Clinical trial NCT02047461
Conditions: Molybdenum Cofactor Deficiency, Type A
Keywords: Molybdenum cofactor deficiency (MoCD) molybdenum cofactor (MoCo) biosynthesis sulfite oxidase (SO) xanthine dehydrogenase aldehyde oxidase S sulfocysteine (SSC)
Sponsor: Origin Biosciences
Start date: 2014-04-01; Completion date: 2022-10-01
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will include a screening period, a 6-month treatment period, followed by long-term extension period expected to last approximately 72 months.

Detailed description:
Patients will receive daily IV infusions of ORGN001 (formerly ALXN1101) starting on Day 1. After a prescribed period, dosing will increase monthly based on defined patient safety measures. After Month 6, patients will continue daily dosing at their last tolerated dose.

Arms: arm 1: daily IV infusions
Interventions: intervention 1: ORGN001 (formerly ALXN1101)
Intervention descriptions: intervention 1: IV infusion

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
NCT Number: NCT02047461 
 
 
Certain information within this protocol has been redacted (i.e., specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information or 
company confidential information. 
 
 
This may include, but is not limited to, redaction of the following: 
 
• Named persons or organizations associated with the study. 
• Proprietary information, such as scales or coding systems. 
• Other information as needed to protect confidentiality of BridgeBio Pharma, Sentynl 
Therapeutics, Inc., or their partners, or to otherwise protect the integrity of the clinical 
study. 






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INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochure for ORGN001 (formerly ALXN1101). I 
have read the ALXN1101-MCD-201 study protocol and agree to conduct the study as outlined. I 
agree to maintain the confidentiality of all information received or developed in connection with 
this protocol. I agree to conduct the trial in accordance with ethical principles that have their 
origin in the Declaration of Helsinki and are consistent with the International Council for 
Harmonisation (ICH)/Good Clinical Practice (GCP) and applicable regulatory requirements. 
 
 
 
 
 
 
______________________________________________ 
Printed Name of Investigator 
 
 
 
 
 
 
______________________________________________  
_____________ 
Signature of Investigator 
 
 
 
 
 
Date 
 




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SYNOPSIS 
Name of Sponsor/Company: Origin Biosciences, Inc. (Origin); previously; Alexion Pharmaceuticals, Inc. 
(Alexion) 
Name of Investigational Product: ORGN001 (formerly ALXN1101) 
Name of Active Ingredient: Cyclic pyranopterin monophosphate monohydrobromide dihydrate 
Title of Study: A Phase 2, Multicenter, Multinational, Open-Label, Dose-Escalation Study to Evaluate the 
Safety and Efficacy of ORGN001 (formerly ALXN1101) in Pediatric Patients with Molybdenum Cofactor 
Deficiency (MoCD) Type A Currently Treated with Recombinant Escherichia coli-derived Cyclic Pyranopterin 
Monophosphate (rcPMP) 
Study centers: This will be a multicenter, multinational study with approximately 5 investigational study 
centers. 
Principal Investigator: TBD 
Investigators: TBD 
Studied period:  
6-Month Initial Treatment Period, followed by an Extension Period 
Estimated date first patient enrolled: February 2014 
Estimated date last patient completed: The Extension Period is expected to last until 
ORGN001 is commercially available or development is stopped.  
Phase of 
development: 
2/3 
Study Rationale 
Molybdenum cofactor deficiency (MoCD) is a rare, life-threatening, autosomal recessive, inborn error of 
metabolism characterized by disruption of the metabolic pathway for production of molybdenum cofactor 
(MoCo), which is essential for the function of sulfite oxidase (SO), 
 dehydrogenase, and aldehyde 
oxidase. While all 3 enzymes are dependent on MoCo, the loss of SO activity is responsible for the severe and 
rapidly progressive neurologic damage seen in MoCD. 
The incidence of MoCD is estimated to be between 1/100,000 and 1/200,000 newborn babies worldwide 
(Schwahn 2015). Affected individuals usually present as neonates with severe symptoms such as intractable 
seizures, burst-suppression or multifocal electroencephalogram (EEG), exaggerated startle reactions, axial 
hypotonia, limb hypertonia, and feeding difficulties. Neuronal injury is severe and is rapidly progressive as a 
result of accumulation of toxic levels of sulfite in the brain and subsequent formation of S-sulfocysteine (SSC). 
Death commonly occurs in the neonatal period, and patients who survive that period develop a severe static 
encephalopathy and developmental delay due to central nervous system (CNS) injury including subcortical cystic 
cavitation, hydrocephalus, diffuse cortical atrophy, and basal ganglia injury. At present, there is no cure. 
Although there are 3 types of MoCD, two-thirds of MoCD patients have Type A, which is due to a mutation in 
the MOCS1 gene localized on 6p21.3. In MoCD Type A, the first of the 4 synthetic steps in the formation of 
MoCo is interrupted, and guanosine triphosphate (GTP) cannot be converted into cyclic pyranopterin 
monophosphate (cPMP). Diagnosis of MoCD Type A is based on clinical presentation and biochemical 
phenotype (such as elevated urinary sulfite and/or SSC, and low or absent uric acid in the urine or plasma), and 
diagnosis is then confirmed by genetic testing. 
ORGN001 (cyclic pyranopterin monophosphate monohydrobromide dihydrate), provides a therapeutic approach 
for the treatment of MoCD Type A by restoring the MoCo biosynthesis. Results of preclinical pharmacology 
studies with ORGN001 suggest that the metabolic derangement in MoCD Type A could be corrected by 
administration of synthetic cPMP, resulting in restoration of enzymatic activity and thus, correction of the 
metabolic pathways that would otherwise lead to the accumulation of toxic metabolites causing CNS injury. 








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Statistical methods: 
The statistical analysis of all safety and efficacy parameters will be conducted on all patients who receive at least 
1 dose of ORGN001. All data collected in this study will be documented using summary tables, figures and 
patient data listings. For categorical variables, frequencies and percentages will be presented. For continuous 
variables, descriptive statistics (n, mean, median, standard deviation [SD], minimum, and maximum) will be 
presented. 
Safety: 
The incidence of treatment-emergent AEs and SAEs will be summarized by System Organ Class (SOC) and 
Preferred Term overall, by severity, and by relationship to study drug. Changes from baseline in vital signs, 
laboratory assessments (chemistry, hematology, and urinalysis) will be summarized. Shifts from baseline in 
laboratory assessments as well as physical examination findings will be summarized for the different time points. 
Efficacy: 
Changes from baseline in urine and blood SSC levels and percentage changes from baseline to the study time 
points will be summarized. Observed values and changes in Bayley-III cognitive, gross, fine motor scaled scores 
and cognitive and motor composite scores will be summarized. The frequency of seizures will be summarized. 
Shifts from baseline in clinical findings from neurologic examinations and neuroimaging findings will be 
presented for the different time points. Growth parameters (body weight, body length, and head circumference) 
will be converted to age-adjusted z-scores and summarized over time. Graphical displays will be presented as 
appropriate. 
Pharmacokinetics: 
Plasma concentration versus time profiles will be graphically summarized. Noncompartmental PK parameters 
such as Cmax, tmax, AUC, and t½ will be determined if possible, and, dose linearity will be explored. Plasma 
concentration and PK parameter summaries will include descriptive statistics, as appropriate. 
 
 
Additional details for statistical analyses will be described in the statistical analysis plan. 


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SUMMARY OF CHANGES 
 
Section 
Description of Change  
1.3 Risk/Benefit Assessment 
Additional text: 
“In vitro and preclinical studies have identified that 
ORGN001 has phototoxic potential. Patients and caregivers 
are instructed to avoid direct sunlight and to use precautions 
when exposed to the sun. Protective measures include 
wearing of sunglasses, a hat, long sleeved shirts, long pants 
and the use of protective sunscreen.” 


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TABLE OF CONTENTS 
ALXN1101-MCD-201 ........................................................................................................1 
SPONSOR SIGNATURE PAGE ......................................................................................2 
INVESTIGATOR’S AGREEMENT ................................................................................3 
PROCEDURES IN CASE OF EMERGENCY ...............................................................4 
SYNOPSIS ..........................................................................................................................5 
SUMMARY OF CHANGES ...........................................................................................10 
TABLE OF CONTENTS ................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..............................15 
1 
INTRODUCTION ....................................................................................................17 
1.1 
Background ..........................................................................................................17 
1.2 
Rationale for the Study ........................................................................................17 
1.3 
Risk/Benefit Assessment ......................................................................................18 
1.4 
Rationale for the Patient Population ..................................................................19 
1.5 
Rationale for Proposed Dosing ...........................................................................19 
1.6 
Rationale for the Overall Design ........................................................................20 
1.7 
Clinical Studies with ORGN001 .........................................................................20 
2 
TRIAL OBJECTIVES AND ENDPOINTS ...........................................................21 
2.1 
Objectives..............................................................................................................21 
2.1.1 
Primary Objective ..........................................................................................21 
2.1.2 
Secondary Objectives.....................................................................................21 
 
 
2.2 
Endpoints ..............................................................................................................21 
2.2.1 
Safety Endpoints ............................................................................................21 
2.2.2 
Efficacy Endpoints .........................................................................................21 
2.2.3 
Pharmacokinetic Endpoint ...........................................................................22 
 
 
3 
INVESTIGATIONAL PLAN ..................................................................................23 
3.1 
Overall Study Design ...........................................................................................23 
3.2 
NUMBER OF PATIENTS ..................................................................................24 
3.3 
Study Treatment and Dose Escalations .............................................................24 
3.4 
SAFETY REVIEW COMMITTEE ...................................................................25 
3.4.1 
Criteria to Hold Dose Escalation ..................................................................25 
3.4.2 
Safety Criteria for Unscheduled Dose Adjustments ...................................26 
3.5 
Criteria for Site or Study Termination ..............................................................26 
4 
SELECTION AND WITHDRAWAL OF PATIENTS .........................................37 
4.1 
Patient Recruitment and Consent ......................................................................37 
4.2 
Patient Inclusion Criteria ....................................................................................37 
4.3 
Patient Exclusion Criteria ...................................................................................37 
4.4 
Patient Withdrawal Criteria ...............................................................................37 
5 
TREATMENT OF PATIENTS ...............................................................................39 
5.1 
Description of Study Drug ..................................................................................39 
5.2 
Prior and Concomitant Medications and Procedures ......................................39 
5.3 
Treatment Compliance ........................................................................................39 
6 
STUDY DRUG MATERIALS AND MANAGEMENT ........................................40 
6.1 
Study Drug ............................................................................................................40 
6.2 
Study Drug Packaging and Labeling .................................................................40 


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6.3 
Study Drug Storage..............................................................................................40 
6.4 
Study Drug Preparation ......................................................................................40 
6.5 
Study Drug Administration ................................................................................40 
7 
STUDY DRUG ACCOUNTABILITY ....................................................................41 
7.1 
Study Drug Handling and Disposal ....................................................................41 
8 
SCREENING ASSESSMENTS ...............................................................................41 
8.1 
Informed Consent ................................................................................................41 
8.2 
Demographic Data and Onset of Disease ...........................................................41 
8.3 
Medical History, Family History, and Genotype ..............................................41 
9 
EFFICACY ASSESSMENTS ..................................................................................41 
9.1 
Neurologic Examinations ....................................................................................42 
9.2 
Bayley Scales of Infant and Toddler Development ...........................................42 
9.3 
THE GROSS MOTOR FUNCTION CLASSIFICATION SYSTEM .............42 
9.4 
Wechsler Preschool and Primary Scale of Intelligence ....................................43 
9.5 
Seizure Diary ........................................................................................................43 
9.6 
Neuroimaging .......................................................................................................43 
9.7 
Growth Parameters .............................................................................................43 
9.8 
Feeding Pattern Assessment................................................................................43 
10 PHARMACODYNAMIC ASSESSMENTS ...........................................................44 
11 PHARMACOKINETIC ASSESSMENTS .............................................................46 
12 SAFETY ASSESSMENTS .......................................................................................48 
12.1 
Vital Signs .............................................................................................................48 
12.1.1 
Additional Blood Pressure Measurements ..................................................48 
12.2 
Physical Examination ..........................................................................................48 
12.3 
Laboratory Assessments ......................................................................................49 
12.3.1 
Hematology .....................................................................................................49 
12.3.2 
Serum Chemistry ...........................................................................................49 
12.3.3 
Coagulation .....................................................................................................50 
12.3.4 
Urinalysis ........................................................................................................50 
12.4 
Electroencephalogram .........................................................................................50 
12.5 
Adverse Event Management ...............................................................................50 
12.5.1 
Definition of an Adverse Event .....................................................................50 
12.5.2 
Definition of a Serious Adverse Event .........................................................51 
12.5.3 
Severity Assessment .......................................................................................52 
12.5.4 
Causality Assessment .....................................................................................52 
12.5.5 
Outcome ..........................................................................................................53 
12.5.6 
Recording Adverse Events ............................................................................53 
12.5.7 
Reporting of Serious Adverse Events to Sponsor .......................................54 
12.5.8 
Reporting Requirements ...............................................................................54 
13 STATISTICAL METHODS AND PLANNED ANALYSES ................................56 
13.1 
General Considerations .......................................................................................56 
13.2 
Determination of Sample Size .............................................................................56 
13.3 
Analysis Population .............................................................................................56 
13.4 
Demographics and Baseline Characteristics .....................................................56 
13.5 
Patient Disposition and Treatment Compliance ...............................................56 
13.6 
Prior and Concomitant Medications ..................................................................56 
13.7 
Efficacy Analyses .................................................................................................56 
13.7.1 
Primary Efficacy Analysis .............................................................................56 


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13.7.2 
Secondary Efficacy Analyses ........................................................................57 
 
 
13.8 
Safety Analyses .....................................................................................................57 
13.8.1 
Adverse Events ...............................................................................................57 
13.8.2 
Laboratory Parameters .................................................................................58 
13.8.3 
Physical Examinations and Vital Signs ........................................................58 
13.8.4 
Electroencephalograms .................................................................................58 
13.9 
Pharmacokinetic Analysis ...................................................................................58 
13.10 Other Statistical Issues ........................................................................................58 
13.10.1 
Missing or Invalid Data .................................................................................58 
13.10.2 
Computing Environment...............................................................................58 
14 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ....................................59 
14.1 
Study Monitoring .................................................................................................59 
14.2 
Audits and Inspections ........................................................................................59 
14.3 
Institutional Review Board .................................................................................59 
15 QUALITY CONTROL AND QUALITY ASSURANCE ......................................60 
16 ETHICS .....................................................................................................................60 
16.1 
Ethics Review .......................................................................................................60 
16.2 
Data Monitoring Committee Review .................................................................60 
16.3 
Written Informed Consent ..................................................................................61 
16.4 
Patient Data Protection .......................................................................................61 
17 DATA HANDLING AND RECORDKEEPING....................................................62 
17.1 
Inspection of Records ..........................................................................................62 
17.2 
Retention of Records............................................................................................62 
17.3 
Retention of Biological Samples .........................................................................62 
17.4 
Data Privacy .........................................................................................................63 
18 PUBLICATION POLICY ........................................................................................63 
19 LIST OF REFERENCES .........................................................................................64 
20 APPENDICES ...........................................................................................................65 
APPENDIX A. 
BLOOD SAMPLING VOLUMES ...................................................66 
APPENDIX B. 
BLOOD SAMPLING VOLUMES TABLE (SCREENING 
THROUGH MONTH 6) ...........................................................................................67 
APPENDIX C. 
--BLOOD SAMPLING VOLUMES (EXTENSION PERIOD AND 
SAFETY FOLLOW-UP VISIT) ..............................................................................69 
APPENDIX D. 
BLOOD SAMPLING VOLUMES FOR UNSCHEDULED DOSE 
ADJUSTMENT .........................................................................................................70 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ..............................................................4 
Table 2: 
Abbreviations and Specialist Terms.......................................................15 
Table 3: 
Schedule of Assessments (Screening and Month 1 of the 6-Month Initial 
Treatment Period) ....................................................................................28 
Table 4: 
Schedule of Assessments (Months 2 through 6 of the 6-Month Initial 
Treatment Period) ....................................................................................31 
Table 5: 
Schedule of Assessments for an Unscheduled Dose Adjustment .........34 
Table 6: 
Schedule of Assessments (Extension Period and Safety Follow-Up) ...35 
Table 7: 
ORGN001 Description .............................................................................39 
Table 8: 
Pharmacokinetic Sampling Schedule .....................................................46 
Table 9: 
Criteria for Child-Pugh Classification ...................................................48 
Table 10: 
Blood Sampling Volumes (Screening Through Month 6) ....................67 
Table 11: 
Sample Volume Collection During the Extension Period and Safety 
Follow--Up Visit .......................................................................................69 
Table 12: 
Sample Volume Collection for an Unscheduled Dose Adjustment .....70 
 
LIST OF FIGURES 
Figure 1: 
ALXN1101-MCD-201 Study Design ......................................................27 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms 
Abbreviation 
Definition 
1H NMR 
Proton nuclear magnetic resonance spectroscopy 
13C NMR 
Carbon nuclear magnetic resonance spectroscopy 
31P NMR 
Phosphorous nuclear magnetic resonance spectroscopy 
AE 
Adverse event 
Alexion 
Alexion Pharma GmbH 
AUC 
Area under the plasma concentration-time curve 
BP 
Blood pressure 
Bayley-III 
Bayley Scales of Infant and Toddler Development-Third Edition 
°C 
Degrees Celsius 
Cmax 
Maximum observed plasma concentration 
CNS 
Central nervous system 
Colbourne 
Colbourne Pharmaceuticals GmbH 
cPMP 
Cyclic pyranopterin monophosphate 
CRF 
Case Report Form 
CT 
Computed tomography 
CYP 450 
Cytochrome P450 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
E. coli 
Escherichia coli 
eCRF 
Electronic Case Report Form 
EEG 
Electroencephalogram 
EMLA 
Eutectic mixture of local anesthetics 
EOI 
End of infusion 
EOS 
End of study 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GMFCS 
Gross Motor Function Classification System 
GMP 
Good Manufacturing Practice 
GTP 
Guanosine triphosphate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
LC-MS/MS 
Liquid chromatography with tandem mass spectrometric detection 
MoCD 
Molybdenum cofactor deficiency 
MedDRA 
Medical Dictionary for Regulatory Activities 
MoCo 
Molybdenum cofactor 
MPT 
Molybdopterin 
MRI 
Magnetic resonance imaging 
MS 
Mass spectroscopy 
MSDS 
Material Safety Data Sheet 
N 
Normal 
NOAEL 
No observed adverse effect level 
Origin 
Origin Biosciences, Inc. 
PD 
Pharmacodynamics 


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PI 
Principal Investigator 
PK 
Pharmacokinetics 
PT 
Prothrombin time 
RBC 
Red blood cell 
rcPMP 
Recombinant E. coli-derived cPMP 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SO 
Sulfite oxidase 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
SSC 
S-sulfocysteine 
t1/2 
Terminal half-life 
tmax 
Time to maximum observed plasma concentration 
UK 
United Kingdom 
US 
United States (of America) 
UV 
Ultraviolet (spectroscopy) 
WBC 
White blood cell 
WHODrug 
World Health Organization Drug Dictionary 
WPPSI 
Wechsler Preschool and Primary Scale of Intelligence 


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1 
INTRODUCTION 
1.1 
Background 
Molybdenum cofactor deficiency (MoCD) is a rare, life-threatening, autosomal recessive, inborn 
error of metabolism characterized by disruption of the metabolic pathway for production of 
molybdenum cofactor (MoCo), which is essential for the function of sulfite oxidase (SO), 
xanthine dehydrogenase, and aldehyde oxidase. While all 3 enzymes are dependent on MoCo, 
the loss of SO activity is responsible for the severe and rapidly progressive neurologic damage 
seen in MoCD. 
The incidence of MoCD is estimated to be between 1/100,000 and 1/200,000 newborn babies 
worldwide (Schwahn 2015). Affected individuals usually present in the neonatal period with 
intractable seizures, burst--suppression or multifocal epileptic electroencephalogram (EEG), 
exaggerated startle reactions, axial hypotonia, limb hypertonia, and feeding difficulties (Johnson 
and Duran 2001; Kikuchi et al, 2012; Vijayakumr et al, 2011). Neuronal injury is severe and is 
rapidly progressive as a result of accumulation of toxic levels of sulfite in the brain and 
subsequent formation of S-sulfocysteine (SSC). Death commonly occurs in the neonatal period, 
and patients who survive that period develop a severe static encephalopathy and developmental 
delay due to central nervous system (CNS) injury including subcortical cystic cavitation, 
hydrocephalus, diffuse cortical atrophy, and basal ganglia injury (Johnson and Duran 2001; 
Johnson et al, 1980). 
Three types of MoCD have been described based on the genetic defect. Two-thirds of MoCD 
patients have Type A, which is due to a mutation in the MOCS1 gene localized on 6p21.3 and 
results in the interruption of the first of the 4 synthetic steps in the formation of MoCo; 
guanosine triphosphate (GTP) cannot be converted into cyclic pyranopterin monophosphate 
(cPMP). Diagnosis of MoCD Type A is based on clinical presentation (encephalopathy, seizures) 
and biochemical phenotype (elevated urinary sulfite and SSC, and low or absent uric acid in the 
urine or plasma). The diagnosis is then confirmed by genetic testing. At present, there is no 
approved therapy available and no cure. 
A treatment targeting MoCo biosynthesis represents a possible therapeutic strategy to treat 
MoCD Type A. A cPMP substitution therapy is expected to reconstitute MoCo biosynthesis and 
restore SO levels, thereby reducing the levels of the neurotoxic compounds, sulfite and SSC. 
1.2 
Rationale for the Study 
The previous sponsor, Alexion Pharma GmbH (Alexion) developed ORGN001 (formerly 
ALXN1101), a synthetic form of cPMP, which is a precursor molecule to MoCo, as a treatment 
for MoCD Type A.  Responsibility for the development of ORGN001 for the treatment of MoCD 
Type A has been assumed by Origin Biosciences, Inc.  ORGN001 provides a therapeutic 
approach for the treatment of MoCD Type A that is intended to restore MoCo biosynthesis. 
Results of preclinical pharmacology studies with ORGN001 suggest that the metabolic 
derangement in MoCD Type A could be corrected by administration of synthetic cPMP, 
resulting in restoration of enzymatic activity and thereby correction of the metabolic pathways 
that lead to the accumulation of toxic metabolites causing CNS injury. 
In vitro, ORGN001 increased molybdopterin (MPT) synthesis and restored SO activity 
(Clinch et al, 2013). Additionally, in a mouse model of MoCD Type A (Lee et al, 2002), 
ORGN001 effectively rescued MOCS1-/- mice from premature death and effectively decreased 
the plasma SSC level.  In 
 repeat dose-toxicity studies in adult rats and dogs, ORGN001 


















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3.4.2 
Safety Criteria for Unscheduled Dose Adjustments 
Doses may be adjusted based on the occurrence of drug-related AEs and changes in clinical 
parameters, as assessed by the SRC. The SRC chair will also convene the DMC if a dose 
escalation is being considered or will notify the DMC if the dose is decreased. If a patient has 
significant clinical worsening related to ORGN001 dosing, the dose may be decreased based 
on the clinical status of the patient and, if available, exposure data. If this occurs within the 
first 2 months, the target dose reduction would be approximately 25% of the starting dose 
 or to a level that is 
expected to result in exposure that is below the NOAEL AUC. If an unscheduled dose 
adjustment is necessary during Months 2 through 6 of the study, the patient’s dose will be 
reduced to the last tolerated dose. Alternatively, after dose escalation is complete, the patient 
can be returned to a prior dose based on the patient’s clinical status at the discretion of the 
treating physician after consultation with the SRC. 
3.5 
Criteria for Site or Study Termination 
For reasonable cause, the Investigator, Institutional Review Board (IRB)/Ethics Committee (EC), 
or Sponsor may terminate the study at a given center, in which case, the care of the patients at 
the site would be transferred to a different Investigator, or all centers, in which case, patients 
would return to the care of their treating physician. Conditions that may warrant termination of 
the study or investigational sites participating in this study include, but are not limited to: 
• Discovery of an unexpected, serious, or unacceptable risk to patients enrolled in 
the study 
• Decision on the part of the Sponsor to suspend or discontinue testing, 
evaluation, or development of the study drug 
• Failure of the Investigator to comply with the approved protocol, pertinent 
guidelines, and/or regulations 
• Submission of knowingly false information from the Investigator to the 
Sponsor and/or regulatory authorities 
The end of the study will be defined as the date of the last patient’s last visit.




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Table 3: 
Schedule of Assessments (Screening and Month 1 of the 6-Month Initial Treatment Period) 
Assessment 
Screening/ 
Baseline Period1,2 
Month 1 of the 6-Month Initial Treatment Period 
Study Day 
Month 
Visit Window (Days) 
Informed consent 
Eligibility 
Demographic data and onset of disease5 
Genotype7 
Family history8 
Medical history9 
Physical examination25 
Vital signs12,25 
Additional BP measurements 
Serum chemistry and hematology13, 25 
Coagulation14 
Urinalysis15, 25 
Growth parameters16 
Feeding pattern17 
Neurologic examination25 
GMFCS 
Bayley-III (age-appropriate test)19 
WPPSI20 
Record seizure diary data21, 25 
Neuroimaging22 
EEG23 
PD sampling, urine24,25 






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medications; MoCD = molybdenum cofactor deficiency; MRI = magnetic resonance imaging; PD = pharmacodynamics; PI = principal investigator; PK = 
pharmacokinetics; rcPMP = recombinant E. coli-derived cPMP; SRC = Safety Review Committee; SSC = S-sulfocysteine; WPPSI = Wechsler Preschool and 
Primary Scale of Intelligence. 
 






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22 Daily IV infusion of ORGN001 (24 hours ± 3 hours apart) can occur at home or while in-clinic 
23 Changes in seizure medications, including the reason for the change, will be recorded. 
24 Assessed only if the patient is seen in-clinic. An in-clinic visit is not required for blood and urine collection on this day. 
Abbreviations: AEs = adverse events; Bayley-III = Bayley Scales of Infant and Toddler Development-Third Edition; CRF = case report form; 
EEG = electroencephalogram; eCRF = electronic case report form; EOI = end of infusion; GMFCS = Gross Motor Function Classification System; 
meds = medications; MRI = magnetic resonance imaging; PD = pharmacodynamics; PK = pharmacokinetics; rcPMP = recombinant E. coli-derived cPMP; SRC 
= Safety Review Committee; SSC = S-sulfocysteine; WPPSI = Wechsler Preschool and Primary Scale of Intelligence. 
 










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All patients who discontinue or are withdrawn from the study will be encouraged to complete the 
Safety Follow-up Visit 
. 
The reasons for premature study withdrawal must be recorded in the patient’s case report form 
(CRF)/electronic case report form (eCRF) and in the source records. 
For patients who are prematurely withdrawn from the study due to clinical safety concerns (eg, 
intolerable AEs), the Investigator must immediately notify the Medical Monitor. In these 
patients, AEs leading to premature withdrawal must be followed until resolution or the patient is 
determined to be medically stable, in the opinion of the Investigator. Patients who withdraw from 
the study will not be replaced. 








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9.1 
Neurologic Examinations 
Neurologic examinations will be performed 
. The 
Day 1 assessment must be performed within 2 hours prior to the first infusion. Neurologic 
examinations are also performed if patients have unscheduled dose adjustments 
 
. Neurologic examination includes, but is not limited to, 
assessment of mental status, cranial nerves, motor strength and tone, sensory examination, deep 
tendon reflexes and primitive reflexes, if present. 
9.2 
Bayley Scales of Infant and Toddler Development 
The Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III) will be 
administered 
 to assess changes in gross motor, fine 
motor, language, and cognitive development. The Bayley-III will be administered to children 
less than 3 years of age. Additionally, for patients over 3 years of age with severe developmental 
delay, the Bayley-III may be more appropriate than the WPPSI and may therefore be 
administered instead. 
The Bayley-III is a standardized and norm-referenced instrument that assesses changes in gross 
motor, fine motor, language, and cognitive development. It is administered in infants and 
children 1 month to 42 months of age. 
The Bayley-III consists of a core battery of the following 5 scales, 3 of which are administered 
by a trained qualified professional with child interaction: the Cognitive Scale, the Language 
Scale (including the Receptive Communication and Expressive Communication subtests), and 
the Motor Scale (including the Fine Motor and Gross Motor subtests). The Social-Emotional 
Scale and Adaptive Behavior Scale together form the Social-Emotional and Adaptive Behavior 
Questionnaire, which is completed by the parent, legal guardian, or primary caregiver. This 
caregiver-administered portion of the Bayley-III will not be administered as part of this study. 
The Bayley-III assessments must be performed in the order specified in the Bayley-III Manual. 
The Language Scale will be administered only to native English speakers in English-speaking 
countries. 
From raw scores, scaled scores, developmental age equivalents, and growth scores can be 
calculated for the Cognitive, Receptive and Expressive Communication, Fine Motor, and Gross 
Motor subtests. Scaled scores also can be used to calculate the Cognitive, Language, and Motor 
composite scores, percentile ranks, and confidence intervals. 
A qualified professional will administer the Bayley-III and determine the appropriateness of each 
assessment. 
9.3 
THE GROSS MOTOR FUNCTION CLASSIFICATION SYSTEM 
Gross motor function using the GMFCS will be assessed 
 
. 
The GMFCS is a 5-level classification system that describes the gross motor function of children 
and youth (up to 18 years of age) on the basis of their self-initiated movement with particular 
emphasis on sitting, walking, and wheeled mobility for children with impaired motor skills. 
Distinctions between levels are based on functional abilities, the need for assistive technology, 
including hand-held mobility devices (walkers, crutches, or canes) or wheeled mobility, and to a 
much lesser extent, quality of movement. 
Children who have motor functions similar to those classified in "Level I" can generally walk 
without restrictions but tend to be limited in some of the more advanced motor skills. Children 


















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• Leads to a change in study dosing outside of the protocol defined 
dosing or discontinuation from the study; 
• Requires significant additional treatment; 
• Does not meet any of the conditions above; however, the Investigator or 
Sponsor considers the result as clinically significant or meeting the definition 
of an AE. 
This definition also includes the signs or symptoms resulting from: 
• Drug overdose 
• Drug withdrawal 
• Drug misuse 
• Drug interactions 
• Extravasation 
• Medication error 
• Occupational exposure 
An AE does not necessarily include the following: 
• Medical or surgical procedures (eg, surgery, endoscopies, tooth extraction, 
transfusion); the condition that leads to the procedure is the AE (eg, 
laparoscopic cholecystectomy is the procedure or treatment for an SAE of 
necrotic gall bladder); 
• Pre-existing diseases or conditions present or detected prior to the 
Screening evaluation that do not worsen; 
• Situations where an untoward medical occurrence has not occurred (eg, 
hospitalization for elective surgery if planned prior to the start of the study, 
social and/or convenience admissions). 
12.5.2 
Definition of a Serious Adverse Event 
Any AE that fulfills any one of the criteria listed below must be recorded as an SAE. An SAE is 
described as any untoward medical occurrence that at any dose: 
Results in death 
Is life-threatening 
Requires hospitalization or prolongation of hospitalizationb  
Hospitalization does not necessarily include the following: 
• Rehabilitation/hospice/nursing facility 
• Emergency Room/Department visit less than 24 hours 
• Elective or preplanned admission/surgery/Day surgery 
• Protocol-specified admission 
• Admission for a pre-existing condition not associated with either a new AE or 
with worsening of a pre-existing AE 
Results in persistent or significant disability/incapacity 


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Is a congenital anomaly/birth defect 
Is an important medical eventc 
a. The term "life-threatening" in the definition of "serious" refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
b. Hospitalization requires inpatient or prolongation of an existing hospitalization. AEs that 
are associated with hospitalization or prolongation of hospitalization are considered SAEs. 
c. Important Medical Event: Medical and scientific judgment should be exercised in deciding 
whether expedited reporting is appropriate in other situations, such as important medical 
events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the patient or may require intervention to prevent one of the other 
outcomes listed in the definition above. These should also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency. 
Severity and seriousness must be differentiated. Severity describes the intensity of an AE while 
the term seriousness refers to an AE that has met the criteria for an SAE as described above. 
12.5.3 
Severity Assessment 
An assessment of severity will be made by the Investigator using the following criteria: 
• Mild: events require minimal or no treatment and do not interfere with the 
patient’s daily activities. 
• Moderate: events result in a low level of inconvenience or concerns with 
the therapeutic measures. Moderate events may cause some interference 
with functioning. 
• Severe: events interrupt a patient’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually incapacitating. 
Change in severity of an AE should be documented based on specific guidance in the eCRF 
Completion Guidelines. 
Severity and seriousness must be differentiated: severity describes the intensity of an AE while 
seriousness refers to an AE that has met the criteria for an SAE. 
12.5.4 
Causality Assessment 
An Investigator causality assessment must be provided for all AEs (both nonserious and serious). 
This assessment must be recorded on the CRF/eCRF and any additional forms as appropriate. 
The definitions for the causality assessments are as follows: 
• Not related (unrelated): This relationship suggests that there is no association 
between the study drug and the reported event. 
• Unlikely related: This relationship suggests that the clinical picture is highly 
consistent with a cause other than the study drug, but attribution cannot be made 
with absolute certainty and a relationship between the study drug and AE cannot 
be excluded with complete confidence. 
• Possibly related: This relationship suggests that treatment with the study drug 
may have caused or contributed to the AE, ie, the event follows a reasonable 


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temporal sequence from the time of drug administration and/or follows a 
known response pattern to the study drug but could also have been produced by 
other factors. 
• Probably related: This relationship suggests that a reasonable temporal sequence 
of the event with the study drug administration exists and the likely association of 
the event with the study drug. This will be based upon the known pharmacological 
action of the study drug, known or previously reported adverse reactions to the 
study drug or class of drugs, or judgment based on the Principal Investigator’s 
clinical experience. 
• Definitely related: Temporal relationship to the study drug. Other conditions 
(concurrent illness, concurrent medication reaction, or 
progression/expression of disease state) do not appear to explain event, 
corresponds with the known pharmaceutical profile, improvement on 
discontinuation, re-appearance on re- challenge. 
12.5.5 
Outcome 
For all AEs, regardless of causal relationships, the Investigator must follow-up on the outcome of 
the event until the event or sequelae either resolves or stabilizes. 
If a patient experiences a SAE with an outcome of death: 
• The SAE resulting in death should have an outcome documented as death/fatal with an end 
date being the date of death. 
• If the patient had additional AEs/SAEs that were ongoing at the time of death, these events 
would be documented as ongoing with no end date. 
• Only 1 event should have an outcome of death/fatal unless an autopsy report or Investigator 
states otherwise. 
12.5.6 
Recording Adverse Events 
All observed or volunteered AEs regardless of causal relationship must be reported as described 
in Section 12.5.4. 
For all AEs, the Investigator must obtain adequate information for the following: 
1. determine the outcome of the AE; 
2. determine if the event meets criteria for an SAE; 
3. assess the severity of the AE; 
4. determine the causality of the AE. 
Adverse events must be documented in clear, unambiguous medical term. Study personnel are 
advised not to use abbreviations or acronyms. 
For each AE, record only the diagnosis on the AE page of the CRF/eCRF. Do not report the 
characteristic signs and symptoms of the diagnosis as additional AEs. 
If a diagnosis is not available, record each sign and symptom as an AE. When a diagnosis 
becomes available, study personnel are to update the source document and the AE page of the 
CRF/eCRF with relevant diagnosis only. 


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For medical or surgical procedures (eg, surgery, endoscopies, tooth extraction, transfusion), the 
condition/diagnosis that leads to the procedure should be recorded as the AE (eg, laparoscopic 
cholecystectomy is the procedure or treatment for an SAE of necrotic gall bladder). 
All AEs that later increase in the frequency and/or severity (medical and scientific judgment 
should be exercised by the Investigator) will be considered new AEs and will be recorded on a 
new line in source and the CRF/eCRF. 
Withdrawal due to an AE or SAE must be clearly differentiated from withdrawal due to other 
reasons. 
12.5.7 
Reporting of Serious Adverse Events to Sponsor 
All AEs must be assessed by the Investigator to determine if they meet criteria for an SAE. All 
SAEs must be reported to the Sponsor or designee immediately or within 24 hours of the 
Investigator or their staff becoming aware of them regardless of the presumed relationship to the 
study drug. 
The Investigator must complete, sign, and date the SAE pages, verify the accuracy of the 
information recorded on the SAE pages with the corresponding source documents, and send a 
copy via email or fax to the contact information provided 
 
 
When further information becomes available, the SAE Form should be updated with the new 
information and reported immediately via the same contact information. 
Additional follow-up information, if required or available, should be entered into the CRF/eCRF 
and sent to the Sponsor within 24 hours of the Investigator site or their staff becoming aware of 
this additional information via the reporting process outlined above. These reporting timelines 
need to be followed for all initial SAE cases and follow-up versions of the initial cases. 
For all SAEs the Investigator must provide the following: 
• Clear identification of the Investigator/Reporter with full contact information, country and 
site number 
• Subject identification details (subject’s unique study identification number) 
• Investigational Medicinal Product(s) administration details (dose and dates) Seriousness 
criteria 
• Appropriate and requested follow-up information in the time frame detailed above 
• Causality of the serious events 
• Outcome of the serious events 
• Medical records and laboratory / diagnostic information 
12.5.8 
Reporting Requirements 
This protocol will use the current IB as the Reference Safety Document. The expectedness and 
reporting criteria of an SAE will be determined by the Sponsor from the Reference Safety 
Document. 
12.5.8.1 
Sponsor Reporting Requirements 
The Sponsor or its legal representative is responsible for notifying the relevant 
regulatory authorities of SAEs meeting the reporting criteria. 


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12.5.8.2 
Investigator Reporting Requirements 
The Investigator must fulfill all local regulatory obligations required for the study Investigators. 
It is the PI’s responsibility to notify the IRB or Independent Ethics Committee (IEC) of all SAEs 
that occur at his or her site. Investigators will also be notified of all unexpected, serious, 
drug--related events (7/15 Day Safety Reports) that occur during the clinical study. Each site is 
responsible for notifying its IRB or IEC (if local) of these additional SAEs. Investigators will 
receive blinded information unless unblinded information is judged necessary for safety reasons. 


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13 
STATISTICAL METHODS AND PLANNED ANALYSES 
13.1 
General Considerations 
Data collected during the study will be presented in summary tables, figures, or by-patient data 
listings. Continuous variables will be summarized using mean, standard deviation (SD), median, 
minimum, and maximum. Categorical variables will be summarized using percentages and 
frequency distributions. No formal hypothesis testing will be performed. 
13.2 
Determination of Sample Size 
At least 4 MoCD Type A patients will be enrolled in the study. The actual sample size 
will depend on the number of eligible patients currently being treated with rcPMP. 
13.3 
Analysis Population 
Efficacy analyses will be performed on the Full Analysis Set (FAS). Due to the small number of 
patients, a Per-Protocol Population will not be utilized for this study. The FAS will include all 
patients who receive at least 1 dose of ORGN001. 
Safety analyses will be performed on the Safety Set, defined as all patients who receive at least 1 
dose of ORGN001. 
13.4 
Demographics and Baseline Characteristics 
All demographic and baseline characteristics information will be summarized for all patients. 
For categorical variables, frequencies and percentages will be presented. Continuous variables 
will be summarized using descriptive statistics (mean, median, SD, and minimum and 
maximum). 
13.5 
Patient Disposition and Treatment Compliance 
The number of patients screened, treated, completing the 6-Month Initial Treatment Period, and 
included in the safety and efficacy analysis sets will be tabulated by counts and percentage of 
patients. Reasons for any patient withdrawals will be provided. 
Treatment compliance with ORGN001 will be presented for all patients. 
13.6 
Prior and Concomitant Medications 
Prior and concomitant medications will be summarized using the Safety Set. Listings of prior 
and concomitant medications will be produced as will listings of seizure medications. 
Medications will be coded using the World Health Organization Drug Dictionary (WHODrug) 
version 01 September 2013 or higher. Medication summaries will be presented by WHODrug 
Anatomical Therapeutic Chemical (ATC) and by WHODrug generic name. 
13.7 
Efficacy Analyses 
Efficacy analyses will be performed on the FAS. 
13.7.1 
Primary Efficacy Analysis 
There is no prespecified primary efficacy endpoint in this study. Secondary efficacy analyses are 
described in Section 13.7.2 
. 




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Treatment-emergent AEs are AEs that begin after the start of ORGN001. Treatment-emergent 
AEs will be summarized by incidence, Preferred Term, System Organ Class (SOC), seriousness, 
severity, relationship to treatment. 
All AEs will be summarized by both event counts and patient counts. For patient counts, if a 
patient has more than one occurrence of an AE for a specific Preferred Term or SOC, the patient 
will be counted only once for that Preferred Term or SOC. The most severe occurrence of an AE 
as well as the most extreme relationship of the AE will be indicated in cases of multiple 
occurrences of the same AE at onset of the AE. 
13.8.2 
Laboratory Parameters 
Changes from Baseline in laboratory assessments (chemistry and hematology) will be 
summarized by visit, and shift tables (L [low], N [normal], H [high]) by visit will be produced 
for clinical laboratory tests. 
13.8.3 
Physical Examinations and Vital Signs 
Physical examinations and Child-Pugh scores (A [a score of 5 to 6], B [a score of 7 to 9], C [a 
score of 10 or above]) will be summarized by visit. Vital signs (systolic and diastolic BP, 
temperature, heart rate, and respiratory rate) and changes from baseline in vital signs will be 
summarized by visit. 
13.8.4 
Electroencephalograms 
The number and percentage of patients with EEG findings will be summarized by visit. 
13.9 
Pharmacokinetic Analysis 
Plasma concentration versus time profiles will be graphically summarized. Non-compartmental 
PK parameters such as Cmax, tmax, AUC, and t½ will be determined if possible, and dose linearity 
will be explored. Plasma concentration and PK parameter summaries will include descriptive 
statistics, as appropriate. Details of PK analyses will be presented in an analysis plan. 
13.10 Other Statistical Issues 
13.10.1 
Missing or Invalid Data 
If a date of a measurement or an event has a missing or an unknown day, the missing or 
unknown Day will be substituted by 15 for the calculation of other variables such as age at which 
the measurement was taken, or the age at the occurrence of an event. If the month or the year of a 
date is missing, no imputation will take place. In general, other missing or invalid observations 
will not be replaced or imputed unless otherwise specified in the SAP. 
13.10.2 
Computing Environment 
Efficacy and safety analyses will be performed using SAS for windows, Version 9.2 or higher 
(SAS Institute Inc., Cary, NC, USA). 
PK analyses will be performed using Phoenix WinNonlin version 6.3 or higher (Pharsight, Cary, 
NC, USA). 


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14 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1 
Study Monitoring 
A representative of the Sponsor or designee may visit the investigational study site to: 
• Determine the adequacy of the facilities and equipment 
• Discuss with the Investigators and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of the Sponsor or its representatives. This will be 
documented in a Clinical Study Agreement between the Sponsor and the Investigator. 
During the study, a representative of the Sponsor or designee will have regular contact with 
the investigational site, for the following: 
• Provide information and support to the Investigators 
• Confirm that facilities and equipment remain acceptable 
• Confirm that all patients have been properly consented 
• Confirm drug accountability 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the CRFs/eCRFs, and that study drug accountability checks are being 
performed 
• Perform source data verification. This includes a comparison of the data in the CRFs/eCRFs 
with the patient’s medical records at the hospital or practice, and other records relevant to the 
study. This will require direct access to all original records for each patient (eg, clinic charts). 
• Record and report any protocol deviations not previously sent to the Sponsor. 
• Confirm AEs and SAEs have been properly documented on CRFs/eCRFs and confirm any 
SAEs have been forwarded to the Sponsor and those SAEs that met criteria for reporting 
have been forwarded to the IRB. 
The monitor will be available between visits if the Investigators or other staff needs 
information or advice. 
14.2 
Audits and Inspections 
Authorized representatives of the Sponsor, a regulatory authority, an IEC or an IRB may visit the 
site to perform audits or inspections, including source data verification. The purpose of an audit 
or inspection by the Sponsor is to systematically and independently examine all study-related 
activities and documents to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, Good Clinical Practice 
(GCP) guidelines of the International Council for Harmonisation (ICH), and any applicable 
regulatory requirements. The Investigator should contact the Sponsor immediately if contacted 
by a regulatory agency about an inspection. 
14.3 
Institutional Review Board 
The PI must obtain IRB/IEC approval for the investigation. All IRB/IEC approvals, including 
initial and continued review, and all materials approved by the IRB/IEC for this study including 
the patient consent form and recruitment materials must be maintained by the Investigator and 
made available for inspection. 


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15 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor or 
designee may conduct quality assurance audits (Section 14.2). 
16 
ETHICS 
This study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH GCP guidelines. 
Investigators and other study personnel must comply with all instructions and regulations 
specified in this protocol and applicable ICH GCP guidelines and must conduct this study in 
accordance with all local, federal, and regulatory agency regulations. 
In accordance to ICH guidelines, pediatric participation in these studies should occur in qualified 
pediatric centers, with personnel who are properly trained and experienced in studying the 
pediatric population and in evaluating and managing potential pediatric AEs. Site personnel 
should be knowledgeable and skilled in dealing with the pediatric population and its 
age- appropriate needs and be encouraged to use measures that minimize discomfort of 
procedures (e.g., topical anesthesia to place IV catheters, use of indwelling catheters instead of 
repeated venipunctures for blood sampling, and collection of some protocol-specified blood 
samples when routine clinical samples are obtained). 
16.1 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate. The Investigator must submit 
written approval to the Sponsor before he or she can enroll any patient into the study. 
No modifications to the protocol should be made without the approval of both the Investigator 
and the Sponsor. Changes that significantly affect patient safety, the scope of investigation, or 
the scientific validity of the study will require IRB/IEC notification prior to implementation, 
except where the modification is necessary to eliminate an apparent immediate hazard to 
patients. Any deviations from protocol must be fully documented. The PI is responsible for 
informing the IRB or IEC of any amendment to the protocol in accordance with local 
requirements. In addition, the IRB or IEC must approve all advertising used to recruit patients 
for the study. The protocol must be re-approved by the IRB or IEC upon receipt of amendments 
and annually, as local regulations require. 
The PI is also responsible for providing the IRB with reports of any reportable serious adverse 
drug reactions from any other study conducted with the study drug. The Sponsor will provide 
this information to the PI. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
16.2 
Data Monitoring Committee Review 
An independent DMC will be appointed by the Sponsor 
 
 who have no direct relationship with the 
study. 
Prior to each scheduled dose escalation, the SRC chair will convene the DMC to review 
laboratory and clinical data in conjunction with the SRC to determine if dose escalation is 
appropriate (Section 3.4). 


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Final decisions regarding the conduct of the study will be made by the Sponsor after consultation 
with the DMC. All appropriate regulatory authorities and ECs will be notified of any significant 
action. 
The DMC may be asked to provide medical and ethical guidance related to the conduct of the 
study as described above. The DMC will review study information as outlined in the DMC 
charter, which is maintained separately from the study protocol. 
Each member of the DMC will be required to sign a contract agreement, which includes a 
confidentiality and financial disclosure statement, assuring no conflicts of interest as a condition 
for membership on the board. 
16.3 
Written Informed Consent 
The PIs at each center will ensure that the patient's parent or legal guardian is given full and 
adequate oral and written information about the nature, purpose, possible risk and benefit of the 
study. The patient's parent or legal guardian must also be notified that they are free to 
discontinue their child from the study at any time. The parent or legal guardian should be given 
the opportunity to ask questions and allowed time to consider the information provided. 
The signed and dated ICF must be obtained before conducting any study procedures. 
The PIs must maintain the original, signed ICF. A copy of the signed ICF must be given to the 
patient's parent or legal guardian. 
Should new information become available during the conduct of the study that might impact 
parent or legal guardian willingness to continue participation in the study, the parent or legal 
guardian will be notified in a timely manner about the new information and asked to sign a new 
ICF. 
16.4 
Patient Data Protection 
Prior to the performance of any study-related procedures, the patient’s parent or legal guardian 
must authorize the release and use of protected health information as required by local, federal 
and regulatory agency law. 
CRFs/eCRFs will be completed at the site either on paper or in the electronic data capture 
system. Copies of pertinent records in connection with the study, including patient charts and 
laboratory data, will be made available to the Sponsor or designee on request in a timely manner 
throughout the course of the study, with due precaution toward protecting patient privacy. 




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17.4 
Data Privacy 
The Sponsor will make every effort to protect patient privacy. For all study data collection, 
patients will be identified by a unique patient number and date of birth in regions where 
permitted. The results from this study may be presented at meetings or in articles. However, 
patient name or initials that could identify a patient will not be used in any such meetings or 
articles. 
18 
PUBLICATION POLICY 
The full terms for publication are outlined in the Clinical Study Agreement, Statement of 
Agreement, or Master Clinical Study Agreement. Publication terms permit publication only after 
publication of multicenter results and require that any data to be submitted for publication 
including abstract submissions or presentations, be submitted to the Sponsor for review at least 
30 days prior to submission. 


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19 
LIST OF REFERENCES 
Clinch K, Watt DK, Dixon RA, Baars SM, Gainsford GJ, Tiwari A, et al. Synthesis of cyclic 
pyranopterin monophosphate, a biosynthetic intermediate in the molybdenum cofactor pathway. 
J.Med.Chem. 2013 Feb 28;56(4):1730-8. 
European Commission Ethical Considerations for Clinical Trials on Medicinal Products 
Conducted with the Paediatric Population: Recommendations of the ad hoc group for the 
development of implementing guidelines for Directive 2001/20/EC relating to good clinical 
practice in the conduct of clinical trials on medicinal products for human use. 2008 European 
Commission. 2008. 
Committee for Medicinal Products for Human Use (CHMP) and Paediatric Committee (PDCO), 
Guideline on the Investigation of Medicinal Products in the Term and Preterm Neonate. 
European Medicines Agency (EMA) London, 2009 European Medicines Agency (EMA). 2009. 
Hitzert MM, Bos AF, Bergman KA, Veldman A, Schwarz G, Santamaria- Araujo JA, et al. 
Favorable outcome in a newborn with molybdenum cofactor type A deficiency treated with 
cPMP. Pediatrics. 2012 Oct;130(4):e1005-e1010. 
Johnson JL, Duran M. The Metabolic and Molecular Bases of Inherited Disease, Chapter 128, 
Molybdenum Cofactor Deficiency and Isolated Sulfite Oxidase Deficiency. 8 ed. McGraw-Hill; 
2001.3163-77 p. 
Johnson JL, Waud WR, Rajagopalan KV, Duran M, Beemer F, Wadman S. Inborn errors of 
molybdenum metabolism: Combined deficiencies of sulfite oxidase and xanthine dehydrogenase 
in a patient lacking the molybdenum cofactor. Proc Natl Acad Sci. 1980 Jun;77(6):3715-9. 
Kikuchi K, Hamano S, Mochizuki H, Ichida K, Ida H. Molybdenum Cofactor Deficiency Mimics 
Cerebral Palsy: Differentiating Factors for Diagnosis. 
Pediatric Neurology. 2012 Apr 16;47:147-9. 
Lee HJ, Adham IM, Schwarz G, Kneussel M, Sass J, Engel W, et al. Molybdenum 
cofactor-deficient mice resemble the phenotype of human patients. Human Molecular Genetics. 
2002 Dec 15;11(26):3309-17. 
Schwahn BC, Galloway P, Bowhay S, Veldman A, Belaidi A, Santamaria- Araujo J, et al. 
Follow-up of two infants with molybdenum cofactor deficiency (MOCD) group A, on long-term 
treatment with cyclic pyranopterin monophosphate (cPMP). J Inherit Metab Dis. 2011;34(suppl 
3):S84. 
Schwahn BC, Spronsen FJ, Balaidi AA, Bowhay S, Christodoulou J, Derks TG, et al. Efficacy 
and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor 
deficiency type A: a prospective cohort study. Lancet. 2015 Nov 14;386(10007):1955-63. 
Veldman A, Santamaria-Araujo JA, Sollazzo S, Pitt J, Gianello R, Yapalito-Lee J, et al. 
Successful Treatment of Molybdenum Cofactor Deficiency Type A With cPMP. Pediatrics. 2010 
May;125(5):e1249-e1254. 
Veldman A, Schwahn B, Galloway P, van Spronsen FBK, Weis I, et al. Efficacy and safety of 
cyclic pyranopterin monophosphate in the treatment of six newborn babies with molybdenum 
cofactor deficiency type A. J Inherit Metab Dis. 2011;34(suppl 3):S84. 
Vijayakumr K, Gunny R, Grunewald S, Carr L, Chong K, DeVile C, et al. Clinical 
Neuroimaging Features and Outcome in Molybdenum Cofactor Deficiency. Pediatric Neurology. 
2011;45:246-52. 
 


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20 
APPENDICES 
• Appendix A 
Blood Sampling Volumes (European Commission2008; European 
Medicines Agency (EMA) 2009) 
• Appendix B 
Blood Sampling Volumes Table (Screening Through Month 6) 
• Appendix C 
Blood Sampling Volumes Table (Extension Period and Safety Follow- Up 
Visit) 
• Appendix D 
Blood Sampling Volumes for Unscheduled Dose Adjustment 











SAP_001.pdf: 
 
 
 
 
 
Statistical Analysis Plan (SAP) for NCT Number: NCT02047461 
 
SAP Date: 
03 May 2019 
 
 
Certain information within this protocol has been redacted (i.e., specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information or 
company confidential information. 
 
 
This may include, but is not limited to, redaction of the following: 
 
• Named persons or organizations associated with the study. 
• Proprietary information, such as scales or coding systems. 
• Other information as needed to protect confidentiality of BridgeBio Pharma, Sentynl 
Therapeutics, Inc., or their partners, or to otherwise protect the integrity of the clinical 
study. 


Confidentiality 
The information contained herein is confidential and the proprietary property of Origin Biosciences  
and any unauthorized use or disclosure of such information without the prior written authorization  
of Origin Biosciences is expressly prohibited. 
 
 
CONFIDENTIAL 
 
Page 1 of 145 
STATISTICAL ANALYSIS PLAN 
 
 
 
A PHASE 2, MULTICENTER, MULTINATIONAL, OPEN LABEL, DOSE-ESCALATION 
STUDY TO EVALUATE THE SAFETY AND EFFICACY OF ORGN001 (FORMERLY 
ALXN1101) IN PEDIATRIC PATIENTS WITH MOLYBDENUM COFACTOR 
DEFICIENCY (MOCD) TYPE A CURRENTLY TREATED WITH RECOMBINANT 
ESCHERICHIA COLI-DERIVED CYCLIC PYRANOPTERIN MONOPHOSPHATE 
 
Protocol Number: ALXN1101-
 
 
 
 
 
Name of Test Drug: 
ORGN001 (formerly ALXN1101) 
Sponsor: 
Origin Biosciences 
 
 
Sponsor Medical Officer: 
 
Chief Medical Officer 
Document Date: 
03 May 2019 
Document Version: 
Version 2.0 
Previous Document Version: 
Version 1.0 (05 January 2015 – Alexion) 
 


Page 2 of 145


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1.
TABLE OF CONTENTS AND LIST OF TABLES
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS AND LIST OF TABLES ....................................................3 
2. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...............................6 
3. 
DESCRIPTION OF THE PROTOCOL .......................................................................8 
3.1. 
Changes from Analyses Specified in the Protocol .....................................................11 
 
 
 
4. 
DEFINITIONS ...........................................................................................................12 
4.1. 
Efficacy .......................................................................................................................12 
4.1.1. 
Neurologic Examinations ...........................................................................................12 
4.1.2. 
Bayley Scales of Infant and Toddler Development-Third Edition .............................12 
4.1.3. 
The Gross Motor Function Classification System ......................................................13 
4.1.4. 
Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition .....................13 
4.1.5. 
Seizure Diary ..............................................................................................................14 
4.1.6. 
Neuroimaging .............................................................................................................14 
4.1.7. 
Growth Parameters .....................................................................................................14 
4.1.8. 
Feeding Pattern Assessment .......................................................................................14 
4.1.9. 
Pharmacodynamics .....................................................................................................14 
4.2. 
Pharmacokinetic Assessments ....................................................................................15 
4.3. 
Safety ..........................................................................................................................15 
4.3.1. 
Adverse Events ...........................................................................................................16 
4.3.2. 
Vital Signs ..................................................................................................................16 
4.3.3. 
Physical Examination .................................................................................................16 
4.3.4. 
Laboratory Assessments .............................................................................................16 
4.3.5. 
Electroencephalogram ................................................................................................16 
5. 
DATA SETS ANALYZED (STUDY POPULATIONS) ...........................................17 
6. 
STATISTICAL ANALYSIS ......................................................................................18 
6.1. 
Study Subjects ............................................................................................................18 
6.1.1. 
Disposition of Subjects ...............................................................................................18 
6.1.2. 
Protocol Deviations ....................................................................................................18 
6.1.3. 
Demographics, Prenatal and Antenatal History, and Disease Characteristics ............18 


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6.1.4. 
Medical/Surgical History ............................................................................................19 
6.1.5. 
Prior and Concomitant Medications and Seizure Medications/Therapies ..................19 
6.2. 
Efficacy Analyses .......................................................................................................20 
6.2.1. 
Primary Analysis ........................................................................................................20 
6.2.2. 
Secondary Analyses ....................................................................................................22 
6.2.3. 
Other Efficacy Analyses .............................................................................................24 
6.3. 
Pharmacokinetic Analyses ..........................................................................................24 
6.4. 
Pharmacokinetic and Pharmacodynamic Analyses ....................................................24 
6.5. 
Safety Analyses ..........................................................................................................24 
6.5.1. 
Study Duration, Treatment Compliance, and Exposure .............................................24 
6.5.2. 
Dose Modification ......................................................................................................25 
6.5.3. 
Adverse Events ...........................................................................................................25 
6.5.4. 
Other Safety Analyses ................................................................................................26 
7. 
REFERENCES ...........................................................................................................28 
8. 
APPENDICES ............................................................................................................29 
 
 
 
 
8.3. 
Technical Specifications for Derived Variables .........................................................29 
8.4. 
Z-Score .......................................................................................................................32 
8.4.1. 
World Health Organization Growth Chart .................................................................32 
8.4.2. 
Centers for Disease Control and Prevention Growth Chart ........................................32 
8.5. 
Visit Windows ............................................................................................................32 
 
 
 
 
 
 
 
 
 
 


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LIST OF TABLES 
Table 1: 
Abbreviations and Acronyms .......................................................................................6 
Table 2: 
Treatment-Emergent Adverse Events .........................................................................25 
Table 3: 
Age and Reference Date .............................................................................................29 
Table 4: 
Criteria for Child-Pugh Classification ........................................................................32 
 
 
 
 
 
 
 
 
 
 
 
 


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2.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
The following abbreviations and acronyms are used in this SAP. 
Table 1: 
Abbreviations and Acronyms 
Abbreviation or Acronym 
Explanation 
AE 
Adverse event 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the plasma concentration-time curve 
Bayley-III 
Bayley Scales of Infant Development-Third Edition 
BMI 
Body mass index 
BP 
Blood pressure 
BQL 
Below quantification level 
CDC 
Centers for Disease Control and Prevention 
Cmax
Maximum observed plasma concentration 
CSR 
Clinical Study Report 
CT 
Computed tomography 
DMC 
Data Monitoring Committee 
DQ 
Developmental quotient 
EEG 
Electroencephalogram 
FAS 
Full Analysis Set 
GMFCS–E&R 
Gross Motor Function Classification System–Expanded and Revised 
HR 
Heart rate 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MoCD 
Molybdenum Cofactor Deficiency Type A 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PI 
Principal Investigator 
PT 
Preferred term 
PTAE 
Pre-treatment adverse events 
rcPMP 
Recombinant Escherichia coli-derived Cyclic Pyranopterin Monophosphate 
RBC 
Red blood cell 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAS 
Statistical Analysis Software 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SOC 
System organ class 
SRC 
Safety Review Committee 
 
 


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Abbreviation or Acronym 
Explanation 
t½ 
Terminal half-life 
TEAEs 
Treatment-emergent adverse events 
tmax 
Time to maximum observed plasma concentration 
WHO 
World Health Organization 
WPPSI 
Wechsler Preschool and Primary Scale of Intelligence 
 
 


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3. 
DESCRIPTION OF THE PROTOCOL 
Protocol Number: ALXN1101-MCD-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Title: A Phase 2, Multicenter, Multinational, Open-label, Dose-Escalation Study to Evaluate the 
Safety Efficacy of ORGN001 (formerly ALXN001) in Pediatric Patients with Molybdenum 
Cofactor Deficiency (MoCD) Type A Currently Treated with Recombinant Escherichia coli-
derived Cyclic Pyranopterin Monophosphate (rcPMP). 
This Phase 2, multinational, multicenter, open-label, dose-escalation study is designed to 
evaluate the safety and efficacy of ORGN001 (formerly ALXN1101) administered to infants and 
children with MoCD Type A currently treated with rcPMP. Eligible subjects will be identified 
through 
 use with rcPMP. This study will include a screening period (Days -21 to 
Day -1), a 6-month study period that includes escalating doses of ORGN001 after the first 
2 months of treatment with ORGN001 (Day 1 [first dose of study drug] to Day 180), and a 
 extension period (after Day 180). 


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Screening evaluations will be performed at any time during the screening period before the first 
dose of ORGN001. Enrolled subjects will attend at least 2 study visits in order for baseline data 
to be obtained. During the screening period, subjects will continue to receive daily IV infusions 
of current rcPMP treatment. During the 6-month initial treatment period, starting on Day 1, 
subjects will begin IV infusions of ORGN001 at the same dose as their current dose of rcPMP 
approximately 24 hours after their last treatment with rcPMP. No further treatments with rcPMP 
will be allowed during the study. Subjects 
 
 will continue to receive daily 
infusions of ORGN001 at home 
 and 
will attend multiple study visits for safety, efficacy, pharmacodynamic (PD), and 
pharmacokinetic (PK) assessments through Month 6 of the initial treatment period and 
 
 the extension period. After the first 2 months of treatment with ORGN001, if the subject’s 
clinical, PK, and safety assessments permit (including the absence of signs and symptoms of 
drug-related toxicity), dosing with ORGN001 will increase every month 
 
 based on the subject’s clinical response, 
safety labs, and when appropriate, exposure data. 
 
 
 
. After the 6-month study period, subjects will enter the 
 
extension period and continue to receive uninterrupted daily dosing of ORGN001 at their final 
tolerated dose based on the dose escalation. After dose escalation is complete, the subject can be 
returned to the prior dose based on the subject’s clinical status at the discretion of the treating 
physician after consultation with the Safety Review Committee (SRC). Subjects who 
prematurely discontinue from the study will attend a safety follow-up visit 
 
 and return to the care of their treating physician. 
The study objectives are as follows: 
Primary Objective: 
The primary objective of this clinical study is to evaluate the safety of ORGN001. 
Secondary Objectives: 
The secondary objectives of this clinical study are to: 
• Characterize the PK of increasing doses of ORGN001 
• Evaluate the effect of ORGN001 on urine and blood 
levels 
• Evaluate the effect of ORGN001 on neurologic, motor, and cognitive functions 
• Evaluate the effect of ORGN001 on central nervous system structure 
• Evaluate the long-term safety of ORGN001 
 
 
 
 
Additional information about the study can be found in the protocol. 


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Results from this study will be summarized in a clinical study report (CSR). 
3.1. 
Changes from Analyses Specified in the Protocol 
Not applicable. 
 
 
 
 
 
 
 
 


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4.
DEFINITIONS
4.1. 
Efficacy
There is no pre-specified primary efficacy endpoint in this study. The secondary efficacy 
endpoints at all key study timepoints include: 
•
Change from baseline in urine and blood 
 levels
•
Change from baseline in clinical findings from neurologic examination
•
Change from baseline in age-appropriate motor and cognitive assessments (Bayley
Scales of Infant Development-Third Edition [Bayley-III], The expanded and revised
Gross Motor Function Classification System [GMFCS-E&R], Wechsler Preschool
and Primary Scale of Intelligence [WPPSI])
•
Change from baseline in seizure frequency
•
Change from baseline in neuroimaging
•
Changes in growth parameters (body weight, body length, head circumference)
•
Change from baseline in feeding patterns
 
 
 
4.1.1. 
Neurologic Examinations 
Neurologic examination includes, but is not limited to, assessment of mental status, cranial 
nerves, motor strength and tone, sensory examination, deep tendon reflexes and primitive 
reflexes, if present. 
4.1.2. 
Bayley Scales of Infant and Toddler Development-Third Edition 
The Bayley-III will be administered to assess changes in gross motor, language, fine motor, and 
cognitive development. The Bayley-III will be administered to children under 3 years of age and 
to subjects with severe developmental delay for whom the WPPSI is not an appropriate 
assessment. 
The Bayley-III is a standardized and norm-referenced instrument that assesses the developmental 
functioning of infants and children 1 month to 42 months of age. The Bayley-III consists of 3 
administered scales: the Cognitive Scale, the Language Scale (administered only to native 
English speakers in English-speaking countries and includes the Receptive Communication and 
Expressive Communication subtests), and the Motor Scale (including the Fine Motor and Gross 
Motor subtests). 
From the raw scores, scaled scores can be calculated for the cognitive scale and the 2 combined 
language scales and motor scales. 


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These scores can then be used to determine composite scores, percentile ranks and confidence 
intervals, development age equivalents, and growth scores. 
Scaled scores range from 1 to 19, with a mean of 10 and a standard deviation (SD) of 3.The 
composite score is scaled to a metric with a mean of 100, a SD of 15, and range from 40 to 160. 
Percentile ranks indicates percentage of individuals in standardization sample, at a given age, 
who obtained scores less than or equal to a given scaled score or composite score. Percentile 
ranks range from 1 to 99, with 50 as the mean and median. 
Developmental age equivalents represent the average age in months at which a given total raw 
score is typical. 
The developmental age equivalent raw score can be used to calculate the developmental quotient 
(DQ). The DQ is the age equivalent score divided by chronological age. 
• DQ = age equivalent scores/chronological age × 100 
o Example: 
12 ����ℎ ������������� ��� ���������� �����
24 ����ℎ� �ℎ����������� ���
× 100 = 50 �� 
Raw scores are also mapped into growth scores, with a mean of 500 and a SD of 100 for each 
subtest. Growth scores provide an equal-interval scale by which progress can be measured over 
time. 
4.1.3. 
The Gross Motor Function Classification System 
The GMFCS–E&R is a 5-level classification system that describes the gross motor function of 
children and youth (up to 18 years of age) on the basis of their self-initiated movement with 
particular emphasis on sitting, walking, and wheeled mobility for children with impaired motor 
skills. 
Distinctions between levels are based on functional abilities, the need for assistive technology, 
including hand-held mobility devices (walkers, crutches, or canes) or wheeled mobility, and to a 
much lesser extent, quality of movement. 
Children who have motor functions similar to those classified in “Level I” can generally walk 
without restrictions but tend to be limited in some of the more advanced motor skills. Children 
whose motor function has been classified at “Level V” are generally very limited in their ability 
to move themselves around even with the use of assistive technology. 
The Investigator or designee will assess the subject according to the levels of the GMFCS–E&R. 
GMFCS-E&R will be assessed 
 
. 
4.1.4. 
Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition 
The WPPSI is an intelligence measure designed for children ages 2 years, 6 months to 7 years, 
7 months. The WPPSI consists of 14 subtests from which the composite scores are derived. For 
subjects with severe developmental delay, the WPPSI may not be an appropriate assessment, and 
therefore, the Bayley-III may be administered instead. WPPSI assessments will be performed 
following the GMFCS-E&R assessment schedule where WPSSI is more appropriate than 
Bayley-III. 


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Most subjects completed WPPSI 4th edition, however, one subject followed the 3rd edition and 
was not included in the study database and listed as a protocol deviation. 
4.1.5. 
Seizure Diary 
At screening, the subject’s parent or legal guardian will be asked to recall the frequency of 
seizures over the prior month and the subject’s history of seizure medication including the start 
and stop dates, dose, and frequency of each seizure medication. If the subject does have seizures, 
the subject’s parent or legal guardian will be given a diary to be used to record data regarding the 
frequency of seizures and any changes in seizure medication for the entire duration of the study. 
4.1.6. 
Neuroimaging 
Magnetic resonance imaging (MRI) scans are the preferred imaging modality and should be 
performed 
 if the subject’s clinical 
condition allows. 
 
 A previous MRI scan 
may be provided in lieu of a scan during the screening period if the previous scan was performed 
within 6 months prior to enrollment and the subject has remained stable;
 
. 
If, in the opinion of the Principal Investigator (PI), an MRI is not possible due to the subject’s 
clinical condition, a computed tomography (CT) scan without contrast should be performed. 
4.1.7. 
Growth Parameters 
Growth parameters (body weight [kg] and length [cm] and head circumference) will be measured 
 
. 
World Health Organization (WHO) growth charts only provide information on children up to 
5 years of age.1 Applicable Centers for Disease Control and Prevention (CDC) growth charts 
will be used for children older than 5 years.2 
4.1.8. 
Feeding Pattern Assessment 
The feeding pattern assessment will be performed to record if a subject is able to feed orally or 
through a nasogastric or gastronomy feeding tube and any changes in the feeding pattern. 
4.1.9. 
Pharmacodynamics 
Blood and urine samples will be evaluated for 
 of the MoCD pathway, 
 
 
                                                 
1 Additional WHO growth chart information and methodology can be found at 
http://www.who.int/childgrowth/publications/technical_report_2/en/index.html. 
2 Additional CDC growth chart information and methodology can be found at 
https://www.cdc.gov/growthcharts/clinical_charts.htm. 


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Pharmacodynamic sampling will be measured 
 
. 
4.2. 
Pharmacokinetic Assessments  
Pharmacokinetic parameters of ORGN001 will include, but not be limited to, maximum 
observed plasma concentration (Cmax), time to maximum observed plasma concentration (tmax), 
area under the plasma concentration-time curve (AUC) and if possible, terminal half-life (t½), 
and dose linearity. 
4.3. 
Safety 
The safety of ORGN001 (formerly ALXN1101) will be assessed based on: 
• Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) 
• Incidence of clinical laboratory abnormalities 
• Change from baseline in clinical laboratory assessments 
• Change from baseline in clinical findings from physical examination 
• Change from baseline in vital sign measurements 
• Change from baseline in electroencephalogram (EEG) results 
In order to monitor subject safety, data will be reviewed daily by the PI or designee during the 
first 2 weeks following initiation of ORGN001. 
 
 
 The SRC
 
 
will review all available clinical data 
 
 prior to each subject’s scheduled dose escalations in conjunction with 
the data monitoring committee (DMC) 
 and at any other time 
during the study as requested by the PI or Sponsor. 
Based on the review of the available data, 
 
 the SRC, in consultation with the 
DMC, may recommend stopping, increasing, decreasing, or maintaining (current dose) the dose 
of ORGN001. 
In addition to the scheduled dose escalations, the PI may also convene the SRC for unscheduled 
dose adjustments based on drug-related AEs and changes in clinical parameters. The SRC chair 
will also convene the DMC if a dose escalation is being considered or will notify the DMC if the 
dose is decreased. Blood and urine samples will be collected for PD and PK assessments on the 
first day the adjusted dose is administered. PD and safety laboratory assessments will be repeated 
 at the
 follow-up visit. 


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4.3.1. 
Adverse Events 
An AE is defined as any unfavorable and unintended sign (e.g., including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a medicinal product or 
procedure, whether or not considered related to the medicinal product or procedure that occurs 
during the course of the clinical study. Adverse events are defined in Protocol Section 15.5. 
4.3.2. 
Vital Signs 
Vital signs will be measured 
 
 and will include assessments of heart rate (HR), respiratory rate (RR), BP, and 
temperature. 
4.3.3. 
Physical Examination 
A complete physical examination will be performed 
 
 
 
 
 
 
. 
Ascites and hepatic encephalopathy scores will be recorded 
 
and the Child-Pugh score will be calculated. 
4.3.4. 
Laboratory Assessments 
Blood samples will be collected for analysis of hematology (complete blood count, including 
platelet count, red blood cell (RBC) count, white blood cell (WBC) count and automated 
differential, hemoglobin, hematocrit, and RBC indices); serum chemistry (sodium, potassium, 
bicarbonate, chloride, blood urea nitrogen, creatinine, calcium, alanine aminotransferase, 
aspartate aminotransferase, alkaline phosphatase, total bilirubin, serum osmolality and total 
serum albumin); coagulation (prothrombin time and international normalized ratio). Urine 
samples will be collected for urinalysis (specific gravity, pH, glucose, protein, blood and 
ketones, urine protein to creatinine ratio). Clinical laboratory evaluations will be performed 
 
 and will be measured 
 
 
4.3.5. 
Electroencephalogram 
Standard EEGs 
 will be performed 
 
. However, additional EEGs may be performed 
at the discretion of the Investigator. Results from a previous EEG may be provided in lieu of 
performing an EEG during the screening period if the previous assessment was performed within 
6 months prior to enrollment and the subject’s seizure frequency has not changed significantly 
since that study. 


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5. 
DATA SETS ANALYZED (STUDY POPULATIONS) 
Efficacy analyses will be performed on the Full Analysis Set (FAS). Due to the small number of 
subjects, a Per-Protocol population will not be utilized for this study. Subject disposition will 
include all subjects. 
The FAS will include all subjects who were MoCD Type A and received at least 1 dose of 
ORGN001. 
Safety analysis set will be performed on the Safety Analysis Set, defined as all subjects who 
received at least 1 dose of ORGN001. 


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6. 
STATISTICAL ANALYSIS 
No formal statistical hypothesis testing will be performed. Efficacy data will be analyzed using 
descriptive statistics. All data collected during the study will be presented in summary tables, 
figures, or by-subject data listings. Continuous variables will be summarized using mean, SD, 
median, minimum, and maximum. Categorical variables will be summarized using percentages 
and frequency distributions. Graphical displays will be produced as appropriate. 
6.1. 
Study Subjects 
6.1.1. 
Disposition of Subjects 
A summary of subject disposition for all treated subjects will be presented and will include a 
summary of the number of subjects enrolled and percentage of subjects who completed the study 
through Month 6 or discontinued/withdrew from the study prior to Month 6, along with reason 
for discontinuation/withdrawal. 
A summary of the number and percentage of subjects who consented to the extension study, the 
number and percentage of subjects who completed 
 
 or discontinued/withdrew from the study, along with reason for discontinuation/ 
withdrawal. 
The number and percentage of subjects in each analysis set will be tabulated. 
By-subject data listings with disposition will be provided as well as a listing of subjects who did 
not meet the inclusion/met the exclusion criteria. 
6.1.2. 
Protocol Deviations 
All protocol deviations will be listed for all subjects. 
6.1.3. 
Demographics, Prenatal and Antenatal History, and Disease Characteristics 
All demographic information, family history, disease characteristics, and medical history will be 
summarized for the FAS. By-subject data listings of all demographic, family history, disease 
characteristics and medical history information will be produced for all subjects. 
6.1.3.1. 
Demographics 
The following demographic variables will be summarized: 
• Gender 
• Race 
• Ethnicity 
• Age (months) at first ORGN001 infusion 


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6.1.3.2. 
Disease Characteristics 
The following disease characteristics will be summarized: 
• Age at onset of first MoCD signs/symptoms (days) 
• Age at genetic diagnosis (days) 
• MoCD Presenting signs and symptoms 
6.1.3.3. 
MoCD Family History 
The following family history, if available will be summarized: 
• Parental consanguinity 
• Number of living or deceased siblings with suspected or confirmed MoCD type A 
• Parental genotype 
6.1.3.4. 
Prenatal and Antenatal History 
The following prenatal and antenatal history, if available will be summarized: 
• Gestational age (weeks) 
• Any complications during pregnancy 
• Delivery type 
• Placental condition 
• History of in utero seizures 
• Apgar scores 
6.1.4. 
Medical/Surgical History 
Medical/surgical history information will be summarized using the number (%) of subjects who 
have a specific medical history. 
Previous vision and hearing assessments will be displayed in by-subject data listings. 
6.1.5. 
Prior and Concomitant Medications and Seizure Medications/Therapies 
Prior and concomitant medications will be summarized using the Safety Set. Prior medications 
are defined as medications taken prior to the first study infusion. Concomitant medications are 
defined as medications received by the subjects on/after first study infusion. 
Medications will be coded using the WHO Drug Dictionary (September 2018). Medication 
summaries, i.e., number (%) of subjects using prior and concomitant medications as well as 
seizure medications, will be presented by WHO Anatomical Therapeutic Chemical (ATC) and 
by generic name. 
A listing of prior and concomitant medications will be produced. A separate listing of antiseizure 
prior and concomitant medications will be produced, including the start and stop dates and total 
number of antiseizure medications per subject. 


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6.2. 
Efficacy Analyses 
All efficacy analyses will be conducted on the FAS. When applicable, summaries will be 
presented by study visit. All endpoints will be presented in listings. 
6.2.1. 
Primary Analysis 
There is no pre-specified primary efficacy endpoint in this study. 
6.2.1.1. 
Handling of Dropouts or Missing Data 
In general, missing or invalid observations will not be replaced or imputed. The following 
imputation rules apply to partially missing start and end dates: 
• Any imputed dates need to be logical. 
• Imputation of start date: 
o Missing day and month: 
 If partial date year < year of the first dose date, then impute December 31. 
 If partial date year = year of the first dose date, then impute to first dose 
date. 
 If partial date year > year of the first dose date, then impute to January 1. 
o Missing day only: 
 If the partial month and year < month and year of the first dose date, then 
impute last day of the start date month. 
 If the partial month and year = month and year of the first dose date, then 
impute the day of first dose. 
 If the partial month and year > month and year of the first dose date, then 
impute first day of the start date month. 
o If the imputed start date is after the stop date, the start date will be imputed to be 
equal to the stop date. 
• Imputation of end date: 
o Missing day and month: 
 If partial date year < year of the last dose date, then impute December 31. 
 If partial date year = year of the last dose date, then impute to last dose 
date. 
 If partial date year > year of the last dose date, then impute to January 1. 
o If partial date has missing day only: 
 If the partial month and year < month and year of the last dose date, then 
impute last day of the start date month. 
 If the partial month and year = month and year of the last dose date, then 
impute the day of last dose. 


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 If the partial month and year > month and year of the last dose date, then 
impute first day of the start date month. 
o If the imputed stop date is before the start date, the stop date will be imputed to be 
equal to the start date. 
For subjects continuing treatment at time of analysis, the data cut-off will be used. 
6.2.1.1.1. Missing Data: Efficacy and Developmental Assessments 
Missing data for efficacy and developmental assessments will be handled as specified in the 
instructions for each instrument. 
 
 
 
 
6.2.1.1.2. Missing Data: Medical/Surgical History and Prior Medications (Including 
Antiseizure Medication) Date Imputation 
For start date partial (month and year are available), then impute day as “01.” 
For start date partial (year only is available), then impute day and month as “01JAN.” 
For end date partial (month and year are available), then impute day as last day of the month. 
For end date partial (year only is available), then impute day and month as the last day of the 
year. 
No overlap between medical history/prior medications and study drug will be allowed. The end 
date of medical history/prior medications will be imputed to the first dose date of study drug – 1 
if there is overlap due to imputation of partial dates. 
6.2.1.1.3. Missing Data: Concomitant Medications Date Imputation 
Start dates of medications that have a missing day will be considered as prior medication if the 
month and year are before the month and year of the first dose of study drug, unless the stop date 
of the medication is after the date of the first dose of study drug, then it is considered both a prior 
and concomitant medication. 
If a medication has a missing month, the medication will be considered to be prior medication 
unless by reference to the stop date that it is concomitant, then it will be both a prior medication 
and concomitant medication. 
If a medication has a completely missing start date and either the stop date is after the first dose 
of study medication or the stop date is completely missing, the medication will be considered 
both a prior and concomitant medication. If the medication has a completely missing start date 
and the stop date is prior to the first dose of study medication, the medication will be considered 
to be a prior medication. 
6.2.1.1.4. Missing Data: Adverse Event Date Imputation 
Follow the general rules outlines in Section 6.2.1.1. 


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6.2.1.2. 
Subgroup Analysis 
No subgroup analyses are planned due to the expected small sample size. 
6.2.1.3. 
Multicenter Studies 
This is a multicenter study; however, the expected sample size is not sufficient to perform any 
meaningful efficacy summaries by center. 
6.2.1.4. 
Hypothesis Testing and Significance Level 
No statistical hypothesis testing will be performed. Efficacy data will be analyzed using 
descriptive statistics. 
6.2.1.5. 
Sensitivity Analyses 
No sensitivity analyses will be performed. 
6.2.2. 
Secondary Analyses 
6.2.2.1. 
Neurologic Examination 
A summary of the frequency and percentage of subjects with neurologic examination findings 
 
 will be presented by visit. 
6.2.2.2. 
Developmental Assessments 
Changes from baseline to post-treatment assessments in the Bayley-III will be summarized using 
descriptive statistics. The raw, scaled, age-equivalent, and DQ scores will be summarized for the 
Cognitive Scale and Fine Motor and Gross Motor subtests. Additionally, the composite score for 
cognitive and motor scales will be summarized for subjects up to 42 months in age or subjects 
with severe disability and the Bayley assessment is more appropriate. Language Scale results 
will be displayed in a by-subject data listing. 
A summary of the frequency and percentage of subjects at each level of the 5-level classification 
system of the GMFCS–E&R will be presented by visit. 
Changes from baseline to post-treatment assessments in the WPPSI will be summarized using 
descriptive statistics. A by-subject data listing of all WPPSI IV assessments will be produced. 
6.2.2.3. 
Seizures 
The number and frequency of subjects with seizures prior to treatment with ORGN001 and over 
each 6-month period on study will be summarized. In addition, the number of subjects with 
medication changes due to seizures will be summarized. A by-subject data listing of seizure data 
and changes in medications since the last visit, along with reasons for the change will be 
produced. 
Seizures collected as AEs will be summarized as AEs. 


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6.2.2.4. 
Neuroimaging 
Shifts from baseline 
 in findings from MRI or CT scan, if MRI/CT scan is 
contraindicated, will be presented for the different visits. A summary of the abnormal findings 
 
 will be provided, as will the number and frequency of subjects 
with changes since previous neuroimaging. 
 
6.2.2.5. 
Feeding Patterns 
The number and frequency of subjects able to feed orally will be summarized by visit. For 
subjects that are not feeding orally, the feeding method will be summarized by visit. Results will 
also be included in by-subject listings. 
6.2.2.6. 
Growth Parameters 
Body weight, length, head circumference, and body mass index (BMI) will be analyzed by 
converting each parameter to age-adjusted z-scores and age percentiles and descriptive statistics 
will be presented for each parameter, as well as, for the change from baseline. The 5th, 25th, 50th, 
75th, 90th, and 95th percentiles will be calculated. 
Weight, length, head circumference, and BMI data including age-adjusted z-scores and 
percentile for each growth parameter-for-age will be presented in a by-subject data listing. 
In addition, the following individual subject’s growth charts will be produced with a flag for start 
of ORGN001 infusion and will include a symbol representing dose changed, if applicable: 
weight-for-age percentiles, length-for-age percentiles, head circumference-for-age percentiles, 
and BMI-for-age percentiles. 
6.2.2.7. 
Pharmacodynamic Assessments 
 
 Levels of 
biochemical markers that are measured in urine will be normalized to urine creatinine levels. 
 The actual value, 
change, and percentage change from baseline in MoCD-associated urine and blood biomarker 
levels will be summarized by visit. 
All 
 levels (plasma and urine) will be graphically displayed for each subject over time. 
In addition, by subject plots will be graphically displayed, 
 
. 
The percentage of change from baseline of each 
 
(example: ([Month x – Baseline] / Baseline × 100)) will be plotted on the same figure. 
 
 


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6.2.3. 
Other Efficacy Analyses 
Not applicable. 
6.3. 
Pharmacokinetic Analyses 
All PK analyses specified in the protocol will be performed 
 
. 
6.4. 
Pharmacokinetic and Pharmacodynamic Analyses 
The relationship between PK and plasma and urine SSC levels will be explored using graphic 
methods or PK/PD modeling. 
 
 
6.5. 
Safety Analyses 
All safety analyses will be conducted on the Safety Set. All safety data available at the time of 
database lock will be provided in subject listings. All AEs will be coded in the Medical 
Dictionary for Regulatory Activities (MedDRA) (version 22.0) and no formal hypothesis testing 
will be performed. 
6.5.1. 
Study Duration, Treatment Compliance, and Exposure 
Summary statistics (mean, SD, median, minimum, and maximum) will be produced for the 
following, using the FAS: 
• Number of ORGN001 infusions 
• Proportion of the number of infusions by expected number of infusions 
• Number of make-up doses 
• Number of missed doses 
• Duration (days) of study participation from informed consent 
• Total time (days/weeks/months) on ORGN001 
By-subject listings will be produced for study duration, treatment compliance, and exposure, as 
well as, for study drug administration. 


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6.5.2. 
Dose Modification 
The proportion of patients with dose modification (dose interruption, dose reduced, dose 
increased, dose stopped) will be listed and summarized using descriptive statistics. 
 
 
 
 
 
 
By-subject listings will be produced for dose modifications. 
6.5.3. 
Adverse Events 
Adverse events will be classified by system organ class (SOC) and preferred term (PT) using of 
MedDRA (version 22.0). The severity/relationship will be assessed. 
The AEs will be determined as occurring prior to treatment with ORGN001 (pre-treatment), or 
as on or after first treatment (treatment-emergent), as described in Section 8.3. Analyses of pre-
treatment adverse events (PTAEs) and treatment-emergent adverse events (TEAEs) will be 
tabulated and presented separately. An incomplete date of AE onset will be compared to 
treatment start date, if unable to determine AE onset date is prior to treatment start, then AE will 
be considered a TEAE. 
Subjects having multiple AEs within a category (e.g., overall, SOC, PT) will be counted once in 
that category. For severity/relationship tables, the subject’s most severe/most related event 
within a category will be counted. Missing relationship to study drug will be considered 
treatment-related. 
Percentages will be based on the total number of treated subjects in the Safety Set. Tables will be 
sorted by descending frequency of SOC and by descending frequency of PT within SOC. 
Listings will be provided for all TEAEs and PTAEs for the Safety Set. TEAEs with missing 
severity will not be included in the counts of patients within a SOC or PT; however, the event 
will be reported in listings. 
AEs will include the displays described in the following sub-sections. 
6.5.3.1. 
Overall Summary of Adverse Events 
All PTAEs and TEAEs will be presented using summary statistics (n, %). The number of 
subjects with events (n, %) will be displayed. 
Table 2: 
Treatment-Emergent Adverse Events 
Relationship 
Severity 
Related AEs (possibly, probably, or definitely related, missing/unknown) 
Not related AEs (not related or unlikely related) 
Mild AEs 
Moderate AEs 
Severe AEs 
Additionally, the number and percentage of subjects who withdrew from the study due to an AE, 
discontinued treatment due to an AE, or who died on study will be presented. These statistics 
will be presented for all TEAEs and separately, for SAEs. 


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6.5.3.2. 
Adverse Events and Serious Adverse Events by System Organ Class and 
Preferred Term 
The number of PTAEs and TEAEs and the number and percentage of subjects with events will 
be presented by SOC and PT. 
6.5.3.3. 
Adverse Events and Serious Adverse Events by System Organ Class, Preferred 
Term, and Relationship 
The number and percentage of subjects with TEAEs will be presented by SOC and PT as 
described above by relationship (related, not related). If a patient has more than 1 occurrence of 
an AE, the strongest relationship to study treatment will be used in the summary table. SAEs will 
be summarized similarly. 
6.5.3.4. 
Adverse Events and Serious Adverse Events by System Organ Class, Preferred 
Term, and Severity 
The number and percentage of subjects with TEAEs will be presented by SOC and PT as 
described above by severity (mild, moderate, severe). If a subject has more than one occurrence 
of an AE, the most severe occurrence will be used in the summary table. SAEs will be 
summarized similarly. 
6.5.3.5. 
Deaths, Other Serious Adverse Events, and Other Significant Adverse Events 
All SAEs will be presented in subject listings. All AEs leading to study treatment withdrawal 
will be listed. A listing of subject deaths will be produced, if applicable. 
6.5.4. 
Other Safety Analyses 
6.5.4.1. 
Analyses for Laboratory Tests 
Descriptive statistics by visit will be presented for each laboratory parameter and for changes 
from baseline. 
Serum Chemistry 
Hematology 
Coagulation 
Urinalysis 
Sodium 
Red blood cell count 
Prothrombin time 
Specific gravity 
Potassium 
Mean corpuscular volume 
International 
Normalized Ratio 
pH 
Bicarbonate 
Mean corpuscular hemoglobin 
 
Glucose 
Chloride 
Mean corpuscular hemoglobin 
concentration 
 
Protein 
Blood urea nitrogen 
White blood cell count 
 
RBC (by dipstick) 
Creatinine 
Neutrophils (absolute and 
percentage) 
 
Ketones (by dipstick) 
Calcium 
Lymphocytes (Absolute and 
percentage) 
 
Urine protein to 
creatinine ratio 
Alanine aminotransferase 
Monocytes (absolute and 
percentage) 
 
 
Aspartate aminotransferase 
Eosinophils (absolute and 
percentage) 
 
 


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Serum Chemistry 
Hematology 
Coagulation 
Urinalysis 
Alkaline phosphatase 
Basophils (absolute and 
percentage) 
 
 
Total bilirubin 
Platelet count 
 
 
Serum osmolality 
Hemoglobin 
 
 
Total Serum Albumin 
Hematocrit 
 
 
For purposes of analyses, laboratory results based upon standardized units will be used. All 
laboratory values, where applicable, will be classified as normal, below normal, or above normal, 
and shift tables will be presented over time. 
Scatter plots of all chemistry and hematology lab test values 
 
 by baseline values will be plotted. For 
hematology, the following tests will be plotted: RBC, WBC count, platelet count, hemoglobin, 
and hematocrit. All data will be presented in by-subject listings and flag for abnormal result will 
be included. 
6.5.4.2. 
Vital Signs 
Vital signs (systolic and diastolic BP, temperature, RR and HR) change from baseline, and 
percent change from baseline in vital signs will be summarized by visit and time point. 
Individual plots of systolic and diastolic BP measurements conducted 
 
 
 will be graphically displayed separately. Listings of vital signs will be produced and flag 
for abnormal result will be included. 
6.5.4.3. 
Physical Examination 
Physical examination results and Child Pugh scores (A[a score of 5 to 6], B[a score of 7 to 9], 
C[a score of 10 or above]) will be summarized by visit. Listings of physical examination and 
Child Pugh scores results will be produced. 
6.5.4.4. 
Electroencephalogram 
The number and frequency of subjects with EEG findings will be summarized by visit. All data 
from local interpretation of EEGs will be presented in by-subject listings. 
Central EEG readings will be summarized in a separate report, if determined to be applicable. 
 


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7. 
REFERENCES 
 
Bayley N. Technical & Administration manuals for Bayley scale of infant and Toddler 
Development (third edition). PsychCorp, a brand of Harcourt Assessment; 2006. 
 


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8. 
APPENDICES 
 
 
 
 
 
 
 
8.3. 
Technical Specifications for Derived Variables 
The following derived data will be calculated prior to analysis. 
Age 
Age will be presented as the number of days or months between date of birth and the reference 
date and will be calculated as follows: 
Age in days: (Visit date – date of birth) + 1 day 
Age in months: ((Visit date – date of birth) + 1 day)/30.4375 
The following ages in Table 3 may be computed, with reference dates indicated. 
Table 3: 
Age and Reference Date 
AGE 
REFERENCE DATE 
Age at study enrollment (months) 
• 
Date of signing ICF 
Age at first symptom (days) 
• 
Date of first symptoms 
Age at first ORGN001 infusion (days) 
• 
Date of first infusion 
Age at each developmental assessment (months) 
• 
Date of developmental assessment 
If the reference date is not complete, then age at reference date will be determined by the month 
and/or year of date of birth and reference date. 
Weight and Height 
Weight in pounds will be multiplied by 0.4536 to be converted to kilograms; and height in inches 
will be multiplied by 2.54 to be converted to centimeters. 
The BMI will be calculated by dividing the subject’s weight in kilograms by the subject’s height 
in meters squared. The units are kg/m2. 
BQL and LLOQ Values for Clinical Laboratory 
 Parameters 
For all clinical laboratory 
 parameters, values that are reported as below 
quantification level (BQL) or lower limit of quantification (LLOQ) will have numeric values set 
equal to the BQL or LLOQ lower limit (e.g., if BQL <2, then value will be set equal to 2). 
However, the original value will be displayed in by-subject data listings. 
Date of Infusion 
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Time from First Infusion to Applicable Assessments (Days) 
For all applicable assessments, time on treatment from first infusion will be calculated as 
follows: 
• If visit date is on or after first infusion = (Visit date – Day 1 Infusion date) + 1 day 
• If visit date is prior to first infusion = (Visit date – Day 1 Infusion date) 
Time from First Infusion to Applicable Assessment (Months) 
For all applicable assessments, time on treatment from first infusion will be calculated as 
follows: 
• If visit date is on or after Day 1 infusion = ((Visit date – Day 1 Infusion date) + 1 
day)/30.4, rounded to 1 decimal place 
• If visit date is prior to Day 1 infusion = (Visit date – Day 1 infusion date)/30.4, 
rounded to 1 decimal place 
Time on Study (Days) 
For each subject, time on study from informed consent to last visit, study completion, 
termination or withdrawal (days) will be calculated as follows: 
• For subjects who completed Month 
 = (date of Month 
 visit date – date of 
informed consent) + 1 day 
• For subjects who withdrew prior to Month 
 = (date of study exit – date of informed 
consent) + 1 day 
Additionally, for each subject, time on study from informed consent to last infusion will be 
similarly calculated. 
Time on Study (months) 
For each subject, time on study from informed consent to last visit, study completion, 
termination or withdrawal (months) will be calculated as follows: 
• For subject who completed Month 
 = ((date of Month 
 visit date – date of 
informed consent) + 1 day )/30.4375, rounded to 1 decimal place 
• For subjects who withdrew prior to Month 
 = ((date of study exit – date of 
informed consent) + 1 day)/30.4375, rounded to 1 decimal place 
Additionally, for each subject, time on study from informed consent to last infusion will be 
similarly calculated. 
Definition of Baseline Values 
Baseline is defined as the last available assessment prior to treatment with ORGN001, except for 
growth parameters and blood and urine 
 whereby baseline is defined as the average of 
all available assessments on or prior to the date of first infusion with ORGN001. 


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Change from Baseline 
Change from baseline will be calculated as follows: 
Change of Baseline = Assessment Value – Baseline Assessment Value 
Percent Change in Assessments from Baseline 
Percent change in values from Baseline will be calculated as follows: 
% Change in Value = (Change in Value) × 100 
 Baseline value 
where Change in Value = (Assessment value – Baseline Assessment value), given that the 
baseline value is non-missing and non-zero and the subsequent value is non-missing. 
Adverse Events 
The analysis of AEs is described in detail in Section 6.5.3. Subject percentages are based on the 
total number of treated subjects in the Safety Set. 
Related AEs are defined as possible, probable, definitely related or unknown/missing. Unrelated 
AEs are defined as unlikely or not related. 
A pre-treatment AE refers to an AE that occurred prior to first ORGN001 infusion. Treatment-
emergent AEs are events with start dates and start times on or after the date and time of the first 
ORGN001 infusion. If the start date of an AE is partially or completely missing and the end 
(stop) date and time of the AE does not indicate that it occurred prior to first infusion, then the 
determination of treatment-emergent status will be based on the following: 
•
If the start year is after the year of the first study drug infusion, then the AE is
treatment-emergent; else,
•
If the start year is the same as the year of the first study drug infusion and
o
the start month is missing, then the AE is treatment emergent; else if
o
the start month is present and is the same or after the month of the first study drug
infusion, then the AE is treatment-emergent; else.
•
If the start date is completely missing, then the AE is treatment-emergent.
All other AEs are considered PTAEs. 
Child-Pugh Score 
Child-Pugh score will be calculated as follows: 
The total of the clinical or biochemical measurement scores (1, 2 or 3) according to Table 4 
determines the Child-Pugh score as Grade A (5-6), Grade B (7-9), or Grade C (10-15). 


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Table 4: 
Criteria for Child-Pugh Classification 
Clinical or Biochemical Measurements 
Points Scored for Increasing Abnormality 
1 
2 
3 
Hepatic encephalopathy (grade) 
Absent 
1 and 2 
3 and 4 
Ascites 
Absent 
Mild 
Moderate 
Total bilirubin (mg/dl) 
<2.0 
2.0-3.0 
>3.0 
Serum albumin (g/dl) 
>3.5 
2.8-3.5 
<2.8 
Prothrombin time INR 
<1.7 
1.7-2.3 
>2.3 
8.4. 
Z-Score 
Definition: Z-scores (or SD scores) are widely used in anthropometry to quantify a 
measurement's distance is from the mean. For example, a measurement that is 1.645 SDs from 
the mean (z-score of 1.645) would be at the 95th percentile of a normal (0,1) distribution; 95% of 
the distribution would be less than this measurement. 
8.4.1. 
World Health Organization Growth Chart 
The WHO growth charts only provide information on children up to 5 years of age.1 
The WHO Antro have developed SAS macros to facilitate data analysis and calculate the 
indictors of the attained growth standards (length-for-age, weight-for-age, head circumference-
for-age, and body mass index-for age). Calculate using the WHO growth chart for patients up to 
5 years of age.2 
8.4.2. 
Centers for Disease Control and Prevention Growth Chart 
The CDC growth charts will be used for children older than 5 years.3 
The CDC has developed SAS macros to facilitate data analysis and calculate the indictors of the 
attained growth standards (length-for-age, weight-for-age, head circumference-for-age, and body 
mass index-for age). Calculate using the WHO growth chart for patients over 5 years of age.4 
8.5. 
Visit Windows 
Visits will be assigned to visit windows. Data is summarized according to the visit windows 
reported in the following table when appropriate (e.g., laboratory parameters, vital signs, 
                                                 
1 Additional WHO growth chart information and methodology can be found at 
http://www.who.int/childgrowth/publications/technical_report_2/en/index.html. 
2 The SAS macro and user instructions can be found at 
https://www.who.int/childgrowth/software/en/. 
3 Additional CDC growth chart information and methodology can be found at 
https://www.cdc.gov/growthcharts/clinical_charts.htm. 
4 The SAS macro and user instructions can be found at 
https://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm. 


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developmental assessments, etc.). If multiple assessments occur within a visit window, the 
assessment closest to the target day will be used. In case of ties, with an equal number of days on 
either side of the target day, the value from the day before the target day shall be used. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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