deviation 
SE 
Standard error 
SOP 
Standard operating procedure 
SPL 
Sound pressure level 
SUSAR 
Serious and unexpected suspected adverse reaction 
TUG 
Timed up and go 
ULN 
Upper Limit of Normal 
US 
United States 
Vd,ss 
Volume of distribution at steady-state 
VSNGP 
Vertical supranuclear gaze palsy 
 
 

 
 
 
1. Précis 
Niemann-Pick disease type C (NPC) is a lethal, autosomal recessive, lysosomal storage disorder characterized 
by neurodegeneration in early childhood and death in adolescence. NPC results from mutation of either the 
NPC1 (~95% of cases) or NPC2 genes. Biochemically, NPC is characterized by the endolysosomal storage of 
unesterified cholesterol and lipids in both the central nervous system and peripheral tissues such as the liver. 
Individuals with NPC demonstrate progressive cerebellar ataxia and dementia. Acute cholestatic liver disease is 
frequently observed in the neonatal/infantile period but subsequently resolves. However, chronic, sub-clinical 
liver disease persists. Intrathecal 2-hydroxypropyl-β-cyclodextrin (HPBCD), also known as adrabetadex () has 
proven effective in reducing signs and prolonging life in NPC1 animal models, and Phase 1/2a data support 
efficacy in NPC1 patients. Adrabetadex has also been shown to be effective in treating liver disease in the NPC1 
cat. 
 
This Phase 1/2a, open-label, multiple ascending dose, multi-center trial will evaluate whether Adrabetadex 
administered intravenously is effective in treating acute liver disease in NPC infants. The objective of this study 
is to determine the safety, tolerability and efficacy of intravenous adrabetadex in NPC disease. The primary 
endpoint is the efficacy of adrabetadex to reduce plasma levels of glycine-conjugated trihydroxycholanic acid 
(“bile acid biomarker”), an NPC-specific pharmacodynamic biomarker. Secondary endpoints are assessment of 
the dose-response relationship for attenuation of liver dysfunction, as determined by reduction in serum 
transaminases (ALT and AST) and liver size. Exploratory lipid, protein, and inflammatory biomarkers will also be 
examined. This study will enroll up to 12 subjects (6 subjects per dose level) and evaluate two dose levels (500 
and 1000 mg/kg). In the first phase of the study, drug will be administered twice a week for six weeks for a total 
of 12 administrations. Subjects who demonstrate either a significant reduction in the glycine-conjugated 
trihydroxycholanic acid biomarker or serum bilirubin (direct bilirubin or direct bilirubin:total bilirubin ratio) will be 
allowed to crossover into a second open-label phase. In this phase of the study, drug will be administered 
monthly for six months for a total of six administrations. Serum transaminases (ALT and AST) and an abdominal 
ultrasound will be obtained at the end of the 6-month open-label extension phase. Efficacy will be assessed by 
reduction in serum transaminases and reduction in  spleen volumes. NPC biomarkers [(cholestane-3β,5α,6β-
triol (CT), glycine-conjugated trihydroxycholanic acid (GCA),phosphocholinerase (PPCS)/lysoSM-509 (Lipid-
509), 24(S)-hydroxycholesterol (24-OHC), 27-hydroxycholesterol (27-OHC), and neurofilament light chain (nfL)] 
will also be obtained at these time points and will be considered exploratory outcome measures. 
 
 
 

 
 
 
2. Introduction 
 
2.1 Niemann-Pick Disease, type C1  
Niemann-Pick disease, type C (NPC) is a recessive lysosomal storage disorder characterized by impaired 
intracellular trafficking and subsequent endolysosomal accumulation of unesterified cholesterol and other lipids 
in the central nervous system and visceral organs (1). NPC results from mutation of either the NPC1 or NPC2 
genes, with the vast majority (~95%) of cases due to impaired NPC1 function. Incidence of classical NPC has 
been estimated to be on the order of 1/89,000-104,000 with potential of a late-onset variant of NPC1 with 
incidence on the order of 1/36,000 (1, 2). The NPC1 phenotype is heterogeneous with respect to both age of 
onset and symptom complex. Visceral disease including hepatosplenomegaly and cholestatic jaundice of 
variable severity can be present in early childhood and is followed by progressive neurological disability (3, 4).  
Common neurological signs and symptoms include vertical supranuclear gaze palsy, cerebellar ataxia, gelastic 
cataplexy, seizures and cognitive impairment. An adult-onset variant with prominent psychiatric symptoms has 
recently been characterized (5).  Diagnosis of NPC1 is frequently delayed, but the recent development of a 
serum-based diagnostic test will facilitate earlier diagnosis (6-8). There are no FDA approved therapies for 
NPC1, although miglustat (Zavesca®) has been approved for use in the European Union and multiple other 
countries (9-12) based on a controlled trial and long-term extension studies.    
 
2.2 Liver Disease in Niemann-Pick Disease, type C1 
In infantile and juvenile forms of the disease, patients frequently present with cholestasis or hepatosplenomegaly. 
NPC has been reported to be the second most common genetic metabolic disorder with neonatal liver disease 
(13), and was diagnosed in up to 8% of neonates presenting with intrahepatic cholestasis in one case series 
(14). In the majority of cases the liver disease becomes subacute, although in other cases the liver disease can 
progress to liver failure. In the majority of cases, liver inflammation and dysfunction persists, as evidenced by 
chronic elevations in serum transaminases and abnormal prothrombin (PT) and activated partial thromboplastin 
(PTT) times. Approximately two-thirds of NPC1 subjects enrolled in the NIH Natural History study (06-CH-0186) 
have had elevated serum transaminases. Liver disease in NPC can result in a lethal degree of hepatic fibrosis 
and the chronic disease predisposes to hepatocellular carcinoma (15-18). Although interim analysis of the Phase 
1/2a trial data indicates that IT therapy has an impact in slowing neurological disease progression, direct CNS 
delivery, appears unlikely to have an effect on peripheral disease, based on liver chemistries. In the NPC1 cat 
model subcutaneous administration of HPBCD 1000 mg/kg biweekly (11 treatments over 21 weeks) reduced 
serum ALT from ~6-fold elevated to 2-fold elevated (19). This was accompanied by correction of the severe 
vacuolization of hepatocyte and Kupffer cell cytoplasm observed in untreated cats. In human NPC patients dosed 
under an individual IND, IV administration of HPBCD (2500 mg/kg biweekly) reduced by ~2-3-fold plasma 
concentrations of cholestane-3β,5α,6β-triol (20) and its metabolite, trihydroxycholanic acid glycine conjugate 
(21). Both cholesterol-derived metabolites are NPC disease-specific biomarkers that monitors oxidizable free 
cholesterol in liver tissue (7). A recently discovered NPC plasma biomarker, lipid-509 (22), has been evaluated 
in treatment settings. 
Taken together, the preclinical and human data suggest that IV HPBCD may be effective in reducing liver 
inflammation and injury and may prevent the long-term sequelae, such as cirrhosis and risk of hepatocellular 
carcinoma. 
 
2.3 Investigational Product Description 
2-hydroxypropyl-β-cyclodextrin (HPBCD) is a cyclic polysaccharide that can be used to solubilize hydrophobic 
compounds such as cholesterol. The potential therapeutic efficacy of HPBCD was first investigated by Camargo 
et al (23) utilizing a NPC1 mouse model (24, 25), but only slight neurological efficacy was observed. Subsequent 
studies by Liu et al (26, 27) and Davidson et al (28) demonstrated delayed progression of neurological signs and 
death in Npc1 mutant mice. Therapeutic efficacy has also been demonstrated in the feline NPC1 model (19). 
Only 0.3% of HPBCD crosses the blood-brain-barrier (29), thus necessitating the use of extremely high 
peripheral doses or direct intrathecal infusion to treat the neurologic signs and symptoms of the disease. A Phase 
1/2a trial of intrathecal HPBCD conducted at the NIH Clinical Center and 18-month data suggest significant 

 
 
 
stabilization of neurological disease progression Based on these data, a multicenter, multinational Phase 2b/3 
trial of intrathecal HPBCD was initiated in the fall of 2015. With the development of a potentially effective therapy 
for the neurological aspects of NPC1, consideration needs to be given to the treatment of visceral issues.    
 
HPBCD, a generally regarded as safe (GRAS) substance, is a membrane-impermeant cyclic oligosaccharide 
with a distinctive truncated cone configuration containing 7 cyclo-α-(1,4)-anhydroglucose units with 
hydroxypropyl groups randomly substituted onto the C2, C3 and C5 positions of the substituent glucoses (Fig. 
1). All HPBCD are amorphous mixtures of different isomers, characterized by the degree of substitution, which 
represents the average of substitution of the hydroxyl with propyl groups per HPBCD molecule. The active drug 
substance in adrabetadex is KLEPTOSE® HPB parenteral grade, which has an average degree of substitution 
of 4.34 or on a molar basis 0.63 ± 0.01.  
 
Cyclodextrins, as well as HPBCDs in general, are used extensively to solubilize pharmaceuticals and various 
regulatory authorities have approved them as excipients. The therapeutic potential of 2-hydroxypropyl-β-
cyclodextrin (HPBCD) was discovered when HPBCD, injected systemically to Npc1-/- mice beginning at either 
postnatal day 7 or 21 and continuing every other day, delayed onset of clinical symptoms, reduced intraneuronal 
cholesterol and glycosphingolipid storage, reduced markers of neurodegeneration, and increased animal 
survival (27, 28). HPBCD enters cells by the endocytic pathway and is delivered to the endolysosomal storage 
organelles where unesterified cholesterol accumulates in NPC deficiency. 
HPBCD replaces the function of NPC1 protein and promotes transport of 
the accumulated unesterified cholesterol to the endoplasmic reticulum for 
esterification by acetyl CoA cholesterol:acyl transferase and subsequent 
efflux (30, 31). While the precise mechanism of HPBCD action to bypass 
or replace NPC1 function is not yet defined, HPBCD normalizes 
intracellular cholesterol trafficking by binding the hydrophobic moieties of 
cholesterol and other lipids. 
 
2.3.1 Non-clinical Toxicology Studies   
The pharmacological properties of HPBCD have been extensively 
studied in Npc1-/- mice and NPC1 cats. The pharmacokinetic properties 
have been studied in rats, dogs, and the Npc1-/- mice and NPC1 cats. The safety of HPBCD was evaluated in a 
comprehensive toxicology program conducted by Janssen Research Foundation (Janssen) to support its use as 
a pharmaceutical excipient. Preclinical toxicology studies included single and repeat-dose toxicity studies, in 
vitro and in vivo genotoxicity assays, carcinogenicity studies, reproductive and developmental toxicity (Segment 
I, II and III) studies and special toxicity (local tolerance and mechanistic toxicity) studies. HPBCDhas been 
approved for use as an excipient in oral and intravenous (IV) pharmaceuticals for over a decade. The Sponsor 
has obtained the rights to reference the Roquette Freres Type IV Drug Master File No. 9420 for HPBCD, the 
drug substance.  
 
2.3.1.1 Acute Toxicity Studies 
After a single IV dose of HPBCD mortality occurred in mice at a dose ≥ 10,000 mg/kg body weight. The most 
common clinical abnormality at all dose levels (5,000-20,000 mg/kg body weight) in mice was viscous urine. At 
lethal doses, typical signs of toxicity included soft feces, sedation, piloerection, clonic convulsions, dyspnea, 
hypothermia, loss of righting reflex, palpebral ptosis, and tremors. IV doses of 2,000 and 4,000 mg/kg body 
weight were not lethal in rats but did result in hyperemia. Rats in the 4,000 mg/kg body weight group also were 
observed with viscous urine, hypotonia, ataxia, and swelling of the ears, nose, and paws. Dogs survived single 
IV doses of 5,000 mg/kg body weight HPBCD. No clinical abnormalities were noted in the females, but coughing, 
diarrhea/soft feces, and emesis were observed in the males.  
 
 
2.3.1.2 Repeat Dose Toxicity Studies 
p=0.002 
 
Figure 1. ADRABETADEX, HPBCD 

 
 
 
Repeat dose studies utilizing IV administration were performed in rats and dogs. Urinary tract changes were 
present after IV administration and included swollen and granular tubular cells in the kidney, swollen epithelial 
cells in the urinary bladder and renal pelvis, and vacuolated cortical tubules in the kidney. The no-observed-
adverse-effect-levels (NOAELs) in the 3-month IV studies were 50 mg/kg body weight in the rat and 100 mg/kg 
body weight in the dog. In rats, higher doses (100 and 400 mg/kg body weight) led to reduced body weight gain. 
Hematological changes and altered serum chemistry were seen at the highest dose (400 mg/kg body weight). 
Urinary parameters were slightly modified and included increases in white blood cells, cylindrical epithelial cells, 
occult blood, and granular casts and decreases in specific gravity and creatinine associated with larger urine 
volume. Adrenal gland, spleen, and kidney weights were increased. Kidneys were pale at necropsy. Histological 
changes in the liver and lung included increased presence of Kupffer cells in the liver and foamy cells and white 
stipples in the lung. Following the 1, 2, or 3 months of recovery, most of these changes reverted to normal. After 
3 months of recovery, the only remaining abnormalities were slightly elevated liver transaminases (400 mg/kg 
body weight), pale kidney (100 and 400 mg/kg body weight), swollen epithelial cells in the urinary bladder and 
pelvic epithelium (all doses levels). The corticotubular changes resolved completely (25 mg/kg body weight), 
almost completely (50 mg/kg body weight), or were partially reversible (100 and 400 mg/kg body weight). In 
dogs, IV administration of 400 mg/kg body weight, HPBCD led to transient soft feces and slightly elevated alanine 
aminotransferase (ALT) and bilirubin or haptoglobin. Macroscopic and microscopic (foamy cells) lung changes 
were seen as well. All of these changes resolved after 1 month of recovery. At the end of the 3-month recovery, 
swollen epithelial cells were still present in the urinary bladder and renal pelvis but vacuolated cortical tubules 
(with swollen lysosomes) were no longer present. Repeat-dose studies extracted from the literature also support 
these findings (32). 
 
2.3.1.3 Reproductive and Developmental Toxicity Studies 
Reproductive function (fertility) was not adversely affected by IV administration of HPBCD in rats. Maternal and 
paternal toxicity was limited to a slight reduction in body weight. No primary embryo toxicity was noted following 
IV administration in rats or rabbits. Associated with maternal toxicity, decreased survival and reduced birth weight 
and body weight evolution of the rat pups were noted at 400 mg/kg/day.. In a 2nd un-dosed generation, all 
variables were normal. No developmental toxicity was noted in any study.  
 
2.3.1.4 Genotoxicity and Mutagenicity 
The genotoxic potential of HPBCD was investigated in Ames tests (S. typhimurium and E. coli), a mammalian 
cell assay, chromosome aberration test, micronucleus tests, and deoxyribonucleic acid (DNA) repair tests. No 
mutagenic potential was evident in any of these studies. 
 
2.3.2 Previous Human Experience with Intravenous HPBCD  
Initial human experience with IV HPBCD derived from NPC1 patients who were dosed with IV HPBCD supplied 
by Johnson and Johnson in attempt to treat the CNS disease, despite its poor penetrance across the blood brain 
barrier. In the USA the investigators were aware of eight such patients receiving IV HPBCD under expanded use 
INDs as of 2017. Doses up to 2500 mg/kg were infused over eight hours (312.5 mg/kg/hr) twice per week. Matsuo 
et al (33) reported on two NPC1 subjects who were given up to 2000 or 2500 mg/kg two or three times per week. 
In one subject dosed with 2500 mg/kg, transient diffuse pulmonary cloudiness and fever were reported in the 
context of an aspiration pneumonia and mechanical ventilation. However, decreased liver size and AST levels 
(from 3.5-fold elevated to 2-fold elevated) were observed in this same subject after 3-4 months of therapy. In a 
second subject, there were no changes in liver size although AST levels were slightly reduced (1.2-fold elevated 
to normal range).  
IV HPBCD is currently under investigation by Cyclo Therapeutics, NCT04860960. To the best of our knowledge, 
as far as we are aware, no serious adverse events have been reported. As of August 2023, Dr. Berry-Kravis is 
aware of 19 patients treated with IV HPBCD under an expanded access program. 
 
2.3.3 Previous Human Experience with Intrathecal HPBCD  
 

 
 
 
In addition to IV administration of HPBCD, NPC1 patients and study participants have received intrathecal (IT) 
HPBCD (i.e., delivered into the cerebrospinal fluid). The results of a sham-controlled 1-year study (parts A and 
B) of up to 1800 mg IT adrabetadex delivered every 2 weeks were announced in 2018 and reported on 
clinicaltrials.gov. In that study, there was no separation between the treated and sham groups in the coprimary 
outcomes: the NPC-CSS scale 4 key domains and the CGIC. There were no substantial or significant 
differences between treatment and sham groups with respect to treatment-emergent adverse events, with the 
exception of hearing loss, which is an expected AE with IT dosing of HPBCD.   
 
2.4 Study Rationale 
As described earlier (section 2.2), NPC1 subjects frequently present with acute cholestatic liver disease in the 
newborn period. In the majority of cases the liver disease becomes subacute, although in other cases the liver 
disease can progress to liver failure. The goal of this therapy is to reduce the risk of progressive hepatic damage 
that results in hepatic fibrosis and need for liver transplantation.   
 
2.5 Route of Administration and Dose Selection Rationale         
  
 
In the NPC1 cat model, subcutaneous administration of HPBCD 1000 mg/kg biweekly (11 treatments over 21 
weeks) reduced serum ALT from approximately 6-fold elevated to 2-fold elevated (19). This was accompanied 
by correction of the severe vacuolization of hepatocyte and Kupffer cell cytoplasm observed in untreated cats.  
 
In two US NPC1 patients dosed under an individual IND, intravenous (IV) administration of HPBCD (2500 mg/kg 
biweekly) reduced by 2-fold plasma cholestane-3β,5α,6β-triol (20), an NPC1 disease-specific biomarker that 
monitors oxidizable free cholesterol in liver tissue (7). Liver volume and AST were reduced in one of two subjects 
in Japan treated with 2500 mg/kg (33). Toxicity appears to be limited. One of two subjects treated demonstrated 
pulmonary infiltrates at 2500 mg/kg, though this occurred in the context of an aspiration pneumonia and 
mechanical ventilation (33). The precise duration of the pulmonary infiltrates was not reported, though the 
aspiration pneumonia resolved after three weeks. IV HPBCD has been used under an emergency IND for acute 
liver failure in NPC1 neonates (see section 2.3.2). 
 
Doses up to 1000 mg/kg have been administered to neonatal subjects < 2 months of age in the US. A 5-week-
old NPC1 subject received 12 doses of adrabetadex, ranging from 250 mg/kg to 1000 mg/kg, over a 6-week 
treatment period under an emergency IND (Sponsor: Marwan Shinawi MD). The NPC biomarker, lipid-509, 
declined from a pre-treatment value of 3240 ng/ml to 1610 ng/ml after 10 doses, consistent with reduction of liver 
lipid storage. Additionally, a 3-week old NPC1 subject received 12 doses, ranging from 250 mg/kg to 500 mg/kg, 
over a 6-week period under an expanded access protocol (Sponsor: Amarilis Sanchez-Valle). The treatment was 
accompanied by a reduction in glycine-conjugated trihydroxycholanic acid (“bile acid biomarker”) from 16 ng/ml 
pre-treatment to 11.1 ng/ml at the end of 6 weeks (12 doses). In both NPC1 neonates, all the adrabetadex doses 
were well tolerated without adverse effects. Right of reference was provided by both Sponsors. 
 
Taken together, the preclinical and human data suggest that adrabetadex administered by the IV route may be 
effective in reducing liver inflammation and injury and may prevent the severe long-term sequellae, such as 
hepatic fibrosis, hepatocellular carcinoma, and liver failure that requires transplantation. The safety, tolerability, 
and clinical efficacy of the drug will be determined in this dose-finding study. 
   
 
 

 
 
 
3. Study Objectives  
The overall goal of this study is to reduce the risk of progressive hepatic fibrosis due to inflammation in infants 
with Niemann-Pick Disease, type C. The objectives of this study are to determine the safety, tolerability and 
efficacy of intravenous adrabetadex in NPC disease following 12 doses given twice weekly for 6 weeks. The 
primary endpoint is the efficacy of adrabetadex to reduce plasma levels of glycine-conjugated trihydroxycholanic 
acid (“bile acid biomarker”), an NPC-specific pharmacodynamic biomarker. Secondary endpoints are 
assessment of the dose-response relationship for attenuation of liver dysfunction, as determined by reduction in 
serum transaminases (ALT and AST) and liver size. Exploratory lipid, protein and inflammatory biomarkers will 
also be examined. Subjects who demonstrate significant reduction either in the glycine-conjugated 
trihydroxycholanic acid biomarker or serum bilirubin (direct bilirubin or direct bilirubin:total bilirubin ratio) will be 
allowed to crossover into the second phase of the study, an open-label phase of six months duration in which IV 
adrabetadex will be administered monthly for a total of six doses. Serum transaminases (ALT and AST) and an 
abdominal ultrasound will be obtained at the end of the six-month open-label extension phase. Efficacy will be 
assessed by reduction in serum transaminases and reduction in spleen volumes. NPC biomarkers (cholestane-
3β,5α,6β-triol, glycine-conjugated trihydroxycholanic acid,PPCS/lipid-509, 24(S)-hydroxycholesterol, 27-
hydroxycholesterol, and neurofilament light chain) will also be obtained at these time points and will be 
considered exploratory outcome measures. 
  
4. Specific Aims 
Aim 1. To conduct a Phase 1/2a, open-label, multi-center, multiple ascending dose study of intravenous 
adrabetadex to evaluate the safety and tolerability in treating cholestatic liver disease in infants with NPC1   
 
Aim 2. To evaluate the efficacy of intravenous adrabetadex to reduce plasma levels of an NPC bile acid 
biomarker 
(glycine-conjugated trihydroxycholanic acid)  
 
Aim 3. To evaluate the dose-response relationship for adrabetadex to attenuate liver dysfunction, as determined 
by reduction in serum transaminases and liver size and exploratory research outcome measures (e.g., NPC1 
disease and inflammatory biomarkers) 
 
 

 
 
 
5. Study Design and Methods 
 
5.1 Study Overview 
The trial will be a Phase 1/2a, open-label, dose-escalation, multi-center study of adrabetadex in subjects with 
NPC dosed twice a week with IV adrabetadex for six weeks for a total of 12 administrations, followed by a six 
month open-label extension phase in which the subjects are dosed monthly with IV adrabetadex for six months 
for a total of six administrations. The study will characterize the safety, tolerability, preliminary efficacy, and 
pharmacodynamics of IV adrabetadex. The primary outcome will be the efficacy of adrabetadex to reduce 
plasma levels of an NPC bile acid biomarker, a cholesterol-derived NPC1 disease-specific biomarker that serves 
as a pharmacodynamic (PD) measure of the effect of the drug to reduce the oxidizable cholesterol pool in liver 
tissue. The secondary outcome measure will be the examination of the dose-response relationship for 
attenuation of liver dysfunction, as determined by reduction in serum transaminases (ALT and AST) and liver 
size. This study will also evaluate the effect of intravenous adrabetadex on a series of disease-associated serum 
biomarkers.       
 
5.2 Subjects 
Approximately 12 subjects will be diagnosed as having either NPC1 or NPC2 based on criteria specified in 
Section 5.4.1. Information about this study will be disseminated through patient support organizations and posted 
on ClinicalTrials.gov. The research group may facilitate diagnostic testing. Both genders will be enrolled.  No 
exclusion will be based upon race or ethnicity.     
 
5.3 Study Size, Duration and Location 
The study will enroll approximately 12 subjects up to a maximum of 15 subjects to account for potential study 
withdrawals, discontinuations or unconfirmed diagnosis of NPC. It is anticipated that this study will take four 
years to complete, with approximately four subjects to be enrolled per year.  
     
Study-related assessments will be conducted at St. Louis Children’s Hospital. 
 
For each subject, the first phase of the protocol will be conducted over seven weeks; one-week inpatient followed 
by five weeks outpatient administrations with a post-dose safety evaluation performed one week after the final 
dose. The second phase of the protocol will be an open label extension conducted in an out-patient setting over 
six months with a post-dose safety evaluation performed one week after the final dose. 
 
5.4 Eligibility Criteria 
 
5.4.1 Inclusion Criteria 
1.  Age 0 to 6 months of age at time of enrollment, both genders, and any race/ethnicity. 
 
2.  Diagnosis of NPC (either NPC1 or NPC2) based upon meeting any of the two following conditions: 
 A.  Two variants classified as pathogenic or likely pathogenic in NPC1/NPC2 on clinical laboratory 
testing , or 
B. One variant classified as pathogenic or likely pathogenic on clinical laboratory testing and a 
positive NPC biochemical marker (oxysterol or bile acid biomarker or PPCS/Lyso509) test, if acid 
sphingomyelinase deficiency and cholesterol ester storage disease have been excluded either by 
clinical molecular testing of the SMPD1 and LIPA genes or by clinical biochemical assay for acid 
sphingomyelinase and lysosomal acid lipase enzymes (or a combination of enzymatic and 
molecular testing). 
Variants will be interpreted using the American College of Medical Genetics guidelines for the 
interpretation of sequence variants and testing must be performed by a CLIA-certified laboratory. 
 
3. Subjects with evidence of NPC-related liver disease as defined by direct bilirubin (DB) >2mg/dL or DB/total 
bilirubin ratio >0.2. 

 
 
 
 
4. Ability to travel to a research site. 
 
5. Willing to participate in all aspects of trial design including serial blood collections. 
 
6. Parent / guardian must provide written informed consent to participate in the study. Because of the age range 
intended for inclusion, assent will not possible.  
 
 
5.4.2 Exclusion Criteria 
1. Age > 6 months at time of enrollment in the trial. 
 
2. A medical condition (such as clinically significant bleeding diathesis or evidence of immune suppression) that 
in the opinion of the investigator precludes placement of an intravenous catheter  
 
 3. An absolute neutrophil count (ANC) of less than 1,500 per microliter. 
 
4. A platelet count less than 75,000 per microliter.  
 
5. History of severe neonatal encephalopathy, per modified Sarnat including level of consciousness as 
stupor/coma, absent spontaneous activity, decerebrate posture, flaccid tone, absent suck, absent moro, 
diverted/nonreactive pupils, lack of heart rate variability, and apnea.. 
 
6. Subjects, who in the opinion of the investigators, are unable to comply with the protocol or have specific health 
concerns that would potentially increase the risk of participation. Examples of inability to comply include 
unwillingness to relocate or travel to a study site, suspected noncompliance with study procedures, behavior 
that jeopardizes the safety or security of the data or study staff, and other causes of inability to comply. 
 
7. Concurrent participation in another investigational drug trial. 
 
8. History of renal disease or evidence of acute kidney injury defined as serum creatinine greater than 1.5 
mg/dL or an increase of at least 0.2-0.3 mg/dL per day. 
 
5.5 Prior and Concomitant Medications 
All concomitant medications will be recorded in the appropriate case report form (CRF).  
 
5.6 Dosing and Dose Adjustments 
Adrabetadex will be administered intravenously to specifically target liver disease. In the first phase of the study, 
dosing frequency will be twice a week with IV adrabetadex for six weeks for a total of 12 administrations. Subjects 
will be evaluated at each study visit for evidence of adverse effects.    
 
Adrabetadex is provided as a 200 mg/mL solution and infused at this concentration and will be administered at 
a rate of 250 mg/kg/hr. A 5 kg infant receiving a 500 mg/kg dose, for example, will receive 12.5 ml of the 200 
mg/ml solution. 
 
Doses to be studied are 500 and 1000 mg/kg.  
 
Six subjects will be studied at each dose level 
 
 
Cohort 1 
Subjects1-6 
  500 mg/kg 
 
Cohort 2 
Subjects 7-12 1000 mg/kg 
 
 

 
 
 
The DSMC will review data from the first phase of the study for all six subjects in Cohort 1 prior to initiation of 
Cohort 2. 
 
Subjects who do not tolerate (section 7.9) the initial 500 mg/kg dose may have the dose decreased to 250 mg/kg/ 
dose and remain at this dose for the remainder of the study.  
 
Subjects who do not tolerate the 250 mg/kg dose will be withdrawn from the study. 
 
Subjects who do not tolerate the first two doses of 1000 mg/kg dose may have the dose decreased to 500 mg/kg 
and remain at this dose level for the remainder of the study.  
 
 
Subjects may be withdrawn for any Grade 3 AE (per NCI’s CTCAE) possibly, probably or definitely related to 
study drug; any Grade 4 toxicity; any subject with pulmonary complications or evidence of renal injury; or 
determination that the limit of safety and/or tolerability has been reached. In the context of adrabetadex 
administration, limit of tolerability is defined as a sustained increased respiratory rate over 30 minutes or 
decreased Sa02 (<90%) resulting in need for, or increase in sustained need for supplemental oxygen, or 
evidence of renal injury as defined as a serum creatinine (SCr) rise > 0.5 mg/dl. 
 
Subjects who demonstrate significant reduction either in the glycine-conjugated trihydroxycholanic acid 
biomarker or serum bilirubin (direct bilirubin or direct bilirubin:total bilirubin ratio) will be allowed to crossover into 
the second phase of the study, an open-label phase of six months duration. In this phase of the study, dosing 
frequency will be monthly with IV adrabetadex for six months for a total of six administrations. Subjects will be 
evaluated at each study visit for evidence of adverse effects.    
 
5.7. Biological Specimens 
Blood (serum and plasma) and urine will be collected as part of this protocol. Research samples will be stored 
locally or in the NICHD biorepository. Coded samples may be sent to collaborating laboratories, the NIH, and 
Mandos, LLC. Biomaterial collected as part of this study may be used for future research related to Niemann-
Pick disease or other projects specifically approved by an Institutional Review Board. Priority will go to studies 
related to Niemann-Pick disease.    
 
5.8 Non-study Drugs 
This protocol will not provide non-study drugs.  
 
5.9 Study Drug 
 Mandos, LLC will provide the study drug and support regulatory aspects of this study. Adrabetadex will not be 
provided under this protocol after completion of this study.   
 
5.12 Withdrawal of Subjects from the Study 
Subjects that are withdrawn from the study either by their choice or investigator action will be provided with 
written notification that their child was withdrawn from the study and provided with written recommendations 
regarding clinical follow-up.    
    
6. Assessments, Procedures, and Testing 
 
6.1 Medical History and Physical/Neurological Examinations 
A medical and medication history will be obtained and a physical exam will be conducted after admission to the 
study center.  This will ensure that the subject’s medical health is adequate to participate in this study.  
 

 
 
 
Subjects will be evaluated with an interim history and physical examination at least daily while admitted to the 
study center.    
 
Anthropomorphic measures including weight and height will be obtained weekly in phase 1 and monthly in phase 
2. 
 
Physical and neurological examinations will be standardized.  
 
6.2 Pulmonary Function Assessment 
A baseline CXR and oxygen saturation will be obtained to assess placement of a peripherally inserted central 
catheter (PICC) and prior to the first administration of the study drug. CXR will only be repeated if clinically 
indicated.   
 
6.3. Liver function assessment 
In phase 1, plasma AST and ALT will be obtained at baseline, 2, 4 and 6 weeks. In phase 2, plasma AST and 
ALT will be obtained at baseline, 2, 4 and 6 months.      
 
6.4 Abdominal Ultrasound   
In phase 1, an abdominal ultrasound exam will be conducted at baseline and 6 weeks to determine liver size 
and spleen volumes.  Liver size is determined by the liver’s midclavicular longitudinal diameter (34). Organ 
volumes are the product of three long axes (longitudinal, transverse and anterior-posterior) (35).At the time of 
this abdominal ultrasound in phase 1, liver elastography will also be obtained. In Phase 2, an abdominal 
ultrasound with liver elastography will be repeated at the end of the six-month protocol. 
 
6.5 Audiological Evaluation.  
An audiological evaluation will be obtained at baseline and at conclusion of phase 1 of the study. Audiology 
assessment will be performed using otoacoustic emissions (OAE). This test does not require sedation. 
 
6.6 Clinical Laboratory Tests 
Clinical laboratory testing will be conducted by St. Louis Children’s Hospital Clinical Laboratories.  
 
6.6.1 Hematology/Chemistry 
Blood samples for the clinical laboratory tests will be collected by a qualified person using either the central line, 
by indwelling catheter, or by venipuncture.  
 
Testing will include the following (phase 1: 2.5 mls/time point; 10 mls total over six weeks, phase 2: 2.5 mls/time 
point; 10 mls total over six months):  
 
Hematology:  complete blood count (CBC) with differential and platelet count, and prothrombin time (PT). 
Clinical chemistry:  electrolytes, glucose, blood urea nitrogen (BUN), creatinine, AST, ALT, GGT, alkaline 
phosphatase, bilirubin (direct and total), albumin, calcium, magnesium, phosphorus, and CK. 
 
In phase 1, testing will occur at baseline, 2, 4 and 6 weeks. In phase 2, testing will occur at baseline, 2, 4, and 6 
months. For study subjects, the amount drawn will not exceed the lesser of 50 ml or 3 ml per kg in an 8 week 
period and collection may not occur more frequently than 2 times per week. 
Lab results do not need to be resulted and reported prior to dosing. 
 
6.6.2 Urinalysis 

 
 
 
Urinalysis will include assessment of protein, blood, leukocytes, glucose, ketones, bilirubin, urobilinogen, pH, 
and specific gravity and microscopic analysis. In phase 1, this testing will occur at baseline, 2, 4 and 6 weeks, 
and in phase 2 at baseline, 2, 4 and 6 months. 
Lab results do not need to be resulted and reported prior to dosing. 
 
6.7 Research Laboratory Testing 
Plasma and serum will be collected for biomarker analysis.  Sample collection, processing and storage will be 
standardized.  Coded samples will be sent to NICHD Biorepository for long-term storage. Testing may be 
performed in clinical or research laboratories. Research testing will include, but is not limited to the following: 
 
Markers of cholesterol homeostasis (phase 1: Baseline, 2, 4 and 6 weeks; 0.5 ml/time point; 2 mls total over 6 
weeks; phase 2: Baseline, 2, 4 and 6 months; 0.5 ml/time point; 2 mls total over 6 months) 
 
 1.  Trihydroxycholanic acid glycine conjugate (bile acid biomarker) 
 
 2. Cholestane-3β,5α,6β-triol 
3. PPCS/Lipid-509  
 
 
Plasma lipidomics  (phase 1: Baseline and 6 weeks; 0.5 ml/time point; 1 ml total over 6 weeks; phase 2: 6 
months; 0.5 ml/time point; 0.5 ml total over 6 months) 
 
 1.  Sphingolipids: sphingoid bases, ceramides, glucosylceramides, lactosylceramides,  
 
 
  
gangliosides 
 
 2.  Lysosphingolipids: lyso-sphingomyelin 
 
 
 
Additional biomarkers for NPC (phase 1: Baseline, 2, 4, and 6 weeks; 1.75ml/time point; 7mls over 6 weeks; 
phase 2: Baseline, 2, 4, and 6 months; 1.75 ml/time point; 7 mls total over 6 months) 
• 
Serum 24(S)-hydroxycholesterol 
• Serum 27-hydroxycholesterol 
• Serum neurofilament light chain 
 
Lab results do not need to be resulted and reported prior to dosing. 
 
 
6.8 Future Research and Other Testing 
Other blood, cellular or urine biomarkers may be assessed. At the discretion of the investigator, blood, and 
urine may be collected and saved for future research.  
Biomarkers of inflammation  (phase 1: Baseline, 4 and 6 weeks; 0.5 ml/time point; 1.5 mls total over 6 weeks; 
phase 2: 6 months; 0.5 ml/time point; 0.5 mls total over 6 months) 
 
 Such as galectin 3 (LGAL3), cathepsin D, lysozyme, C-Reactive Protein High Sensitivity (hsCRP), 
and inflammatory cytokines 
 
 
Bile acids  (phase 1: Baseline, 2, 4 and 6 weeks; dried blood spot; total volume minimal; phase 2: Baseline, 2, 
4 and 6 months; dried blood spot; total volume minimal) 
 The blood, urine, and derivatives thereof (e.g., peripheral B-cells, ribonucleic acid (RNA) or deoxyribonucleic 
acid (DNA)), collected under this protocol, can be stored for future research not specifically lined in this protocol. 
Such research could involve, but is not limited to, proteomic, genomic, biochemical, metabolomic, and molecular 
analysis of these samples. Corresponding clinical data may also be used for future research. Future research 
using these samples will relate to Niemann-Pick disease or other projects specifically approved by an Institutional 
Review Board. Priority will go to studies related to Niemann-Pick disease. This research may occur at the NIH 
or at outside laboratories. If sent to outside laboratories samples will be coded and patient identifiers will be 
removed. If a biospecimen is sent to a clinical laboratory for testing, identifiers will not be removed and the result 
will become part of the medical record.  

 
 
 
 
6.9 Collaborating laboratories and entities 
Dr. Patricia Dickson  
Washington University, St. Louis, MO 
Dr. Xuntian Jiang 
 
Washington University, St. Louis, MO 
Dr. Forbes D. Porter  
NICHD, NIH, Bethesda, MD 
 
Mandos, LLC   
 
Thousand Oaks, CA 
 
Additional laboratories can be added by amendment of this protocol. 
 
 
 

 
 
 
7. Human Subjects Protections 
 
7.1 Institutional Review Board 
This protocol and informed consents will be reviewed and approved by the Washington University Institutional 
Review Board (IRB). The IRB will meet all FDA requirements governing IRBs (Code of Federal Regulations 
(CFR), Title 21, Part 56). 
 
7.2  Ethical Conduct of the Study 
The investigator will conduct this study in compliance with FDA regulations. 
 
7.3 Patient Information and Informed Consent 
Written informed consent will be obtained from parents or guardians prior to any intervention under this protocol. 
The informed consent form (ICF), as specified by the Washington University IRB, must follow the Protection of 
Human Subjects regulations listed in the CFR, Title 21, Part 50.  
 
Verbal or written screening for inclusion/exclusion criteria may be conducted prior to obtaining informed consent.  
 
The background of the proposed study and the benefits and risks of the procedures and study will be explained 
to the guardians. The Principal Investigator or an Associate Investigator will obtain consent. The original signed 
and dated informed consent will be placed into subject’s medical record. A copy will be given to the guardian.  
 
7.4  Subject Selection 
Subjects will be diagnosed as having NPC based on criteria specified in Section 5.4.1. For potential subjects for 
whom a definitive diagnosis is not available, the researchers may provide NPC-specific diagnostic testing before 
subject enrollment.  
 
Information regarding this study will be distributed through parent support organizations such as, but not limited, 
to National Niemann-Pick Disease Foundation (NNPDF), Ara Parseghian Medical Research Foundation 
(APMRF), Dana's Angels Research Trust (DART), Support of Accelerated Research for Niemann-Pick Type C 
(SOAR-NPC), and Fight NPC.  
 
Information about the study will be posted on ClinicalTrials.gov.  
 
7.5 Gender and Ethnic/Racial Background 
Subjects of either gender or any ethnic/racial background will be eligible for this study. NPC1 is an autosomal 
recessive disorder, thus gender distribution is expected to be equal. NPC1 is a panethnic disorder, but several 
genetic isolates, due to founder effects, exist. These include Acadians in Nova Scotia, Hispanics in parts of 
Colorado and New Mexico, and a Bedouin Group in Israel. It is expected that the subject’s ethnic/racial 
demographics will reflect disease demographics. The small size of this study could result in random skewing of 
the expected distribution for either gender or ethnic/racial background.  
 
This is a pilot study involving a small sample size from a limited patient population with a rare disease. Subjects 
will be screened to determine if they are eligible to participate in the trial prior to enrollment. Selection bias will 
be minimized as much as possible by screening all interested NPC subjects until the maximum accrual number 
has been met. 
 
7.6  Research Involving Children 
This study will involve physically and cognitively impaired children. Consent will be obtained from 
parents/guardians. If possible, consent will be obtained from both parents/guardians. Verbal consent can be 
given by a second parent/guardian if only one parent has accompanied the child to the study site. Due to the 
age range included in this study assent will not be possible.   

 
 
 
 
This study is consistent with 45 CFR 46.405. Specifically, the research involves greater than minimal risk but 
presents the prospect of direct benefit to the individual child involved in the research. Given that NPC is a 
progressive, lethal neurological disorder with no FDA approved therapy, the risks in this protocol are 
commensurate with the disease process. The preclinical data in animal models suggest that the risk is justified 
by the potential benefit should this drug prove to be efficacious in humans.  
 
7.7 Subject Withdrawal 
Guardians/parents will be informed that they have the right to withdraw from the study at any time for any reason 
without prejudice to their medical care. Subjects may be withdrawn from the study for any of the following 
reasons: 
• 
Parent/guardian request 
• 
Parent/guardian is unwilling or unable to comply with the protocol 
• 
Medical reason, at the discretion of the Investigator or Medical Monitor 
• 
Occurrence of the following:   
a. any Grade 3 AE (per NCI’s CTCAE) possibly or definitely related to study drug  
b. any Grade 4 toxicity 
c. any subject with pulmonary complications or evidence of renal injury 
d. determination that the limit of safety and/or tolerability has been reached. In the context of 
adrabetadex administration, limit of tolerability is defined as a new oxygen requirement or 
evidence of renal injury. 
e. evidence of development or worsening of liver synthetic function (monitored by serum albumin 
and PT) or evidence of development or worsening of hepatic encephalopathy (monitored by 
serum ammonia levels). 
 
Although study treatment will cease, subjects will be encouraged to remain on study in order to collect all of the 
data prescribed in the protocol. The reasons for subject withdrawal will be recorded in the subject’s CRF.  
 
For a withdrawal due to a safety issue, subjects will be followed until the safety issue is resolved or returns to 
baseline level. Additionally, any appropriate referrals will be made as needed.  
 
Any usable data from withdrawn subjects will be included in safety and efficacy evaluations. Withdrawn 
subjects may be replaced. 
 
7.8 Adverse event assessments 
Adverse events will be assessed using CTCAE version 5.0. Safety and tolerability of adrabetadex will be 
determined as presented in Table 1 except for respiratory and audiological complications. 
 
Subjects will be withdrawn or dose decreased if they experience systemic (decreased blood pressure, heart rate, 
allergic rash, wheezing), respiratory (sustained increased respiratory rate over 30 minutes or decreased Sa02 
(<90%)), or central nervous system (altered level of consciousness, seizures) symptoms during drug infusion or 
within 2 hours post-infusion. Subjects will be withdrawn or dose decreased if CXR demonstrates pulmonary 
infiltrates likely related to drug administration. If the etiology of pulmonary infiltrates is not known, they dose may 
be repeated and a subsequent CXR obtained.  If the subsequent CXR demonstrates increased pulmonary 
infiltrates, subject will be withdrawn.     
 
 
 
 
 
 

 
 
 
 
Table 1.  Decision Table for Evaluating the Safety and Tolerability of IV adrabetadex in  
Individual Subjects (respiratory and audiological excluded) 
 
 
Safety Profile of Individual Patient  
Safety Decisions* 
A 
No AEs and no SAEs or Any number of 
Common Terminology Criteria for Adverse 
Events (CTCAE) Grade 1 drug-related AEs; 
≤ 1 CTCAE Grade 2 drug-related AE; or 
Repeat the current dose 
B 
2 CTCAE Grade 2 drug-related AEs (or  
 
Repeat the current dose,  
Study a lower dose (if applicable) 
 
C 
≥ 3 CTCAE Grade 2 drug-related AEs or 
≥ 1 drug-related SAE 
Study a lower dose, or withdraw the 
subject 
and 
Evaluate the risk/benefit profile for 
dose escalation of other subjects 
D 
Any CTCAE Grade 3 drug related AE;  
Any CTCAE Grade 4 drug-related AE;  
Any 
subject 
with 
drug-related 
pulmonary 
complications or thromboembolic complications 
Determination that the limit of safety and/or 
tolerability has been reached  
 
 
Withdraw the subject  
and 
Evaluate the risk/benefit profile in 
other subjects for dose escalations to 
or above the dose resulting in Grade 
3 toxicity  
 and  
Temporarily 
or 
permanently 
halt 
study, pending DSMC review, if two 
subjects develop the same Grade 3 
toxicity or if any subjectt develops a 
Grade 4 toxicity  
 
 
7.9  Discontinuation or Temporary Suspension of the Study 
The DSMC or Principal Investigator may terminate this study at any time for safety or administrative reasons. 
The DSMC or Principal Investigator will terminate the study if the occurrence of AEs or other findings suggests 
an unacceptable risk to the health of the subjects. The study will be interrupted if two subjects, based on two 
concurrent assessments, develop the same Grade 3 drug-related adverse event (unless related to disease 
progression of NPC), or if any subject that develops a Grade 4 adverse event, (unless the AEs are of an 
accidental nature that could not be reasonably attributable to adrabetadex or related to disease progression of 
NPC). Following review by the DSMC, the study may be resumed as planned, resumed with subjects at a lower 
dose or discontinued.  
 
7.10 Potential Benefits and Financial Compensation 
The treatment has the potential to provide benefit to the subject by reducing the effect of the underlying disease. 
In addition, this study will improve understanding of the safety and potential efficacy effects of administering IV 
adrabetadex in subjects with NPC1.  
 
No financial compensation will be offered to subjects, guardians, or families. Travel, lodging, and per diem 
expenses may be covered per site policy. 
 
7.11 Conflicts of Interest 
NIH (Dr. Forbes D. Porter) has been awarded US Patent 8,497,122, entitled "Biomarkers for Niemann-Pick C 
Disease and Related Disorders," for use of oxysterols as biomarkers for Niemann-Pick C disease. NIH (Dr. 

 
 
 
Forbes D. Porter) has filed patent applications for use of protein biomarkers in NPC1. Dr. Jiang has filed a patent 
application for the use of bile acid biomarkers in NPC1. Additional patent applications may be filed by institutions 
involved in this study that relate to the treatment or monitoring of therapy for NPC1.   
 
Dr. Forbes D. Porter and NICHD have a Cooperative Research Agreement with Mandos, LLC for the 
development of intrathecal adrabetadex. Dr. Porter is an associate investigator on a Rush University protocol 
that supports expanded access for adrabetadex.  
 
Mandos, LLC will provide adrabetadex.  Mandos, LLC. may provide additional support to facilitate completion of 
this study. Mandos, LLC may use data obtained from this study to develop adrabetadex as a commercial product.  
     
Collaborating or associate investigators may have funding or consulting relationships with pharmaceutical 
companies developing therapies for NPC1. Although these collaborating or associate investigators provide 
invaluable input, they are not directly responsible for the recruitment or enrollment of subjects into the Phase 
1/2a protocol at the Washington University  
 
 

 
 
 
8 Potential Risks and Discomforts 
Individual procedures and associated personal risks are briefly described, below. 
 
8.1 Medical Evaluations 
There are no significant risks associated with the physical, neurological, and neuropsychiatric examinations. 
Multiple independent evaluations may be stressful to an infant. Clinical photographs or video may be obtained 
and these could potentially be embarrassing to some subjects. 
 
8.2. Risk of Intravenous Adrabetadex 
The risks of intravenous adrabetadex are not known. Animal studies and human experience with HPBCD and 
adrabetadex to date suggest that intravenous administration of adrabetadex is generally safe and well-tolerated; 
however, a major purpose of this study is to further evaluate the safety and tolerability of intravenous adrabetadex 
in NPC1 subjects, as well as dose-response as assessed by reduction in plasma biomarkers and reduction in 
serum transaminases and liver size.  
 
IV administration of an experimental drug could have untoward consequences including permanent disability or 
death. 
  
Known toxic effects from the cat disease model include acute respiratory distress and death, and apparent 
irreversible deafness:  
• 
Cats receiving 8,000 mg/kg HPBCD by subcutaneous injection developed acute respiratory distress and 
died due to this complication.  
• 
Cats receiving multiple subcutaneous doses of 4,000 mg/kg or a single subcutaneous dose of 8,000 
mg/kg HPBCD developed apparent irreversible deafness (36).  
• 
A majority of mice receiving a single 8000 mg/kg subcutaneous dose of HPBCD had hearing loss due to 
loss of outer hair cells (37). However, chronic dosing at 4000 mg/kg showed an initial hearing loss that 
subsequently recovered suggesting that homeostatic mechanisms could adjust to the lower dosing.    
• 
Pulmonary toxicity has been reported in young pigs receiving IV HPBCD infusions (38).  Infusion of 1 
g/kg of 40% HPBCD in normal saline over 40 minutes resulted in cardiovascular instability. Five infusions 
over two weeks of 0.25-0.5 g/kg over 40 minutes resulted in inflammatory pulmonary changes.  
   
No adverse events related to pulmonary function have been reported for the children receiving IV or IT HPBCD 
under individual use INDs cited in the initial IND. The investigators are not aware of any pulmonary adverse 
events being reported in the eight other individuals receiving IV HPBCD under expanded access INDs in the 
United States. Those individuals are typically receiving 2500 mg/kg HP-β-CD every week. Individuals in the US 
are receiving Kleptose HPB, from which adrabetadex is derived.  Matsuo et al (33) reported in one subject 
transient diffuse pulmonary infiltrates and fever following infusions of IV HPBCD, which occurred after 23 months 
of therapy and in the context of recovery from an aspiration pneumonia. These resolved with prednisolone and 
antihistamine pretreatment and interpreted by the authors as a drug-related immunological reaction. The adverse 
pulmonary event appears to be related to high peripheral dosing. The HPBCD used by Matsuo et al is not the 
same preparation as adrabetadex.    
 
While an allergic or anaphylactic reaction to adrabetadex is unlikely, the drug administration will take place in 
the Neonatal Intensive Care Unit, the Pediatric Intensive Care Unit, or the Infusion Center at St. Louis Children’s 
Hospital, which provide close monitoring for acute adverse effects such as anaphylactic response to 
adrabetadex. Nursing and medical staff are trained in Code Blue procedures as well as Advanced Life Support, 
and many staff members are trained in Pediatric Advanced Life Support. Emergency resuscitation carts (Code 
Carts) are in place on every Patient Care Unit. 
 
Exact doses for emergency resuscitation drugs for pediatric subjects (defined as less than 18 years of age) who 
weigh less than 50 kg are calculated immediately upon each admission and recorded on the Pediatric Emergency 

 
 
 
Drug Sheet (PEDS). These include medications necessary for managing anaphylactic reactions (epinephrine, 
diphenhydramine and hydrocortisone). A copy of this document is kept on the subject’s medical record as well 
as on the Code Cart on the Patient Care Unit for the duration of the admission. Code teams include a pediatrician. 
   
8.3 Phlebotomy  
Phlebotomy is a risk/discomfort of this study. An anesthetic cream such as EMLA is an option to reduce 
discomfort. Infection and bruising are possible at the site of the blood draw. T At each time point the maximum 
blood draw is 6 mL. In Phase 1, the maximum blood draw over 6 weeks is 24mL. In Phase 2, the maximum blood 
draw over 6 months will be 24mL. Nursing staff will monitor blood-drawing volumes. If blood limits are an issue, 
testing will be prioritized by the investigators. Safety laboratory tests will take priority over investigational testing. 
Not obtaining a test due to blood limit prioritization will not be considered a protocol deviation.  
  
8.4 Audiological Evaluation 
Otoacoustic emissions (OAE) monitors for ototoxicity. OAE test is used to find out how well the inner ear, or 
cochlea, works. OAEs are sounds given off by the inner ear when responding to a sound.  While the infant or 
child is sleeping, a small earphone, or probe is placed in the ear. The probe puts sounds in the ear and measures 
the sounds that come back. 
 
8.5 Sedation 
Sedation for study procedures may be performed at the discretion of the research team in consultation with the 
guardians and anesthesiology. The medical and anesthesia clearance may determine that the subject is not fit 
for sedation during study procedures due to pre-existing medical conditions that would cause this elective 
procedure to be more risky. If that is the case, and sedation is necessary, the subject would be excluded from 
the study. If during the procedure complications of sedation arise or the level of sedation is inadequate, the 
procedure will be terminated. 
 
The major risk associated with sedation is respiratory collapse. In order to minimize this possible complication, 
sedation will be performed by experienced pediatric physicians. Facilities for maintenance of a subject’s airway, 
artificial ventilation, and circulatory resuscitation will be immediately available and ready for use. The 
anesthesiologist will also select the anesthetic agent used based on their clinical judgment. Another risk of 
sedation is aspiration. Intubation decreases the risk of aspiration and may be used if in the opinion of the 
anesthesiologist that it is indicated. Death is a rare complication of sedation when performed by a licensed 
anesthesiologist under controlled conditions. 
 
8.6 Chest X-ray 
A chest X-ray (CXR) will be obtained on the first admission to check placement of a peripherally inserted central 
catheter or other central IV line for drug administration, and this will serve as a baseline study should pulmonary 
symptoms be observed during the study. 
 
There is no discomfort and minimal exposure to radiation with a CXR. X-rays usually have no side effects in the 
diagnostic range. The CXR is one of the lowest radiation exposure medical examinations performed today. The 
effective radiation dose from this procedure is about 0.8 mSv, which is about the same as the average person 
receives from background radiation in 10 days. Female participants should always inform any study coordinators, 
nurses and the x-ray technologist if there is any possibility that they are pregnant. The amount of radiation the 
subject will receive in this study is up to 0.04 rem, which is below the guideline of 5 rem per year allowed for 
research subjects by the NIH Radiation Safety Committee. The average person in the US receives a radiation 
exposure of 0.3 rem per year from natural sources, such as the sun, cosmic radiation, and the earth's air and 
soil. If the subject/guardian would like more information about radiation, he/she will ask the investigator for a 
copy of the pamphlet, An Introduction to Radiation for NIH Research Subjects.  
 

 
 
 
While there is no direct evidence that the amount of exposure received from participating in this study is harmful, 
there is indirect evidence it may not be completely safe. There may be a very slight increase in the risk of cancer. 
The subject/guardian will inform one of the doctors if he/she has had any radiation exposure in the past year, 
either from other research studies or from medical tests or care, so the doctors can make sure that the subject 
will not receive too much radiation. Radiation exposure includes x-rays taken in radiology departments, cardiac 
catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive materials were injected 
into the subject’s body. If the subject is pregnant or breast feeding, she may not participate in this research study. 
It is best to avoid radiation exposure to unborn or nursing children since they are more sensitive to radiation than 
adults. 
 
8.7 Liver/Spleen Ultrasound 
The risks of an abdominal ultrasound are limited to mild discomfort of the technicians pressing the probe against 
the abdominal wall.      
 
8.8 Peripherally Inserted Venous Catheter (PICC) and Risks 
Insertion of a peripherally inserted venous catheter (PICC line) or other central IV line may be required for 
administration of the adrabetadex drug in this study due to the limited peripheral IV access in the neonatal 
patients, the dosing frequency, and the number of doses. The preferred central IV line of choice is a PICC line. 
In situations where a PICC of insufficient gauge to support the IV infusion and compliance with protocol activities, 
or where an indwelling central line is otherwise medically indicated, alternative central IV lines, such as a Broviac, 
can be used for drug delivery. In the open label extension, the increased age of the patients and reduced dosing 
frequency will permit administration of the drug via peripheral IV access. Study procedures will be performed at 
a high-volume center with a dedicated pediatric service. At the time of subject consent, there will be discussion 
with the parents or guardian regarding the nontherapeutic nature of the PICC line procedure and the requirement 
for procedural sedation. A centrally placed, venous catheter is required for administration of adrabetadex. For 
this study, we expect to utilize a PICC line. The PICC line will be placed by a qualified and experienced person. 
In the neonatal population, insertion of a PICC line is normally accompanied by sedation and will not be withheld 
to avoid its risks. Rare risks associated with this procedure include bleeding at the site of insertion, thrombosis 
on or in the catheter, and systemic infection. 
 
 
 

 
 
 
9.  Study Procedures and Schedule 
 
9.1  Overview of Study 
Subjects who have been screened for eligibility will be admitted to the Neonatal Intensive Care Unit or the 
Pediatric Intensive Care Unit depending on age for inpatient baseline qualification assessments after written 
informed consent has been obtained. In phase 1 of the study, the first admission will last approximately 7 days.  
Subjects may then be followed as outpatients for the subsequent five weeks, or they may remain inpatient if 
clinically indicated. Upon initiation of the study, a PICC line or other intravenous access will be placed and 
baseline laboratory testing and liver/spleen ultrasound will be obtained.  Drug will be administered twice a week 
with an interval of 4 ± 1 days.  A total of 12 doses will be given. Subjects who demonstrate significant reduction 
either in the glycine-conjugated trihydroxycholanic acid biomarker or serum bilirubin (direct bilirubin or direct 
bilirubin:total bilirubin ratio) will be allowed to crossover into the second phase of the study, an open-label phase 
of six months duration. In this phase of the study, dosing frequency will be monthly with IV adrabetadex for six 
months for a total of six administrations. Subjects will be evaluated at each study visit for evidence of adverse 
effects.    
 
9.2 Subject Screening 
Review of eligibility may be performed through chart review, written query or via telephone. Medical records 
may be requested.  A screening log will be maintained indicating status. 
 
9.2 Outline of Protocol Admissions and Testing     
 
Time  
Major Events  
 
 
 
Admission Type 
 
Length  
 
Phase 1 
 
Week 1 
Enrollment and consent 
 
 
Inpatient 
 
 
7 days 
 
 
PICC/IV line placement 
 
 
Liver/spleen ultrasound 
 
 
Obtain baseline laboratory testing 
 
 
Administration of 1st and 2nd dose 
 
Weeks 2-6 
Administration of doses 3-12   
 
Outpatient* 
 
 
10 days 
 
 
Obtain laboratory testing 
 
Week 6 
Liver/Spleen ultrasound 
 
 
Outpatient* 
 
 
  1 day 
 
 
PICC line removal 
 
 
 
 
Week 7 
Post-dose safety evaluation  
 
Outpatient* 
 
 
  1 day 
 
Phase 2 
 
Month 1 
Initiation of open-label extension 
 
Outpatient* 
 
 
  1 day 
 
one month ±7 days month after dose 12 
 
Obtain baseline laboratory testing 
 
Administration of dose 13 
 
Months 2-6 
Administration of doses 14-18  
 
Outpatient* 
 
 
   1 day 
 
 
Obtain laboratory testing 
 
Month 6 
Liver/Spleen ultrasound 
 
 
Outpatient* 
 
 
   1 day 
 
 
Post-dose safety evaluation 
 

 
 
 
*May be performed as inpatient if the patient remains hospitalized 
 
9.3 Baseline Admissions  
Subjects who have been screened for eligibility will be admitted to the Neonatal Intensive Care Unit or the 
Pediatric Intensive Care Unit for baseline qualification assessments. Written informed consent will be obtained. 
Baseline evaluation will include the following: 
 
1.  Admission to the clinical research unit 
 
2.  Confirmation of eligibility 
 
3.  Collect vital signs including temperature, respiration, SaO2, heart rate, and blood pressure  
 
4.  History and physical examination and neurological assessment 
 
5.  Collect blood and urine samples for clinical and research laboratory testing 
 
7.  Audiological evaluation 
 
8.  Abdominal ultrasound (liver and spleen volume) 
 
9.  Placement of a PICC line or other IV access 
 
10. CXR 
 
9.4 First Two Intravenous Drug Administrations 
Subjects will be admitted to the Neonatal Intensive Care Unit or the Pediatric Intensive Care Unit for 7 ± 2 days.  
IV adrabetadex is provided as a 200 mg/mL solution and will be administered undiluted via PICC or other central 
line at a rate of 250 mg/kg/hr. A 5 kg infant receiving a 500 mg/kg dose, for example, will receive 12.5 ml of the 
200 mg/ml solution. The 20% solution is isotonic with an osmolarity of 290 ± 30.0 mOsm/kg and is suitable for 
delivery through central IV access. 
Rate may be decreased in 25 mg/kg/hr increments to 175 mg/kg/hr if required. The rate and reason for reduction 
will be recorded. Dose will be either 500 or 1000 mg/kg.  
 
For study participants in whom a PICC line or other central line cannot be placed, adrabetadex may be 
administered via peripheral IV. If administered via peripheral IV, adrabetadex will be diluted 4-fold into sterile 
saline prior to infusion. A 5 kg infant receiving a 500 mg/kg dose, for example, will receive 50 ml of the diluted 
adrabetadex (50 mg/ml solution). 
 
Vital signs (temperature, heart rate, respiratory rate, supine blood pressure, and SaO2) and standard neurological 
checks will be conducted at least every 30 minutes during and then for the first two hours after drug 
administration, then every 2 hours until 6 hours post infusion, and then at least every 6 hours until 24 hours post 
infusion for the first two drug infusions.   
 
Abnormal vital signs that meet criteria to be classified as adverse events according to section 11 will be reported 
as adverse events.  
 
9.6 Doses 3-12 
These drug administrations may occur as an outpatient. Interval between dosing will be 4 ± 1 days. 
 
IV adrabetadex will be administered IV at a rate of 250 mg/kg/hr. Rate may be decreased in 25 mg/kg/hr 
increments to 175 mg/kg/hr if required. The rate and reason for reduction will be recorded.     
 
Vital signs (temperature, heart rate, respiratory rate, supine blood pressure, and SaO2) and standard neurological 
checks will be conducted at least every 30 minutes during and then for the two hours after drug administration. 
Subject may be discharged 2 hours post administration if no issues. 
 
9.7 Phase 1: Final Evaluation 
The final evaluation will occur 2 ± 1 days after the 12th adrabetadex infusion. This will include a liver/spleen 
ultrasound. PICC line will be removed.    

 
 
 
 
9.8 Post-dose Safety Evaluation 
Subject will be evaluated by history 7 ± 2 days after the 12th adrabetadex infusion. History will be taken in person 
or by telephone by the study coordinator and consist of an interim medical history. The study coordinator will 
document the conversation and history. If discharged to home then study team will follow-up by phone on a 
weekly basis for two additional weeks.  
 
9.9 Phase 2: Open-Label extension (Doses 13-18)  
Subjects who demonstrate significant reduction either in the glycine-conjugated trihydroxycholanic acid 
biomarker or serum bilirubin (direct bilirubin or direct bilirubin:total bilirubin ratio) will be allowed to crossover into 
the second phase of the study, an open-label phase of six months duration. In this phase of the study, dosing 
frequency will be monthly with IV adrabetadex for six months for a total of six administrations. Subjects will be 
evaluated at each study visit for evidence of adverse effects.    
 
Entry into the open-label extension phase will occur after completion of phase 1 final evaluation. Doses 13-18 
may be administered as an outpatient. In the extension phase, the subjects will continue at the same dose 
(mg/kg) as they received for the 12th adrabetadex infusion. 
 
Because the adrabetadex drug will be infused through peripheral IV access for doses 13-18, the 200 mg/mL 
solution will be diluted 4-fold into sterile saline prior to infusion. A 5 kg infant receiving a 500 mg/kg dose, for 
example, will receive 50 ml of the diluted adrabetadex (50 mg/ml solution). 
 
IV adrabetadex will be administered via peripheral IV access at a rate of 250 mg/kg/hr. Rate may be decreased 
in 25 mg/kg/hr increments to 175 mg/kg/hr if required. The rate and reason for reduction will be recorded. 
 
Vital signs (temperature, heart rate, respiratory rate, supine blood pressure, and SaO2) and standard neurological 
checks will be conducted at least every 30 minutes during and then for the two hours after drug administration. 
Subject may be discharged 2 hours post administration if no issues. 
 
If there is evidence of clinical deterioration during the open label phase (based on assessment by the patient’s 
physician), dosing frequency may be increased. Increasing dosing frequency more frequently than monthly will 
necessitate reinsertion of a PICC line (see Section 8.8). 
 
9.10 Phase 2: Post-dose Safety Evaluation 
Subject will be evaluated by history 7 ± 2 days after the 18th adrabetadex infusion. History will be taken in person 
or by telephone by the study coordinator and consist of an interim medical history. The study coordinator will 
document the conversation and history. If discharged to home then study team will follow-up by phone on a 
weekly basis for two additional weeks.  
 
 
9.11 Adrabetadex dose 
The subjects will be enrolled in two cohorts.   
 
Two dose levels will be evaluated.  Dose levels for each cohort are: 
 
 
Cohort 1    
500  mg/kg 
 
 
 
Cohort 2          1000  mg/kg  
 
 
 
          
Subjects who do not tolerate the first dose of 500 mg/kg dose may have the dose decreased to 250 mg/kg dose. 
Subjects who do not tolerate 250 mg/kg dose will be withdrawn from the study.  Subjects who do not tolerate the 

 
 
 
first two doses of the 1000 mg/kg dose may have the dose decreased to 500 mg/kg. Decisions regarding 
tolerability will be made by the DSMC in conjunction with the investigators and local monitor.    
 
If a subject withdraws from the protocol prior to the 12th drug infusion, they may be replaced.    
 
 

 
 
 
10.  Statistical Analysis Plan 
This Phase 1/2a study is intended to provide safety, tolerability, pharmacodynamic, and pharmacokinetic data 
that will be critical to assessing the feasibility, design, and conduct of future studies in the NPC1 population. As 
part of this trial we will test whether biochemical response of plasma biomarkers, serum AST/ALT, or abdominal 
ultrasound can be used to guide identify a biochemically, and potentially a clinically, effective dose. These data 
would potentially guide the development of a future Phase 2/3 trial.    
 
Assessment of safety and tolerability will be made by evaluation of summary statistics of adverse events and 
unanticipated problems. One purpose of this trial is to obtain pilot data on clinical outcome measures and 
biomarkers to identify outcome measures that appear to respond to therapy and to inform power calculations for 
a subsequent trial focused on establishing therapeutic efficacy.      
 
The primary outcome measure for this trial is the plasma NPC1 bile acid biomarker. This bile acid is a metabolite 
of cholesterol, is elevated >99% of NPC1 subjects, is largely generated in the liver and therefore provides a 
biochemical measure of oxidizable lysosomal unesterified cholesterol in liver tissue (21). Serial plasma bile acid 
biomarker concentrations were measured in two NPC1 subjects over four years, during which period IV HP-β-
CD treatment was initiated under an individual expanded use Investigation New Drug application. Following 
initiation of treatment, plasma bile acid biomarker concentrations were decreased by 46% and 62% in Subjects 
1 and 2 after 3 and 9 months of treatment (p<0.05), respectively, and was even lowered into the normal reference 
range (<24.5 ng/ml) in Subject 2. Plasma bile acid biomarker concentrations were measured in a third NPC1 
subject receiving weekly IV adrabetadex also under an individual expanded use Investigation New Drug 
application. Plasma bile acid biomarker concentrations were decreased by 75% after 6 weeks of therapy, with 
the trihydroxycholanic acid glycine conjugate concentration was lowered into the normal reference range (<13.5 
ng/ml).  
 
These data from three subjects previously treated with IV adrabetadex support the utility of this plasma NPC 
biomarker as a potential outcome measure to monitor the effects of IV adrabetadex on peripheral tissues. 
Utilizing this data, we would have approximately 80% power to detect a 33% reduction in the plasma biomarker 
concentration in 5 subjects. Utilizing this data, we would have approximately 57, 80 and 99% power to detect a 
25, 33 and 50%, respectively, reduction in plasma biomarker concentration in 5 subjects. 
 
The secondary outcome measure for this trial is the plasma AST and ALT levels.   
  
For group comparisons, such as comparing mean values of primary outcome measurements, the statistical 
significance of differences in mean values will be determined by a two-tailed single-factor ANOVA or Student’s t 
test. To perform correlations, such as for comparison of primary/secondary outcome data with NIH severity scale 
values or clinical assessments, data will be analyzed using Pearson and Spearman correlations, as appropriate. 
A p-value of 0.05 or less was considered significant. A Bonferroni posttest correction will be used to adjust for 
multiple comparisons (e.g., when analyzing the panel of secondary outcome measures). 
 
 
 

 
 
 
11.  Adverse Events, Protocol Deviations, and Data Safety Monitoring 
 
11.1 Definitions 
Adverse event:  An adverse event (AE) means any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related.  
 
Suspected adverse reaction: This is defined as any AE for which there is a reasonable possibility that the drug 
caused the AE. For the purposes of IND safety reporting, ‘‘reasonable possibility’’ means there is evidence to 
suggest a causal relationship between the drug and the AE. Suspected adverse reaction implies a lesser degree 
of certainty about causality than adverse reaction, which means any AE caused by a drug. 
 
Life-Threatening AE or Life-Threatening Suspected Adverse Reaction: An AE or suspected adverse 
reaction is considered ‘‘life-threatening’’ if, in the view of the Investigator/Sponsor, its occurrence places the 
subject at immediate risk of death. It does not include an AE or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death. 
 
Serious Adverse Event or Serious Suspected Adverse Reaction: An AE or suspected adverse reaction is 
considered ‘‘serious’’ if, in the view of the Investigator/Sponsor, it results in any of the following outcomes:  
 
 
1.  Death 
 
2.  A life-threatening adverse event 
 
3.  Inpatient hospitalization or prolongation of hospitalization 
 
4.  A persistent or significant incapacity or substantial disruption of the ability to conduct normal  
 
 
life functions 
 
5.  A congenital anomaly/birth defect 
 
Unexpected AE or Unexpected Suspected Adverse Reaction: An AE or suspected adverse reaction is 
considered “unexpected” if it is not listed in the protocol or consent or is not listed at the specificity or severity 
that has been observed.  
 
11.2 Adverse Event Classification 
Relationship to Investigational Drug: The following two classifications should be used when evaluating the 
relationship of AEs and serious adverse events (SAEs) to the investigational drug: 
 
• 
Unrelated: No relationship between the experience and the administration of study drug; rather, related 
to other etiologies such as concomitant medications or subject’s clinical state. The reaction can be 
reasonably explained by the known characteristics of the subject’s clinical state or other modes of therapy 
administered to the subject. 
 
• 
Related: A reaction that follows at least a plausible temporal sequence from administration of the study 
drug. 
 
11.3 Severity of an Adverse Event 
Severity will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE), Version 5.0 (Published: 27 NOV 2017; v.5.0): 
 
Grade 1  
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only;  
 
 
 
 
intervention not indicated. 
 
Grade 2  
Moderate; minimal, local or noninvasive intervention indicated; limiting age- 
 
 
 
 
appropriate instrumental activities of daily living (ADL). 
 

 
 
 
Grade 3  
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation 
of hospitalization indicated; disabling; limiting self- care ADL. 
 
Grade 4  
Life-threatening consequences; urgent intervention indicated.  
 
Grade 5  
Death related to AE. 
 
 
11.4 Monitoring of Adverse Event Data  
The investigators will review each subject weekly during an admission. This may be by group email or conference 
call. 
 
A local monitor and an independent Data Safety Monitoring Committee (DSMC) will review data on subjects 
completing and enrolled in the study.  Review will occur after the first two subjects complete the study, and after 
each additional subject completes the study. Review may occur earlier if indicated by clinical circumstances.       
 
11.4.1 Review of Safety and Tolerability 
The evaluation of tolerability of a dose in an individual subject will be reviewed by the Principal Investigator with 
input from the Protocol Investigators, local monitor, and the DSMC. See Table 1.   
 
11.4.2 Review of Respiratory Compromise 
The study will be discontinued if two subjects demonstrate respiratory compromise associated with drug infusion 
at 500 mg/kg dose. If three subjects demonstrate drug related respiratory compromise associated with drug 
infusion in cohort two (1000mg/kg group) dosing for all remaining subjects (cohort 2) will be decreased to 
500mg/kg.     
 
11.4.3 Review of High Frequency Hearing Loss 
Although not anticipated at the doses being evaluated, high frequency hearing loss is an expected complication 
of adrabetadex administration.   
 
11.5 Data Safety Monitoring Committee 
An independent Data Safety Monitoring Committee (DSMC) will review safety data from this study after the first 
two subjects complete the study and after each additional subject completes the study. Members will be 
“independent” in that they have no other involvement in the study. The DSMC will review data from each cohort 
prior to dose escalation. The DSMC will submit brief safety reports to the sponsor-investigator regarding the 
safety and progress of the trial.  The DSMC may also meet ad hoc at the request of the sponsor-investigator. A 
local monitor, also independent to the study, will review reports to and from the DSMC. Reports from the DSMC 
and local monitor will be submitted to the institutional IRB along with a recommendation from the local monitor 
as to whether the study should continue with modification, continue without modification, or terminate. 
 
11.6 Documentation of Adverse Events  
Subjects will be evaluated and interviewed to identify AEs during the course of the study. AEs may also be 
identified through clinical and neurological examinations, laboratory tests, etc. Any events occurring prior to 
dosing will be recorded on the Medical History CRF. Events occurring after administration of the first dose of 
study medication will be recorded on the AE CRF. AE that occur up to and including 30 days after administration 
of the last dose of study drug must be reported.  
 
All AEs spontaneously reported by the subject or in response to a question from study personnel or revealed by 
observation, physical examination, or other diagnostic procedures will be recorded on the Adverse Event Form 
for that visit. Any clinically relevant deterioration in laboratory assessments or other clinical findings is considered 

 
 
 
an AE and must be recorded on the AE CRF, unless otherwise stated in the protocol. AE information recorded 
on AE CRFs will be entered into the database on an ongoing basis.  
 
For SAEs, a Serious Adverse Event Form must also be completed with as much information as possible and 
submitted in the time frame described below. When new significant information is obtained as well as when the 
outcome of an event is known, the Investigator should record the information on a new SAE form. If the subject 
was hospitalized, a copy of the discharge summary and any other relevant hospital records (e.g., admission 
report, laboratory test results, etc., must be included as part of the patient medical file). 
  
All AEs considered to be related to study medication and all SAEs will be followed until resolved or until stable.  
 
11.7 Notification about Serious Adverse Events and Serious Unexpected Adverse Reactions 
 
11.7.1 Investigator Reporting  
Investigators must report any SAE, whether or not considered drug related, including those listed in the protocol 
or Investigator Brochure. The report must include an assessment of whether there is a reasonable possibility 
that the drug caused the event.  
 
The study site will document all SAEs that occur (whether or not related to study drug) on the appropriate SAE 
form. The collection period for all SAEs will begin after informed consent is obtained and end after procedures 
for the final study visit have been completed.  
 
All SAEs must be submitted within 24 hrs and will be reviewed by the principal investigator or qualified designee 
and reported to the FDA and IRB according to applicable regulations and guidance.  The site, within 48hrs, will 
submit all copies of the submitted MedWatch Form FDA 3500 to safety@mandoshealth.com.   
 
SAE’s will be reported to the responsible IRB per institutions policy.   
 
SAE Reporting Contact Information: 
 
Sponsor/Principal Investigator: 
Medical Monitor 
Patricia Dickson, MD 
4444 Forest Park Ave 
St. Louis, MO 63110 
(314) 273-2943 
pdickson@wustl.edu 
 
Phillip Tarr, MD 
One Children’s Place 
St. Louis, MO 63110 
(314) 454-6173 
tarr@wustl.edu 
11.7. Adverse Events Exempt from IRB Reporting  
The following will not be reported to the IRB as AEs:  
 
1.  Findings present at initial evaluation; 
 
2.  Abnormal laboratory tests that have no clinical consequence; 
 
3. Abnormal clinical tests in which the clinical response would be considered standard care (such as iron 
supplementation of iron deficiency anemia), and are unlikely to be related to the protocol. 
 
4.  Problems listed in Table 2 unless an increase in frequency is noted. 
 
 

 
 
 
Table 2. Adverse Events Associated with NPC1 
Category 
Adverse Event 
HEENT 
  
Eyes 
Ptosis 
Abnormal eye movements (including vertical supranuclear gaze 
palsy and abnormalities of both vertical and horizontal eye 
movements) 
Audiologic 
Progressive high frequency hearing loss 
Abnormalities in Auditory Brain Stem Responses 
Oromotor/Speech  
Dysarthria 
Dysphagia, choking/gagging on food or saliva 
Copious secretions/drooling 
Respiratory 
Aspiration 
Aspiration pneumonia 
Sleep apnea  
Gastrointestinal/ 
Genitourinary 
Hepatomegaly 
Elevated liver enzymes 
Splenomegaly 
Gastrostomy tube related to dysphasia 
Bladder/bowel incontinence 
Diarrhea  
Constipation 
Lymphatic 
Enlarged tonsils and adenoids 
Hematologic 
Epistaxis 
Thrombocytopenia  
Decreased serum iron, % saturation (not typically associated  
with low MCV) 
Musculoskeletal/Extremities Hyperreflexia, clonus 
Motor impairment 
Gross motor ataxia, impaired ambulation, balance,  
coordination, decreased muscular strength, muscle contractures 
Fine motor ataxia, tremor 
Neurological 
Seizures 
Cognitive Impairment:  
Learning difficulty, long/short term memory loss  
Sleep Disruptions: 
Gelastic cataplexy 
Narcolepsy 
Sleep schedule inversion 
Fatigue, daytime sleepiness 
Psychiatric/Behavioral 
Mood swings, diagnosis of major depressive disorder, bipolar 
disorder, schizophrenia  
ADD/ADHD diagnosis (not more common than in general pediatric
population) 
ADD: attention deficit disorder; ADHD: attention deficit hyperactivity disorder; HEENT: head, 
eyes, ears, nose, throat; MCV: mean corpuscular volume 
 
11.8 Protocol Deviations 

 
 
 
The following anticipated minor deviations in the conduct of the protocol will not be reported to the site IRBs 
unless they occur at a rate greater than that which is anticipated to occur (frequency will be assessed on a 12 
month basis). 
 
 
 
 
 
 
 
 
 
 
Expected Frequency 
Inability to obtain a blood or urine sample  
 
 
 
 
15% 
Technical issues preventing analysis of a blood  
   Sample (e.g. hemolysis) 
 
 
 
 
 
 
15% 
Procedure or sample not obtained at specified time  
 
 
15% 
Drug administration occurring outside of defined time range 
 
10% 
 
Not obtaining a test due to blood limit prioritization will not be considered a protocol deviation. 
 
 
 
 

 
 
 
12. Investigational Product 
 
12.1 Identify of the Investigational Product 
Adrabetadex will be provided to the pharmacies at the St. Louis Children’s Hospital as a 200 mg/ml injectable 
solution in 100 ml vials.  
 
The formulation of adrabetadex involves dissolving the Active Pharmaceutical Ingredient in water for injection, 
adding sodium chloride to 0.9% w/v and adjusting the pH if necessary with 0.01N sodium hydroxide and brought 
to the final volume with water for injection. The product is a clear, colorless solution that is free from visible 
foreign matter. 
 
The investigational product will be labeled as an investigational product with the drug name, concentration and 
dosage instructions.   
  
The St. Louis Children’s Hospital pharmacy will dispense the product for administration by the Patient Care 
Unit.  
 
12.2 Storage of the Investigational Product 
Investigational product should be stored between 15-25 °C. 
 
12.3 Investigational Product Accountability 
The St. Louis Children’s Hospital pharmacy is responsible for the accountability of the investigational product. 
This will include documentation of receipt, storage, and dispensing of the investigational agent. The St. Louis 
Children’s Hospital pharmacy will return or destroy (per instruction of the IND sponsor) unused investigational 
drug at the conclusion of the study. 
 
 
 

 
 
 
13. Study Administration 
Quality assurance and quality control systems with written SOPs will be implemented and maintained to ensure 
this trial will be conducted and data will be generated, documented (recorded), and reported in compliance with 
the protocol, GCP, and the applicable regulatory requirements.  
 
An external monitoring service will be used for monitoring. The monitoring visits must be conducted according 
to the applicable ICH and GCP guidelines to ensure protocol adherence, quality of data, drug accountability, 
compliance with regulatory requirements, and continued adequacy of the investigational site and its facilities. 
During these visits, CRFs and other data related to the study will be reviewed and any discrepancies or omissions 
will be resolved. The Clinical Monitor will be given access to study-relevant source documents (including medical 
records) for purposes of source data verification. 
 
Quality control will be applied to each stage of data handling to ensure that all data are reliable and have been 
processed correctly. 
 
13.1 Data Handling and Recordkeeping 
 
13.1.1 Electronic Data 
Clinical data will be stored into REDCap, a secure, web-based application available through the Clinical and 
Translational Science Award (CTSA) at WUSM. 
 
13.1.2 Case Report Form Completion 
CRFs will be completed for each study subject. It is the Investigator’s responsibility to ensure the accuracy, 
completeness, legibility, and timeliness of the data reported in the subject’s CRF. Source documentation 
supporting the CRF data should indicate the subject’s participation in the study and should document the dates 
and details of study procedures, AEs, and subject status. 
 
The Investigator will maintain copies of the CRFs at the study site. Completed electronic CRFs are to be signed 
off by the Investigator or his/her designee. 
 For subjects who discontinue or terminate from the study, the CRFs will be completed as much as possible, and 
the reason for the discontinuance or termination clearly and concisely specified on the appropriate CRF. 
 
In addition, electronic data capture will be used for the study. Clinical data are entered into REDCap, a secure, web-
based application available through the Clinical and Translational Science Award (CTSA) at WUSM. Access to 
our REDCap system is protected by multiple layers of security, running on Linux platforms configured for strict 
user permission policies. Our REDCap database is hosted on scalable cloud based services hosted in the WUSM 
secure network. User access is provided via an external secure web server. All web communication between the 
user web browser and the web server is SSL encrypted. Further protections are provided via strict Linux 
permission configurations on the servers themselves. 
All database transactions are continually backed to facilitate PITR (point in time recovery) methods and are 
stored for approximately 30 days. Uploaded files are stored on secure cloud services and are only accessible via 
the WUSM secure network. 
Access to the data and various systems are protected by WUSTL Key authentication per University best 
practices. 
.  
 

 
 
 
13.1.3 Retention of Study Records 
The Investigator will maintain all study records according to ICH/GCP guidelines and applicable regulatory 
requirements. Records will be retained for at least two years after the last marketing application approval and 
until there are no pending or contemplated marketing applications or two years after formal discontinuation of 
the clinical development of the investigational product or according to applicable regulatory requirements. If the 
Investigator withdraws from the responsibility of keeping the study records, custody must be transferred to an 
appropriate person willing to accept the responsibility. If a custodial change occurs, it must be documented.  
 
13.2 Confidentiality 
To maintain subject privacy, all CRFs, study drug accountability records, study reports, and communications will 
identify the subject by the assigned subject number. The Investigator will grant monitor(s) and auditor(s) from 
the Sponsor or its designee and regulatory authority(ies) access to the subject’s original medical records for 
verification of data gathered on the CRFs and to audit the data collection process. The subject’s confidentiality 
will be maintained and will not be made publicly available to the extent permitted by the applicable laws and 
regulations. 
 
Subjects will be notified that registration information, results, and other information about this study will be 
submitted to ClinicalTrials.gov, a publicly available trial registry database; however, protected health information 
of individual subjects will not be used. 
 
All information regarding the investigational product is privileged and confidential information. The Investigator 
agrees to use this information to accomplish the study and will not use it for other purposes without consent from 
NIH. It is understood that there is an obligation to provide complete data obtained during the study. The 
information obtained from the clinical study will be used towards the development of the investigational product 
and may be disclosed to regulatory authority(ies), other Investigators, corporate partners, or consultants, as 
required. 
 
13.3 Publication Policy 
All information concerning use of adrabetadex in the context of this trial is considered confidential and shall 
remain the property of the investigators. In accordance with NIH policy, data will be shared outside of the 
consortium group principally through publications and presentations at scientific conferences. Publications 
reporting the results of this trial will be submitted in a timely way. Data will be made available to Mandos, LLC 
under a Cooperative Research Agreement. There are no anticipated delays or impediments to free publication 
of these results regardless of the outcome. 
 
13.4 Direct Access to Source Data 
The Investigators will permit trial-related monitoring, audits, IRB review, and regulatory inspections as requested 
by FDA, the Sponsor, or the Sponsor designee, including direct access to source data/documents (i.e., original 
medical records, laboratory reports, hospital documents, progress reports, signed informed consent forms, etc.), 
in addition to CRFs. 
 
13.5 Protocol Amendments 
Changes to the conduct of the study should be prepared as a protocol amendment and receive written approval 
by the IRB prior to implementation, except when necessary to eliminate immediate hazards to the subjects or 
when the changes involve only logistical or administrative aspects of the trial (e.g., change of monitor, telephone 
numbers). Sponsor and regulatory authorizes will be notified as appropriate. 
 
 
 
 

 
 
 
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