Clinical trial NCT02629393
Conditions: Molybdenum Cofactor Deficiency, Type A
Keywords: Molybdenum Cofactor Deficiency (MoCD) Molybdenum Cofactor (MoCo) biosynthesis sulfite oxidase (SO) S sulfocysteine (SSC) xanthine oxidoreductase aldehyde oxidase
Sponsor: Origin Biosciences
Start date: 2016-05-01; Completion date: 2022-10-01
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To evaluate the safety and efficacy of ORGN001(formerly ALXN1101) in neonate patients with MoCD Type A

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: ORGN001 (formerly ALXN1101)
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
NCT Number: NCT02629393 
 
 
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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Origin Biosciences, Inc. – Confidential 
ALXN1101-MCD-202 
A Phase 2/3, Multicenter, Multinational, Open-Label Study to Evaluate the 
Efficacy and Safety of ORGN001 (formerly ALXN1101) in Neonates, Infants, 
and Children with Molybdenum Cofactor Deficiency (MoCD) Type A 
Sponsor: 
Origin Biosciences, Inc. 
USA 
Former Sponsor: 
Alexion Pharma GmbH 
Giesshübelstrasse 30 
8045 Zürich 
SWITZERLAND 
IMP Name: 
ORGN001 
Former IMP Name: 
ALXN1101 
Sponsor Contact: 
Origin Biosciences, Inc. 
Medical Monitor: 
Origin Biosciences, Inc. 
IND Number: 
117502 
EudraCT Number: 
2013-002702-30 
Version: 
5.0 
Date of Original Protocol: 
27 August 2015 
Date of Protocol Amendment 1: 
24 February 2016 
Date of Protocol Amendment 2: 
15 February 2019 
Date of Protocol Amendment 3: 
14 November 2019 
Date of Protocol Amendment 4: 
29 January 2020 


Protocol ALXN1101-MCD-202 Amendment 4 
29 January 2020 
 
 
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Origin Biosciences, Inc. – Confidential 
 
 
This protocol contains confidential information and is provided for exclusive use of Investigators. This 
information may only be disclosed to those persons involved in this study who have a need to know with the 
obligation not to further disseminate this information. This information may not be disclosed to other individuals 
unless such disclosure is required by federal or state law or regulations subject to the foregoing. These restrictions 
on disclosure will apply equally to all future oral or written information supplied to you by Origin Biosciences, 
Inc. which is designated as “privileged” or “confidential.” 


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Origin Biosciences, Inc. – Confidential 
 
SPONSOR SIGNATURE PAGE 
 
PROTOCOL TITLE:  
A Phase 2/3, Multicenter, Multinational, Open-Label Study to 
Evaluate the Efficacy and Safety of ORGN001 (formerly 
ALXN1101) in Neonates, Infants, and Children with 
Molybdenum Cofactor Deficiency (MoCD) Type A 
 
PROTOCOL NUMBER: ALXN1101-MCD-202 Amendment 4 
 
______________________________    _____________ 
 
 
 
 
 
 
 
 
 
 
 
Date 
Chief Medical Officer 
Origin Biosciences, Inc. 
 
______________________________    _____________ 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
Senior Director, Regulatory Affairs 
Origin Biosciences, Inc. 
 
____________________________    _____________ 
 
 
 
 
 
 
 
 
 
 
 
Date 
Senior Director, Clinical Operations 
Origin Biosciences, Inc. 
 
DocuSign Envelope ID: 15DCB121-8FA1-4791-AC5E-E1528290966D
1/30/2020
2/3/2020
2/3/2020


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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator Brochure for ORGN001. I have read and understood all 
clinical and administrative sections of the ALXN1101-MCD-202 protocol, entitled “A Phase 2/3, 
Multicenter, Multinational, Open-Label Study to Evaluate the Efficacy and Safety of ORGN001 
(formerly ALXN1101) in Neonates, Infants, and Children with Molybdenum Cofactor 
Deficiency (MoCD) Type A,” and agree to conduct the study in accordance with this protocol, 
all applicable government regulations, and the principles of the World Medical Association 
Declaration of Helsinki, where applicable. I also agree to maintain the confidentiality of all 
information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 


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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Clinical Study Lead 
 
Origin Biosciences, Inc. 
 
 
 
 
Responsible Physician  
 
Origin Biosciences, Inc. 
 
 
 
 
Serious Adverse Event 
Reporting 
 
 
 
 


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1.
SYNOPSIS
Name of Sponsor/Company: Origin Biosciences, Inc. (Origin) 
Name of Investigational Product: ORGN001 
Name of Active Ingredient: Cyclic pyranopterin monophosphate monohydrobromide dihydrate 
Title of Study: A Phase 2/3, Multicenter, Multinational, Open-Label Study to Evaluate the Efficacy and Safety of 
ORGN001 (formerly ALXN1101) in Neonates, Infants, and Children with Molybdenum Cofactor Deficiency 
(MoCD) Type A 
Study center(s): This will be a multicenter, multinational study with approximately 10 investigational study centers. 
Principal Investigator: 
Investigators: A list containing all Investigators and their contact information will be provided when site selection is 
completed. 
Study period (months): approximately 36 months (long-term follow-up 
until approval or decision reached on further development) 
Estimated date first patient enrolled: 1Q2016 
Estimated date last patient completed: 4Q2022 
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). Molybdenum 
cofactor is essential for proper functioning of the enzymes sulfite oxidase (SO), xanthine oxidoreductase, and 
aldehyde oxidase. The loss of SO activity is responsible for the severe and rapidly progressive neurologic damage 
seen in neonates presenting with MoCD. Less frequently, older infants and children may present with neurologic 
symptoms related to MoCD such as seizures, movement disorder and developmental delay/disability that appears to 
have a less rapidly evolving course.   
Although there are three types of MoCD, two-thirds of MoCD patients have Type A, which is due to a mutation in 
the MOCS1 gene localized on chromosome 6p21.2. In MoCD Type A, the first of four synthetic steps in the 
formation of molybdenum cofactor is interrupted, and guanosine triphosphate (GTP) cannot be converted into cyclic 
pyranopterin monophosphate (cPMP). Diagnosis of MoCD Type A in neonates is based on clinical and laboratory 
presentation (eg, seizures, exaggerated startle response, high-pitched cry, intracranial hemorrhage, axial hypotonia, 
limb hypertonia, feeding difficulties, elevated urinary sulfite and/or S-sulfocysteine [SSC], or low or absent uric acid 
in the urine or blood) and is then confirmed by genetic testing. The clinical presentation after the neonatal period 
appears to be more heterogeneous and may progress less rapidly.   
The incidence of MoCD is estimated to be between 1/100,000 and 1/200,000 newborn babies worldwide. Affected 
individuals usually present as neonates with severe symptoms that are observed as part of standard clinical practice. 
These include, but are not limited to, intractable seizures, burst-suppression on electroencephalogram (EEG), 
exaggerated startle reactions, axial hypotonia, limb hypertonia, and feeding difficulties. Death commonly occurs in 
the neonatal period, and patients who survive that period may develop a severe static encephalopathy and 
developmental delays 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 for MoCD. 
Results from nonclinical pharmacology studies with ORGN001 suggest that the metabolic derangement in MoCD 
Type A could be corrected by administration of synthetic cPMP. Restoration of MoCo biosynthesis and SO activity 
is expected to result in correction of the metabolic pathways that would otherwise lead to accumulation of toxic 
metabolites that cause CNS injury. 
These results are supported by data obtained in pediatric patients with MoCD Type A treated with a recombinant 
Escherichia coli-derived cPMP product (rcPMP) from Colbourne Pharmaceuticals GmbH (Colbourne; formerly 
known as Orphatec Pharmaceuticals GmBH), which has been administered on a named-patient basis following 
individual physician requests. Published individual case reports suggest that intravenous (IV) administration of 
rcPMP restores MoCo-dependent enzyme activities, reduces concentrations of disease biomarkers (eg, SSC in urine), 
and has the potential to improve neurologic outcome. 


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In addition to clinical experience with rcPMP, 
 healthy volunteers received ORGN001 in a first-in-human study, 
ALXN1101-MCD-101, in which ORGN001 was well tolerated at doses 
 administered IV. 
 
 
 
 
 
Across both cohorts, no deaths or life-threatening TEAEs occurred, and no one withdrew due to a TEAE. 
 
 
 
To date, ORGN001 has been well-tolerated, and there have been no serious 
adverse reactions with causality attributed to ORGN001 reported, and no patient has withdrawn or discontinued as a 
result of an adverse event (AE). 
 
This study is designed to evaluate the efficacy and safety of ORGN001 in neonates, infants, and children with MoCD 
Type A.  
Objectives 
Primary: 
• 
To evaluate the safety and efficacy of ORGN001 in neonate, infant, and pediatric patients with MoCD Type 
A who are either treatment-naïve or who have received compassionate use ORGN001 
 
Secondary:  
 
  
• 
To evaluate the effect of ORGN001 on growth and development using age-appropriate assessments  
• 
To evaluate the effect of ORGN001 on pediatric measures of functional ability and activities of daily living 
 
 
 
 
  
Endpoints 
Primary Efficacy Endpoint: 
• 
Overall survival (OS) 
 
Secondary Efficacy Endpoints: 
 
 
• 
Changes in growth parameters (height, weight, body mass index [BMI], head circumference) through Month 
12 
• 
Feeding pattern assessments through Month 12 
• 
Gross Motor Function Classification System Expanded and Revised (GMFCS-E&R) results through Month 
12 
• 
Assessments of the Bayley Scales of Infant Development® – Third Edition (Bayley-III) Cognitive and Motor 
Scales as measured through Month 12 
o 
For children aged 3 and above, for whom the Bayley-III is no longer appropriate, the Wechsler 
Preschool and Primary Scale of Intelligence – Fourth Edition (WPPSI-IV) will be 
administered.  
o 
For patients with severe developmental delay, the WPPSI may not be an appropriate 
assessment, and therefore, the Bayley-III may be administered instead. 
• 
Functional ability and activities of daily living, measured by the Pediatric Evaluation of Disability Inventory 
(PEDI) through Month 12 
• 
Gross Motor Function Measure (GMFM)-88 results through Month 12 
 
 


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Safety Endpoints: 
The type, frequency, severity, timing, and relationship to study drug to any AEs, serious AEs (SAEs), and changes in 
vital signs, electrocardiograms, and safety laboratory tests 
Methodology:  
This Phase 2/3, multinational, multicenter, open-label study is designed to evaluate the efficacy and safety of daily 
IV administration of ORGN001 to neonates, infants, and children with MoCD Type A. For the purposes of this 
study, neonate patients are defined as those from 1 to 28 days of age (inclusive) at the time of first ORGN001 dose 
administration, with day 1 of age corresponding to the day of birth. Infants are defined as those from 29 days to 
<2 years of age. Children are defined as those from 2 to 5 years of age (inclusive). Patients must be treatment-naïve 
or may have previously received ORGN001 through the expanded access program (EAP). 
In neonate patients with signs and symptoms consistent with MoCD Type A, treatment should be initiated as soon as 
feasible, in an effort to prevent the irreversible neurologic damage that is expected to occur. 
 
• 
Eligible neonates with a prenatal diagnosis of MoCD Type A will undergo Screening/Baseline assessments 
(eg, brain imaging) prior to or as soon as possible after birth and prior to receiving their first daily IV 
infusion of ORGN001. Given the life-threatening and devastating nature of the disease and the potential for 
a favorable benefit:risk profile for treatment with ORGN001, patients with a prenatal diagnosis may be 
treated prior to onset of signs and symptoms associated with MoCD Type A. Additionally, if it is not 
possible to obtain brain imaging prior to treatment, the priority would be to treat the neonate and obtain 
brain imaging as soon as feasible afterwards. For those patients, the patient’s legal guardians (per 
country-specific requirement) may be asked prior to delivery to provide informed consent for participation 
in the study. 
 
 
 
• 
Eligible neonates who do not have a prenatal diagnosis of MoCD Type A but who have onset of the signs 
and symptoms that may serve as the basis for diagnosis will undergo Screening/Baseline assessments as 
soon as possible prior to receiving their first daily IV infusion of ORGN001. Data from procedures 
conducted as part of standard of care prior to study participation may be collected as part of Medical 
History. Genetic confirmation of the diagnosis of MoCD Type A may be obtained after initiation of 
ORGN001 therapy. 
 


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Eligible patients beyond the neonatal period with genetically confirmed evidence of MoCD Type A, a biochemical 
profile, and clinical picture consistent with MoCD Type A may also be enrolled following completion of 
Screening/Baseline assessments. Data from procedures conducted as part of standard of care prior to study 
participation may be collected as part of Medical History. Genetic confirmation of the diagnosis of MoCD Type A 
may be obtained after initiation of ORGN001 therapy in certain cases. 
 
In all patients, ORGN001 will be administered daily from Day 1 of the study. Completion of a brain MRI may be 
delayed until after the initiation of ORGN001 if not feasible to complete prior to study drug initiation. 
 
 patients will continue to 
receive daily infusions of ORGN001 at home 
 
 and will return to the clinic for study visits for safety, efficacy, and PK assessments.  
 
A Safety Review Committee (SRC) and an external, independent Data Monitoring Committee (DMC) will review 
safety, efficacy, and PK data for this study periodically and will be consulted on an ad hoc basis for individual cases. 
Continuation of ORGN001 treatment will be based on treating physician assessment as well as recommendations by 
the combined SRC and DMC regarding the benefit: risk assessment for each patient. 
 
 
 
Patients with a genetic diagnosis other than MoCD Type A will be discontinued from ORGN001 treatment as they 
are not expected to receive any treatment benefit. Patients who discontinue prematurely from treatment will be 
followed for 28 days, 
. 
 
Dose Selection Strategy: A population PK (PopPK)-based approach has been utilized to create a dosing scheme that 
targets the higher end of the originally acceptable exposure range for ORGN001 (no observable adverse effect level 
[NOAEL]: AUC 
 at the highest dose studied in the original toxicology study that was limited 
by solubility issue. Since then, higher doses have been studied and were all well tolerated in rats and dogs using an 
improved IV formulation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A PopPK model was derived to characterize ORGN001 clinical PK in healthy adult volunteers (Study ALXN1101-
MCD-101) and children with MoCD Type A (Study ALXN1101-MCD-201). Due to 
 renal clearance of 
ORGN001 in adults (Study ALXN1101-MCD-101), a function was included to account for the expected impact of 


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renal function maturation (Rhodin 2009) on ORGN001 PK in neonate patients. 
Dosing will be based upon the gestational age (GA) of the patient.
Following Investigator and Safety Review Committee (SRC) reviews (as well as Data Monitoring 
Committee [DMC] review of data prior to the first dose adjustment for each patient as well as subsequent periodic 
review of cumulative data); recommended dosing may follow the guidance in Table 3.  
The dosing strategy in Table 3 has been simplified compared to the original guidance. This is justified given 1) the 
much greater safety margin with respect to the NOAEL described above; 2) the excellent safety profile of ORGN001 
thus far with all patients tolerating the maximum 1200 μg/kg dose well and no safety signals identified 
; and 3) the fact 
that dose increments 
 were well tolerated in Study ALXN1101-MCD-201. 
Table 3: 
Dosing and Dose Adjustment for Term and Preterm Neonate Patients, Older Infants, and 
Children in Study ALXN1101-MCD-202 
Study Day 
Term Neonate (GA ≥ 37 weeks) 
and Older Infants/Children 
Dose (µg/kg/day) 
Preterm Neonate (GA < 37 weeks) 
Dose (µg/kg/day) 
Day 1 
700 
525 
Day 28 
1000 
900 
Month 3 
1200 
1200 
Abbreviations:  GA=gestational age. 
Doses may be adjusted based on drug-related AEs or changes in clinical parameters, laboratory data, or PK findings 
and will occur following consultation with the medical monitor and, if applicable, with the SRC. 
Day 1 PK samples will be analyzed, and PK assessments will be completed for a DMC meeting that will be 
scheduled prior to the first dose adjustment. If the Day 1 AUC is greater than the upper of the target AUC range 
, there will be a dose recommendation for a decrease by the percentage that the individual 
AUC is greater than the midpoint of the target AUC range 
. 
If the Day 1 AUC is less than the lower limit of the target AUC range 
, there will be a dose 
recommendation for an increase by the percentage that the individual AUC is less than the midpoint of the target 
AUC range 
. 
Number of patients (planned):  
There will be no minimum or maximum number of patients for this study. 
Diagnosis and main criteria for inclusion 
Inclusion criteria: 
Patients must meet all of the following inclusion criteria to be considered for enrollment in this study: 
•
Male or female neonatal patient (1 to 28 days of age [inclusive] at the time of ORGN001 administration,
with day 1 of age corresponding to the day of birth) or infant (29 days to <2 years of age) or child (2 to 5
years of age [inclusive]) with MoCD Type A, previously untreated with ORGN001 or treated with
ORGN001 through the EAP
•
In neonates, diagnosis of MoCD Type A, based on:
o
Prenatal genetic diagnosis, or
o
Onset of clinical and/or laboratory signs and symptoms consistent with MoCD Type A (eg, seizures,
exaggerated startle response, high-pitched cry, axial hypotonia, limb hypertonia, feeding difficulties,
elevated urinary sulfite and/or SSC, elevated xanthine in urine or blood, or low or absent uric acid in the
urine or blood) within the first 28 days after birth
•
In infants or children, diagnosis of MoCD Type A, based on:


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o 
Confirmed genetic diagnosis (genetic confirmation of the diagnosis of MoCD Type A may be obtained 
after initiation of ORGN001 therapy in certain cases), biochemical profile, and clinical presentation 
consistent with MoCD Type A 
• 
Parent or legal guardian must have signed the informed consent form (ICF) prior to any study procedures 
being performed. 
 
Exclusion criteria: 
Patients will be excluded from participating in the study if they meet any of the following criteria: 
• 
Diagnosis other than MoCD Type A (may be determined after the initiation of study drug) 
• 
Condition that is considered by the treating physician to be a contraindication to therapy, including evidence 
of abnormalities on brain imaging not attributable to MoCD Type A, or that might otherwise interfere with 
the patient’s participation in the study, pose any additional risk for the patient, or confound patient 
assessments  
• 
Antenatal and/or postnatal brain imaging prior to initiation of treatment with ORGN001 that indicates 
cortical or subcortical cystic encephalomalacia, clinically significant intracranial hemorrhage, or other 
abnormalities on brain imaging determined by the treating physician to be clinically significant 
• 
Modified Glasgow Coma Scale (mGCS) for Infants and Children score of less than 7 for more than 24 hours 
(does not apply to children less than 1 day in age). 
Investigational product, dosage, and mode of administration:  
ORGN001, which is a synthetic form of cPMP, is supplied as a sterile, 
 white to slightly yellow 
lyophilized powder 
 to be reconstituted using 
 sterile Water for 
Injection and administered by IV infusion. 
 
Dosing with ORGN001 in neonates will be based upon the schedule presented in Table 3. Following Investigator and 
SRC/DMC review (prior to the 
 dose adjustment of each patient 
 as well as subsequent periodic 
reviews of cumulative data), doses may be adjusted, based on drug-related AEs, changes in clinical parameters, or 
PK findings. 
 
Dosing with ORGN001 in infants and children will be based upon the schedule presented in Table 3. Following 
Investigator and SRC/DMC review (prior to the 
 dose adjustment of each patient 
 as well as 
subsequent periodic reviews of cumulative data), doses may be adjusted, based on drug-related AEs, changes in 
clinical parameters, or PK findings. 
Duration of treatment:  
ORGN001 will be administered once daily throughout the study.  
Reference therapy, dosage, and mode of administration:  
None 
Criteria for evaluation 
Refer to the efficacy, safety, and PK endpoints for a description of the assessments to be analyzed. 
Statistical methods: 
Efficacy, safety, and PK
 data will be analyzed in this study. 
 
Safety analyses will be performed on the Safety Set, which includes all patients who receive at least 1 dose of 
ORGN001. 
 
Efficacy analyses will be performed on two modified Full Analysis Sets (Neonate mFAS and Pediatric PmFAS), as 
well as the Full Analysis Set. 
 
Safety:  The incidence of TEAEs 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 laboratory assessments (chemistry, 
hematology, and urinalysis) will be summarized. Incidence of abnormalities for clinical laboratory assessments 
(serum chemistry and hematology) will be summarized by visit.  
 


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Primary Efficacy Endpoint Analyses:  Overall survival is defined as the interval in months from the date of birth to 
the date of death or date last known alive (patients still on study will be censored at the data cut-off), whichever 
occurs first. 
 
Secondary Efficacy Endpoints Analyses: 
 
 
 
Body weight, length, head circumference, and 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 through Month 12.  
 
Feeding patterns through Month 12 will be analyzed via the frequency and percentages of each feeding method at 
each visit where feeding pattern was recorded. 
 
Changes in motor function through Month 12 will be summarized based on data from the administration of the 
GMFCS-E&R, which is a 5-level classification system that classifies gross motor functional capabilities and 
limitations as usual performance in the home, school, and community setting. 
 
The Bayley-III Cognitive and Motor scaled scores and composite scores, as well as percentile ranks, and age 
equivalents, will be summarized through Month 12. Where appropriate, the WPPSI-IV will be used instead of the 
Bayley-III.  
 
Changes in PEDI standard and scaled scores will be summarized by self-care, mobility, and social function domains 
through Month 12. 
 
Changes in acquisition of motor development milestones will be summarized through Month 12 based on data from 
the administration of the GMFM-88, which measures patient-initiated motor activities in 5 dimensions: Lying and 
Rolling; Sitting; Crawling and Kneeling; Standing; and Walking, Running, and Jumping. A percent score can be 
obtained for each dimension and for the total of all GMFM dimensions. Patients who use mobility aids and/or 
orthoses will be assessed without those aids. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol ALXN1101-MCD-202 Amendment 3 
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SUMMARY OF CHANGES 
Table 4: 
Changes Between Amendment 1 and Amendment 3 
Section 
Description of Change  
 
Cover page  
• Protocol title updated to reflect addition of infants and 
children to the study population. (This change has been 
carried through to all other locations in which the protocol 
title is shown.) 
• Updated to reflect new sponsor, Origin Biosciences, Inc., 
who acquired the program from Alexion Pharma GmbH in 
September 2018.  
• Updated responsible study personnel. 
• The protocol number ALXN1101-MCD-202 will remain 
unchanged. 
 
Investigational medicinal product name 
 
On the acquisition of ORGN001 by Origin Biosciences, Inc., 
the IMP ALXN1101 (cyclic pyranopterin monophosphate 
monohydrobromide dihydrate) has been renamed ORGN001. 
  
Sponsor Signature Page 
 
• Updated responsible medical officer. 
• Added additional signatories. 
 
Procedures in Case of Emergency 
Updated contact information for reporting SAEs. 
 
2 Synopsis 
 
 
• The study period has been adjusted to accommodate long-
term follow-up until approval or decision reached on further 
development of ORGN001, and last patient completion date 
has been adjusted to 4Q2022. 
• The study background/ rationale, study objectives, 
endpoints, methodology, inclusion/exclusion criteria, and 
statistical methods have been updated to reflect the changes 
detailed in sections below that have been made to expand 
the study subject population to include older infants and 
children with MoCD. 
 
2.1 Background 
The background has been revised to include information on 
older children and infants with MoCD. 
2.2 Rationale for the Study 
Additional text: 
“Responsibility for the development of ORGN001 in the 
treatment of MoCD Type A was assumed by Origin 
Biosciences, Inc, in September 2018.” 
 
2.3 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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Section 
Description of Change  
 
2.4 Rationale for Patient Population 
Additional text: 
• “However, the clinical presentation after the neonatal period 
appears to be more heterogeneous and may progress less 
rapidly in some patients. In an effort to more fully 
characterize the potential impact of ORGN001 in MoCD 
Type A, the study has thus been modified to include infants 
and children with MoCD Type A, who are treatment-naïve 
or may have previously received ORGN001 through the 
early access program (EAP). Infants are defined as those 
from 29 days to <2 years of age in Amendment 3. Children 
are defined as those from 2 to 5 years of age (inclusive).” 
• “In infants or children, eligibility will be determined by 
confirmed genetic diagnosis (genetic confirmation of the 
diagnosis of MoCD Type A may be obtained after initiation 
of ORGN001 therapy in certain cases), biochemical profile, 
and clinical presentation consistent with MoCD Type A.” 
 
2.5 Rationale for Proposed Dosing 
Additional text and tables have been added on the basis of a 
population PK (PopPK) model: 
• “Since then, higher doses have been studied and were all 
well tolerated in rats and dogs using an improved IV 
formulation. Accordingly, the revised NOAEL values in a 
 rat study provide a considerable increase in the 
safety margins 
.” 
• “The dosing strategy in Table 9 has been simplified 
compared to the original guidance. This is justified given 1) 
the much greater safety margin with respect to the NOAEL 
in the 
 rat study described above; 2) the excellent 
safety profile of ORGN001 thus far with all patients 
tolerating the maximum 1200 μg/kg/day dose and no safety 
signals identified 
 
 
; and 3) the fact that dose increments 
 
 were well tolerated in Study ALXN1101-MCD-
201.” 
 
2.6 Rationale for Overall Study Design 
Additional text: 
“Less frequently, older infants and children may present with 
neurologic symptoms related to MoCD such as seizures, 
movement disorder, and developmental delay/disability that 
appears to have a less rapidly evolving course.” 
 
3.1 Objectives 
• Primary objective updated to include infants and pediatric 
patients who are either treatment-naïve or who have 
received compassionate use ORGN001. 
• Secondary objectives 
 encompass evaluation of 
 
the effect of ORGN001 on growth and 
development using age-appropriate assessments,
 
 
. 
 


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Section 
Description of Change  
 
3.2 Endpoints 
Primary efficacy endpoint modified to overall survival. 
Secondary efficacy endpoints modified to include variables (eg, 
changes in growth parameters, feeding pattern assessments, and 
developmental assessments) appropriate to the expanded study 
subject population and study period. 
 
 
4.1 Overall Study Design 
Additional text: 
• “Infants are defined as those from 29 days to < 2 years. 
Children are defined as those from 2 years to 5 years 
(inclusive) at the time of informed consent.” 
 
 
 
• “Eligible patients beyond the neonatal period with 
genetically confirmed evidence of MoCD Type A, a 
biochemical profile, and clinical picture consistent with 
MoCD Type may also be enrolled following completion of 
Screening/Baseline assessments.” 
• “Data from procedures conducted as part of standard of care 
prior to study participation may be collected as part of 
Medical History. Genetic confirmation of the diagnosis of 
MoCD Type A may be obtained after initiation of 
ORGN001 therapy in certain cases.” 
• “Due to the rare nature of the disease and no currently 
available treatment, patients exceeding 36 months of 
treatment may continue to receive study drug until 
ORGN001 becomes commercially available or development 
has stopped. For patients receiving ORGN001 past month 
36, a safety visit will occur 
. Assessments 
performed during those visits are for the purposes of 
ongoing safety to receive ORGN001 and may only occur if 
ORGN001 is not yet commercially available for the 
patient.” 
 
 
 
 
4.2 Number of Patients 
Revised so that no minimum or maximum number of patients is 
projected for enrollment in the study. 


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Section 
Description of Change  
 
4.3 Study Assessments 
• Updated to include any differences in assessment between 
neonates, infants, and children as based on the Schedules of 
Assessments (which are referenced throughout rather than 
all information being duplicated in these subsections). 
• Vital signs assessment 
 
specified as predose (Section 4.3.6). Additional systolic and 
diastolic blood pressure measurements to be collected 
 
 30 
minutes post-EOI was added as a time point. 
• Serum osmolality added as a parameter of blood 
chemistry/hematology sample analysis to align with the 
assessment table and CRF (Section 4.3.8). 
• Wechsler Preschool and Primary Scale of Intelligence – 
Fourth Edition (WPPSI-IV) added as an alternative to the 
Bayley-III for those patients developmentally beyond the 
Bayley-III (Section 4.3.12). 
 
5 Schedules of Assessments: 
(Screening/Baseline and 12-Month Study 
Period) 
 
 
• WPPSI-IV listed as alternative to the Bayley-III. 
 
 
 
• Brain ultrasound specified for neonates only. 
• Footnote added that additional systolic and diastolic blood 
pressure measurements are to be collected 
 
 approximately 30, 60, 90, and 120 minutes 
post-EOI and at 6 and 12 hours post-EOI. 
 
5 Schedules of Assessments: 
(Long-Term Treatment Period and Safety 
Follow Up) 
• WPPSI-IV listed as alternative to the Bayley-III. 
• Safety Follow-up ET Visit column has had developmental 
assessments added as included and a footnote made stating 
that these assessments will only occur 
 for 
children continuing on ORGN001 past the study follow up 
period where ORGN001 is not commercially available. 
 
5 Schedules of Assessments: 
(Following Recommendation by the Safety 
Review Committee for an Unscheduled Dose 
Adjustment) 
• PD blood sampling to occur predose. 
• PK blood sampling to occur at EOI (±5 minutes), 1 to 2 
hours after the EOI, and 3 to 4 hours after the EOI. 
 
6.3 Definition of Study End 
Additional text: 
“Due to the rare nature of the disease and no currently available 
treatment, patients exceeding 36 months of treatment may 
continue to receive study drug until ORGN001 becomes 
commercially available or development has stopped.” 


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Section 
Description of Change  
 
7.2 Patient Inclusion Criteria 
Additional text for the first criterion: 
“or infant (29 days to < 2 years of age) or child (2 to 5 years of 
age [inclusive]) with MoCD Type A, previously untreated with 
ORGN001 or treated with ORGN001 through the EAP” 
 
Additional criterion added: 
• In infants or children, diagnosis of MoCD Type A, based 
on:  
– 
Confirmed genetic diagnosis (genetic confirmation of 
the diagnosis of MoCD Type A may be obtained after 
initiation of ORGN001 therapy in certain cases), 
biochemical profile, and clinical presentation consistent 
with MoCD Type A 
 
  
 
 
 
 
 
 
 
10 Pharmacodynamics Assessments 
Timing of additional blood and urine sample collection 
following unscheduled dose adjustments changed to be as 
follows: 
On the first day the adjusted dose is administered, the patient 
will be administered study drug in-clinic, and a pre-dose blood 
sample will be collected on the 
 day of the dose adjustment 
. A urine sample will be 
collected at any time during 
 the dose 
adjustment visit. 
11 Pharmacokinetics Assessments 
• PK samples were specified for collection
 
. 
• An additional PK sample was added to occur at 1 to 2 hours 
after EOI on regularly scheduled collection days, on any day 
 
 of an unscheduled dose adjustment. 
 
 
 
13.5.8 Reporting of Serious Adverse Events to 
Sponsor 
  
 
 
Additional text: 
“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” 
 
 
 


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Section 
Description of Change  
 
 
 
 
 
14.1 Determination of Sample Size 
 
“There will be no minimum or maximum number of patients for 
this study. The final sample size and determination of study 
success relative to efficacy will depend on the overall survival 
rate as each successive patient reaches study completion.” 
14.2 Analysis Populations 
A Full Analysis Set (FAS) has been defined for performance of 
the efficacy analyses; the FAS is defined as patients with a 
confirmed diagnosis of MoCD Type A who have no antenatal 
and/or postnatal brain imaging prior to initiation of treatment 
with ORGN001 that indicates cortical or subcortical cystic 
encephalomalacia or clinically significant intracranial 
hemorrhage. 
 
Additional text: 
“Additionally, two modified Full Analysis Sets (mFAS) will be 
used to support the analyses on the FAS: 
• Neonate mFAS (NmFAS),
 
 
 
• Pediatric mFAS (PmFAS), 
 
 
14.3 Efficacy and Pharmacokinetic Endpoints 
Primary Efficacy Endpoint: 
Changed to be overall survival. 
 
Secondary Efficacy Endpoints: 
 
• Changes in growth parameters (height, weight, BMI, head 
circumference) through Month 12 
• Feeding pattern assessments through Month 12  
• GMFCS-E&R results through Month 12 
• 
GMFM-88 results through Month 12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Section 
Description of Change  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14.4 Demographics and Baseline 
Characteristics 
Fas, NmFAS, and PmFAS added. 
 
14.7 Efficacy Analyses 
Fas, NmFAS, and PmFAS added. 
 
 
 
 
14.7.2 Primary Efficacy Analysis 
 
“The primary efficacy analysis will summarize overall survival, 
defined as the interval in months from the date of birth to the 
date of death or date last known alive (patients still on study 
will be censored at the data cutoff date), whichever occurs first.  
The analysis of OS will be based on the Kaplan-Meier 
methodology for estimation of survival parameters. The median 
duration of OS will be estimated based on the 50th percentile of 
the Kaplan-Meier distribution; additional summary statistics, 
including the 25th and 75th percentiles, 95% confidence 
intervals (CIs) on the median and the other percentiles and 
proportion of censored patients. The analysis of OS will be 
done using the FAS, the NmFAS, and the PmFAS.” 
14.7.3 Secondary Efficacy Analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Section 
Description of Change  
 
 
Text added: 
• “Body weight, length, head circumference, and BMI will be 
analyzed by converting each parameter to age-adjusted z-
scores and age percentiles, and descriptive statistics will be 
presented to each parameter through Month 12.” 
• “Changes in motor function through Month 12 will be 
summarized based on data from the administration of the 
GMFCS-E&R, which is a 5-level classification system that 
classifies gross motor functional capabilities and limitations 
as usual performance in the home, school, and community 
setting.” 
• “The Bayley-III Cognitive and Motor scaled scores and 
composite scores, as well as percentile ranks, and age 
equivalents will be summarized through Month 12. Where 
appropriate, the WPPSI-IV will be used instead of the 
Bayley-III.” 
• “PEDI standard and scaled scores will be summarized by 
self-care, mobility, and social function domains through 
Month 12.” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix B Blood Sampling Volume Tables 
• PK sampling time point blood draws added 1-2 hours after 
the EOI 
 
 
• Total amount of blood drawn per time point adjusted 
 
; total amount of blood drawn per 12-month study period 
adjusted
. 
 
 


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Table 5: 
Summary of Changes Between Amendment 2 and Amendment 3 
Section 
Description of Change  
 
Cover page  
• Protocol title updated to reflect addition of infants and 
children to the study population. (This change has been 
carried through to all other locations in which the protocol 
title is shown.) 
• Updated responsible study personnel. 
 
Sponsor Signature Page 
 
• Updated responsible medical officer. 
• Added additional signatories. 
 
Procedures in Case of Emergency 
Updated contact information for reporting SAEs. 
 
2 Synopsis 
• The study period has been adjusted to accommodate long-
term follow-up until approval or decision reached on further 
development of ORGN001, and last patient completion date 
has been adjusted to 4Q2022. 
• The study background/ rationale, study objectives, 
endpoints, methodology, inclusion/exclusion criteria, and 
statistical methods have been updated to reflect the changes 
detailed in sections below that have been made to expand 
the study subject population to include older infants and 
children with MoCD. 
 
2.1 Background 
The background has been revised to include information on 
older children and infants with MoCD. 
2.2 Rationale for the Study 
Additional text: 
“Responsibility for the development of ORGN001 in the 
treatment of MoCD Type A was assumed by Origin 
Biosciences, Inc, in September 2018.” 
 
2.3 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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Section 
Description of Change  
 
2.4 Rationale for Patient Population 
Additional text: 
• “However, the clinical presentation after the neonatal period 
appears to be more heterogeneous and may progress less 
rapidly in some patients. In an effort to more fully 
characterize the potential impact of ORGN001 in MoCD 
Type A, the study has thus been modified to include infants 
and children with MoCD Type A, who are treatment-naïve 
or may have previously received ORGN001 through the 
early access program (EAP). Infants are defined as those 
from 29 days to <2 years of age in Amendment 3. Children 
are defined as those from 2 to 5 years of age (inclusive).” 
• “In infants or children, eligibility will be determined by 
confirmed genetic diagnosis (genetic confirmation of the 
diagnosis of MoCD Type A may be obtained after initiation 
of ORGN001 therapy in certain cases), biochemical profile, 
and clinical presentation consistent with MoCD Type A.” 
 
2.5 Rationale for Proposed Dosing 
Additional text and tables have been added on the basis of a 
population PK (PopPK) model: 
• “Since then, higher doses have been studied and were all 
well tolerated in rats and dogs using an improved IV 
formulation. Accordingly, the revised NOAEL values in a 
 rat study provide a considerable increase in the 
safety margins
.” 
• “The dosing strategy in Table 9 has been simplified 
compared to the original guidance. This is justified given 1) 
the much greater safety margin with respect to the NOAEL 
in the 
 rat study described above; 2) the excellent 
safety profile of ORGN001 thus far with all patients 
tolerating the maximum 1200 μg/kg/day dose and no safety 
signals identified 
 
 
; and 3) the fact that dose increments 
 
 were well tolerated in Study ALXN1101-MCD-
201.” 
 
2.6 Rationale for Overall Study Design 
Additional text: 
“Less frequently, older infants and children may present with 
neurologic symptoms related to MoCD such as seizures, 
movement disorder, and developmental delay/disability that 
appears to have a less rapidly evolving course.” 
 
3.1 Objectives 
• Primary objective updated to include infants and pediatric 
patients who are either treatment-naïve or who have 
received compassionate use ORGN001. 
• Secondary objectives updated to encompass evaluation of 
 
the effect of ORGN001 on growth and 
development using age-appropriate assessments,
 
 
 
 


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Section 
Description of Change  
 
3.2 Endpoints 
Primary efficacy endpoint modified to overall survival. 
Secondary efficacy endpoints modified to include variables (eg, 
changes in growth parameters, feeding pattern assessments, and 
developmental assessments) appropriate to the expanded study 
subject population and study period. 
 
 
4.1 Overall Study Design 
Additional text: 
• “Infants are defined as those from 29 days to < 2 years. 
Children are defined as those from 2 years to 5 years 
(inclusive) at the time of informed consent.” 
 
 
 
• “Eligible patients beyond the neonatal period with 
genetically confirmed evidence of MoCD Type A, a 
biochemical profile, and clinical picture consistent with 
MoCD Type may also be enrolled following completion of 
Screening/Baseline assessments.” 
• “Data from procedures conducted as part of standard of care 
prior to study participation may be collected as part of 
Medical History. Genetic confirmation of the diagnosis of 
MoCD Type A may be obtained after initiation of 
ORGN001 therapy in certain cases.” 
• “Due to the rare nature of the disease and no currently 
available treatment, patients exceeding 36 months of 
treatment may continue to receive study drug until 
ORGN001 becomes commercially available or development 
has stopped. For patients receiving ORGN001 
 
 a safety visit will occur 
. Assessments 
performed during those visits are for the purposes of 
ongoing safety to receive ORGN001 and may only occur if 
ORGN001 is not yet commercially available for the 
patient.” 
 
 
 
 
4.2 Number of Patients 
Revised so that no minimum or maximum number of patients is 
projected for enrollment in the study. 


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Section 
Description of Change  
 
4.3 Study Assessments 
• Updated to include any differences in assessment between 
neonates, infants, and children
 
 
 
• Vital signs assessment 
 
specified as predose (Section 4.3.6). Additional systolic and 
diastolic blood pressure measurements to be collected 
 
 30 
minutes post-EOI was added as a time point. 
• Serum osmolality added as a parameter of blood 
chemistry/hematology sample analysis to align with the 
assessment table and CRF (Section 4.3.8). 
• Wechsler Preschool and Primary Scale of Intelligence – 
Fourth Edition (WPPSI-IV) added as an alternative to the 
Bayley-III for those patients developmentally beyond the 
Bayley-III (Section 4.3.12). 
 
5 Schedules of Assessments: 
(Screening/Baseline and 12-Month Study 
Period) 
 
 
. 
• WPPSI-IV listed as alternative to the Bayley-III. 
 
 
 
• Brain ultrasound specified for neonates only. 
• Footnote added that additional systolic and diastolic blood 
pressure measurements are to be collected 
 
 at approximately 30, 60, 90, and 120 minutes 
post-EOI and at 6 and 12 hours post-EOI. 
 
5 Schedules of Assessments: 
(Long-Term Treatment Period and Safety 
Follow Up) 
• WPPSI-IV listed as alternative to the Bayley-III. 
• Safety Follow-up ET Visit column has had developmental 
assessments added as included and a footnote made stating 
that these assessments will only occur 
 for 
children continuing on ORGN001 past the study follow up 
period where ORGN001 is not commercially available. 
 
5 Schedules of Assessments: 
(Following Recommendation by the Safety 
Review Committee for an Unscheduled Dose 
Adjustment) 
• PD blood sampling to occur predose. 
• PK blood sampling to occur at EOI (±5 minutes), 1 to 2 
hours after the EOI, and 3 to 4 hours after the EOI. 
 
6.3 Definition of Study End 
Additional text: 
“Due to the rare nature of the disease and no currently available 
treatment, patients exceeding 36 months of treatment may 
continue to receive study drug until ORGN001 becomes 
commercially available or development has stopped.” 


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Section 
Description of Change  
 
7.2 Patient Inclusion Criteria 
Additional text for the first criterion: 
“or infant (29 days to < 2 years of age) or child (2 to 5 years of 
age [inclusive]) with MoCD Type A, previously untreated with 
ORGN001 or treated with ORGN001 through the EAP” 
 
Additional criterion added: 
• In infants or children, diagnosis of MoCD Type A, based 
on:  
– 
Confirmed genetic diagnosis (genetic confirmation of 
the diagnosis of MoCD Type A may be obtained after 
initiation of ORGN001 therapy in certain cases), 
biochemical profile, and clinical presentation consistent 
with MoCD Type A 
 
 
 
 
 
 
10 Pharmacodynamics Assessments 
Timing of additional blood and urine sample collection 
following unscheduled dose adjustments changed to be as 
follows: 
On the first day the adjusted dose is administered, the patient 
will be administered study drug in-clinic, and a pre-dose blood 
sample will be collected on the first day of the dose adjustment 
. A urine sample will be 
collected at any time during 
 the dose 
adjustment visit. 
11 Pharmacokinetics Assessments 
 
 
• An additional PK sample was added to occur at 1 to 2 hours 
after EOI on regularly scheduled collection days, 
 
or on 
the first day of an unscheduled dose adjustment. 
 
 
 
14 Statistical Methods and Planned Analyses 
Added text: 
• “Assessments will be binned into analysis visits in such a 
way that the assessment closest to the target study day 
among all assessments observed within a window around 
the target day will be designated for analyses over time. 
 
 
 
• “Continuous variables will be summarized using mean, SD, 
median, minimum, and maximum. Categorical variables 
will be summarized using percentages and frequency 
distributions. Confidence intervals will be provided for all 
means and percentages to aid in interpretation.” 
 
14.1 Determination of Sample Size 
Previous section contents deleted; revised to read as follows: 


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Section 
Description of Change  
 
“There will be no minimum or maximum number of patients for 
this study. The final sample size and determination of study 
success relative to efficacy will depend on the overall survival 
rate as each successive patient reaches study completion.” 
 
14.2 Analysis Populations 
A Full Analysis Set (FAS) has been defined for performance of 
the efficacy analyses; the FAS is defined as patients with a 
confirmed diagnosis of MoCD Type A who have no antenatal 
and/or postnatal brain imaging prior to initiation of treatment 
with ORGN001 that indicates cortical or subcortical cystic 
encephalomalacia or clinically significant intracranial 
hemorrhage. 
 
Additional text: 
“Additionally, two modified Full Analysis Sets (mFAS) will be 
used to support the analyses on the FAS: 
• Neonate mFAS (NmFAS),
 
 
 
• Pediatric mFAS (PmFAS), 
 
” 
 
14.3 Efficacy and Pharmacokinetic Endpoints 
Primary Efficacy Endpoint: 
Changed to be overall survival. 
 
 
 
• Changes in growth parameters (height, weight, BMI, head 
circumference) through Month 12 
• Feeding pattern assessments through Month 12  
• GMFCS-E&R results through Month 12 
• 
GMFM-88 results through Month 12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Section 
Description of Change  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14.4 Demographics and Baseline 
Characteristics 
Fas, NmFAS, and PmFAS added. 
 
14.5 Patient Disposition and Extent of 
Exposure 
Text added: 
“The number of patients screened, treated, continuing treatment 
after confirmation of enrollment criteria, and completing the 12-
month and 36-month study periods will be tabulated. Reasons 
for any patient withdrawals will be provided. The number of 
patients in the safety and efficacy analysis sets, along with 
reasons for exclusion from analysis sets, will be tabulated.” 
14.7 Efficacy Analyses 
Fas, NmFAS, and PmFAS added. 
 
14.7.1 Use of Natural History Study ALX-
MCD-502 
Entire section new (compared to Amendment 2) 
14.7.2 Primary Efficacy Analysis 
 
“The primary efficacy analysis will summarize overall survival, 
defined as the interval in months from the date of birth to the 
date of death or date last known alive (patients still on study 
will be censored at the data cutoff date), whichever occurs first.  
The analysis of OS will be based on the Kaplan-Meier 
methodology for estimation of survival parameters. The median 
duration of OS will be estimated based on the 50th percentile of 
the Kaplan-Meier distribution; additional summary statistics, 
including the 25th and 75th percentiles, 95% confidence 
intervals (CIs) on the median and the other percentiles and 
proportion of censored patients. The analysis of OS will be 
done using the FAS, the NmFAS, and the PmFAS.” 
14.7.3 Secondary Efficacy Analyses 
 
 
 
 
 
 
 
 


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Section 
Description of Change  
 
Text added: 
• “Body weight, length, head circumference, and BMI will be 
analyzed by converting each parameter to age-adjusted z-
scores and age percentiles, and descriptive statistics will be 
presented to each parameter through Month 12.” 
• “Changes in motor function through Month 12 will be 
summarized based on data from the administration of the 
GMFCS-E&R, which is a 5-level classification system that 
classifies gross motor functional capabilities and limitations 
as usual performance in the home, school, and community 
setting.” 
• “The Bayley-III Cognitive and Motor scaled scores and 
composite scores, as well as percentile ranks, and age 
equivalents will be summarized through Month 12. Where 
appropriate, the WPPSI-IV will be used instead of the 
Bayley-III.” 
• “PEDI standard and scaled scores will be summarized by 
self-care, mobility, and social function domains through 
Month 12.” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14.8.1 Adverse Events 
Text added: 
“Summaries will include both the number of patients affected 
and the number of events. For patient counts in summaries by 
severity or relationship, 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 in the most extreme category 
of severity or relationship observed.” 
Appendix B Blood Sampling Volume Tables 
Modifications made herein to match time points from the 
Schedules of Assessments and elsewhere changed within the 
document: 


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Section 
Description of Change  
 
• PK sampling time point blood draws added 1-2 hours after 
the EOI 
 
 
• Total amount of blood drawn per time point adjusted 
 
; total amount of blood drawn per 12-month study period 
adjusted 
. 
 
Table 6: 
Summary of Changes Between Amendment 3 and Amendment 4 
Section 
Description of Change  
 
Administrative 
Updates to table numbers throughout the protocol to account for 
additional summary of changes table for protocol amendment 4 
 
 
 
 
 
4.3.7 
Electrocardiograms will be collected for each patient at 
Screening/Baseline when feasible,
 
 
and at any Safety Follow-up Visit, and at the 
Early Termination Visit, if applicable, or as per SRC 
recommendation. 
4.3.8 
 
 
 
 
 
 
 
 
 
 
 
 
If the PK collection kit is not received in time for PK sample 
collection on Day 1, PK samples may be drawn any time
 
PK samples should be collected at EOI (±5 minutes), 1 
to 2 hours after EOI, and 3 to 4 hours after EOI.  If the sample 
is collected on Day 1, a pre-dose sample should also be 
collected.   
5.  Table 10 
, Schedule of 
Assessments 
Addition of pre-dose pharmacokinetic sampling to footnote “o”:  
• 
Pharmacokinetic sampling will be conducted at the EOI ±5 
minutes, 1 to 2 hours after EOI, and 3 to 4 hours after EOI 
.  On Day 1 
only a pre-dose sample will also be collected. 
 
 
 
 
Addition of time point 30 minutes has been added to footnote 
“c”: 


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Section 
Description of Change  
 
• 
 additional systolic and diastolic 
blood pressure measurements are to be collected at 
approximately 30, 60, 90, and 120 minutes post- EOI, and 
at 6 and 12 hours post-EOI. 
5. Table 12 
: Schedule of 
Assessments (Following Recommendation by 
the Safety Review Committee for an 
Unscheduled Dose Adjustment) 
To match protocol language, addition of tick box for urinalysis 
on First Day Adjusted Dose is Administered.  
10. Pharmacodynamic Assessments 
The PD blood draw volume for the safety follow up visit was 
updated: 
• 
At any Safety Follow-up Visit, a PD blood sample
 
will be collected. 
11. Pharmacokinetic Assessments 
Addition of pre-dose pharmacokinetic sampling: 
 
 
o 
Pre-dose at Day 1 only 
o 
at the EOI ±5 minutes 
o 
1 to 2 hours after EOI 
o 
3 to 4 hours after EOI 
 
Clarification to language in the following section: 
Following recommendation by the SRC for an unscheduled 
dose adjustment, blood samples will be collected for assessment 
of PK parameters, as follows:  
On the first day the adjusted dose is administered, the 
patient will be administered study drug in-clinic, and a 
blood sample will be collected at the EOI (±5 
minutes), 1 to 2 hours after the EOI, and at 3 to 4 hours 
after the EOI. The time of infusion, PK sample 
collection, the dose administered, and the start and stop 
time of IV infusion are to be recorded in the CRF.  
 
following an unscheduled dose adjustment, a 
PK sample will be collected at 1 to 2 hours after 
EOI. 
Appendix B, Blood Sampling Volumes 
Tables; Table 15 
: Blood 
Sampling Volumes (in mL) During the 12-
Month Study Period 
• 
Addition of pre-dose pharmacokinetic sampling on Day 1 
o 
Update to blood volumes in table to account for 
pre-dose sample collection 
 
 (planned dose-escalation visits) 
Appendix B, Blood Sampling Volumes Table 
16 
:  Blood Sampling 
Volumes During the Long-Term Extension 
Period, After a Dose Adjustment, and at the 
Safety Follow-up 
• 
Update to 
 account for pre-dose 
sample collection on unscheduled dose adjustment and 
safety follow up visits.   


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Table of Contents 
1. 
SYNOPSIS ...................................................................................................................6 
SUMMARY OF CHANGES .........................................................................................................14 
2. 
INTRODUCTION ......................................................................................................39 
2.1. 
Background .................................................................................................................39 
2.1.1. 
Treatment Options for MoCD Type A .......................................................................40 
2.2. 
Rationale for the Study ...............................................................................................40 
2.3. 
Risk/Benefit Assessment ............................................................................................41 
2.4. 
Rationale for Patient Population .................................................................................42 
2.5. 
Rationale for Proposed Dosing ...................................................................................43 
2.6. 
Rationale for the Overall Design ................................................................................44 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................46 
3.1. 
Objectives ...................................................................................................................46 
3.2. 
Endpoints ....................................................................................................................46 
4. 
INVESTIGATIONAL PLAN .....................................................................................49 
4.1. 
Overall Study Design ..................................................................................................49 
4.2. 
Number of Patients .....................................................................................................51 
4.3. 
Study Assessments......................................................................................................51 
4.3.1. 
Demographic Data ......................................................................................................51 
4.3.2. 
Genotype Assessment .................................................................................................51 
4.3.3. 
Medical History ..........................................................................................................51 
4.3.4. 
Family History ............................................................................................................51 
4.3.5. 
Physical Examination .................................................................................................51 
4.3.6. 
Vital Signs ..................................................................................................................52 
4.3.7. 
Electrocardiograms .....................................................................................................52 
4.3.8. 
Laboratory Samples and Assessments ........................................................................52 
 
 
4.3.9. 
Growth Parameters .....................................................................................................54 
4.3.10. 
Feeding Patterns ..........................................................................................................54 
4.3.11. 
Neurologic Examination and Neuroimaging ..............................................................54 
4.3.12. 
Bayley Scales of Infant Development (or Wechsler Preschool and Primary 
Scale of Intelligence – Fourth Edition) .......................................................................54 
4.3.13. 
Gross Motor Function Measure–88 ............................................................................55 


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4.3.14. 
Gross Motor Function Classification System Expanded and Revised .......................56 
4.3.15. 
Pediatric Evaluation of Disability Index .....................................................................56 
4.3.16. 
Ophthalmologic Examination .....................................................................................57 
4.3.17. 
Electroencephalogram and Seizure Activity ..............................................................57 
4.3.18. 
Vital Status ..................................................................................................................58 
4.3.19. 
Concomitant Medications and Procedures .................................................................58 
4.3.20. 
Modified Glasgow Coma Scale for Infants and Children ..........................................58 
4.3.21. 
Follow-up Visits for Patients Who Discontinue .........................................................58 
5. 
SCHEDULES OF ASSESSMENTS ..........................................................................58 
6. 
SAFETY REVIEW COMMITTEE AND DATA MONITORING 
COMMITTEE .............................................................................................................65 
6.1. 
Safety Review Committee ..........................................................................................65 
6.1.1. 
Safety Criteria for Unscheduled Dose Adjustments ...................................................65 
6.1.2. 
Criteria for Adjustment or Stopping Doses ................................................................65 
6.1.3. 
Criteria for Site or Study Termination ........................................................................66 
6.2. 
Data Monitoring Committee .......................................................................................66 
6.3. 
Definition of Study End ..............................................................................................67 
7. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................68 
7.1. 
Patient Recruitment and Consent ................................................................................68 
7.2. 
Patient Inclusion Criteria ............................................................................................68 
7.3. 
Patient Exclusion Criteria ...........................................................................................69 
7.4. 
Patient Withdrawal Criteria ........................................................................................69 
8. 
TREATMENT OF PATIENTS ..................................................................................71 
8.1. 
Description of Study Drug ..........................................................................................71 
8.2. 
Prior and Concomitant Medications and Procedures ..................................................71 
8.3. 
Treatment Adherence ..................................................................................................71 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................73 
9.1. 
Study Drug ..................................................................................................................73 
 
 
9.3. 
Study Drug Storage .....................................................................................................73 
9.4. 
Study Drug Preparation ..............................................................................................73 
9.5. 
Study Drug Administration.........................................................................................74 
9.6. 
Study Drug Accountability .........................................................................................74 


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9.7. 
Study Drug Handling and Disposal ............................................................................74 
10. 
PHARMACODYNAMICS ASSESSMENTS............................................................76 
11. 
PHARMACOKINETICS ASSESSMENTS ...............................................................77 
12. 
EFFICACY ASSESSMENTS ....................................................................................79 
13. 
SAFETY ASSESSMENTS ........................................................................................80 
13.1. 
Physical and Neurological Examination .....................................................................80 
13.2. 
Vital Signs ..................................................................................................................80 
13.3. 
Laboratory Assessments .............................................................................................80 
13.4. 
Electroencephalogram ................................................................................................81 
13.5. 
Adverse and Serious Adverse Events .........................................................................81 
13.5.1. 
Definition of an Adverse Event ..................................................................................81 
13.5.2. 
Detection of Adverse Events ......................................................................................82 
13.5.3. 
Recording Adverse Events .........................................................................................82 
13.5.4. 
Definition of a Serious Adverse Event .......................................................................83 
13.5.5. 
Severity Assessment ...................................................................................................83 
13.5.6. 
Causality Assessment .................................................................................................84 
13.5.7. 
Outcome ......................................................................................................................84 
13.5.8. 
Reporting Adverse Events and Serious Adverse Events to Sponsor ..........................85 
13.5.9. 
Sponsor Reporting Requirements ...............................................................................85 
13.5.10. 
Investigator Reporting Requirements .........................................................................86 
14. 
STATISTICAL METHODS AND PLANNED ANALYSES ...................................87 
14.1. 
Determination of Sample Size ....................................................................................87 
14.2. 
Analysis Populations ..................................................................................................87 
14.3. 
Efficacy and Pharmacokinetic Endpoints ...................................................................87 
14.4. 
Demographics and Baseline Characteristics ...............................................................89 
14.5. 
Patient Disposition and Extent of Exposure ...............................................................89 
14.6. 
Prior and Concomitant Medications ...........................................................................89 
14.7. 
Efficacy Analyses .......................................................................................................89 
14.7.1. 
Use of Natural History Study ALX-MCD-502 ..........................................................89 
14.7.2. 
Primary Efficacy Analysis ..........................................................................................90 
14.7.3. 
Secondary Efficacy Analyses .....................................................................................90 
 
 
14.8. 
Safety Analyses ..........................................................................................................91 


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14.8.1. 
Adverse Events ...........................................................................................................91 
14.8.2. 
Laboratory Parameters ................................................................................................92 
14.8.3. 
Physical Examinations and Vital Signs ......................................................................92 
14.8.4. 
Electrocardiograms .....................................................................................................92 
14.8.5. 
Electroencephalograms ...............................................................................................92 
14.9. 
Pharmacokinetic Analysis ..........................................................................................92 
14.10. 
Other Statistical Issues ................................................................................................93 
14.10.1. 
Computing Environment ............................................................................................93 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................94 
15.1. 
Study Monitoring ........................................................................................................94 
15.2. 
Audits and Inspections ................................................................................................94 
15.3. 
Institutional Review Board/Ethics Committee ...........................................................95 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................96 
17. 
ETHICS ......................................................................................................................97 
17.1. 
Ethics Review .............................................................................................................97 
17.2. 
Written Informed Consent ..........................................................................................97 
17.3. 
Patient Data Protection ...............................................................................................98 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................99 
18.1. 
Inspection of Records .................................................................................................99 
18.2. 
Retention of Records ..................................................................................................99 
18.3. 
Retention of Biological Samples ................................................................................99 
18.4. 
Data Privacy ..............................................................................................................100 
19. 
PUBLICATION POLICY ........................................................................................101 
20. 
REFERENCES .........................................................................................................102 
APPENDIX A. BLOOD SAMPLING VOLUMES ..................................................................104 
APPENDIX B. BLOOD SAMPLING VOLUMES TABLES ..................................................105 
APPENDIX C. MODIFIED GLASGOW COMA SCALE FOR INFANTS AND 
CHILDREN ..............................................................................................................107 
 
LIST OF TABLES 
 
Table 1: 
Emergency Contact Information ...................................................................................5 


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Table 3: 
Dosing and Dose Adjustment for Term and Preterm Neonate Patients, Older 
Infants, and Children in Study ALXN1101-MCD-202 ..............................................10 
Table 4: 
Changes Between Amendment 1 and Amendment 3 .................................................14 
Table 5: 
Summary of Changes Between Amendment 2 and Amendment 3 ............................22 
Table 6: 
Summary of Changes Between Amendment 3 and Amendment 4 ............................30 
Table 7: 
Abbreviations and Special Terms ...............................................................................37 
 
 
Table 9: 
Dosing and Dose Adjustment for Term and Preterm Neonate Patients, Older 
Infants, and Children in Study ALXN1101-MCD-202 ..............................................44 
Table 10: Schedule of Assessments (Screening/Baseline and 12-Month Study Period) ............59 
Table 11: Schedule of Assessments (Long-Term Treatment Period and Safety Follow 
Up) ..............................................................................................................................62 
Table 12:  Schedule of Assessments (Following Recommendation by the Safety 
Review Committee for an Unscheduled Dose Adjustment) .......................................64 
Table 13: ORGN001 Description ...............................................................................................71 
 
Table 15: Blood Sampling Volumes (in mL) During the 12-Month Study Period ..................105 
Table 16: Blood Sampling Volumes During the Long-Term Extension Period, After a 
Dose Adjustment, and at the Safety Follow-up ........................................................106 
 
LIST OF FIGURES 
 
Figure 1: 
The Metabolic Pathway for Molybdenum Cofactor ...................................................39 
Figure 2: 
Study Design for Study ALXN1101-MCD-202a ........................................................50 
 


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Table 7: 
Abbreviations and Special Terms  
Abbreviation 
Definition 
AE 
Adverse event 
Alexion 
Alexion Pharma GmbH (former Sponsor) 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
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 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CI 
Confidence interval 
Cmax 
Maximum observed plasma concentration 
CNS 
Central nervous system 
Colbourne 
Colbourne Pharmaceuticals GmbH  
cPMP 
Cyclic pyranopterin monophosphate 
CRF 
Case Report Form (paper or electronic) 
CSR 
Clinical study report 
CYP 450 
Cytochrome P450 
DMC 
Data Monitoring Committee 
DWI 
Diffusion-weighted imaging 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
E. coli 
Escherichia coli 
EDC 
Electronic data capture  
EEG 
Electroencephalogram 
EOI 
End-of-infusion 
GA 
Gestational age 
GCP 
Good Clinical Practice 
GCS 
Glasgow Coma Scale 
GLP 
Good Laboratory Practice 
GMFCS-E&R 
Gross Motor Function Classification System Expanded and Revised 
GMFM-88 
Gross Motor Function Measure – 88 
GTP 
Guanosine triphosphate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
IV 
Intravenous(ly) 
JP 
Japanese Pharmacopeia 
LC-MS/MS 
Liquid chromatography with tandem mass spectrometric detection 
mFAS 
Modified Full Analysis Set 
MedDRA 
Medical Dictionary for Regulatory Activities 
MoCD 
Molybdenum cofactor deficiency 
MoCo 
Molybdenum cofactor 
MRI 
Magnetic resonance imaging 
NOAEL 
No observable adverse effect level 
Origin 
Origin Biosciences, Inc. (Sponsor) 
OPC 
Objective performance criterion 
OS 
Overall survival 
PD 
Pharmacodynamic(s) 
PEDI 
Pediatric Evaluation of Disability Inventory 


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Abbreviation 
Definition 
Ph Eur 
European Pharmacopoeia 
PK 
Pharmacokinetic(s) 
PopPK 
Population PK 
Q.S. 
Quantity sufficient 
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 
TEAE 
Treatment-emergent adverse event 
USP 
United States Pharmacopeia 
WHODrug 
World Health Organization Drug Dictionary 
WPPSI-IV 
Wechsler Preschool and Primary Scale of Intelligence – Fourth 
Edition 


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2.
INTRODUCTION
2.1. 
Background
Molybdenum cofactor deficiency (MoCD) is a rare, life-threatening, autosomal recessive, inborn 
error of metabolism that is characterized by disruption of the metabolic pathway for production 
of molybdenum cofactor (MoCo). Molybdenum cofactor is essential for functioning of the 
enzymes sulphite oxidase (SO), xanthine oxidoreductase, and aldehyde oxidase activity 
(Schwarz 2009). The loss of SO activity is responsible for the severe and rapidly progressive 
neurologic damage seen in neonates presenting with MoCD (Reiss 2003; Schwarz 2009). Less 
frequently, older infants and children may present with neurologic symptoms related to MoCD 
such as seizures, movement disorder, and developmental delay/disability that appears to have a 
less rapidly evolving course. 
Although there are three types of MoCD, two-thirds of MoCD patients have Type A, which is 
due to a mutation in the MOCS1 gene localized on chromosome 6p21.2. In MoCD Type A, the 
first of four synthetic steps in the formation of molybdenum cofactor is interrupted, and 
guanosine triphosphate (GTP) cannot be converted into cyclic pyranopterin monophosphate 
(cPMP). Diagnosis of MoCD Type A in neonates is based on clinical and laboratory presentation 
(eg, seizures, exaggerated startle response, high-pitched cry, intracranial hemorrhage, axial 
hypotonia, limb hypertonia, feeding difficulties, elevated urinary sulfite and/or S-sulfocysteine 
[SSC], or low or absent uric acid in the urine or blood) and is then confirmed by genetic testing. 
The clinical presentation after the neonatal period appears to be more heterogeneous and may 
progress less rapidly. 
The biosynthetic pathway for MoCo synthesis involves 3 major steps; see Figure 1 
(Schwarz 2009). 
Figure 1: 
The Metabolic Pathway for Molybdenum Cofactor 
The incidence of MoCD is estimated to be between 1/100,000 and 1/200,000 newborn babies 
worldwide (Schwahn 2015). Affected individuals with MoCD Type A usually present as 


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neonates with severe symptoms that are observed as part of standard clinical practice. These 
include, but are not limited to, intractable seizures, burst-suppression on multifocal epileptic 
encephalogram, exaggerated startle reactions, axial hypotonia, limb hypertonia, and feeding 
difficulties (Van der Knaap 2005; Johnson 2001; Vijayakumar 2011). Death commonly occurs in 
the neonatal period and patients who survive that period may develop a severe static 
encephalopathy and developmental delays due to central nervous system (CNS) injury, including 
subcortical cystic cavitation, hydrocephalus, diffuse cortical atrophy, and basal ganglia injury. 
2.1.1. 
Treatment Options for MoCD Type A 
There is no available approved treatment for MoCD Type A. Current management strategies are 
symptomatic and aim to provide relief from MoCD Type A clinical manifestations as well as to 
provide palliative care. Administration of a diet with restrictions on the sulfur-containing amino 
acids cysteine, methionine, and taurine has been attempted in the related disorder of SO 
deficiency (Touati 2000). 
2.2. 
Rationale for the Study 
The previous Sponsor, Alexion Pharma GmbH (Alexion) developed ORGN001 (formerly known 
as ALXN1101), a synthetic form of cPMP and a precursor molecule to MoCo, as a treatment for 
MoCD Type A. Responsibility for the development of ORGN001 in the treatment of MoCD 
Type A was assumed by Origin Biosciences, Inc, in September 2018. ORGN001 provides a 
therapeutic approach for the treatment of MoCD Type A that is intended to restore MoCo 
biosynthesis. Results from nonclinical pharmacology studies with ORGN001 suggest that the 
metabolic abnormality in MoCD Type A could be corrected by administration of synthetic 
cPMP, resulting in restoration of enzymatic activity and correction of the metabolic pathways 
that lead to accumulation of toxic metabolites that cause CNS injury. 
A comprehensive nonclinical package, including proof-of-concept in a knock-out mouse model, 
in vitro and in vivo safety pharmacology and pharmacokinetic (PK) studies (in rats and dogs), 
cytochrome inhibition/induction, metabolism characterization, and transporter profiling in 
various species, and a standard battery of toxicology studies in vitro and in vivo (rats and dogs), 
has been generated to support the clinical use of ORGN001. Two additional Good Laboratory 
Practice (GLP)-compliant toxicity studies in juvenile animals 
 
 have been performed to support the use of ORGN001 in the target patient 
population. 
 
 
 
The use of ORGN001 as a potential treatment for MoCD Type A is supported by preliminary 
clinical evidence obtained from pediatric patients with MoCD treated with a recombinant 
Escherichia coli-derived cPMP product (rcPMP) from Colbourne Pharmaceuticals GmbH 
(Colbourne; formerly known as Orphatec Pharmaceuticals GmBH)
 
. Published individual case 
reports suggest that intravenous (IV) administration of rcPMP may restore MoCo-dependent 
enzyme activities, as evidenced by reduction in the concentrations of disease biomarkers. 
Elevated urinary SSC concentrations observed before initiation of treatment were corrected with 
rcPMP substitution. Recombinant E.coli-derived cPMP substitution also resulted in improved 


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neurologic outcomes for patients with MoCD Type A (Veldman 2010a; Hitzert 2012a). Safety 
data from published literature describing these patients has indicated that rcPMP infusions were 
well tolerated (Veldman 2010a; Hitzert 2012a).  
Schwahn and colleagues reported on an observational, prospective cohort study of 16 neonates 
diagnosed with MoCD (11 Type A and 5 Type B) for up to 5 years that included patients 
reported by Veldman and Hitzert (Schwahn 2015; Hitzert 2012a; Veldman 2010b; Veldman 
2010a; Veldman 2010a; Veldman 2010a). Rapid, near-normalization of urinary biomarkers 
occurred within 2 days of rcPMP treatment but was only observed in patients with Type A 
disease. Biomarker response was maintained for up to 5 years on continued rcPMP treatment. 
Moreover, patients exhibited clinical responses; seizure activity observed in 9 of 11 patients with 
MoCD Type A was either completely suppressed or substantially reduced following 
administration of rcPMP. Clinical deterioration was reported to have stopped upon starting 
rcPMP in 8 patients. Three patients with MoCD Type A that were treated with rcPMP prior to 
the onset of severe encephalopathy did not develop clinically significant disability. Their initial 
magnetic resonance imaging (MRI) scans demonstrated no signs of necrosis or cystic lesions. 
After 2 to 4 years of cPMP treatment, their MRI scans were normal or demonstrated minimal 
atrophy and hypomyelination. These 3 patients remained seizure free and progressed towards 
developmental milestones. Notably, 2 of these 3 patients were suspected to have MoCD 
prenatally, and all started rcPMP supplementation within 7 days from the onset of symptoms, 
emphasizing the importance of early initiation of treatment with cPMP. Additionally, the 
disparity in between the number of patients with MoCD Type A who experienced near 
normalization of biomarkers compared with those who did not develop clinically significant 
disability on rcPMP illustrate how the acute and profound neurotoxicity associated with MoCD 
leaves a narrow treatment window whereby cPMP supplementation may prevent irreversible 
damage. Given that some of the neurotoxicity occurs in utero, it is perhaps unsurprising that 
prenatal diagnosis, early inducement of labor, and prompt treatment with cPMP have been 
associated with favorable outcomes (Schwahn 2015; Hitzert 2012b).  
Considering the identical molecular structures of ORGN001 and rcPMP, and the clinical results 
reported with rcPMP, it is anticipated that treatment with ORGN001 will benefit patients with 
MoCD Type A in Study ALXN1101-MCD-202 by reconstituting MoCo synthesis, restoring SO 
enzymatic activity, and resulting in reduced concentrations of toxic metabolites (sulfite and 
SSC).  
2.3. 
Risk/Benefit Assessment 
Within a few hours to days after birth, newborn infants with MoCD Type A present a severe 
clinical picture, with profound and progressive neuronal damage. Death is common in the 
neonatal period, with a median survival of patients with MoCD of 3 years (Mechler 2015). 
Currently, no approved therapy is available for the treatment of patients with MoCD Type A. 
Treatment strategies for individuals with this disorder are symptomatic and with a goal to 
provide relief from clinical disease manifestations and along with palliative care for the patient.  
Safety data from the completed Study ALXN1101-MCD-101 in healthy adult volunteers and the 
ongoing Study ALXN1101-MCD-201 in patients with MoCD Type A support the study of 
ORGN001 as a treatment for MoCD Type A. 
 healthy volunteers received ORGN001 in 
the Phase 1 first-in-human study, ALXN1101-MCD-101, in which ORGN001 was well-tolerated 


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at doses 
 administered IV. 
 
 
 
 
 
 Across both cohorts, no deaths or life-threatening TEAEs 
occurred, and no patient had to withdraw due to a TEAE.  
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.  
An ongoing Phase 2 study, ALXN1101-MCD-201, is designed to transition patients with MoCD 
Type A from the recombinant form of cPMP produced by Colbourne to ORGN001. 
 
To date, ORGN001 
has been well-tolerated, and there have been no serious adverse reactions with causality 
attributed to ORGN001 reported, and no patient has withdrawn or discontinued as a result of an 
adverse event (AE). 
Due to the life-threatening and debilitating nature of the disease, lack of treatment, and shortened 
life expectancy of these patients, there is a significant need to provide safe and effective 
treatment for patients with MoCD Type A. A treatment paradigm that targets the underlying 
cause of the disease, the inability to synthesize MoCo from its precursor, GTP, may restore 
MoCo biosynthesis and SO function, and ameliorate MoCD disease progression. 
2.4. 
Rationale for Patient Population 
Preliminary data suggest that the metabolic derangement of MoCD starts in utero and patients 
demonstrate symptoms associated with sulfite toxicity within hours of birth (Veldman 2010a; 
Hitzert 2012a). This observation supports the premise that irreversible neurologic injury may 
occur very early in life and that immediate postnatal treatment with ORGN001 may alter the 
outcome of this devastating disorder. 
Selection of the patient population to determine ORGN001 efficacy and safety in Study 
ALXN1101-MCD-202 was based on the population that is most likely to benefit from 
ORGN001 treatment. Considerations were given to the age of onset of the disease and the extent 
of CNS injury at time of diagnosis and/or planned treatment. Consequently, the population 
initially identified to be enrolled in Study ALXN1101-MCD-202 comprised patients from 1 to 
28 days of age (inclusive) at the time of first ORGN001 dose administration (neonates), with 
Day 1 of age corresponding to the day of birth. However, the clinical presentation after the 
neonatal period appears to be more heterogeneous and may progress less rapidly in some 
patients. In an effort to more fully characterize the potential impact of ORGN001 in MoCD Type 
A, the study has thus been modified to include infants and children with MoCD Type A, who are 
treatment-naïve or may have previously received ORGN001 through the early access program 
(EAP). Infants are defined as those from 29 days to <2 years of age. Children are defined as 
those from 2 to 5 years of age (inclusive). In neonates, eligibility will be determined by prenatal 
genetic diagnosis of MoCD Type A or presence of signs and symptoms consistent with the 
diagnosis of MoCD Type A. Genetic testing will be performed to confirm the MoCD Type A 


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genotype. In infants or children, eligibility will be determined by confirmed genetic diagnosis 
(genetic confirmation of the diagnosis of MoCD Type A may be obtained after initiation of 
ORGN001 therapy in certain cases), biochemical profile, and clinical presentation consistent 
with MoCD Type A. 
2.5. 
Rationale for Proposed Dosing 
A population PK (PopPK)-based approach has been utilized to create a dosing scheme that 
targets the higher end of the originally acceptable exposure range for ORGN001 (NOAEL: area 
under the plasma concentration-time curve 
) at the highest dose studied 
in the original toxicology study that was limited by solubility issues. Since then, higher doses 
have been studied and were all well tolerated in rats and dogs using an improved IV formulation. 
Accordingly, the revised NOAEL values in a 
 rat study provide a considerable increase 
in the safety margins 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A PopPK model was derived to characterize ORGN001 clinical PK in healthy adult volunteers 
(Study ALXN1101-MCD-101) and children with MoCD Type A (Study ALXN1101-MCD-201). 
Due to 
 renal clearance of ORGN001 in adults (Study ALXN1101-MCD-101), a function 
was included to account for the expected impact of renal function maturation (Rhodin 2009) on 
ORGN001 PK in neonate patients. 
 
Dosing will be based upon the gestational age (GA) of the patient. Day 1 dosing for term 
(≥ 37 weeks GA) and preterm neonate (< 37 weeks GA) patients will begin with ORGN001 IV 
infusions of 700 and 525 μg/kg/day, respectively. Following Investigator and Safety Review 
Committee (SRC) reviews (as well as Data Monitoring Committee [DMC] review of data prior 
to the first dose adjustment for each patient as well as subsequent periodic review of cumulative 
data), recommended dosing may follow the guidance in Table 9.  
The dosing strategy in Table 9 has been simplified compared to the original guidance. This is 
justified given 1) the much greater safety margin with respect to the NOAEL in the 
 rat 


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study described above; 2) the excellent safety profile of ORGN001 thus far with all patients 
tolerating the maximum 1200 μg/kg/day dose and no safety signals identified
 
; and 3) the fact that dose increments 
 were well tolerated in Study 
ALXN1101-MCD-201. 
 
Table 9: 
Dosing and Dose Adjustment for Term and Preterm Neonate Patients, Older 
Infants, and Children in Study ALXN1101-MCD-202 
Study Day 
Term Neonate (GA ≥ 37 weeks) and 
Older Infants/Children 
Dose (µg/kg/day) 
Preterm Neonate (GA < 37 weeks)  
Dose (µg/kg/day) 
Day 1 
700 
525 
Day 28 
1000 
900 
Month 3 
1200 
1200 
Abbreviations:  GA = gestational age. 
 
Doses may be adjusted based on drug-related AEs or changes in clinical parameters, laboratory 
data, or PK findings and will occur following consultation with the medical monitor and, if 
applicable, with the SRC. 
 
ORGN001 drug product has been developed for IV use. Administration via the parenteral route 
results in rapid and consistent onset of action necessary for treatment of neonatal patients with 
MoCD. The dose can be adapted to the last recorded body weight or body weights recorded by 
the home care giver and/or physician visits with appropriate documentation; the flexibility to 
adjust doses based on changes in body weight enable accurate dosing. 
2.6. 
Rationale for the Overall Design 
This is a Phase 2/3 open-label, multicenter study to assess the safety and efficacy of ORGN001 
in neonates, infants, and children with MoCD Type A. 
A placebo-controlled study is not feasible or ethical due to the severity of the untreated disease 
and reports of improved outcomes in MoCD Type A neonates treated with rcPMP; also, the lack 
of available treatment precludes inclusion of an active control arm. ORGN001 safety will be 
reviewed continuously, on an individual patient basis, as well as at a group level. An SRC, 
 
 
 will review all available safety, efficacy and PK data on a 
periodic basis. 
In neonate patients with signs and symptoms consistent with MoCD Type A, treatment should be 
initiated as soon as feasible, in an effort to prevent the irreversible neurologic damage that is 
expected to occur. Less frequently, older infants and children may present with neurologic 


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symptoms related to MoCD such as seizures, movement disorder, and developmental 
delay/disability that appears to have a less rapidly evolving course.  


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Objectives 
Primary: 
• To evaluate the safety and efficacy of ORGN001 in neonate, infant, and pediatric patients 
with MoCD Type A who are either treatment-naïve or who have received compassionate 
use ORGN001  
 
Secondary: 
 
 
  
• To evaluate the effect of ORGN001 on growth and development using age-appropriate 
assessments 
• To evaluate the effect of ORGN001 on pediatric measures of functional ability and 
activities of daily living 
 
 
 
 
 
 
 
 
  
3.2. 
Endpoints 
Primary Efficacy Endpoint: 
• Overall survival (OS) 
 
Secondary Efficacy Endpoints: 
 
 
• Changes in growth parameters (height, weight, body mass index (BMI), head 
circumference) through Month 12 
• Feeding pattern assessments through Month 12 
• Gross Motor Function Classification System Expanded and Revised (GMFCS-E&R) 
results through Month 12 
• Assessments of the Bayley Scales of Infant Development – Third Edition (Bayley-III) 
Cognitive and Motor Scales as measured through Month 12 


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− For children aged 3 and above, for whom the Bayley-III is no longer appropriate, 
the Wechsler Preschool and Primary Scale of Intelligence – Fourth Edition 
(WPPSI-IV) will be administered.  
− For patients with severe developmental delay, the WPPSI may not be an 
appropriate assessment, and therefore, the Bayley-III may be administered 
instead. 
• Functional ability and activities of daily living, measured by the Pediatric Evaluation of 
Disability Inventory (PEDI) through Month 12 
• Gross Motor Function Measure (GMFM)-88 results through Month 12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Safety Endpoints: 
• The type, frequency, severity, timing, and relationship to study drug of any AEs, serious 
AEs (SAEs), and changes in vital signs, electrocardiograms, and safety laboratory tests 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This Phase 2/3, multicenter, multinational, open-label study is designed to evaluate the efficacy 
and safety of daily IV administration of ORGN001 to neonates, infants, and children with MoCD 
Type A. For the purposes of this study, neonate patients are defined as those from 1 to 28 days of 
age (inclusive) at the time of first ORGN001 administration, with day 1 of age corresponding to 
the day of birth. Infants are defined as those from 29 days to < 2 years. Children are defined as 
those from 2 years to 5 years (inclusive) at the time of informed consent.  
Eligible neonates with a prenatal diagnosis of MoCD Type A will undergo Screening/Baseline 
assessments (eg, brain imaging) prior to or as soon as possible after birth and prior to receiving 
the first IV infusion of ORGN001. Given the life-threatening and devastating nature of the 
disease and the potential for a favorable benefit:risk profile for treatment with ORGN001, 
patients with a prenatal diagnosis may be treated prior to the onset of signs and symptoms 
associated with MoCD Type A. Additionally, if it is not possible to obtain brain imaging prior to 
treatment, the priority would be to treat the neonate and obtain brain imaging as soon as feasible 
afterwards. For those patients, the patient’s legal guardians (per country-specific requirements) 
may be asked to provide informed consent for participation in the study prior to delivery.
 
 
 
Eligible neonates who do not have a prenatal diagnosis of MoCD Type A but who have the onset 
of signs and symptoms that may serve as the basis for diagnosis will undergo Screening/Baseline 
assessments as soon as possible prior to receiving their first daily IV infusion of ORGN001. Data 
from procedures conducted as part of standard of care prior to study participation may be 
collected as part of Medical History. Genetic confirmation of the diagnosis of MoCD Type A 
may be obtained after initiation of ORGN001 therapy. 
Eligible patients beyond the neonatal period with genetically confirmed evidence of MoCD Type 
A, a biochemical profile, and clinical picture consistent with MoCD Type may also be enrolled 
following completion of Screening/Baseline assessments. Data from procedures conducted as 
part of standard of care prior to study participation may be collected as part of Medical History. 
Genetic confirmation of the diagnosis of MoCD Type A may be obtained after initiation of 
ORGN001 therapy in certain cases. 
This study will include a Screening Period, a 12-month Study Period, and a 2-year long-term 
Treatment Period (Months 13 through 36). Due to the rare nature of the disease and no currently 
available treatment, patients 
 may continue to receive study 
drug until ORGN001 becomes commercially available or development has stopped. For patients 
receiving ORGN001 past month 36, a safety visit will occur 
. Assessments 
performed during those visits are for the purposes of ongoing safety to receive ORGN001 and 
may only occur if ORGN001 is not yet commercially available for the patient. 
The study will enroll both term and preterm neonates as well as infants and children who meet 
inclusion and exclusion criteria. In neonates, due to the roles that renal clearance and body 
weight play in the PK of ORGN001, dosing will be based upon the GA of the patient. Day 1 
dosing for term (≥ 37 weeks GA) and preterm neonate (< 37 weeks GA) patients will begin with 


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ORGN001 IV infusions of 700 μg/kg/day and 525 μg/kg/day, respectively. ORGN001 infusions 
should be administered every 24 hours ± 3 hours apart while hospitalized or at home. 
Based on the Investigator and SRC/DMC review of all available data prior to the first (Day 28) 
dose adjustment, each patient’s dose may be initially escalated on or before Day 28, with 
incremental adjustments up to 1200 μg/kg/day by Month 3. Post administration of the increased 
dose, patients will undergo an electrocardiogram (ECG) as well as PK sampling. If any dose is 
not tolerated, the dose will be reduced based on an ad hoc consultation with the SRC/DMC (also 
see Section 6.1.2 for rules on stopping or delaying dosing). 
 
 
patients 
will 
 to receive daily infusions of ORGN001 
 
 and will return to the clinic for study visits to assess safety, 
efficacy, and PK. 
Every effort will be made to prevent or, if unavoidable, minimize pain that may occur in 
association with study-related procedures and assessments. Pain will be monitored as per 
protocol at each study site and treated appropriately. An alternative blood sampling schedule for 
infants, for whom less blood volume should be collected, must be used 
  
 
 
Figure 2: 
Study Design for Study ALXN1101-MCD-202a 
 
a Patients who reach 36 months of treatment may continue to receive study drug until ORGN001 becomes commercially 
available or development has stopped. 
 
 


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4.2. 
Number of Patients 
No minimum or maximum number of patients is projected for enrollment in the study.  
4.3. 
Study Assessments  
No study procedures may be performed prior to obtaining informed consent. Screening/Baseline 
and Day 1 assessments may all occur on the same day. 
For neonates born prior to 37 weeks of gestation, the Month 12 assessments will be performed at 
the target time point, adjusted for prematurity by scheduling the visit date plus the addition of the 
difference between gestational age and full-term gestation of 40 weeks. 
Results of all study assessments will be recorded in the appropriate case report form (CRF). 
Analyses of study assessments are described in Section 14. 
4.3.1. 
Demographic Data 
At Screening/Baseline, the patient’s date of birth, gender, gestational age, race, and ethnicity will 
be recorded. The date of first recognition of MoCD-associated signs or symptoms will be 
documented, as available. 
4.3.2. 
Genotype Assessment 
MoCD-related genotype data will be recorded at Screening/Baseline. If not available, a blood 
sample will be collected for genetic analysis of the MOCS1 gene. This sample should be 
collected at Screening/Baseline or as early as possible. Genotype of MoCD Type A will be 
verified as soon as possible but is not required before dosing is initiated. 
4.3.3. 
Medical History 
A complete medical history, including signs and symptoms of MoCD disease, complications 
during pregnancy, Apgar score, and any history of in-utero seizures, if available, must be 
recorded at Screening/Baseline for each patient.  
4.3.4. 
Family History 
Whether the patient has any siblings (living or deceased) with suspected or confirmed MoCD 
will be recorded as well as whether the sibling has participated in any other Origin-sponsored 
studies of MoCD. The degree of parental consanguinity and parental genotypes, if known, should 
be recorded. Information on parity, delivery type, and placental condition should also be 
captured. Family history, including the medical history for parents and siblings, will be recorded 
at Screening/Baseline. 
4.3.5. 
Physical Examination 
A physical examination consistent with standard of care must be performed
 
.  


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4.3.6. 
Vital Signs 
Vital sign assessments will include blood pressure, heart rate, respiratory rate, and 
temperature.  
Additional systolic and diastolic blood pressure measurements are to be collected 
 at approximately 30, 60, 90, and 120 minutes post-EOI and at 6 and 12 hours post-
EOI. 
4.3.7. 
Electrocardiograms 
Electrocardiograms will be collected 
 Electrocardiograms 
should be performed before any blood draws or treatment infusions when those assessments 
occur at the same study visit. 
4.3.8. 
 Laboratory Samples and Assessments 
Patients will provide urine samples for assessment of pharmacodynamics (PD) and standard 
urinalysis. Blood will be collected for blood chemistry, hematology, PK, and PD. Prior to first 
infusion of ORGN001, if feasible, at least 1 blood sample and 1 urine sample must be collected 
for PD analysis. This sample collection is essential to establishing whether there are biochemical 
abnormalities present that are associated with MoCD prior to the initiation of treatment with 
ORGN001, which would then be expected to rapidly correct those abnormalities for patients with 
MoCD Type A. Pharmacodynamic blood and urine samples will be evaluated for biomarkers 
associated with MoCD, including, but not limited to: SSC, 
 
. 
Samples will be collected as follows
•
PD urine
•
PD blood


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• Blood chemistry and hematology
 
 
• Standard urinalysis  
 
 
 
 
 
 
 
  
• PK 
 
 
 
 
 
 
 
 
If the PK collection kit is not received in time for PK sample collection on Day 1, PK samples 
may be drawn any time 
 
 PK samples should be collected at EOI (±5 minutes), 1 to 2 hours after EOI, and 3 to 4 
hours after EOI.  If the sample is collected on Day 1, a pre-dose sample should also be collected. 
Capillary blood samples may be collected for analysis of PK, in lieu of venous sampling. 
 
 
 
Samples for blood chemistry/hematology should be collected prior to the first ORGN001 
infusion on Day 1, if feasible, or may be performed as soon as possible (within 24 hours) after 
the first infusion. Unless otherwise indicated, if the initial Screening/Baseline sample is not 
collected until after the first ORGN001 infusion on Day 1, that will be the only blood 
chemistry/hematology sample collected on Day 1 for the study. Analysis of blood 
chemistry/hematology samples will include complete blood count (CBC), electrolytes, blood 
urea nitrogen (BUN), creatinine, calcium, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase, total bilirubin, serum osmolality, and total serum 
albumin. 
If a dose adjustment is recommended by the SRC/DMC, additional urine or blood samples may 
be collected for any of the above assessments.  
See Appendix A and Appendix B for further details regarding blood sample collection and blood 
volume limits. 
 
 
 
 


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4.3.9. 
Growth Parameters 
Body weight, body length, and head circumference will be recorded at Screening/Baseline and 
prior to first infusion on Day 1 when feasible; otherwise, these assessments can be performed 
within 24 hours after first infusion. Measures of growth should also be performed daily
 
 
 
 
4.3.10. 
Feeding Patterns 
Whether the patient is able to feed orally or feeds through a nasogastric or 
feeding 
tube will be recorded. 
This assessment should be performed at Screening/Baseline, prior to first infusion, when 
feasible, but may be performed within 24 hours after the first infusion. Other feeding pattern 
assessments should be performed 
 
 
 
. 
4.3.11. 
Neurologic Examination and Neuroimaging 
A neurologic examination that is consistent with standard of care will be performed  
 
. The Day 1 
assessment must be performed within 2 hours prior to the first infusion. Neurologic examination 
includes, but is not limited to, spontaneous or abnormal movements, muscle tone, primitive 
reflexes, and deep tendon reflexes and is part of the physical examination. 
For neonate patients, prior to initiation of ORGN001 treatment, a brain ultrasound will be 
performed in utero and/or after delivery and changes will be assessed over time 
 
.  
Brain MRI will be performed 
 
, if available and if clinical conditions allow. Additional scans may be requested, as 
needed. Completion of a brain MRI may be delayed until after initiation of ORGN001 therapy, if 
not feasible to complete prior to treatment.
 
 
 
4.3.12. 
Bayley Scales of Infant Development (or Wechsler Preschool and Primary Scale 
of Intelligence – Fourth Edition) 
The Bayley Scales of Infant Development – Third Edition is a standardized and norm-referenced 
instrument that assesses developmental functioning of infants and children 1 month to 42 months 
of age; it consists of 5 scales, 3 of which are administered with child interaction by a qualified 
trained professional: the Cognitive Scale, the Language Scale (including the Receptive 
Communication and Expressive Communication subtests), and the Motor Scale (including the 


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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 but 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 Bayley-III will be administered
 
, if applicable to assess changes in 
gross motor, fine motor, and cognitive development. 
 
 
The Language Scale will be administered only to native English speakers in English-speaking 
countries. 
From raw scores, scaled scores and developmental age equivalents can be calculated for the 
Cognitive, Receptive Communication, 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 (CIs). 
A qualified, trained professional will administer the Bayley-III.  
Please refer to the Bayley-III Manual for specific definitions of terms and assessments (Bayley 
2005). 
The WPPSI-IV may be used instead of the Bayley-III depending upon whether the Bayley-III is 
not appropriate for the patient; similarly, for patients developmentally delayed such that the 
WPPSI-IV is an inappropriate assessment, the Bayley-III will be used regardless of whether the 
child is aged 3 or above. 
4.3.13. 
Gross Motor Function Measure–88 
Gross motor function will be assessed 
 
 
, if applicable.  Administration of the GMFM-88 must be on the same day/time 
as the Bayley-III. 
The GMFM-88 measures patient-initiated motor activities in 5 dimensions: 
• A: Lying and Rolling 
• B: Sitting 
• C: Crawling and Kneeling 
• D: Standing 
• E: Walking, Running, and Jumping 
Each item is rated from 0 to 3, with 0 equaling “does not initiate,” and 3 equaling “completes 
item according to all descriptors.” A percent score can be obtained for each dimension, and for 
the total of all GMFM dimensions. Patients will be assessed without orthoses or aids. 
Following scoring of the Bayley-III Gross Motor subtest, items that have duplicate positioning 
for the GMFM-88 will also be scored. The remaining GMFM-88 items will then be administered 


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and scored. This is necessary to avoid positional redundancy, fatigue for the infant, and to ensure 
valid skill measurement of spontaneous gross motor skills. 
4.3.14. 
Gross Motor Function Classification System Expanded and Revised 
The GMFCS-E&R will be assessed 
 
, if applicable.
 
 
The GMFCS-E&R is a 5-level (Level I through Level V) classification system of gross motor 
function of children and youth (up to 18 years of age), on the basis of 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. The GMFCS-E&R classifies gross 
motor functional capabilities and limitations as usual performance in the home, school, and 
community settings. 
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" have very little voluntary control of 
movement, have no means of independent mobility, are generally transported by their caregivers, 
and require assistance for all activities of daily living. 
4.3.15. 
Pediatric Evaluation of Disability Index 
The PEDI measures functional ability and activities of daily living, including self-care, mobility, 
and social function. The PEDI Functional Skills scales consist of 3 domains: 
• Self-Care: Getting Dressed, Keeping Clean, Home Tasks, and Eating and Mealtime 
• Mobility: Basic Movement and Transfers, Standing and Walking, Steps and Inclines, 
Running and Playing, and Wheelchair 
• Social: Interaction, Communication, Everyday Cognition, and Self-Management 
Functional Skills scales  
The PEDI will be assessed 
 
, if applicable. 
 
 The PEDI must be performed only after completion of 
the Bayley-III and the GMFM-88 at those visits where all 3 assessments are administered. 
Normative standard scores are available for 21 age groups, based on a child’s chronological age, 
and allow for evaluation of the child’s functioning relative to others of the same age. They have a 
mean of 50, with a standard deviation (SD) of 10. Scaled scores indicate performance along a 
continuum from 0-100, with increasing numbers representing increased functional performance. 
Scaled scores provide a means to evaluate a child’s current functional skills and progress in these 
skills over time. Scaled scores are especially helpful in documenting improvements in functional 
skills for children not expected to exhibit or regain normative levels of functioning. 


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4.3.16. 
Ophthalmologic Examination 
Ophthalmologic evaluation 
 is to include the following: 
• Ocular history  
• External inspection of the eyes and lids  
• Ocular motility assessment  
• Pupillary examination  
• Red reflex examination  
• Age-appropriate visual acuity  
• Attempt at ophthalmoscopy  
Vision assessment in children younger than 3 years or in any nonverbal child is accomplished by 
evaluating the child’s ability to fix and follow objects. A standard assessment strategy is to 
determine whether each eye can fixate on an object, maintain fixation, and then follow the object 
into various gaze positions. Failure to perform these maneuvers indicates significant visual 
impairment. The assessment should be performed binocularly and then monocularly. 
If poor fixation and following is noted, a significant bilateral or unilateral eye or brain 
abnormality is suspected, and referral for more formal vision assessment is advisable. It is 
important to ensure that the child is awake and alert because disinterest or poor cooperation can 
mimic a poor vision response. 
Where feasible, visual acuity is documented for each eye in the clinical report form. Also, lens 
dislocation or subluxation is to be documented separately for each eye if present.  
4.3.17. 
Electroencephalogram and Seizure Activity 
Electroencephalograms (EEGs) are to be performed for those patients with documented or 
suspected seizure activity. Where feasible, a standard EEG 
 
 should be performed prior to the first infusion. If that timing is not possible, the 
EEG may be performed within 24 hours of initiation of ORGN001 therapy. Subsequent EEGs 
should be performed in accordance with standard of care. 
The 
 
patient’s parent/legal guardian will be given a diary to be used to record data regarding the 
frequency of seizures and any changes in anticonvulsants for the entire duration of the study. 
The patient’s parent/legal guardian will be asked at every visit if there has been a presence of 
seizure activity or any change in seizure activity since the last study visit. Based on a review of 
the seizure diary as well as observation and review of neurologic examination findings, the 
Investigator/designee will determine if anticonvulsants, change in medication, or further 
neuroimaging is warranted. 


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4.3.18. 
Vital Status 
Vital status will be recorded at specific time points 
 
 to ascertain whether the patient is alive, with respiratory and brain function 
capable of supporting life. 
4.3.19. 
Concomitant Medications and Procedures 
Record any medications that the patient is receiving during the study. Record any nonstudy 
procedures that the patient undergoes during the study. 
4.3.20. 
Modified Glasgow Coma Scale for Infants and Children 
The Glasgow Coma Scale (GCS) is a clinical tool designed to assess coma and impaired 
consciousness. A modified GCS score of 12 in infants or children suggests a severe head injury, 
a score of 8 suggests need for intubation and ventilation, and a score of 6 suggests need for 
intracranial pressure monitoring (see Appendix C). The modified GCS will be administered to 
patients at every visit, within the first month of the study 
 
. 
4.3.21. 
Follow-up Visits for Patients Who Discontinue 
For patients who discontinue ORGN001, Follow-up Visits should be held 
 
 following the last administration of ORGN001. 
 
 
5. 
SCHEDULES OF ASSESSMENTS 
The detailed Schedule of Assessments for the initial 12-month Treatment Period and the 
Schedule for the long-term Treatment Period are provided
 
. 
 


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Table 10: 
Schedule of Assessments (Screening/Baseline and 12-Month Study Period) 
Assessment 
Screening / 
Baseline 
12-Month Study Period 
Study Day 
Month 
Visit Window (Days) 
Informed consent 
Eligibility 
Demographic data 
Genotype 
Family history 
Medical history 
Physical examinationb 
Vital signsb 
Vital status 
Additional BP 
measurementsc 
Chemistry and 
Hematologyb,d 
 
 
Urinalysisb,e 
Growth parameters 
Feeding pattern 
Neurologic examinationb 
Modified Glasgow Coma 
Scale 
Bayley-III (or WPPSI-IV)f 
GMFM-88g 
GMFCS-E&R 
PEDIh 
Ophthalmologic 
examination 
Seizure activityb,i 


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Assessment 
Screening / 
Baseline 
12-Month Study Period 
Study Day 
Month 
Visit Window (Days) 
Brain MRIj 
Brain ultrasoundk (neonates 
only) 
ECGb,l 
EEGm 
PD sampling, urine 
PD sampling, bloodb,n 
PK samplingb,o 
 
 
ORGN001 infusionp 
 
Daily 
Concomitant 
medications/proceduresb 
X 
Continuous monitoring 
Assess AEsb 
Continuous monitoring 
Follow-up Visits 
Note regarding blood samples: The total blood volume will not exceed the amount considered acceptable for the patient’s clinical condition and the institution’s guidelines 
. If an Investigator decides to deviate from these limits, the deviation must be fully documented and the Investigator should provide justification 
for the deviation. 
 
 
With agreement from the Sponsor, some Baseline assessments may be completed after dosing has begun due to urgency of study drug initiation. 
a For neonate patients born prior to 37 weeks of gestation, the Month 12 assessments will be performed at target time point, adjusted for prematurity by scheduling the visit date 
plus the addition of the difference between gestational age and full-term gestation of 40 weeks. 
b These assessments will be performed when any dose adjustment occurs: physical examination, vital signs, neurologic examination, ECG, PD sampling (blood), PK sampling, 
serum chemistry, hematology, urinalysis, evaluation for seizure activity, assessment of concomitant medications, assessment of AEs. Electrocardiograms should be performed 
prior to any blood draws or treatment administration scheduled for the same study visits. 
c 
 additional systolic and diastolic blood pressure measurements are to be collected at approximately 30, 60, 90, and 120 minutes post- EOI, and at 6 and 12 
hours post-EOI. 
d Include complete blood count, electrolytes, blood urea nitrogen, creatinine, calcium, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, 
serum osmolality, and total serum albumin. 
e Include specific gravity, pH, glucose, protein, blood and ketones (by dipstick and microscopic examination), and urine protein to creatinine ratio. 


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f The Bayley-III (or WPPSI-IV, as age-appropriate) may be administered within ± 3 days 
 
. 
g Administration of the GMFM-88 must be on the same day as the Bayley-III (or WPPSI-IV). 
h The PEDI must be performed only after completion of the Bayley-III (or WPPSI-IV) and the GMFM-88 at those visits where all 3 assessments are administered 
i The patient’s parent/legal guardian will be given a diary to be used to record data regarding the frequency of seizures and any changes in anticonvulsants for the entire duration 
of the study. The patient’s parent/legal guardian will be asked if there has been a presence of seizure activity or any change in seizure activity since the last study visit. Based on 
a review of the seizure diary as well as observation and review of neurologic examination findings, the Investigator/designee will determine if anticonvulsants, change in 
medication, or further neuroimaging is warranted. 
j Brain MRI should be obtained prior to the first infusion, where feasible. Completion of a brain MRI may be delayed until after initiation of ORGN001 therapy, if not feasible to 
complete prior to treatment. Brain MRI will be performed for the identified study visits 
, if available and if clinical conditions 
allow. Additional scans may be requested, as needed. 
k For neonate patients, prior to initiation of ORGN001 treatment, a brain ultrasound will be performed in utero and/or after delivery and changes will be assessed over time 
(through Day 21) at Screening/Baseline and on Days 3 and 21; see also Section 4.3.11. 
l Electrocardiograms should be performed prior to any blood draws or treatment administration scheduled for the same study visits. Electrocardiogram at Screening/Baseline, only 
if feasible. 
m Perform EEG for patients with documented or suspected seizure activity at Baseline. Where feasible, a standard EEG 
 should be 
performed within 24 hours of first infusion. Subsequent EEGs should be performed in accordance with standard of care. 
n Pharmacodynamic blood sampling will be conducted predose 
. 
o Pharmacokinetic sampling will be conducted at the EOI ±5 minutes, 1 to 2 hours after EOI, and 3 to 4 hours after EOI 
.  On Day 1 
only a pre-dose sample will also be collected. 
p On those days where PK samples are collected, the patient’s infusion of ORGN001 must be administered at the study site. 
Abbreviations:  AEs=adverse events; Bayley-III=Bayley Scales of Infant Development-Third Edition; BP=blood pressure; EEG=electroencephalogram; EOI= end-of-infusion; 
GMFCS-E&R=Gross Motor Function Classification System Expanded and Revised; GMFM=Gross Motor Function Measure; PD=pharmacodynamics; PEDI=Pediatric 
Evaluation of Disability Inventory; PK=pharmacokinetics; WPPSI-IV=Wechsler Preschool and Primary Scale of Intelligence – Fourth Edition. 
 
 


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Table 11: 
Schedule of Assessments (Long-Term Treatment Period and Safety Follow Up) 
Assessment 
Long-Term Treatment Period 
Safety Follow Up/ET 
Visita 
Month 
Visit Window (Days) 
Physical examination 
Vital signs 
Vital status 
Chemistry and Hematologyb 
Urinalysisc 
Growth parameters 
Feeding pattern 
Neurologic examination 
Bayley-III (or WPPSI-IV)d 
GMFM-88e 
GMFCS-E&R 
PEDIf 
Ophthalmologic examination 
Seizure activityg 
Brain MRI 
ECGh 
PD sampling, urine 
PD sampling, bloodi 
PK samplingj 
ORGN001 infusionk 
Daily 
 
Assess concomitant medications/procedures 
X 
X 
X 
X 
X 
Assess AEs 
X 
X 
X 
X 
X 
Note regarding blood samples: The total blood volume will not exceed the amount considered acceptable for the patient’s clinical condition and the institution’s guidelines 
. If an Investigator decides to deviate from these limits, the deviation must be fully documented and the Investigator should provide justification for 
the deviation. 
 
 
a These assessments will only occur every 6 months for children continuing on ORGN001 past the study follow up period where ORGN001 is not commercially available. 
b Include complete blood count, electrolytes, blood urea nitrogen, creatinine, calcium, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, 
serum osmolality, and total serum albumin 
c Include specific gravity, pH, glucose, protein, blood and ketones (by dipstick and microscopic examination), and urine protein to creatinine ratio. 
d The Bayley-III (or WPPSI-IV, as age-appropriate) may be administered within ± 14 days 
. 
e Administration of the GMFM-88 must be on the same day as the Bayley-III (or WPPSI-IV). 


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f The PEDI must be performed only after completion of the Bayley-III (or WPPSI-IV) and the GMFM-88 at those visits where all 3 assessments are administered.  
g The patient’s parent/legal guardian will be asked if there has been a presence of seizure activity or any change in seizure activity since the last study visit. Based on a review of 
the seizure diary as well as observation and review of neurologic examination findings, the Investigator/designee will determine if anticonvulsants, change in medication, or 
further neuroimaging is warranted. 
h Electrocardiograms should be performed prior to any blood draws scheduled for the same study visits. 
i Pharmacodynamic blood sampling will be conducted predose 
. 
j Pharmacokinetic sampling will be conducted at the EOI ±5 minutes, 1 to 2 hours after EOI, and 3 to 4 hours after EOI 
. 
k On those days where PK samples are collected, the patient’s infusion of ORGN001 must be administered at the study site.  
Abbreviations:  AEs=adverse events; Bayley-III=Bayley Scales of Infant Development-Third Edition; ECG=electrocardiogram; ET=early termination; GMFCS-E&R=Gross 
Motor Function Classification System Expanded and Revised; GMFM=Gross Motor Function Measure; MRI=magnetic resonance imaging; PD=pharmacodynamics; 
PEDI=Pediatric Evaluation of Disability Inventory; PK=pharmacokinetics; WPPSI-IV=Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition. 
 
 
 


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Table 12:  Schedule of Assessments (Following Recommendation by the Safety Review Committee for an Unscheduled Dose 
Adjustment) 
Assessment 
Specific Time 
First Day Adjusted Dose is 
Administered 
 Follow-Up Visita 
Physical examination 
Any time during study visit 
Vital signs 
Any time during study visit 
Neurologic examination 
Prior to the first blood draw 
Chemistry and Hematologyb 
Any time during study visit 
Urinalysisc 
Any time during study visit 
Seizure activityd 
Any time during study visit 
PD sampling, urine 
Any time during study visit 
PD sampling, blood 
Predose 
PK samplinge 
EOI (±5 minutes) 
PK samplinge 
1 to 2 hours after EOI 
PK samplinge 
3-4 hours after the EOI 
ORGN001 infusione 
Any time during study visit 
Assess concomitant medications/procedures 
Any time during study visit 
ECGf 
Any time during study visit 
Assess AEs 
End of the study visit 
Note regarding blood samples: The total blood volume will not exceed the amount considered acceptable for the patient’s clinical condition and the institution’s guidelines 
. If an Investigator decides to deviate from these limits, the deviation must be fully documented and the Investigator should provide justification for 
the deviation. 
 
 
a Patients return to the clinic 
 after the first day the adjusted dose is administered. Once the patient has completed the 
 Follow-up Visit, the patient resumes regularly 
scheduled study visits. If the 
 Follow-up Visit falls on a day when developmental assessments (eg, Bayley-III) were scheduled to be assessed, the study visit that includes 
the developmental assessments will be rescheduled for the following week. 
b Include complete blood count, electrolytes, blood urea nitrogen, creatinine, calcium, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, 
serum osmolality, and total serum albumin 
c Include specific gravity, pH, glucose, protein, blood and ketones (by dipstick and microscopic examination), and urine protein to creatinine ratio. 
d Changes in anticonvulsants, including the reason for the change, will be recorded. 
e On those days where PK samples are collected, the patient’s infusion of ORGN001 must be administered at the study site. 
f Electrocardiograms should be performed prior to any blood draws or treatment administration scheduled for the same study visits. 
 
Abbreviations:  AE=adverse event; ECG=electrocardiogram; EOI=end-of-infusion; PD=pharmacodynamics; PK=pharmacokinetics. 


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6. 
SAFETY REVIEW COMMITTEE AND DATA MONITORING 
COMMITTEE 
6.1. 
Safety Review Committee 
To monitor patient safety, data will be reviewed regularly by the Investigator or designee 
throughout the study. 
 
 The SRC will review 
 
 data for each individual at the following time points: 
• 
 in advance of the first dose adjustment 
 
 
• At any other time during the study, as requested by the Investigator or Sponsor, 
 
  
Note that the DMC also will review each patient’s record 
, prior 
to any study dose escalation 
. Further information on the DMC is available in 
Section 6.2. 
 
 Based on SRC review of the available data, 
 
 
the SRC may recommend stopping, increasing, decreasing, or maintaining (current dose) the dose 
of ORGN001. 
The Investigator or Sponsor may also convene the SRC for unscheduled dose adjustments, based 
on drug-related AEs or changes in clinical parameters.  
6.1.1. 
Safety Criteria for Unscheduled Dose Adjustments 
Doses may be adjusted, based on drug-related AEs or changes in clinical parameters and 
laboratory data. Dose changes will occur following consultation with the medical monitor and, if 
applicable, with the SRC. If a patient has significant clinical worsening related to ORGN001 
dosing, the dose may be decreased, based on the patient’s clinical status and, if available, 
exposure data.  
6.1.2. 
Criteria for Adjustment or Stopping Doses 
The following are examples of possible clinical conditions and potential actions to be taken with 
respect to study drug administration in a given child or group of children. This list is not 
comprehensive. Consideration of dose changes for each patient will be assessed individually by 
the treating physician, based on the patient’s clinical status and review with the medical monitor. 
• Scenario 1: Any study drug-related SAE that results in the death of a single patient 
Action: No further dose escalations will take place in any patient; pending evaluation, all 
other patients will maintain their current dose level and no new patient will be enrolled in 
the study. A substantial amendment to the Clinical Trial Authorization will be submitted 


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to the relevant Competent Authorities for approval prior to restarting enrollment and 
allowing further dose escalations in the event that any study drug-related SAE results in 
the death of a single patient.  
• Scenario 2: One or more study drug-related SAEs in a single patient 
Action: If the treating physician, in consultation with the medical monitor, determines 
that a dose reduction could be expected to reduce the risk of the SAE and not increase the 
risk of MoCD-related symptoms, the patient may be treated with a lower dose of 
ORGN001. Subsequent dose escalation for that patient may be considered, based on 
clinical assessment by the treating physician in consultation with the medical monitor. 
• Scenario 3: The same study drug-related SAE occurs in 2 different patients. 
Action: In addition to the actions taken under Scenario 2, dosing in subsequent patients 
may be limited, to achieve concentrations below those observed in the patients with 
drug-related SAEs, patient to clinical assessment by the treating physician in consultation 
with the medical monitor. 
• Scenario 4: PK exposure in a single patient exceeds the AUC NOAEL limit by 
greater than 10% 
Action: The patient’s dose is reduced to a dose level that results in exposure that is below 
the NOAEL exposure.  
6.1.3. 
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, patient care would be 
transferred to a different Investigator. If all centers are terminated, patients would return to the 
care of their treating physicians. Conditions that may warrant termination of the study or 
investigational sites include, but are not limited to: 
• Discovery of an unexpected, serious, or unacceptable risk to patients enrolled in the 
study 
• Sponsor decision to suspend or discontinue testing, evaluation, or development of the 
ORGN001 
• Failure of the Investigator to comply with the approved protocol, pertinent guidelines, 
and/or regulations 
• Submission of false information knowingly from the Investigator to the Sponsor 
and/or regulatory authorities 
6.2. 
Data Monitoring Committee 
 
 
The DMC will have access to all safety data, in 
accordance with its primary function of ensuring patient safety. The DMC may make 


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recommendations to the Sponsor regarding safety issues, study conduct, and/or modifying, 
extending, or stopping the study. 
 
 
The DMC will review each patient’s record 
, prior to any study 
dose escalation
 
. The SRC may request additional ad hoc DMC meetings, as 
needed. 
 
 
 
Each member of the DMC will be required to sign a contract agreement, including 
confidentiality and financial disclosure statements, assuring no conflicts of interest, as a 
condition for membership on the committee. 
6.3. 
Definition of Study End 
The end of the study will be defined as the date of the last patient’s last visit. 
After Month 36, treatment with ORGN001 may be continued if determined to be clinically 
indicated. Due to the rare nature of the disease and no currently available treatment, patients 
exceeding 36 months of treatment may continue to receive study drug until ORGN001 becomes 
commercially available or development has stopped. 


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7.
SELECTION AND WITHDRAWAL OF PATIENTS
7.1. 
Patient Recruitment and Consent
Eligible patients will be identified via prenatal diagnosis of MoCD Type A, or as soon as 
possible after birth, based on genetic evaluation or, if no prenatal diagnosis is made, presentation 
of signs and symptoms consistent with MoCD Type A. The Investigator at each site will be 
responsible for discussing therapeutic options for the patient with his/her parent or legal 
guardian. 
Should a parent or legal guardian choose to enroll his/her child in this study, he/she will have to 
provide informed consent. Before recruitment and enrollment, the parent or legal guardian of 
each prospective patient will be given a full explanation of the study by the Investigator or 
his/her designee and will be allowed to read the approved Informed Consent Form (ICF). After a 
comprehensive description of the protocol, review of the ICF, and all questions have been 
answered, the patient’s parent or legal guardian will have the opportunity to decide if he/she 
wants the child to participate in the study. Once the Investigator is assured that the patient’s 
parent or legal guardian understands the implications of participating in the study, written 
informed consent must be obtained. The site will keep the original ICF and provide a copy to the 
parent/legal guardian. After the ICF is signed, the patient will be assessed for eligibility for 
inclusion into the study. Informed consent must be obtained prior to performing any 
study-related procedures and may be obtained before the Screening/Baseline Visit.  
Legal guardians who have their child diagnosed with MoCD Type A prenatally may be asked to 
sign a separate ICF to allow study procedures to begin on their child as soon after birth as 
possible. 
7.2. 
Patient Inclusion Criteria 
Patients must meet all of the inclusion criteria to be considered eligible for enrollment in this 
study. 
•
Male or female neonatal patients (1 to 28 days of age [inclusive] at the time of
ORGN001 administration, with day 1 of age corresponding to the day of birth), or
infant (29 days to < 2 years of age) or child (2 to 5 years of age [inclusive]) with
MoCD Type A, previously untreated with ORGN001 or treated with ORGN001
through the EAP
•
In neonates, diagnosis of MoCD Type A, based on:
−
Prenatal genetic diagnosis, or
−
Onset of clinical and/or laboratory signs and symptoms consistent with MoCD
Type A (eg, seizures, exaggerated startle response, high-pitched cry, axial
hypotonia, limb hypertonia, feeding difficulties, elevated urinary sulfite and/or
SSC, elevated xanthine in urine or blood, or low or absent uric acid in the urine or
blood) within the first 28 days after birth
•
In infants or children, diagnosis of MoCD Type A, based on:


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− Confirmed genetic diagnosis (genetic confirmation of the diagnosis of MoCD 
Type A may be obtained after initiation of ORGN001 therapy in certain cases), 
biochemical profile, and clinical presentation consistent with MoCD Type A 
• Parent or legal guardian must have signed the ICF prior to any study procedures being 
performed 
7.3. 
Patient Exclusion Criteria 
Patients will be excluded from participating in the study if they meet any of the following 
criteria: 
• Diagnosis other than MoCD Type A (may be determined after the initiation of study 
drug) 
• Condition that is considered by the treating physician to be a contraindication to 
therapy, including evidence of abnormalities on brain imaging not attributable to 
MoCD, or that might otherwise interfere with the patient’s participation in the study, 
pose any additional risk for the patient, or confound patient assessments 
• Antenatal and/or postnatal brain imaging prior to initiation of treatment with 
ORGN001 that indicates cortical or subcortical cystic encephalomalacia, clinically 
significant intracranial hemorrhage, or other abnormalities on brain imaging 
determined by the treating physician to be clinically significant 
• mGCS for Infants and Children score of less than 7 for more than 24 hours (does not 
apply to children less than 1 day in age) 
7.4. 
Patient Withdrawal Criteria 
The study staff should notify the Sponsor and the site monitor of all study withdrawals as soon as 
possible. The patient’s parent/legal guardians may withdraw consent at any time. Every effort 
should be made to ensure that the patient’s parents/legal guardians are willing to comply with 
study participation, prior to conducting the Screening/Baseline procedures. 
Investigators may choose to discontinue a patient’s treatment due to an AE, as well as conditions 
or illnesses that preclude compliance with the protocol from the standpoint of the patient’s safety 
or wellbeing (safety, behavioral, or administrative reasons). Patients may be withdrawn from the 
study for reasons including, but not limited to: 
• Diagnosis other than MoCD Type A  
• The discretion of the Investigator, in consultation with the medical monitor/SRC, as 
appropriate, regarding an AE or other medical reason (eg, clinically significant 
Baseline abnormalities on MRI or brain ultrasound) 
• Patient (and/or parent or legal guardian) request 
• Patient and/or parent or legal guardian is unwilling or unable to adhere to the protocol 
requirements 
All patients who discontinue or are withdrawn from the study will be encouraged to complete the 
Safety Follow-up Visits 
 following treatment discontinuation, 


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whenever possible. The reasons for premature study withdrawal must be recorded in the patient’s 
CRF and in the source records. 
For patients who are prematurely withdrawn from the study due to clinical findings (eg, AE[s]), 
the Investigator must immediately notify the Sponsor’s medical monitor. In these patients, AEs 
leading to premature withdrawal must be followed until resolution of the event 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. 
Patients who withdraw from the study will return to the care of their treating physician. 


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8. 
TREATMENT OF PATIENTS 
This is an open-label study designed to evaluate the safety and efficacy of ORGN001 
administered to neonates, infants, and children with MoCD Type A. All enrolled neonate patients 
meeting inclusion and exclusion criteria will receive treatment with study drug (ORGN001 
infusion) as soon as possible after birth. 
8.1. 
Description of Study Drug 
Table 13: 
ORGN001 Description 
 
Study Drug 
Product Name 
ORGN001 
Dosage Form 
Powder for solution for infusion 
Potency 
 
Route of Administration 
IV use 
Physical Description 
Sterile, 
 white to slightly yellow lyophilized powder 
Manufacturer 
  
8.2. 
Prior and Concomitant Medications and Procedures 
Prior medications, defined as any drug or substance taken by the patient within 28 days prior to 
the time the parent or legal guardian signs the ICF until the first ORGN001 dose, and 
concomitant medications, defined as any drug or substance taken by the patient after the first 
ORGN001 dose until completion of the last study visit, will be recorded on the patient’s CRF.  
Prior procedures, defined as any therapeutic intervention (eg, surgery/biopsy, physical therapy) 
performed within 28 days prior to the time the parent or legal guardian signs the ICF until the 
first ORGN001 dose (not to exclude the collection of data on relevant procedures as part of 
Medical History conducted more than 28 days prior to consent), and concomitant procedures, 
defined as any therapeutic intervention (eg, surgery/biopsy and physical therapy) performed after 
the first ORGN001 dose drug until completion of the last study visit, will be recorded on the 
patient’s CRF. If possible, elective surgical procedures should not be performed during the initial 
12-month study period. 
ORGN001 is not an inhibitor of cytochrome P450 (CYP450) enzymes in vitro; therefore, 
concurrent administration of ORGN001 is unlikely to affect systemic exposure of other CYP 
substrates. CYP isoforms responsible for biotransformation of ORGN001 are unknown. 
Changes in a patient’s anticonvulsants, including the reason for the change, will be recorded. 
Adverse events related to administration of these therapies or procedures must be documented on 
the appropriate CRF. 
8.3. 
Treatment Adherence 
The Investigator or designee must ensure that the parent or legal guardian of each study patient is 
adequately informed of the study drug regimen required for compliance with the study protocol. 
Daily infusions of ORGN001 at home will be administered by the patient’s parent or legal 
guardian with the support, 
. If a 
parent or legal guardian is unable to administer ORGN001 on a given day, study drug may be 
administered by an alternate caregiver, provided that training for ORGN001 administration by 


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the alternate caregiver has been documented. Patient adherence to the study drug regimen will be 
monitored throughout the study by reviewing study drug administration records and study drug 
accountability. Study drug accountability (including accounting of study drug returns) will be 
reviewed with the patient’s parent or legal guardian at each study visit. 
 
Missed treatments must be clearly documented in the patient’s study records and recorded in the 
CRF. Additionally, these must be documented as protocol deviations. 


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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Study Drug 
ORGN001 drug product 
 is a sterile, nonpyrogenic, white to slightly yellow 
lyophilized powder in a stoppered, 
 
 vial. The drug product is designed to be reconstituted in 
 sterile 
Water for Injection and administered by IV infusion. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
9.3. 
Study Drug Storage 
ORGN001 vials must be stored frozen at -10°C to -25°C and protected from light. Following 
reconstitution, ORGN001 should be administered within 4 hours. Reconstituted ORGN001 may 
be stored at 2°C to 8°C or room temperature prior to administration. If stored at 2°C to 8°C, 
reconstituted ORGN001 should be allowed to come to room temperature before infusion. 
Reconstituted ORGN001 must not be heated 
 
other than by ambient air temperature. 
 
9.4. 
Study Drug Preparation 
To account for the impact of body weight on the mass (mg) of administered study drug, body 
weight will be assessed 
 
 The dose may be adjusted due to weight changes recorded by 
the home caregiver and/or physician visits with proper documentation. 


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Reconstitute ORGN001 with 
 sterile Water for Injection. 
 
 
 
9.5. 
Study Drug Administration 
Starting on Day 1, patients will begin daily IV infusions of ORGN001 at a dose of either 
700 µg/kg (term neonates, infants, and children) or 525 µg/kg (preterm neonates). ORGN001 
drug product is to be administered at an infusion rate of 1.5 mL/min, 
 
. Based on a review of Day 1-related exposure parameters, each patient’s dose 
may be initially escalated 
 with incremental increases up to 1200 µg/kg/day 
by Month 3. 
 
 
 
The parent, legal guardian, and any authorized caregiver will be trained on proper storage, 
preparation, and administration of study drug for dosing at home,
 
. 
 
 
9.6. 
Study Drug Accountability 
Each investigational study site must maintain accurate records demonstrating dates and amount 
of study drug received, to whom dispensed (patient-by-patient accounting), and accounts of any 
study drug accidentally or deliberately destroyed. 
Unless otherwise notified, all vials, both used and unused, must be saved for study drug 
accountability. At the end of the study, a final reconciliation must be made between the amount 
of study drug supplied, dispensed, and subsequently destroyed or returned to the Sponsor. 
A written explanation will be provided for any discrepancies. After reconciliation, the 
Investigator must destroy or return all unused vials of study drug, as instructed by the Sponsor. 
If any study drug supplies are to be destroyed at the site, the Investigator must obtain prior 
approval by the Sponsor. The Investigator must notify the Sponsor, in writing, of the method, the 
date, and the location of destruction. 
Destruction of unused vials of study drug by the Investigator must be in compliance with federal, 
state, country, and local regulations. 
9.7. 
Study Drug Handling and Disposal 
ORGN001 should be handled with care. Aseptic technique should be used for dose preparation. 
In the event of a spill, use universal precautions for clean-up. Dispose of any spilled material in 


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compliance with federal, state, country, and/or local regulations.
 
 


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10.
PHARMACODYNAMICS ASSESSMENTS
Pharmacodynamic assessments will be performed using spot urine samples collected at all study 
visits,
 and using venous blood samples collected predose 
. 
Pharmacodynamic assessments also will be collected at Safety Follow-up Visits and any 
unscheduled dose adjustment visits. 
An alternative blood sampling schedule for infants, for whom less blood volume should be 
collected, must be used 
. 
Samples will be evaluated for biomarkers of the MoCD pathway including, but not limited to: 
SSC,
Prior to first infusion, at least 1 blood sample and 1 urine sample must be collected. 
Following recommendation by the SRC for an unscheduled dose adjustment, additional blood 
and urine samples will be collected to evaluate changes in SSC, xanthine, uric acid, urinary 
creatinine, 
 as follows:  
•
On the first day the adjusted dose is administered, the patient will be administered
study drug in-clinic, and a pre-dose blood sample will be collected on the 
 day of 
the dose adjustment 
. A urine sample will be 
collected at any time during 
 the dose adjustment visit. 
•
At any Safety Follow-up Visit, a PD blood sample
 will be collected. 
Under no circumstance will the total blood volume obtained exceed the amount considered 
acceptable for the patient’s clinical condition and the institution’s guidelines 
. If an Investigator decides to deviate from these limits, the deviation must be fully 
documented, and the Investigator should provide justification for the deviation. 


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11. 
PHARMACOKINETICS ASSESSMENTS 
Pharmacokinetic assessments will be performed 
 
. Pharmacokinetic samples also will be collected at Safety Follow-up Visits and any 
unscheduled dose adjustment visits. 
An alternative blood sampling schedule for infants, for whom less blood volume should be 
collected, must be used 
 
. 
Blood samples will be collected for assessment of PK parameters (Cmax, AUC, t1/2). Details of 
PK sampling time points are specified below. Dosing date, time, amount, precise time of infusion 
prior to PK sample collection, and exact time of PK sample collection must be recorded in the 
CRF. 
Pharmacokinetic samples will be collected 
 
: 
• Pre-dose at Day 1 only 
• at the EOI ±5 minutes 
• 1 to 2 hours after EOI 
• 3 to 4 hours after EOI 
If the PK collection kit is not available for Day 1 PK sample collection, samples may be drawn 
any time from Day 2 to Day 7, when the patient is still in the hospital. In such a case, PK 
samples should be collected using the following schedule: 
• at the EOI ±5 minutes 
• 1 to 2 hours after EOI 
• 3 to 4 hours after EOI 
Day 1 PK samples will be analyzed and PK assessment completed in time for a scheduled 
combined SRC/DMC meeting prior to each patient’s recommended 
 dose escalation 
 
 
 
 
 
 
. 
Following recommendation by the SRC for an unscheduled dose adjustment, blood samples will 
be collected for assessment of PK parameters, as follows:  
• On the 
 day the adjusted dose is administered, the patient will be administered 
study drug in-clinic, and a blood sample will be collected at the EOI (±5 minutes), 1 
to 2 hours after the EOI, and at 3 to 4 hours after the EOI. The time of infusion, PK 


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sample collection, the dose administered, and the start and stop time of IV infusion 
are to be recorded in the CRF.  
 following an unscheduled dose adjustment, a 
PK sample will be collected at 1 to 2 hours after EOI. 
 
 
 
Under no circumstance will the total blood volume obtained exceed the amount considered 
acceptable for the patient’s clinical condition and the institution’s guidelines 
 
. If an Investigator decides to deviate from these limits, the deviation must be fully 
documented, and the Investigator should provide justification for the deviation. 
 
 
 
 
 
 
 


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12. 
EFFICACY ASSESSMENTS  
Efficacy assessments are described in Sections 4.3.9, 4.3.10, 4.3.11, 4.3.12, 4.3.13, 4.3.14, 
4.3.15, 4.3.16, 4.3.17, 4.3.19, 4.3.20, and 4.3.21. 


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13. 
SAFETY ASSESSMENTS 
Safety assessment data are collected from the time of signing informed consent, 
 
. 
 
 
13.1. 
Physical and Neurological Examination 
A complete physical examination, 
 
 
will be performed 
 
 
. 
13.2. 
Vital Signs 
 
 At all outpatient study visits, the vital sign measurement to be recorded 
in the CRF is the first set of vital signs taken. 
13.3. 
Laboratory Assessments 
 
 The 
Investigator or delegate will review, sign, and date laboratory reports, as well as indicate if 
abnormal results are clinically significant or not clinically significant. Abnormal results will be 
followed, at the discretion of the Investigator. An alternative blood sampling schedule for 
infants, for whom less blood volume should be collected, must be used 
 
. 
Following recommendation by the SRC for an unscheduled dose adjustment, blood and urine 
samples will be collected for assessment of hematology, serum chemistry, and urinalysis as 
follows: 
• On the day of dose change, study drug will be administered at the study site. A urine 
sample will be collected. 
• Seven days after the adjusted dose is administered, a blood and a urine sample will be 
collected at any time during this study visit. 
Under no circumstance will the total blood volume obtained exceed the amount considered 
acceptable for the patient’s clinical condition and the institution’s guidelines 
 
. If an Investigator decides to deviate from these limits, the deviation must be fully 
documented, and the Investigator should provide justification for the deviation. 
 
 
 


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Hematology samples will be analyzed for CBC, which includes platelet count, red blood cell 
(RBC) count, white blood cell count and automated differential (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils), hemoglobin, hematocrit, and RBC indices (mean corpuscular 
volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration). 
Serum chemistry samples will be analyzed for electrolytes, BUN, creatinine, calcium, ALT, 
AST, alkaline phosphatase, total bilirubin, total serum albumin, and serum osmolality. 
Urine samples will be analyzed for specific gravity, pH, glucose, protein, blood and ketones (by 
dipstick and microscopic examination), and urine protein to creatinine ratio. 
13.4. 
Electroencephalogram 
Standard EEGs 
 will be performed to monitor patients with 
documented or suspected seizure activity in accordance with standard of care. 
13.5. 
Adverse and Serious Adverse Events 
13.5.1. 
Definition of an Adverse Event 
An AE is defined as any unfavorable or unintended sign (eg, 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 study. 
Exacerbations of a chronic or intermittent pre-existing condition, including either an increase in 
frequency and/or intensity of the condition, are all to be considered AEs. 
Abnormal test findings may be considered AEs. If an abnormal laboratory value is identified, 
Investigators are strongly encouraged to report a diagnosis, or a sign or symptom rather than an 
isolated abnormal test value. An abnormal test finding should be documented as an AE if any of 
the following conditions are met:  
• Is associated with a sign or symptom 
• Requires additional diagnostic testing (repeat tests are not considered additional 
testing) 
• Requires a medical or surgical intervention 
• Leads to a change in study dosing outside of the protocol-defined dosing or 
discontinuation from the study 
• Or does not meet any of the defined conditions, but the Investigator or Sponsor 
considers the result as clinically significant or meeting the definition of an AE. 
This definition also includes signs or symptoms resulting from misuse or abuse of the product 
from drug overdose, drug withdrawal, medication error, as well as outside what is foreseen in the 
protocol, such as drug interactions and extravasation. 
An AE does not include the following:  


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• Medical or surgical procedures (eg, surgery, endoscopies, tooth extraction, and 
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/Baseline 
evaluation that do not worsen 
• Situations where an untoward medical occurrence has not occurred (eg, 
hospitalization for elective surgery, social, and/or convenience admissions)  
13.5.2. 
Detection of Adverse Events 
The Investigator is responsible for detecting, assessing, documenting, and reporting all AEs. All 
serious and nonserious AE information will be collected from the time informed consent is 
signed until study completion. 
Adverse events reported by the patient and/or parent or legal guardian, and/or identified in 
response to an open-ended question from study personnel, or revealed by observation, physical 
examination, or other study procedures, must be collected and recorded as described in 
Section 13.5.3. 
13.5.3. 
Recording Adverse Events 
All observed or volunteered AEs, regardless of causal relationship, must be recorded and 
reported. 
For all AEs, the Investigator must obtain adequate information in order to:  
• determine the AE outcome  
• determine if the event meets criteria for an SAE  
• assess the AE severity  
• determine AE causality  
Adverse events must be documented in clear, unambiguous medical terms. Study personnel are 
to be advised to refrain from using abbreviations or acronyms. 
For each AE, record only the diagnosis on the AE page of the CRF. 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 AE page of the CRF with relevant diagnosis 
only. 
All AEs that later increase in 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 
on the AE page or the CRF. For medical or surgical procedures (eg, surgery, endoscopy, tooth 
extraction, or transfusion), the condition/diagnosis leading to the procedure should be recorded 
as the AE (eg, laparoscopic cholecystectomy is the procedure or treatment for an SAE of necrotic 
gall bladder). Withdrawal due to an AE or SAE must be clearly differentiated from withdrawal 
due to other reasons. 


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Initial AEs should be closed out, with an end date consistent with the date that the AE increased 
in frequency and/or severity. The new AE should be recorded on a new line of the AE page, with 
onset date consistent with the date of increase in frequency and or severity. 
13.5.4. 
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 or reaction is described as any untoward medical occurrence, that at any dose: 
1. Results in death 
2. Is life-threatening (NOTE: 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.) 
3. Hospitalization or prolongation of hospitalization. (NOTE: Hospitalization requires 
inpatient or prolongation of an existing hospitalization. Adverse events that are associated 
with hospitalization or prolongation of hospitalization are considered SAEs). 
Hospitalization does not necessarily include the following:  
a. rehabilitation/hospice/nursing facility 
b. Emergency room/department visit less than 24 hours in duration 
c. Elective or preplanned admission/surgery 
d. Protocol-specified admission, or admission for a pre-existing condition not associated 
with either a new AE or with worsening of a pre-existing AE 
4. Results in persistent or significant disability/incapacity 
5. Is a congenital anomaly/birth defect 
6. Is an important medical event 
NOTE: 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 which 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 event, and 
both AEs and SAEs can be assessed as severe, while the term seriousness refers to an AE that 
has met the criteria for an SAE, as described above. 
13.5.5. 
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. 


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• 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. 
Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of intensity to be performed. Adverse events characterized as 
intermittent require documentation of onset and duration of each episode if the severity of the 
intermittent event changes. 
13.5.6. 
Causality Assessment 
An Investigator causality assessment must be provided for all AEs. This assessment must be 
recorded in the CRF 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 causal association 
between 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 study drug may have 
caused or contributed to the AE, ie, the event follows a reasonable 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 study drug administration exists, and the likely causal association of the 
event with study drug. This will be based upon the known pharmacological action of 
study drug, known or previously reported adverse reactions to the study drug or class 
of drugs, or judgment based on the clinical experience of the Investigator. 
• 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, which corresponds with the known 
pharmaceutical profile, improves with study drug discontinuation, and/or reappears 
with study drug rechallenge. 
13.5.7. 
Outcome 
For all AEs, regardless of casual relationships, the Investigator must follow-up on the event 
outcome until the event or sequelae either resolves or stabilizes. 
If a patient experiences an 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. 


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• 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 one event should have an outcome of death/fatal, unless an autopsy report or 
Investigator states otherwise. 
13.5.8. 
Reporting Adverse Events and Serious Adverse Events to Sponsor 
All nonserious AEs must be recorded on the CRF upon awareness. 
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 staff becoming aware of the events. The Investigator must complete, sign, and 
date the email cover page, complete the SAE CRF pages, verify accuracy of the information 
recorded on the SAE pages with the corresponding source documents, and send a copy via email 
to the contact information provided 
 
  
 
Additional follow-up information, if required or available, should be entered into the CRF, and 
sent to Sponsor within 24 hours of the Investigator site or 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.  
All SAEs will be recorded from the time the ICF is signed until 30 days following study 
completion.  
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 
13.5.9. 
Sponsor Reporting Requirements 
The Sponsor or its legal representative is responsible for notifying the relevant regulatory 
authorities of SAEs meeting the reporting criteria. This protocol will use the current Investigator 
Brochure as the Reference Safety document. Serious adverse event expectedness and reporting 
criteria will be determined by the Sponsor from the Reference Safety document. 


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13.5.10. 
Investigator Reporting Requirements 
The Investigator must fulfill all local regulatory obligations required for the study Investigators. 
It is the Investigator’s responsibility to notify the IRB/EC of all SAEs that occur at his/her site. 
Investigators also will be notified of all unexpected, serious, drug-related events that occur 
during the study. Each site is responsible for notifying its IRB/EC of these additional SAEs. 


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14. 
STATISTICAL METHODS AND PLANNED ANALYSES 
Assessments will be binned into analysis visits in such a way that the assessment closest to the 
target study day among all assessments observed within a window around the target day will be 
designated for analyses over time. The visit windows will span from above the midpoint of the 
target day and prior visit target day up to and including the midpoint between the target day and 
next visit target day. 
All data collected during the study will be presented in data listings, tables, and figures as 
described below. Continuous variables will be summarized using mean, SD, median, minimum, 
and maximum. Categorical variables will be summarized using percentages and frequency 
distributions. Confidence intervals will be provided for all means and percentages to aid in 
interpretation. 
14.1. 
Determination of Sample Size 
There will be no minimum or maximum number of patients for this study. The final sample size 
and determination of study success relative to efficacy will depend on the OS rate as each 
successive patient reaches study completion. 
14.2. 
Analysis Populations 
Safety analyses will be performed on a Safety Set, defined as all patients who received at least 
1 infusion of ORGN001. 
Efficacy analyses will be performed on the Full Analysis Set (FAS), defined as patients with a 
confirmed diagnosis of MoCD Type A who have no antenatal and/or postnatal brain imaging 
prior to initiation of treatment with ORGN001 that indicates cortical or subcortical cystic 
encephalomalacia or clinically significant intracranial hemorrhage.  
Additionally, two modified Full Analysis Sets (mFAS) will be used to support the analyses on 
the FAS: 
• Neonate mFAS (NmFAS), 
 
• Pediatric mFAS (PmFAS)
 
 
Available efficacy data of all patients excluded from the FAS will be displayed in listings and 
described in narratives. 
14.3. 
Efficacy and Pharmacokinetic Endpoints 
Primary Efficacy Endpoint: 
• The primary efficacy analysis will be OS 
Secondary Efficacy Endpoints: 
 
 


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• Changes in growth parameters (height, weight, BMI, head circumference) through 
Month 12 
• Feeding pattern assessments through Month 12  
• GMFCS-E&R results through Month 12  
• Bayley-III Cognitive and Motor scaled scores and composite scores, as well as 
percentile ranks and age equivalents, through Month 12 (or WPPSI-IV scores, if 
applicable) 
• The normative standard and scaled scores from the PEDI Functional Skills scales, 
including Self-Care, Mobility, and Social items through Month 12 
• GMFM-88 results through Month 12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.4. 
Demographics and Baseline Characteristics 
All demographic and Baseline characteristics information will be summarized for the Safety Set, 
the FAS, the NmFAS, and the PmFAS.  
14.5. 
Patient Disposition and Extent of Exposure 
The number of patients screened, treated, continuing treatment after confirmation of enrollment 
criteria, and completing the 12-month and 36-month study periods will be tabulated. Reasons for 
any patient withdrawals will be provided. The number of patients in the safety and efficacy 
analysis sets, along with reasons for exclusion from analysis sets, will be tabulated. 
Extent of exposure with ORGN001 will be summarized among both the Safety Set and FAS, 
with respect to number of infusions, number of missed and partial infusions, and duration of 
treatment period. 
14.6. 
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 anticonvulsants. 
Medications will be coded using the World Health Organization Drug Dictionary (WHODrug) 
version 01 Sep 2013 or higher. Medication summaries will be presented by WHODrug 
Anatomical Therapeutic Chemical (ATC) and by WHODrug generic name. 
14.7. 
Efficacy Analyses 
Efficacy analyses will be performed on the FAS, NmFAS, and PmFAS. Baseline is defined as 
the last available assessment prior to treatment with ORGN001.  
14.7.1. 
Use of Natural History Study ALX-MCD-502 
Data from natural history study ALX-MCD-502 will be used to support the current study in 
order to guide interpretation by representing the expected clinical time course for patients 
with MoCD Type A in the absence of ORGN001 treatment. 
 
 
 
 
 
 
 
  
 
 
 
 


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14.7.2. 
Primary Efficacy Analysis 
The primary efficacy analysis will summarize OS, defined as the interval in months from the 
date of birth to the date of death or date last known alive (patients still on study will be censored 
at the data cutoff date), whichever occurs first.  
The analysis of OS will be based on the Kaplan-Meier methodology for estimation of survival 
parameters. The median duration of OS will be estimated based on the 50th percentile of the 
Kaplan-Meier distribution; additional summary statistics, including the 25th and 75th percentiles, 
95% confidence intervals (CIs) on the median and the other percentiles and proportion of 
censored patients. The analysis of OS will be done using the FAS, the NmFAS, and the PmFAS.  
14.7.3. 
Secondary Efficacy Analyses 
 
 
Body weight, length, head circumference, and BMI will be analyzed by converting each 
parameter to age-adjusted z-scores and age percentiles, and descriptive statistics will be 
presented to each parameter through Month 12.  
Changes in motor function through Month 12 will be summarized based on data from the 
administration of the GMFCS-E&R, which is a 5-level classification system that classifies gross 
motor functional capabilities and limitations as usual performance in the home, school, and 
community setting.  
The Bayley-III Cognitive and Motor scaled scores and composite scores, as well as percentile 
ranks, and age equivalents will be summarized through Month 12. Where appropriate, the 
WPPSI-IV will be used instead of the Bayley-III.  
 
Changes in PEDI standard and scaled scores will be summarized by self-care, mobility, and 
social function domains through Month 12. 
Changes in gross motor development will be summarized through Month 12 based on data from 
the administration of the GMFM-88, which measures patient-initiated motor activities in 5 
dimensions: Lying and Rolling; Sitting; Crawling and Kneeling; Standing; and Walking, 
Running, and Jumping. A percent score can be obtained for each dimension and for the total of 
all GMFM dimensions. Patients who use mobility aids and/or orthoses will be assessed without 
those aids. 
All secondary efficacy analyses will be done using the FAS, the NmFAS, and the PmFAS.  
 
 
 
 
  
 
 


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14.8. 
Safety Analyses 
Safety analyses will be performed on the Safety Set, which includes all patients who receive at 
least 1 dose of ORGN001. 
14.8.1. 
Adverse Events 
All AEs arising after signing the ICF will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA; Version 22.0 or higher) and displayed in listings. 
 
 
 
 
 
 
 
 


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Treatment-emergent adverse events are AEs with onset on or after the first date of ORGN001 
administration. Treatment-emergent adverse events will be summarized by System Organ Class 
(SOC) and Preferred term for all events and those considered at least possibly related (including 
missing relationship) to ORGN001 by the Investigator, both overall and by severity. Serious 
TEAEs will be tabulated by SOC and Preferred term. 
Summaries will include both the number of patients affected and the number of events. For 
patient counts in summaries by severity or relationship, 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 in the most 
extreme category of severity or relationship observed. 
14.8.2. 
Laboratory Parameters 
Incidence of abnormalities for clinical laboratory assessments (chemistry and hematology) will 
be summarized by visit. Laboratory analytes and their changes from baseline will be summarized 
by visit. 
14.8.3. 
Physical Examinations and Vital Signs 
Adverse physical examination changes will be reported as AEs and analyzed as such. Vital signs 
and their changes from baseline will be summarized by visit. 
14.8.4. 
Electrocardiograms 
Listings of ECG results will be produced. 
14.8.5. 
Electroencephalograms 
Listings of EEG results will be produced. 
14.9. 
Pharmacokinetic Analysis 
Plasma concentration-versus-time profiles will be graphically summarized. Plasma concentration 
and PK parameter summaries will include descriptive statistics, as appropriate. 
 
 


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14.10. 
Other Statistical Issues 
14.10.1. 
Computing Environment 
Efficacy and safety analyses will be performed using SAS for windows, Version 9.3 or higher 
(SAS Institute Inc., Cary, NC, USA). 
Pharmacokinetic analyses will be performed using Phoenix WinNonlin Version 6.3 or higher 
(Pharsight, Cary, NC, USA). 


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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
A Sponsor’s representative or designee may visit the investigational study site to: 
• Determine the adequacy of facilities and equipment 
• Discuss with the Investigators and other personnel their responsibilities with regard to 
protocol adherence, and responsibilities of the Sponsor or its representatives. This 
will be documented in a Clinical Study Agreement between the Sponsor and the 
Investigator, as appropriate. 
During the study, a Sponsor’s representative 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, and that study drug accountability checks are being 
performed 
• Perform source data verification. This includes a comparison of data in the CRFs 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 that AEs and SAEs have been properly documented on CRFs, and confirm 
that any SAEs have been forwarded to the Sponsor. Confirm that SAEs meeting 
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. 
15.2. 
Audits and Inspections 
Authorized representatives of the Sponsor, a regulatory authority, an EC, 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 examine systematically and independently all study-related 
activities and documents, to determine whether study-related activities were conducted, and 
whether data were recorded, analyzed, and accurately reported, according to the protocol, Good 
Clinical Practice (GCP) guidelines of the International Conference on Harmonisation (ICH), and 
any applicable regulatory requirements. The Investigator should contact the Sponsor 
immediately if contacted by a regulatory agency about an inspection. 


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15.3. 
Institutional Review Board/Ethics Committee 
The Investigator must obtain IRB/EC approval for the investigation. All IRB/EC approvals, 
including initial and continued review, and all materials approved by the IRB/EC for this study, 
including the ICF and any recruitment materials must be maintained by the Investigator and 
made available for inspection. 
 


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16. 
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 15.2).  


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17. 
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 with 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 from 
procedures (eg, topical anesthesia to place IV catheters, use of indwelling catheters rather than 
repeated venipunctures for blood sampling, and collection of some protocol-specified blood 
samples when routine clinical samples are obtained). 
17.1. 
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 EC, as appropriate. The Investigator must submit 
written approval to the Sponsor before he/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 
scientific validity of the study will require IRB/EC 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 Investigator is responsible for 
informing the IRB or EC of any amendment to the protocol, in accordance with local 
requirements. In addition, the IRB or EC must approve all advertising used to recruit patients for 
the study. The protocol must be reapproved by the IRB or EC upon receipt of amendments and 
annually, as local regulations require. 
The Investigator is also responsible for providing the IRB/IEC with any reportable serious 
adverse drug reactions from any other study conducted with the study drug. The Sponsor will 
provide this information to the Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or EC, according to local regulations and guidelines. 
17.2. 
Written Informed Consent 
The Investigator 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 possible 
benefit of the study. The patient's parent or legal guardian also must be notified that he/she is 
free to discontinue his/her child from the study at any time. The parent or legal guardian should 
be given the opportunity to ask questions and time to consider the information provided. 
The signed and dated ICF must be obtained before conducting any study procedures. 


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The Investigators 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 study that might affect parent or legal 
guardian willingness to continue study participation, the parent or legal guardian will be notified 
in a timely manner about the new information and asked to sign a new ICF. 
17.3. 
Patient Data Protection 
Prior to performing 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. 
Case Report Forms will be completed at the site either on paper or in the electronic data capture 
(EDC) system. Copies of pertinent records in connection with the study, eg, patient charts or 
laboratory data, will be made available to the Sponsor or designee on request, in a timely manner 
throughout the study, with due precaution toward protecting patient privacy. 


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18. 
DATA HANDLING AND RECORDKEEPING 
18.1. 
Inspection of Records 
The Sponsor or designee will be allowed to conduct site visits for the purpose of monitoring any 
aspect of the study. The Investigator agrees to allow the monitor to inspect the drug storage area, 
study drug stocks, drug accountability records, patient charts, study source documents, and other 
records relative to study conduct. 
18.2. 
Retention of Records 
The Investigator must maintain all study-related documentation, in accordance with local 
retention requirements, for a period of 2 years after the last marketing application approval or, if 
not approved, 2 years following discontinuation of the test article for investigation. If it becomes 
necessary for the Sponsor or the regulatory authority to review any study-related documentation, 
the Investigator must permit access to such records. No records may be destroyed without 
Sponsor written approval. 
18.3. 
Retention of Biological Samples 
If a patient’s parent or legal guardian has provided consent for long-term storage of biological 
samples, and if permitted by local regulatory authorities, any remaining samples will be stored at 
a central location for a maximum of 15 years after the last patient’s last study visit, or longer, if 
requested by regulatory authorities. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Study samples and data for biochemical analysis will be single-coded. The link between a patient 
enrollment number and any biochemical results will be maintained and stored in a secure 
environment with restricted access. The link will be used to identify relevant samples for 
analysis, facilitate correlation of biochemical results with clinical data, allow regulatory audit, 
and trace samples for destruction in the case of consent withdrawal, when the patient or 
consenting guardian has requested disposal/destruction of collected samples not yet analyzed. 
If a patient's parent or legal guardian withdraws consent to the use of donated biological samples, 
the samples will be destroyed, and the action will be documented. If samples are already 
analyzed, the Sponsor is not obliged to destroy results of this research. 


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18.4. 
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. 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. 


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19. 
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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20. 
REFERENCES 
 
 
1.  Schwarz G, Mendel RR, Ribbe MW. Molybdenum cofactors, enzymes and pathways. 
Nature 2009 Aug 13;460(7257):839-47. 
 
2.  Reiss J, Johnson JL. Mutations in the molybdenum cofactor biosynthetic genes MOCS1, 
MOCS2, and GEPH. Hum.Mutat. 2003 Jun;21(6):569-76. 
 
3.  Schwahn B, Spronsen F, Balaidi A, Bowhay S, Christodoulou J, Derks T. Efficacy and 
safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor 
deficiency type A: a prospective cohort study. The Lancet 2015 Sep 3. 
 
4.  Van der Knaap M, Valk J. Molybdenum Cofactor Deficiency and Isolated Sulfite 
Oxidase Deficiency. In Magnetic Resonanace of Myeliniationand Myelin Disorders. 3 ed. 
Springer; 2005. p. 372-6. 
 
5.  Johnson JL, Duran M. Molybdenum Cofactor Deficiency and Isolated Sulfite Oxidase 
Deficiency. In The Metabolic and Molecular Bases of Inherited Disease. 8 ed. McGraw-Hill; 
2001. p. 3163-77. 
 
6.  Vijayakumar K, Gunny R, Grunewald S, Carr L, Chong KW, DeVile C, Robinson R, 
McSweeney N, Prabhakar P. Clinical neuroimaging features and outcome in molybdenum 
cofactor deficiency. Pediatr.Neurol. 2011 Oct;45(4):246-52. 
 
7.  Touati G, Rusthoven E, Depondt E, Dorche C, Duran M, Heron B, Rabier D, Russo M, 
Saudubray JM. Dietary therapy in two patients with a mild form of sulphite oxidase deficiency. 
Evidence for clinical and biological improvement. J.Inherit.Metab Dis. 2000 Feb;23(1):45-53. 
 
8.  Veldman A, Santamaria-Araujo JA, Sollazzo S, Pitt J, Gianello R, Yaplito-Lee J, Wong 
F, Ramsden CA, Reiss J, Cook I, et al. Successful treatment of molybdenum cofactor deficiency 
type A with cPMP. Pediatrics 2010 Maya;125(5):e1249-e1254. 
 
9.  Hitzert MM, Bos AF, Bergman KA, Veldman A, Schwarz G, Santamaria-Araujo JA, 
Heiner-Fokkema R, Sival DA, Lunsing RJ, Arjune S, et al. Favorable outcome in a newborn with 
molybdenum cofactor type A deficiency treated with cPMP. Pediatrics 2012 Octa;130(4):e1005-
e1010. 
 
10.  
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 Mayb;125(5):e1249-e1254. 
 
11.  
Hitzert MM, Bos AF, Bergman KA, Veldman A, Schwarz G, Santamaria-Araujo JA, 
Heiner-Fokkema R, Sival DA, Lunsing RJ, Arjune S, et al. Favorable outcome in a newborn with 
molybdenum cofactor type A deficiency treated with cPMP. Pediatrics 2012 Octb;130(4):e1005-
e1010. 
 
12.  
Mechler K, Mountford WK, Hoffmann GF, Ries M. Ultra-orphan diseases: a 
quantitative analysis of the natural history of molybdenum cofactor deficiency. Genet.Med. 2015 
Mar 12. 


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13.  
Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, Chatelut 
E, Grubb A, Veal GJ, Keir MJ, et al. Human renal function maturation: a quantitative description 
using weight and postmenstrual age. Pediatr.Nephrol. 2009 Jan;24(1):67-76. 
 
14.  
Bayley N. Bayley Scales of Infant Development. Third ed. 2005. 
 
15.  
Jeffreys H. An invariant form for the prior probability in estimation problems. 
Proc.R.Soc.Lond A Math.Phys.Sci. 1946;186(1007):453-61. 
 


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APPENDIX A. BLOOD SAMPLING VOLUMES 
 
 
 
 
The following procedures for blood collection should be adhered to: 
1. Number of attempts: The number of attempts for sampling blood is limited to 3 times per 
day. This means that, after 3 punctures for collection of blood have been performed and 
no or insufficient blood could be collected, no other puncture will be done on the same 
day.  
2. Volume of blood samples: Per study patient, the study-related blood loss (including any 
losses in the collection procedure) should not exceed 3% of the total blood volume during 
a period of 4 weeks and should not exceed 1% at any single time. The total volume of 
blood is estimated at 80 to 90 mL/kg body weight. Three percent (3%) is 2.4 mL blood 
per kg of body weight. If an Investigator decides to deviate from these limits, the 
deviation must be fully documented, and the Investigator should provide justification for 
the deviation. If the required blood volume cannot be obtained, due to the 
above-mentioned safety limits, priority will be given to safety-relevant investigations. 
3. EMLA (eutectic mixture of local anesthetics) cream/plaster: To minimize the possible 
pain and discomfort due to collection of blood, the Investigator should apply an EMLA 
cream/plaster at the puncture site. 
 
References:  
 
European Commission. 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 the 
good clinical practice in the conduct of clinical trials on medicinal products for human use. 2008.  
European Medicines Agency. Committee for the Medicinal Products for Human Use (CHMP) 
and Paediatric Committee (PDCO), Guidance on the Investigation of Medicinal Products in the 
Term and Preterm Neonate. [EMEA/536810/2008-2009]. 2009.  
 


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APPENDIX B. BLOOD SAMPLING VOLUMES TABLES 
Table 15: 
Blood Sampling Volumes (in mL) During the 12-Month Study Period 
Sample 
Marker or 
Specific 
Time 
 
Screening/
Baseline 
Daya 
-1 
Genotype (if not 
previously done) 
 
Serum Chemistryb 
 
Hematologyb 
 
Biochemical PD 
Markers 
SSC,
 
ORGN001 PKc 
Pre-dose 
EOI 
1-2 hours 
after the 
EOI 
3-4 hours 
after the 
EOI  
 
 
  
 
Total amount per time 
point (mL) 
 
a Screening/Baseline and Day 1 sampling can be performed on the same day.  
b Chemistry and hematology samples will be assessed 
. Capillary samples may be considered if collecting venous samples is not possible. 
c Pharmacokinetic sampling will be performed on the first day of any dose increase. 
 
  
Abbreviations:  EOI=end of infusion; mL=milliliters; PD=pharmacodynamic; PK=pharmacokinetics; SSC=S-sulfocysteine; 
 


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Table 16: 
Blood Sampling Volumes During the Long-Term Extension Period, After a Dose Adjustment, and at the Safety 
Follow-up 
Sample 
Marker or Specific 
Time 
Long-Term Extension Period 
Visits after an 
Unscheduled Dose 
Adjustment 
Safety 
Follow 
Up 
 
 
 
 
Serum Chemistry a 
Hematology a 
Biochemical PD 
Markers 
SSC,
 
ORGN001 PK b 
EOI 
1-2 hours after the EOI 
3-4 hours after the EOI 
 
 
 
a Chemistry and hematology samples will be assessed 
. Capillary samples may be considered if collecting venous samples is not possible. 
b Pharmacokinetic sampling will be performed on the first day of any dose adjustment. 
Abbreviations:  EOI=end of infusion; mL=milliliters; PD=pharmacodynamic; PK=pharmacokinetics; SSC=S-sulfocysteine;
 
 


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APPENDIX C. MODIFIED GLASGOW COMA SCALE FOR INFANTS 
AND CHILDREN 
 
Modified Glasgow Coma Scale for Infants and Children 
Area Assessed 
Infants 
Children 
Scorea 
Eye opening 
Open spontaneously 
Open spontaneously 
4 
Open in response to verbal stimuli 
Open in response to verbal stimuli 
3 
Open in response to pain only 
Open in response to pain only 
2 
No response 
No response 
1 
 
Verbal response 
Coos and babbles 
Oriented, appropriate 
5 
Irritable cries 
Confused 
4 
Cries in response to pain 
Inappropriate words 
3 
Moans in response to pain 
Incomprehensible words or nonspecific 
sounds 
2 
No response 
No response 
1 
 
Motor responseb 
Moves spontaneously and 
purposefully 
Obeys commands 
6 
Withdraws to touch 
Localizes painful stimulus 
5 
Withdraws in response to pain 
Withdraws in response to pain 
4 
Responds to pain with decorticate 
posturing (abnormal flexion) 
Responds to pain with decorticate 
posturing (abnormal flexion) 
3 
Responds to pain with decerebrate 
posturing (abnormal extension) 
Responds to pain with decorticate 
posturing (abnormal extension) 
2 
No response 
No response 
1 
a Score:  
 ≤ 12 suggests a severe head injury 
 ≤ 8 suggests need for intubation and ventilation 
 ≤ 6 suggests need for intracranial pressure monitoring 
b If the patient is intubated, unconscious, or preverbal, the most important part of the scale is motor response. This section should 
be carefully evaluated. 
Adapted from Davis RJ et al: Head and spinal cord injury. In Textbook of Pediatric Intensive Care, edited by MC Rogers. 
Baltimore, Williams & Wilkins. 1987; James H, Anas N Perkin RM: Brain Insults in Infants and Children. New York,. Grune 
& Stratton, 1985; and Morray JP et al: Coma scale for use in brain-injured children. Critical Care Medicine. 12:1018. 1984.  
 
Reference: 
Wilberger J, Dupre D. Traumatic Brain Injury 2013 Oct [cited 2015 Aug 27] Available from 
http://www.merckmanuals.com/professional/injuries-poisoning/traumatic-brain-injury-
tbi/traumatic-brain-injury.