Conditions: Inherited Metabolic Disorders (IMD)
Keywords: inherited metabolic disorders cerebral adrenoleukodystrophy Hurler syndrome globoid cell leukodystrophy Krabbe disease metachromatic leukodystrophy hematopoietic stem cells hematopoietic stem cell transplant umbilical cord blood umbilical cord blood transplant MGTA-456 myeloablative conditioning regimen bone marrow transplant mucopolysaccharidosis-1H
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 8
Healthy volunteers: no

Brief summary:
This study is designed to assess the safety and efficacy of using MGTA-456 in patients with Inherited Metabolic Disorders (IMD) undergoing stem cell transplantation.

Detailed description:
This phase 2 study is designed to evaluate the safety and efficacy of MGTA-456 in patients with IMD after receiving myeloablative conditioning and HSCT. MGTA-456 is an expanded CD34+ cell therapy product candidate given to induce rapid and sustained hematopoietic engraftment. In patients with selected IMDs, transplant is expected to replace defective or missing protein and preserve neurodevelopment. Since MGTA-456 offers increased numbers of HSCs over standard umbilical cord blood, it is expected to reduce the risks of prolonged neutropenia and thrombocytopenia and graft failure, and potentially transplant-related mortality (TRM). Patients with Hurler syndrome (also referred to as mucopolysaccharidosis-1H (MPS-1H)), cerebral adrenoleukodystrophy (cALD), metachromatic leukodystrophy (MLD) or globoid cell leukodystrophy (GLD) (also referred to as Krabbe disease) are eligible for this study.

Arms:
arm 1: MGTA-456 is an expanded CD34+ cell therapy investigational product used in replacement of single umbilical cord blood transplantation.

Interventions: intervention 1: MGTA-456
Intervention descriptions: intervention 1: Hematopoietic stem cell transplantation will be done with the cell therapy product MGTA-456.

Protocol document:
Prot_000.pdf: 
Study IMD-001 (Amendment v08) 
10/Jan/2020 
CONFIDENTIAL 
1 
 
 
Confidential 
May not be used, divulged, published or otherwise disclosed without the consent of Magenta 
 
 
Magenta Therapeutics 
MGTA-456 
 
 
 
 
 
 
CLINICAL TRIAL PROTOCOL IMD-001 
A Phase 2, Single-arm, Open-label Study to Evaluate the Safety and Efficacy 
of MGTA-456 in Patients with Inherited Metabolic Disorders (IMD) 
Undergoing Hematopoietic Stem Cell (HSC) Transplantation (HSCT) 
 
 
 
 
 
 
 
 
 
Sponsor: 
Magenta Therapeutics, Inc. (Magenta) 
Document Type: 
Amended Protocol 
IND Number: 
16729 
Version: 
08 
Development Phase: 
2 
Document Status: 
FINAL 
Date: 
10/Jan/2020 
 
 
 
 
 
 








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5.2 
Treatment Arms ...............................................................................................................43 
5.3 
Permitted Dose Adjustments and Interruptions of Study Treatment ...............................43 
5.4 
Treatment Assignment .....................................................................................................43 
5.5 
Treatment Blinding ..........................................................................................................43 
5.6 
Treatment Exposure .........................................................................................................43 
5.7 
Recommended Treatment of Adverse Events .................................................................43 
5.7.1 
Slow Engraftment/Graft Failure ......................................................................................44 
5.7.2 
Anemia ............................................................................................................................44 
5.7.3 
Thrombocytopenia ...........................................................................................................44 
5.7.4 
Nutrition ..........................................................................................................................44 
5.7.5 
Acute Graft Versus Host Disease ....................................................................................44 
5.7.6 
Infusional Reaction ..........................................................................................................44 
5.7.7 
Engraftment Syndrome/Transfusion Related Acute Lung Injury (TRALI) ....................45 
5.7.8 
Autoimmune Cytopenia ...................................................................................................45 
5.8 
Concomitant Treatment ...................................................................................................45 
5.8.1 
Pre-medications ...............................................................................................................46 
5.8.2 
Stem Cell Engraftment Enhancement .............................................................................46 
5.8.3 
Anti-Oxidants and Anti-Inflammatories ..........................................................................46 
6. 
DISCONTINUATION AND STUDY COMPLETION .................................................47 
6.1 
Discontinuation of Study .................................................................................................47 
6.2 
Study Completion and Post-Study Treatment .................................................................47 
6.2.1 
Lost to Follow-up ............................................................................................................47 
6.3 
Withdrawal of Consent ....................................................................................................47 
6.4 
Study Stopping Rules ......................................................................................................47 
6.5 
Early Study Termination .................................................................................................49 
7. 
PROCEDURES AND ASSESSMENTS .........................................................................50 
7.1 
Informed Consent Procedures .........................................................................................54 
7.2 
Patient Demographics and Other Baseline Characteristics .............................................54 
7.2.1 
Lansky Performance Status .............................................................................................54 
7.2.2 
Pre-existing Anti-HLA Donor-Specific Antibodies ........................................................55 
7.2.3 
Human Leukocyte Antigen Typing .................................................................................55 
7.2.4 
Chest X-ray ......................................................................................................................55 
7.2.5 
 .......................................................................................................................55 


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7.3 
Efficacy/Pharmacodynamics ...........................................................................................56 
7.3.1 
Assessment of Engraftment and Graft Failure ................................................................56 
7.3.2 
Chimerism Studies ...........................................................................................................56 
7.3.3 
 .........................................................................56 
7.4 
Safety ...............................................................................................................................57 
7.4.1 
Physical Examination ......................................................................................................57 
7.4.2 
Vital Signs .......................................................................................................................57 
7.4.3 
Height and Head Circumference .....................................................................................57 
7.4.4 
Laboratory Evaluations ...................................................................................................57 
7.4.4.1 Hematology .....................................................................................................................58 
7.4.4.2 Clinical Chemistry ...........................................................................................................58 
7.4.4.3 Viral Testing/Infection Surveillance ...............................................................................58 
7.4.5 
Electrocardiogram and Echocardiogram .........................................................................58 
7.4.6 
Pregnancy Testing ...........................................................................................................58 
7.4.7 
Pulmonary Function Tests (PFT) ....................................................................................58 
7.4.8 
Graft Versus Host Disease Assessments .........................................................................59 
7.4.9 
Survival Information .......................................................................................................59 
7.4.10 
Assessment of Infusional Toxicities ................................................................................59 
7.4.11 
Assessment of Infectious Events After Transplantation .................................................59 
7.4.12 
Transfusion Support ........................................................................................................59 
7.5 
Pharmacokinetics .............................................................................................................59 
7.6 
Other Assessments ...........................................................................................................60 
7.6.1 
 .............................................................60 
7.6.2 
 .................................................................................................................60 
7.6.3 
 .........................................................................................60 
7.6.4 
 ......................................................61 
7.6.5 
 ..............................................................................61 
7.6.5.1 
 .................................................................61 
7.6.5.2 
 ..............................................................................................61 
7.6.5.3 
 .............................................................61 
7.6.5.4 
 ...................................................................................................61 
7.6.5.5 
 ......................................................................................62 
7.6.5.6 
 ...........................................................................................62 


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8. 
SAFETY MONITORING ...............................................................................................63 
8.1 
Adverse Events ................................................................................................................63 
8.1.1 
Non-Serious AE Documentation .....................................................................................64 
8.2 
Serious Adverse Event Reporting ....................................................................................65 
8.2.1 
Definition of a Serious Adverse Event ............................................................................65 
8.2.2 
SAE Reporting .................................................................................................................66 
8.3 
Pregnancy Reporting .......................................................................................................67 
8.4 
Prospective Suicidality Assessment ................................................................................68 
8.5 
Early Phase Safety Monitoring ........................................................................................68 
9. 
DATA REVIEW AND DATABASE MANAGEMENT ................................................69 
9.1 
Site Monitoring ................................................................................................................69 
9.2 
Data Collection ................................................................................................................69 
9.3 
Database Management and Quality Control ....................................................................69 
9.4 
Data Monitoring Committee ............................................................................................70 
10. 
DATA ANALYSIS .........................................................................................................71 
10.1 
Analysis Sets ...................................................................................................................71 
10.2 
Patient Demographics and Other Baseline Characteristics .............................................71 
10.3 
Treatments - Study Drug, Rescue Medication, Other Concomitant Therapies, 
Compliance ......................................................................................................................71 
10.4 
Analysis of the Primary Variable(s) ................................................................................71 
10.4.1 
Endpoints .........................................................................................................................71 
10.4.2 
Statistical Model, Hypothesis, and Methods of Analysis ................................................71 
10.4.3 
Handling of Missing Values, Censoring, and Discontinuations ......................................71 
10.4.4 
Supportive Analyses ........................................................................................................72 
10.5 
Analysis of Secondary and Exploratory Variables ..........................................................72 
10.5.1 
Secondary and Exploratory Endpoints ............................................................................72 
10.5.2 
Safety ...............................................................................................................................72 
10.5.2.1 Vital Signs .......................................................................................................................72 
10.5.2.2 ECG Evaluations .............................................................................................................72 
10.5.2.3 Clinical Laboratory Evaluations ......................................................................................72 
10.5.2.4 Adverse Events ................................................................................................................72 
10.5.2.5 Concomitant Medications/Significant Non-Drug Therapies ...........................................73 
10.5.2.6 Other Safety Evaluations .................................................................................................73 






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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ABW 
actual body weight 
AE 
adverse event 
aGVHD 
acute graft versus host disease 
AHR 
aryl hydrocarbon receptor 
AIBW 
adjusted ideal body weight 
AIC 
autoimmune cytopenia 
ALC 
absolute lymphocyte count 
ALT 
alanine aminotransferase 
ALD 
Adrenoleukodystrophy 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ATG 
antithymocyte globulin 
AUCcum 
cumulative area under the plasma concentration-time curve 
AUC 
area under the plasma concentration-time curve 
AUC∞ 
area under the plasma concentration-time curve from time zero to infinity 
AUClast 
area under the plasma concentration-time curve from time zero to time of last 
measurable concentration 
BLA 
Biologics License Application 
BMT 
bone marrow transplant 
BU 
busulfan 
BUN 
blood urea nitrogen 
cALD 
cerebral adrenoleukodystrophy 
CBU 
cord blood unit 
CFR 
Code of Federal Regulations 
cGVHD 
chronic graft versus host disease 
CLIA 
Clinical Laboratory Improvement Amendment 
Cmax 
maximum observed concentration 
CMV 
Cytomegalovirus 
CNS 
central nervous system 
CsA 
cyclosporine A 
CSF 
cerebrospinal fluid 
CTCAE 
Common Toxicity Criteria Adverse Event 
CY 
cyclophosphamide 
DNA 
deoxyribonucleic acid 
DMC 
data monitoring committee 


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Abbreviation 
Definition 
DUCBT 
double umbilical cord blood transplantation 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
ERT 
enzyme replacement therapy 
EBV 
Epstein-Barr virus 
FDA 
Food and Drug Administration 
GAG 
Glycosaminoglycan 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulating factor 
GGT 
gamma-glutamyl transferase 
GLD 
globoid cell leukodystrophy 
GM-CSF 
macrophage-colony stimulating factor 
GVHD 
graft versus host disease 
HR 
hazard ratio 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
HNA 
human neutrophil antigen 
HSC 
hematopoietic stem cells 
HSCT 
hematopoietic stem cell transplantation 
HSV 
herpes simplex virus 
HTLV1/2 
human T cell lymphotropic virus ½ 
IB 
Investigator’s Brochure 
IBW 
ideal body weight 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IMD 
inherited metabolic disorders 
IRB 
institutional review board 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 


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Abbreviation 
Definition 
IVIg 
intravenous immunoglobulin 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LLOQ 
lower limit of quantification 
LMW 
low molecular weight 
LVEF 
left ventricular ejection fraction 
MAC 
myeloablative conditioning 
Magenta 
Magenta Therapeutics, Inc. 
MFI 
mean fluorescence intensity 
MedDRA 
medical dictionary for regulatory activities 
MLD 
metachromatic leukodystrophy 
MMF 
mycophenolate mofetil 
MP 
Methylprednisolone 
MRI 
magnetic resonance imaging 
MPS-HAQ 
Mucopolysaccharidosis-Health Assessment Questionnaire 
MPS-IH 
mucopolysaccharidosis-IH 
MSD 
matched sibling donor 
NFS 
neurological function score 
NMAC 
non-myeloablative conditioning 
NOAEL 
no observed adverse effect level 
NRE 
non-reducing-end 
PES 
pre-engraftment syndrome 
PFT 
pulmonary function test 
PK 
pharmacokinetic 
PMBC 
peripheral blood mononuclear cells 
PO 
oral(ly) (per oral) 
SAB 
single antigen bead 
SAE 
serious adverse event 
SOP 
standard operating procedure 
SR-1 
StemRegenin-1 
SUCBT 
single umbilical cord blood transplantation 
TEAE 
treatment-emergent adverse events 
TID 
three times a day 
TRALI 
transfusion-related acute lung injury 
TNC 
total nucleated cell 
TREC 
T cell receptor excision circles 


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Abbreviation 
Definition 
TRSALI 
transfusion-related acute lung injury 
TRM 
transplant-related mortality 
UCB 
umbilical cord blood 
UCBT 
umbilical cord blood transplant 
ULN 
upper limit of normal 
US 
United States 
VLCFA 
very long chain fatty acids 
WHO 
World Health Organization 


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SYNOPSIS 
 
Protocol number 
IMD-001 
Title 
A Phase 2, single-arm, open-label study to evaluate the safety and efficacy of MGTA-456
in patients with selected inherited metabolic disorders (IMD) undergoing hematopoietic 
stem cell (HSC) transplantation (HSCT) 
Brief title 
MGTA-456 in patients with inherited metabolic disorders undergoing HSCT 
Sponsor and Clinical 
Phase 
Magenta Therapeutics, Inc.; Phase 2 
Intervention type 
Intravenous (IV) administration of HSC therapy product 
Study type 
Interventional 
Purpose and rationale 
To evaluate the safety and efficacy of MGTA-456 after myeloablative conditioning to 
induce rapid and sustained hematopoietic engraftment with replacement of the specific 
protein product missing or defective in the patient with an IMD. The study aims to 
enhance the efficacy of umbilical cord blood (UCB) transplantation (UCBT), to preserve 
neurodevelopment in patients with selected IMDs. Since MGTA-456 offers increased 
numbers of HSCs over standard UCB, it is expected to reduce the risks of prolonged 
neutropenia and thrombocytopenia and graft failure, and potentially transplant-related 
mortality (TRM). 
Primary Objective(s) 
To evaluate the effect of MGTA-456 on the rate and incidence of neutrophil recovery in 
patients with IMD undergoing HSCT 
Secondary Objectives 
• 
To evaluate the safety of MGTA-456 in patients with IMD undergoing HSCT 
• 
To characterize engraftment following transplantation with MGTA-456 and to 
evaluate the effect of MGTA-456 on chimerism in the CD3 and CD33/66 (or 
CD15) hematopoietic compartments 
• 
To assess the incidence of acute and chronic graft versus host disease (GVHD) 
• 
To assess transplant-related mortality (the incidence of TRM) 
Study design 
This is a Phase 2, open-label, single-arm study in which patients with IMDs will receive 
MGTA-456 as a stand-alone HSC graft after MAC. Approximately 12 patients with IMD 
will be enrolled and followed for one year, with the option to include up to approximately 
15 additional patients in an expansion cohort. 
Population 
Children age < 2.5 years with Hurler syndrome, age 2-17 years with cerebral 
adrenoleukodystrophy (cALD), age <16 years with metachromatic leukodystrophy 
(MLD) and age ≤ 10 years with globoid cell leukodystrophy (GLD) (also referred to as 
Krabbe). 
Inclusion criteria 
Male and female, age < 2.5 years with Hurler syndrome, age 2-17 years with cerebral 
adrenoleukodystrophy (cALD), age < 16 years with metachromatic leukodystrophy 
(MLD) and age ≤ 10 years with globoid cell leukodystrophy (GLD) (also referred to as 
Krabbe). 
Diagnosed with one of the following IMDs: 
• 
Hurler syndrome (Mucopolysaccharidosis I Hurler [MPS-IH]) 
• 
MLD: asymptomatic late-infantile, or asymptomatic/minimally symptomatic 
juvenile onset patients 
• 
GLD, or early attenuated disease 
• 
cALD with Loes score ≤10, and with neurologic functional score (NFS) ≤1. 


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Patient must have a minimum life expectancy of 6 months in the judgment of the 
Investigator. 
Recipients must meet the following criteria: 
• 
Lansky score ≥50% 
• 
Renal: serum creatinine ≤2.5 × upper limit of normal (ULN) corrected for age 
• 
Hepatic: total bilirubin and alanine aminotransferase (ALT) ≤3 × ULN corrected 
for age 
• 
Pulmonary function: oxygen saturation ≥92% without an oxygen requirement; 
an exception may be made as documented in the medical record for patients 
with abnormal sleep studies (such as Hurler patients) 
• 
Cardiac: left ventricular ejection fraction ≥30. 
Required graft characteristics: 
• 
The UCB unit must be at least 6/8 HLA-A, HLA-B, HLA-C, and HLA-DRB1 
matched with the recipient at the allele level. This is based upon a recent 
publication which showed that allele-level matching at HLA-A, HLA-B, HLA-C 
and HLA-DRB1 between the UCB unit and its recipient is associated with best 
survival and lowest occurrence of graft failure in children with non-malignant 
diseases. 
• 
The UCB units must come from a qualified UCB bank(s) per institutional 
standard operating procedures (SOPs). Any matched unit not from a qualified 
UCB bank must be pre-approved for use by the Sponsor. If the UCB unit is 
“unlicensed” (most commonly based on location [e.g., European countries], 
testing by non-CLIA (Clinical Laboratory Improvement Amendment) approved 
laboratories, or collection before May 25, 2005), the Sponsor will make the final 
decision on patient eligibility based on the reason why the UCB unit is 
unlicensed 
• 
The minimal total nucleated cell (TNC) count for the selected UCB unit is to be 
1.0 × 107/kg of the recipient’s body weight 
• 
In a case where there is a better HLA-matched UCB unit with a lower cell dose, 
it may be selected over a less well-matched unit with a higher cell dose 
• 
The patient must not have donor-specific anti-HLA antibodies considering HLA 
A, B, C, DRB1, DQ and DP (Mean Fluorescence Intensity [MF]I >1000). 
• 
A suitable back-up HSC source (UCB unit or unaffected haploidentical donor) 
must be available. 
• 
Cord blood grafts require genetic testing and/or demonstration of enzyme 
activity for patients with Hurler syndrome, MLD or GLD and are tested for very 
long chain fatty acids (VLCFA) to confirm there is no evidence of VLCFA 
consistent with ALD 
Exclusion criteria 
• 
Availability of 8/8 HLA-matched related donor who is not a carrier of the same 
genetic defect. 
• 
Active infection at Screening (defined as requiring parenteral antibiotics because 
of persistent changes consistent with infection based on imaging studies and/or 
positive cultures) including active infection with Aspergillus or other fungus 
within 30 days prior to screening, or severe concomitant diseases which in the 
judgment of the Investigator would lead to the patient’s inability to tolerate the 
protocol specified conditioning regimen. 
• 
Prior myeloablative conditioning. 






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1. 
INTRODUCTION 
1.1 
Background 
1.1.1 
Inherited Metabolic Disease 
Inherited metabolic diseases (IMD), including cerebral adrenoleukodystrophy (cALD), globoid 
cell leukodystrophy (GLD or Krabbe), metachromatic leukodystrophy (MLD), and Hurler 
syndrome are a group of rare, inherited disorders that result in a progressive loss of neuromotor 
and cognitive abilities. Untreated, these disorders are progressive and lethal. Enzyme 
replacement of lysosomal disorders cannot correct the central nervous system (CNS) defects due 
to lack of penetration of the blood-brain-barrier. The only effective neurologic therapy for MLD, 
GLD, cALD, and Hurler syndrome is allogeneic hematopoietic stem cell transplantation (HSCT), 
after which immature cells of hematopoietic origin migrate to tissues, including the CNS 
(Orchard et al 2007; Prasad et al 2008). 
In cALD, mutations in the ABCD1 gene cause a defect in peroxisome membrane transport and 
lead to accumulation of VLCFA. High levels of VLCFA in turn cause inflammation and 
demyelination within the CNS white matter resulting in progressive disease. Microglia derived 
from allogeneic bone marrow progenitors are hypothesized to ameliorate the defect by 
processing VLCFA. One general mechanism known as cross-correction has been shown in 
Hurler syndrome where microglia capable of providing the α-L-iduronidase enzyme to the CNS 
of Hurler patients supply the defective enzyme and serve as a permanent source of cellular 
enzyme replacement (Krivit et al 1995). This same mechanism is thought to provide clinical 
benefit to those with early and/or attenuated MLD and GLD. 
While allogeneic HSCT is considered the standard of care for these diseases, the morbidity and 
mortality of transplantation are significant, with peri-transplant mortality reported as 20% to 
30% (Prasad et al 2008; Boelens et al 2013). Transplant-related mortality (TRM) is in part 
caused by the conditioning regimen, which traditionally has included myeloablative doses of 
chemotherapy and/or radiation and was independent of the specific indication. Reducing TRM is 
a high priority in this patient population. 
Most of the mortality in patients with IMD occurs within the first 6 months of HSCT, most often 
secondary to transplant-related complications. The best outcomes are achieved in patients 
receiving a genotypic-identical sibling donor bone marrow transplant (BMT) or a human 
leukocyte antigen (HLA)-matched, unrelated UCB transplant (UCBT) prior to the onset of 
irreversible neurologic complications (Boelens et al 2013). 
UCB has become a preferred choice for patients lacking a HLA matched related donor due to its 
rapid availability and permissiveness for HLA allele mismatching. In one center, an outcome 
study of 159 patients with IMDs undergoing UCBT (Prasad et al 2008; Figure 1), overall 
survival was 71.8% at 1 year. Median time to neutrophil engraftment was 22 days with a 
cumulative incidence by Day 42 of 87%. Platelet engraftment occurred in a median of 87 days 
with a cumulative incidence of 71% at 180 days. Factors significantly affecting neutrophil 
engraftment included HLA match of at least 5/6 (hazard ratio [HR] 1.4, p=0.04), higher CD34+ 
cell dose (HR 1.76, p<0.01) and higher TNC (HR 1.78, p<0.01) (Figure 1). In terms of GVHD, 
the incidence of grade II-IV acute graft versus host disease (aGVHD) was approximately 41% 
and grade II-IV was 10.2%. Chronic GVHD was observed in 20.9% at 1 year. Graft failure 


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occurred in 8.2% of patients; however additional studies have reported higher rates of 
approximately 20% (Miller et al 2011; Martin et al 2006; Beam et al 2007). 


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Figure 1: 
Impact of Graft Characteristics on the Probability of Engraftment and Overall Survival 
 
 
MSD=matched sibling donor; CB=cord blood; MUD=matched unrelated donor; MMUD=mismatched unrelated donor; OS=overall survival; TNC=total 
nucleated cell. Event-free survival is defined as alive with donor-derived engraftment. 


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Note: Probability plots are shown for the each of the 4 quartiles. Panels A, E, and I depict the impact of cryopreserved TNCs (x 107/kg recipient weight) on 
neutrophil engraftment, platelet engraftment, and OS, respectively. Panels B, F, and J depict the impact of infused TNCs (x 107/kg recipient weight) on 
neutrophil engraftment, platelet engraftment, and OS, respectively. Panels C, G, and K depict the impact of infused CD34 cells (x 105/kg recipient weight) on 
neutrophil engraftment, platelet engraftment, and OS, respectively. Panels D, H, and L depict the impact of infused CFUs (x 104/kg recipient weight) on 
neutrophil engraftment, platelet engraftment, and OS, respectively. P values are shown with each plot for the quartile analysis. 
Source: Prasad et al 2018 








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In the double UCB (DUCBT) cohort of CHSC835X2201, the incidence of neutrophil recovery 
was 100% for both adult (n=15) and pediatric patients (n=3) occurring at a median of 16 days 
(6-30) and 7 days, respectively. The incidence of platelet recovery was 73% and 67% for adult 
and pediatric patients at a median of 59 days for adults (range, 28 to 108 days) and 22 and 
59 days for the 2 of 3 pediatric patients. Of the 18 patients, 1 had transient hypotension 4 hours 
after the infusion of MGTA-456 which was subsequently demonstrated to be due to an occult 
bacterial contamination of the MGTA-456 product. Otherwise, no infusional toxicities were 
noted and no other adverse effects were attributed to MGTA-456. Grade III aGVHD was 
diagnosed in 3 adult patients and Grade IV aGVHD was reported in one patient. None of the 
pediatric patients developed Grade III or IV aGVHD. The adverse event (AE) profiles between 
day 0 and day 30 were comparable to those commonly observed after UCB transplantation. In 
addition, no patient had late graft failure with the longest follow-up of 687+ days. In terms of 
other transplant outcomes, overall survival for adult and pediatric patients combined (10/18, 
55.6%) was similar to the historical cohort. Primary causes of death were acute GVHD (n=4), 
alveolar hemorrhage (n=2), idiopathic pneumonia (n=1), and relapse (n=1). 
In the single UCB (SUCBT) cohort of CHSC835X2201 (n=9), there were 8 adults and 
1 pediatric patient. The incidence of neutrophil recovery was 100%, at a median of 17 days 
(range: 7-32 days) for the adults and day 8 for the single pediatric patient. For adults transplanted 
with MGTA-456 as a stand-alone product, the incidence of platelet recovery was 63% at 
Day 180 at a median of 50.5 days (range 42 to 181 days). The single pediatric patient had platelet 
recovery after 97 days. 
The primary endpoint of the SUCBT clinical trial was to determine the safety of MGTA-456. 
There were no infusional toxicities noted within the first 24 hours after transplant and no other 
adverse effects were observed that could be attributed to the product infusion. In addition, no 
patient had late graft failure within the follow-up period. In terms of other transplant outcomes, 
Grade II-IV and Grade III-IV aGVHD occurred in 4 and 2 of 9 patients, respectively, at a median 
of 34.5 days after transplant. Thus far, TRM has been low with 1 of 9 dying due to non-disease 
related reasons. 
The median follow-up is 6 months (range: 1 to 38 days). At time of the last data cut off, 6 of 9 
were alive with deaths due to relapse (n=2), alveolar hemorrhage (n=1). 
Overall, the median time to engraftment for the 27 patients in the study was 14 days (range 6 to 
32 days), which compares favorably with the time to neutrophil recovery reported for DUCBT 
patients at the University of Minnesota receiving the same conditioning regimen and GVHD 
immune prophylaxis, which was 26 days (Brunstein et al 2010). The pace of hematopoietic 
recovery was remarkably rapid in patients where MGTA-456 with a CD34 cell dose 
>10 million/kg could be administered. Similarly, the fraction of patients achieving platelet 
recovery was greater in patients receiving MGTA-456 and the pace of platelet recovery was 
accelerated relative to DUCBT patients (for details see the published results of the DUCBT 
patients enrolled in this study (Wagner et al 2016). Of note, the length of hospitalization was 
significantly reduced in recipients of MGTA-456 (median of 27 days compared to 46 days in the 
control population, p<0.001). 
Study CHSC835X2202 was a single-arm, open-label study evaluating the safety and tolerability 
of MGTA-456 as single stand-alone graft (SUBCT) in patients with hematologic malignancies 
undergoing a reduced dose conditioning to minimize TRM in an older population or those with 








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2. 
OBJECTIVES AND ENDPOINTS 
 
Objective 
Endpoint 
Primary 
To evaluate the effect of 
MGTA-456 on the rate of 
neutrophil recovery in 
patients with IMD undergoing 
HSCT 
Incidence of engraftment with 
MGTA-456, engraftment 
defined as achieving an 
absolute neutrophil count 
(ANC) ≥0.5 × 109/L for 
3 consecutive days 
Time to neutrophil recovery 
defined as the first day of 
3 consecutive days with an 
ANC ≥0.5 × 109/L 
Secondary 
To evaluate the safety of 
MGTA-456 in patients with 
IMD undergoing HSCT 
Incidence of infusion 
toxicities (incidence of 
MGTA-456-related AEs that 
limit MGTA-456 
administration) 
Incidence of TEAEs 
To characterize engraftment 
following transplantation with 
MGTA-456 and to evaluate 
the effect of MGTA-456 on 
chimerism in the CD3 and 
CD33/66 (or CD15) 
hematopoietic compartments 
Incidence of late 
hematological graft failure 
defined as meeting 1 of the 
following 3 criteria: 
(1) <5% donor whole blood 
or myeloid chimerism in 
peripheral blood or bone 
marrow beyond Day 42 
post-transplant in patients 
with prior hematopoietic 
recovery with ≥5% donor 
cells by Day 42 
post-transplant; (2) Sustained 
decline in the ANC to 
<500/mm3 for 3 consecutive 
measurements on different 
days, unresponsive to growth 
factor therapy after initial 
hematopoietic recovery by 
Day 42; (3) Subsequent bone 
marrow aplasia identified 
after initial hematopoietic 
recovery by Day 42 
Number of days with 
neutropenia from the day of 
transplant through Day 42 






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3. 
INVESTIGATIONAL PLAN 
3.1 
Study Design 
This is a Phase 2, open-label, single-arm study in which patients with IMD will receive 
MGTA-456 as a stand-alone HSC graft after MAC. Approximately 12 patients will be enrolled 
into 1 of 2 sequential cohorts, with the option to include up to approximately 15 additional 
patients in an expansion cohort following dosing of Cohort 2. Cohort 1 will comprise 
approximately 6 patients who will receive MGTA-456 fresh expanded CD34+ cells and Cohort 2 
will comprise approximately 6 patients who will receive MGTA-456 cryopreserved expanded 
CD34+ cells. Up to approximately 15 additional patients may be included in an expansion cohort 
following dosing of Cohort 2; these patients will receive MGTA-456 cryopreserved expanded 
CD34+ cells. All patients will be followed up to the end of study visit at 1 year after 
post-transplant. The design is presented in Figure 3. 
Figure 3: 
Study Design 
 
Note: Up to approximately 15 additional patients may be included in the study following dosing of Cohort 2 and will receive 
cryopreserved MGTA-456 product. 
 
 
For each patient in Cohort 1 (see Section 3.1.1) and Cohort 2 (see Section 3.1.2), the study will 
consist of an approximately 50-day screening period (Day -60 to Day -10). The patient must 
meet all eligibility criteria before the expansion culture will be initiated. Following MGTA-456 
manufacturing, patients will be admitted to begin the transplant conditioning regimen (Day -9 to 
Day -1 [see Section 5.1.2 for details]). The day of MGTA-456 administration will be considered 
Day 0 and will consist of the infusion of the expanded CD34+ fraction followed by the infusion 
of the CD34-depleted fraction of the cord blood unit (CBU). Infusional toxicity will be assessed 
within 48 hours after transplant. Each patient will remain hospitalized until neutrophil recovery 
is achieved (refer to Section 7.3.1 for neutrophil recovery definition). The patient will be 
monitored with protocol-specific procedures for 1 year following transplant to assess 
engraftment, graft failure, and late hematological graft failure (refer to Section 7.3.1 for 
definitions) and other study endpoints. 
Any patient (or guardian) withdrawing their consent or any patient withdrawn because of an 
event unrelated to the study, at any time during the study, will be replaced to ensure 
approximately 6 evaluable patients in each cohort. 
After 1 year, patients may be transferred to a separate long-term follow up study, if eligible and 
willing (after signature of the specific study informed consent form [ICF]). 




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For both cohorts, starting on Day 0 of the study, 2 therapeutic cell preparations will be infused 
sequentially in the following order. 
1. A minimal dose of 10 × 106 CD34+ cells per kg body weight within a range of 20 x 106 to 
270 × 106 TNC per kg body weight will be administered. 
2. The remaining and entire CD34-depleted fraction derived from the same UCB unit as the 
ex vivo expanded CD34+ cells (the CD34-depleted fraction). All available CD34-negative 
cells will be administered. 
The MGTA-456 production process results in a median >800-fold TNC expansion and a median 
>300-fold CD34+ cell expansion. The absolute number of CD34+ cells in the final product is 
affected by the number of CD34+ cells available in the starting UCB unit and the rate of 
differentiation of the unit during the culture. Due to differences between UCB units, the final 
CD34+ cell fraction of MGTA-456 constituted a median of 31.5% of all nucleated cells (range of 
19.3% to 53.7%; see Table 2 for a comparison of TNC required to achieve the target CD34 cell 
dose). Furthermore, the final CD34+ cell dose is also affected by the patient's body weight 
resulting in a range of administered TNC and CD34+ cell doses. 
Overcoming the engraftment barrier in IMD patients (who have not received prior 
immunosuppressive or cytoreductive therapy prior to transplant conditioning as is typical in 
oncology patients) undergoing UCBT is challenging, and historically required fully 
myeloablative conditioning regimens (Prasad et al 2008; Boelens et al 2013). It is expected that 
the higher dose of CD34+ cells present in MGTA-456 compared to a conventional UCB unit will 
promote engraftment in IMD patients. The need for high doses of CD34+ cells must be balanced 
with potential safety risks associated with the infusion of high numbers of nucleated cells. 
Therefore, the study will target the administration of a CD34+ cell dose (targeting 10 × 106 
CD34+ cells per kg body weight compared to typically less than 1 × 106 CD34+ cells per kg 
body weight in a conventional UCB unit) and allow the use of up to 270 × 106 TNC/kg body 
weight in the IMD pediatric population which is the upper limit of the dosing window that has 
been investigated and has showed a favorable safety profile in oncology patients. 
The rationale for selecting the above cell doses is based on the following observations: 
• Higher CD34+ cell doses speed up neutrophil engraftment and establish long term 
chimerism in IMD (Martin et al 2006, Boelens et al 2013). 
• MGTA-456 has shown a relationship between infused cell dose and engraftment 
(Figure 2, Investigator Brochure attached) 
• In IMD specifically, the successful use of reduced dose conditioning regimens has 
been impeded by a suboptimal engraftment (Aldenhoven et al 2015a). However, IMD 
patients, unlike malignancy patients, do not typically receive myelotoxic and 
immunosuppressive chemotherapy as initial therapy for malignancy prior to HSCT. 
Additionally, in models of IMD in mice (e.g., Hurler syndrome) the accumulation of 
toxic byproducts in the bone marrow leads to impaired homing of stem cells (Watson 
et al 2014; Aldenhoven et al 2015a). 
• Even with MAC, there is a substantial risk of graft failure. In the COBLT trial report 
on UCBT in IMD, the median number of CD34+ cells was 0.2 × 106/kg (range: 0.04 




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4. 
POPULATION 
The study population will include pediatric patients age < 2.5 years with Hurler syndrome, age 2- 
17 years with cerebral adrenoleukodystrophy (cALD), age < 16 years with metachromatic 
leukodystrophy (MLD) and age ≤ 10 years with globoid cell leukodystrophy (GLD) (also 
referred to as Krabbe) Approximately 12 patients will be enrolled in the study, with the 
possibility of expanding to include up to approximately 15 additional patients. 
The study will enroll pediatric patients with an IMD in which enzyme replacement treatment is 
not effective in preventing CNS deterioration likely due to the enzyme’s inability to cross the 
blood brain barrier. Furthermore, only those disorders will be included for which there is 
considerable published evidence either from registries or from single institutions demonstrating 
the efficacy of allogeneic HSCT in limiting disease progression. Therefore, we will recruit only 
patients with diseases and disease stages in which allogeneic HSCT is considered ‘standard’ and 
in which HSCT is considered a treatment option per International EBMT guidelines (The EBMT 
Handbook 2008-Chapter 41) and a recent publication (Boelens et al 2014). Therefore, Hurler 
syndrome, cALD, MLD, and GLD will be included. 
Any patient (or guardian) withdrawing their consent or any patient withdrawn because of an 
event unrelated to the study, at any time during the study, will be replaced to ensure 
approximately 6 patients in each cohort. 
The patient must meet all inclusion criteria before the expansion culture will be initiated. 
After 1 year, patients may be transferred to a separate long-term follow up study, if eligible and 
willing (after signature of the specific study ICF). 
4.1 
Inclusion Criteria 
Patients must fulfill all the following criteria to be eligible for this study: 
1. Written informed consent must be obtained from the patient or parent/guardian before any 
assessment is performed. Study assents will also be prepared for children and adolescents 
to review when applicable. 
2. Male and female, age < 2.5 years with Hurler syndrome, age 2-17 years with cerebral 
adrenoleukodystrophy (cALD), age < 16 years with metachromatic leukodystrophy 
(MLD) and age ≤ 10 years with globoid cell leukodystrophy (GLD) (also referred to as 
Krabbe)Diagnosed with 1 of the following IMD: 
a. Hurler syndrome (mucopolysaccharidosis MPS-IH) 
b. MLD; asymptomatic late-infantile, or asymptomatic/minimally symptomatic juvenile 
onset patients 
c. GLD; asymptomatic infants, or asymptomatic/minimally symptomatic attenuated 
disease 
d. ALD; with active cerebral disease as established by radiographic review of brain MRI 
demonstrating a Loes score ≤10 and with a neurological function score (NFS) ≤1 
(Moser, Arch Neurol 2005;62:1073-1080) 


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3. Able to complete all study procedures, measurements and visits; and parent/guardian and 
patient has adequately supportive psychosocial circumstances, in the opinion of the 
Investigator. 
4. Patient must have a minimum life expectancy of 6 months in the judgment of the 
Investigator. 
5. Recipients must meet the following: 
• Lansky score ≥50% 
• Renal: serum creatinine ≤2.5 × upper limit of normal (ULN) corrected for age 
• Hepatic: total bilirubin and ALT ≤3 × ULN corrected for age 
• Pulmonary function: oxygen saturation ≥92% without an oxygen requirement (an 
exception may be made as documented in the medical record for patients with 
abnormal sleep studies [such as patients with Hurler syndrome]) 
• Cardiac: left ventricular ejection fraction (LVEF) ≥30%. 
6. Graft Characteristics 
• The unrelated UCB grafts must be at least 6/8 HLA-A, HLA-B, HLA-C, and 
HLA-DRB1 matched with the recipient at the allele level. This is based upon a recent 
publication which showed that allele-level matching at HLA-A, HLA-B, HLA-C and 
HLA-DRB1 between the UCB unit and its recipient is associated with best survival 
and lowest occurrence of graft failure in children with non-malignant diseases. 
• UCB units must come from a qualified UCB bank(s) per institutional standard 
operating procedures (SOPs). A matched UCB unit from an unlicensed bank must be 
pre-approved by the sponsor before use. If the UCB unit is unlicensed (most 
commonly based on location [eg, European countries], testing by non- Clinical 
Laboratory Improvement Amendment (CLIA)-approved laboratories, or collection 
before 25 May 2005), Magenta will make the final decision on patient eligibility 
based on the reason why the UCB unit is unlicensed. 
• The minimal TNC count for the selected UCB unit is to be 1.0 × 107/kg body weight. 
• In a case where there is a better HLA-matched UCB unit with a lower cell dose, it 
may be selected over a less well-matched unit with a higher cell dose 
• The patient must not have donor specific anti HLA antibodies considering HLA A, B, 
C, DRB1, DQ and DP (MFI >1000). 
• A suitable back-up HSC source (UCB unit or unaffected haploidentical donor) must 
be available. 
• Cord blood grafts require genetic testing and/or demonstration of enzyme activity for 
patients with Hurler syndrome, MLD or GLD and are tested for very long chain fatty 
acids (VLCFA) to confirm there is no evidence of VLCFA consistent with ALD. 


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4.2 
Exclusion Criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the Investigator, to ensure that the study population will 
be representative of all eligible patients. 
1. Availability of a HLA 8/8 matched-related donor who is not a carrier of the same genetic 
defect. 
2. Active infection at screening (defined as requiring parenteral antibiotics because of 
persistent changes consistent with infection based on imaging studies and/or positive 
cultures) including active infection with Aspergillus or other fungus within 30 days prior to 
screening, or severe concomitant diseases which in the judgment of the Investigator would 
lead to the patient’s inability to tolerate conditioning regimen. 
3. Prior myeloablative conditioning. 
4. Prior use of an investigational study drug or procedure within 3 months before Screening 
that might confound study outcomes. Use of investigational study drugs is prohibited 
throughout the course of the study unless approved by Magenta. Except for approved 
Enzyme Replacement Therapy (ERT), use of investigational study drugs is prohibited 
throughout the course of the study unless approved by Magenta. 
5. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotropin (hCG) laboratory test. 
6. Females of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant (including women whose career, lifestyle, or sexual orientation 
precludes intercourse with a male partner and women whose partner have been sterilized by 
vasectomy or other means), unless they are using highly effective methods of contraception 
from the day of transplant and for 1 year after infusion. Highly effective contraception 
methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception). 
• Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception. 
7. Sexually active male patients unless they are using condoms as contraception starting on 
the first day of conditioning regimen (Day -9) until 1 year after infusion or off immune 
suppression, whichever is last. 
8. History of human immunodeficiency virus (HIV) infection. 


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5. 
TREATMENT 
5.1 
Study Treatment 
Details on the management of study medication, and instructions for administration are outlined 
in the Site Operations Manual. 
Descriptive information regarding potential treatment risks, including infusional toxicity, 
peri-infusion infection, and pre-engraftment syndrome (PES) may be found in the IB. 
5.1.1 
Investigational Treatment 
Starting on Day 0 of the protocol, the day of stem cell infusion, 2 separate therapeutic cell 
preparations will be infused sequentially in the following order. 
1. A minimal dose of 10 × 106 CD34+ cells/kg body weight within a range of 20 x 106 to 
270 × 106 TNC/kg body weight. 
2. The entire CD34-depleted fraction derived from the same UCB unit as the ex vivo 
expanded CD34+ cells (referred to as the CD34-negative fraction). 
The CD34-depleted fraction will be infused approximately one hour after the CD34+ fraction 
when all side effects relative to the CD34+ fraction have resolved, but may be infused as late as 
24 hours after the CD34+ fraction if adverse events occurred with the expanded fraction or other 
reason approved by the principal investigator. 
Each patient will be treated only once. A back-up HSC graft must be available in the event that 
the MGTA-456 product does not meet release criteria. 
 
5.1.2 
Additional Study Treatment 
 
5.1.2.1 
Conditioning Regimen 
The dosing scheme using busulfan (BU), CY, and rabbit antithymocyte globulin (ATG) 
serotherapy will be used uniformly at all clinical sites participating in this study based on 
Bartelink et al 2008, Bartelink et al 2009, Bartelink et al 2014, and Prasad et al 2008. 
The conditioning regimen will be initiated on Day -9 and will consist of: 
• BU will be administered via IV for 4 days (Days -9 to -6). 
(A) Patients will receive a total of 4 doses (recommended initial dose: 120 mg/m2 for 
age >1 year and 80 mg/m2 for age <1 year) given once daily over 3 hours and 
adjusted to achieve targeted dose range (see below). Initial dose may also be 
determined by institutional nomogram or test dose. 
OR 
 
(B) Patients will receive a total of 16 doses (recommended initial dose 1 mg/kg) 
given every 6 hours and adjusted to achieve the targeted dose range (see below). 
Initial dose may also be determined by institutional nomogram or test dose. 


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• Leveteracetam (Keppra) prophylaxis against seizures will be given starting with a 
loading dose on the day before the first dose of BU and continued until 24 hours after 
the final dose of BU. 
• CY will be administered via IV for 4 days (Days -5 to -2) at a dose of 50 mg/kg each 
day (total dose 200 mg/kg). Mesna prophylaxis will be administered per institutional 
protocol. The CY dose will be adjusted if the patient’s actual body weight is more 
than 125% of the ideal body weight (IBW). The first dose of CY will begin >24 hours 
after the final dose of BU. 
• ATG (rabbit; Thymoglobulin-Sanofi/Genzyme) will be administered over at least 
6 hours at 2.5 mg/kg/dose each day on Days -5 to -2. If no initial adverse reactions 
occur, the infusion rate may be increased per institutional guidelines. 
 
GVHD prophylaxis will consist of cyclosporine A (CsA) and mycophenolate mofetil (MMF). 
Pre-medications for the conditioning regimen should be administered per Section 5.8.1. 
Table 3: 
Conditioning Regimen Scheme and GVHD Prophylaxis 
 
Day 
Conditioning Regimen 
GVHD Prophylaxis 
Day -9 
BUa IV given once daily over 3 hours (A) OR q6h IV given over 
2 hours (B) 
-- 
Day -8 
BUa IV given once daily over 3 hours (A) OR q6h IV given over 
2 hours (B) 
-- 
Day -7 
BUa IV given once daily over 3 hours (A) OR q6h IV given over 
2 hours (B) 
-- 
Day -6 
BUa IV given once daily over 3 hours (A) OR q6h IV given over 
2 hours (B) 
-- 
Day -5 
CY 50 mg/kg once daily over 1 hour + Mesna prophylaxis 
ATG once daily IV over at least 6 hoursb 
-- 
Day -4 
CY 50 mg/kg once daily over 1 hour + Mesna prophylaxis 
ATG once daily IV over at least 6 hoursb 
-- 
Day -3 
CY 50 mg/kg once daily over 1 hour + Mesna prophylaxis 
ATG once daily IV over at least 6 hoursb 
Begin CsA and 
MMF 
Day -2 
CY 50 mg/kg once daily over 1 hour + Mesna prophylaxis 
ATG once daily IV over at least 6 hoursb 
-- 
Day -1 
-- 
-- 
Day 0 
MGTA-456 infusion 
Day 1 
-- 
Begin G-CSFc 
Abbreviations: ANC=absolute neutrophil count; CY=cyclophosphamide; BU=busulfan; ATG=antithymocyte 
globulin; CsA=Cyclosporine A; MMF=mycophenolate mofetil; G-CSF= granulocyte-colony stimulating factor; 
IV=intravenous; q6h=every 6 hours; Css=steady state concentration 


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a BU will be targeted to achieve cumulative AUC of 74 to 82 mg*h/L (18,050 to 20,000 μM*min/L) OR 
770 to 850 ng/mL Css. 
b If the first dose of ATG is well tolerated, subsequent doses may be administered over a shorter time frame per 
institutional guidelines. 
c G-CSF will be started on Day+1 and continued until the ANC ≥2,500/μL for 2 consecutive days. 
 
Dosing of BU: 
Busulfan dosing will target a cumulative AUC of 74 to 82 mg*hr/L with a goal of 
78 mg*hr/L (equivalent to 18,050 to 20,000 μM*min/L with a goal of 
19,025 μM*min/L). 
Pharmacokinetic evaluation of BU: 
The BU cumulative exposure (AUCcum) goal is an AUC range of 74 to 82 mg*hr/L with a 
target of 78 mg*hr/L for dose adjustments. This is equivalent to 18,050 to 
20,000 μM*min/L with a goal of 19,025 μM*min/L. 
The BU daily exposure goal is an AUC range 18 to 20 mg*hr/L with a goal of 
19 mg*hr/L. This is equivalent to approximately 4500 to 5000 μM*min/L with a goal of 
4570 μM*min/L. 
The BU single dose goal (if dosage regimen is Q6h) is an AUC range of 4.5 to 5 mg*hr/L 
with a target of 4.8 mg*hr/L. This is equivalent to approximately 1100 to 
1220 uM*min/L with a goal of 1160 uM*min/L. 
The steady state concentration (Css) goal is 770 to 850 ng/mL with a target of 810 ng/mL. 
(A) Once daily dosing: BU will be given IV over 3 hours and adjusted to maintain an 
AUC target or Css target as indicated above. Recommended calculation of the AUC is 
performed on blood samples obtained: predose, 15 minutes, 1 hour, 3 hours, 5 hours, 
and 7 hours after the end of infusion. Recommended calculation of Css is performed 
on blood samples obtained: predose, 60 minutes, 115 minutes (5 minutes before end), 
150 minutes, 3 hours, 4 hours, 5 hours, and 6 hours (prior to next dose). Busulfan 
dose is adjusted when the predicted cumulative AUC or Css falls outside the range. If 
possible, an evaluation of the AUC or Css after dose adjustment may be performed on 
subsequent days and used to confirm that the BU exposure is within the range. 
Busulfan PK may alternatively be calculated based on institutional guidelines, 
including the use of test doses, to achieve the specified target AUC or Css. Initial 
starting BU doses may also be calculated according to institutional nomogram or test 
dose. 
OR 
(B) Q6h dosing: BU will be given IV over 2 hours and adjusted to achieve an AUC target 
or Css target as indicated above. Recommended calculation of the AUC is performed 
on blood samples obtained: predose, 15 minutes, 1 hour, 3 hours, 5 hours, and 7 hours 
after the end of infusion. Recommended calculation of Css is performed on blood 
samples obtained: pre dose, 60 minutes, 115 minutes (5 minutes before end), 
150 minutes, 3 hours, 4 hours, 5 hours, 6 hours (prior to next dose). Busulfan dose is 
adjusted when the predicted cumulative AUC or Css falls outside the range. If 
possible, an evaluation of the AUC or Css after dose adjustment may be performed on 
subsequent days and used to confirm that the BU exposure is within the range. 


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Busulfan PK may alternatively be calculated based on institutional guidelines, 
including the use of test doses, to achieve the specified target AUC or Css. Initial 
starting BU doses may also be calculated according to institutional nomogram or test 
dose. 
 
Calculations used for AUC/Css conversions are as follows: 
• AUC(mg*h)/L = AUC (μM*min)/L* 246 μg/μM * 1 mg/1000μg * 1hr/60 min 
• Css (ng/ml) = AUC (μM*min)/L* 246 μg/μM * 1 hr/60 min * 1000 ng/1 μg * 
1 L/1000 mL/(Dosing frequency) 
 
For Css calculations: 
• Dosing frequency for single dose AUC for Q6h dosage regimen = 6 
• Dosing frequency for single day AUC for Q6h or Q24h = 24 
• Dosing frequency for total exposure (cumulative) for Q6h or Q24h AUC = 96 
Dosing of CY: 
Route of Administration: The total daily dose will be given as a 1-hour IV infusion in 
5% dextrose in normal saline (D5NS). Patients should receive additional hydration with 
3000 mL/m2/day of appropriate maintenance IV fluids starting 10 hours prior to CY and 
continued until 24 hours after the final dose. Patients will also receive mesna prophylaxis 
per institutional guidelines. 
Dose Adjustment: Adjustment of the dose is required if the actual body weight (ABW) 
is more than 125% of the IBW for the age and gender. The dose should be calculated 
using adjusted ideal body weight (AIBW): 
IBW Formula: 
Less than 60 inches: 
• IBW = (ht2 × 1.65)/1000 where ht = cm, IBW = kg 
More than 60 inches 
• Males IBW = 39.0 + [2.27 × (ht – 60)] where ht = inches, IBW = kg 
• Females IBW = 42.2 + [2.27 × (ht – 60)] where ht = inches, IBW = kg 
AIBW Formula: 
• AIBW = IBW + [(0.25) × (ABW - IBW)] 
Immunosuppression: 
All patients will receive the immunosuppression regimen per the study treatment plan as 
described below: 
• CsA: Initiate on Day -3. Administer per institutional guidelines with adjustment to 
maintain target serum trough levels of 200 to 400 ng/ml. Cyclosporine A weaning 
begins at Day 270 if the patient is stably engrafted and has no active GVHD. The 




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5.7.1 
Slow Engraftment/Graft Failure 
The clinical management of slow engraftment/graft failure will be per institutional guidelines. 
Management of slow engraftment is triggered by the assessment of peripheral blood and bone 
marrow on Day 21. If at Day 21, the ANC is ≤0.5 × 109/L and bone marrow cellularity is ≤5%, 
G-CSF dose may be doubled or granulocyte macrophage-colony stimulating factor (GM-CSF) 
may be added at 250 mcg/m2/d, the availability of the back-up UCB unit(s) that was put on hold 
at the time of patient enrolment is confirmed and a Day 28 bone marrow biopsy is scheduled. 
If on Day 28 ANC remains ≤0.5 × 109/L and bone marrow cellularity is ≤5%, consideration will 
be given to performing a second HSC infusion using the previously identified back up source 
after some form of preconditioning per institutional standard of care. Patients will remain on- 
study for one-year unless they undergo a second HSC infusion. The patient will come off study 
at the time of the second HSC infusion and the event will be captured on the eCRF. 
Use of medication, including non-drug therapies, for slow engraftment must be recorded on the 
eCRF. 
 
5.7.2 
Anemia 
Transfusions of packed red blood cells are indicated for symptomatic management of anemia. An 
attempt should be made to maintain the hematocrit >24% and hemoglobin >8 g/dL. Irradiated 
(1500 to 3000 cGy) blood products will be used in accordance with the institutional standard of 
care and all red blood cell transfusions will be recorded in the eCRF. 
5.7.3 
Thrombocytopenia 
Prophylactic platelet transfusions should be given to maintain the platelet count >10 × 109/L or 
above the level at which signs of bleeding are known to occur, whichever is greater. All aspirin 
containing drugs are to be avoided. The patients should receive no intramuscular injections while 
thrombocytopenic. Irradiated (1500 to 3000 cGy) blood products will be used in accordance with 
the institutional standard of care and all platelet transfusions will be recorded in the eCRF. 
5.7.4 
Nutrition 
All patients will be candidates for total parenteral nutrition; length of use is per institutional 
guidelines. 
 
5.7.5 
Acute Graft Versus Host Disease 
Patients will be considered evaluable for aGVHD unless they are known to have autologous 
recovery or die before Day 28 without GVHD. Organ involvement will be staged using the 
criteria outlined in the Appendix 2. Biopsy of each organ site at diagnosis or major change in 
disease activity will be performed unless clinical circumstances make it impossible. 
5.7.6 
Infusional Reaction 
MGTA-456 expanded cell product, like other blood products, may cause infusional reactions, 
including hemodynamic effects or acute hypersensitivity. Furthermore, the co-infusion of 
residual components of the expansion culture carries theoretical attendant risks. These 
time-limited events are expected to occur within the first 24 hours (Regan et al 2010, Kharbanda 


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et al 2014), and may range from mild to moderate in severity and may include gastrointestinal 
(nausea, vomiting, diarrhea and abdominal cramps), respiratory (cough, dyspnea), cardiovascular 
(hypotension, hypertension, bradycardia), neurological, or dermatological (skin flushing, rash) 
events, infection, and anaphylaxis (Martín-Henao et al 2010). 
Emergency drugs such as epinephrine, hydrocortisone, diphenhydramine, and atropine in 
appropriate dosages and dilutions should be available at the bedside and administered per 
institutional guidelines. Oxygen with nasal prongs for standby use should be present in the room. 
5.7.7 
Engraftment Syndrome/Transfusion Related Acute Lung Injury (TRALI) 
Engraftment syndrome is a syndrome characterized by fever, fluid retention, rash and pulmonary 
infiltrates proximal to the time of neutrophil recovery after high dose conditioning and HSCT, 
likely mediated by activated leukocytes and proinflammatory cytokines. Treatment is supportive, 
including antipyretics, oxygen and diuretics, and systemic corticosteroids or therapies directed to 
specific proinflammatory cytokines (e.g., IL6). 
TRALI is a rare but serious syndrome characterized by sudden acute respiratory distress 
following transfusion. It is defined as new, acute lung injury during or within six hours after 
blood product administration in the absence of other risk factors for acute lung injury. TRALI is 
thought to be caused by activation of recipient neutrophils by donor-derived antibodies targeting 
HLA or human neutrophil antigen (HNA), in most cases. Non-antibody-mediated cases occur 
and may be mediated by biologic response modifiers present in the transfused blood product, 
along with recipient factors. Treatment is supportive and consists of oxygen, ventilator support 
and management of fluid balance. 
 
5.7.8 
Autoimmune Cytopenia 
Autoimmune cytopenia is the single or combination of auto/alloimmune hemolytic anemia, 
idiopathic thrombocytopenic purpura, and/or autoimmune neutropenia developing after HSCT. 
The mechanism of AIC development is not clearly understood but is postulated to be from 
immune dysregulation leading to aberrant antibody production. An increased incidence of AIC 
has been observed in transplant for non-malignant diseases, in particular for IMDs and Hurler 
Syndrome with rates between 20 to 56% (Deambrosis et al, 2018; Page et al 2008; Khalil et al 
2014). Age at transplant is an independent risk factor for AIC with incidence in infants reported 
up to 56% (Page et al 2008; Kruizinga et al 2018). Based on an evolving understanding of AIC, 
if investigation of a cytopenia reveals a single auto-antibody towards one cell line, it is 
recommended to test for antibodies to all lineages (red cell, platelet, and neutrophil) to guide 
early treatment. Recommended first line treatment is steroids, intravenous immunoglobulin 
(IVIg), and rituximab. Initiating plasmapheresis earlier in therapy is suggested to remove the 
auto-reactive antibody already produced. 
 
5.8 
Concomitant Treatment 
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the timeframe 
defined in the entry criteria prior to the start of the study and during the study, must be recorded 
on the eCRF. 


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Medication entries should be specific to trade name, the single dose and unit, the frequency and 
route of administration, the start and discontinuation date and the reason for therapy. In general, 
concomitant medications and therapies deemed necessary for the supportive care and safety of 
the patient (eg, approved enzyme replacement therapy [ERT]) are allowed. 
5.8.1 
Pre-medications 
Leveteracetam will be administered to all patients in accordance with institutional guidelines as 
seizure prophylaxis during BU therapy, starting with a loading dose on the day before the first 
dose of BU and continuing for at least 24 hours after the last dose of BU. The following pre- 
medications will be administered 30 minutes prior to each dose of ATG including: 
acetaminophen (10 mg/kg orally; maximum dose 500 mg); diphenhydramine (1 mg/kg IV or PO; 
maximum dose 50 mg), and methylprednisolone (1 mg/kg IV; maximum dose 125 mg). Mesna 
will be administered per the institutional guidelines beginning prior to the first infusion of CY 
and continuing through at least Day -2. Anti-emetics will be administered as needed per 
institutional guidelines. 
Pre-medication for the MGTA-456 infusion will be per institution’s standard of care for HSC 
product infusions. 
 
5.8.2 
Stem Cell Engraftment Enhancement 
G-CSF will be administered starting on Day +1 (5 mcg/kg IV once daily) and continued until the 
ANC ≥2,500/μl for 2 consecutive days. G-CSF is used after UCB transplantation to limit the 
duration of neutropenia (Section 5.1.2.1). 
 
5.8.3 
Anti-Oxidants and Anti-Inflammatories 
Anti-oxidant and anti-inflammatory drugs should be used for patients with cALD following the 
institutional guidelines. 


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6. 
DISCONTINUATION AND STUDY COMPLETION 
6.1 
Discontinuation of Study 
Patients who decide they do not wish to participate in the study further should NOT be 
considered withdrawn from the study UNLESS they withdraw their consent (see Section 6.3). 
Where possible, they should return for the assessments listed for the final visit in Table 5. If they 
fail to return for these assessments, every effort (e.g., telephone, e-mail, letter) should be made to 
contact them as specified in Section 6.2.1. 
Patients may withdraw from the study at any time. Each patient will be treated only once. 
 
6.2 
Study Completion and Post-Study Treatment 
Each patient will be encouraged to complete the study in its entirety. Study completion is defined 
as the patient completing a 1-year end of study visit, and any repeat assessments associated with 
this visit have been documented and followed-up appropriately by the Investigator, or in the 
event of an early study termination decision, the date of that decision. Patients will remain 
on-study for 1 year unless they undergo a second HSC infusion (see Section 5.7.1). 
Following the completion of this study, patients may be eligible to participate in a separate 
clinical trial for long-term safety monitoring. 
The Investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
6.2.1 
Lost to Follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating an 
intention to discontinue or withdraw, the Investigator should show due diligence by documenting 
in the source documents steps taken to contact the patient (eg, dates of telephone calls, registered 
letters, etc.). A patient should not be formally considered lost to follow-up until his/her 
scheduled end of study visit would have occurred. 
6.3 
Withdrawal of Consent 
A patient may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient does not want to participate in the study 
anymore, does not want any further visits or assessments and does not want any further study 
related contact. 
If a patient withdraws consent, the Investigator must make every effort to determine the primary 
reason for this decision and record this information. No further assessments should be conducted. 
All biological material that has not been analyzed at the time of withdrawal must not be used. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up. 
6.4 
Study Stopping Rules 
If there is an indication that the use of MGTA-456 in IMD patients is associated with an 
unacceptably high rate of graft failure, TRM, or Grade III-IV aGVHD the study will be placed 


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on hold, available data will be reviewed and a decision on study continuation will be made 
jointly with the DMC. 
The stopping rules described below will be assessed for Cohort 1 and 2 separately: 
• Excess graft failure: graft failure will be defined as the absence of ANC recovery 
>0.5 x 109/L for 3 consecutive days or lack of myeloid chimerism (<5%) by Day 42. 
The expected rate of graft failure is approximately 15% (publication pending). 
Enrollment will be stopped if 2/2, 2/3, 2/4, 2/5, or 3/6 events are observed. 
• Excess TRM by Day 100. The expected mortality rate by Day 100 after transplant is 
approximately 10% (publication pending). Enrollment will be stopped if 2/2, 2/3, 2/4, 
2/5, or 3/6 events are observed. 
• Excess Grade III-IV acute GVHD by Day 100. The expected rate of Grade III-IV 
aGVHD is approximately 15% (Harris et al 2018). Enrollment will be stopped if 2/2, 
2/3, 2/4, 2/5, or 3/6 events are observed. 
• One death within 30 days of treatment, regardless of cohort. 
With 6 patients per cohort, the stopping rules would ensure a reasonable probability (83%) that 
the cohort would not be stopped if the true event rate was 15% or lower while also ensuring an 
appropriate probability that the study would be stopped if the true event rate was high (66% 
probability for true event rates greater than 40%). Enrollment will be allowed to continue while 
monitoring for safety events that would reach a stopping rule. 
Table 4 shows some of the properties of the stopping rule for up to 10 patients (e.g., if after 
6 patients it is decided to continue to enroll more patients before moving to the next cohort). 
Table 4: 
Stopping Rule Properties 
 
Cohort 
Size 
Number of 
events 
triggering 
stop 
Probability that 
the true rate is 
>15% given the 
data 
Probability 
that the true 
rate is >10% 
given the data 
Probability of 
stopping when 
true rate is 
15% 
Probability of 
stopping 
when true 
rate is 40% 
2 
2 
>99% 
>99% 
3% 
16% 
3 
2 
98% 
>99% 
6% 
36% 
4 
2 
95% 
98% 
11% 
53% 
5 
2 
92% 
97% 
16% 
67% 
6 
3 
98% 
>99% 
17% 
66% 
7 
3 
96% 
99% 
17% 
71% 
8 
3 
94% 
98% 
19% 
76% 
9 
3 
92% 
97% 
21% 
81% 
10 
4 
97% 
>99% 
22% 
81% 


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6.5 
Early Study Termination 
The study may be terminated at any time for any reason by Magenta. Should this occur, patients 
who are still on study should be seen as soon as possible and treated as a prematurely withdrawn 
patient. The Investigator may be informed of additional procedures to be followed to ensure that 
adequate consideration is given to the protection of the patient’s interests. 
The Investigator will be responsible for informing institutional review boards 
(IRBs)/independent ethics committees (IECs) of the early termination of the trial. 


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7. 
PROCEDURES AND ASSESSMENTS 
Patients should be seen for all visits on the designated day, with the assessments performed as 
per schedule, within the allowed visit/assessment window specified in the Site Operations 
Manual. However, in the event the patient cannot return to the Transplant Center on the 
scheduled date, every attempt will be made to obtain the required laboratory tests and shipped to 
the Transplant Center. Patients who prematurely withdraw from the study for any reason should 
be scheduled for a visit as soon as possible, at which time all the assessments listed for the final 
visit will be performed. 








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7.1 
Informed Consent Procedures 
Voluntary written informed consent must be obtained before any study-related 
procedures are performed, in accordance with ICH guidelines and requirements of 
informed consent (Title 21 Code of Federal Regulations [CFR] Parts 50.20 and 50.25). 
Consent must be documented by the use of a written consent form approved by Magenta 
and the site’s IRB or IEC in accordance with Title 21 CFR Part 50.27. 
For minor patients, the patient’s parent/guardian will give consent and the patient should 
be informed about the study to the extent possible given his/her understanding. Minor 
patients capable of understanding/reading, will be given a dedicated information form to 
review. 
The process of obtaining informed consent should be documented in the patient source 
documents. A copy of the signed informed consent will be provided to the person signing 
the form, and the original will be retained in the source documents of the patient. 
Pregnancy outcomes must be collected for the female partners of any males administered 
study treatment in this study if conception occurred within the first week after 
MGTA-456 administration. Consent to report information regarding these pregnancy 
outcomes should be obtained from the mother. 
In the event that Magenta wants to perform testing on the samples that are not described 
in this protocol. 
A copy of the approved version of all consent forms must be provided to Magenta or 
designee after IRB/IEC approval. 
7.2 
Patient Demographics and Other Baseline Characteristics 
Patient demographic and baseline characteristic data to be collected on all patients 
include date of birth, age, sex, race, and predominant ethnicity. 
Relevant medical history (including history of disease, enzyme replacement therapy, and 
response to treatment) and current medical conditions will be recorded until the day of 
transplantation. 
Any event or change in the patient’s condition or health status occurring prior to 
MGTA-456 administration will be reported as medical history, as indicated in the 
assessment schedule (Table 5). 
 
7.2.1 
Lansky Performance Status 
Performance status will be recorded as defined by the Lansky Scale for patients less than 
16 years of age (Table 6). 






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7.4 
Safety 
Safety assessments are specified in the following sections; methods for assessment and 
recording are specified in the Site Operations Manual, with Table 5 detailing when each 
assessment is to be performed. 
 
7.4.1 
Physical Examination 
A complete physical examination will include the examination of general appearance, 
skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities, vascular, and nervous system. If indicated based on medical 
history and/or symptoms, rectal, external genitalia, breast, and/or pelvic exams may be 
performed. 
Information for all physical examinations must be included in the source documentation 
at the study site and will be recorded on the eCRF. Significant findings that are present 
prior to MGTA-456 infusion may be recorded as medical history. Significant findings 
observed after MGTA-456 administration which meet the definition of an AE must be 
appropriately recorded on the AE eCRF. 
7.4.2 
Vital Signs 
Vitals signs will include body weight, body temperature, systolic and diastolic blood 
pressure, pulse rate, and pulse oximetry will be obtained at specified times in Table 5. 
 
7.4.3 
Height and Head Circumference 
Height in centimeters will be measured at Screening and Study Day 360/EOS for all 
patients. Head circumference will be measured in centimeters at Screening and Study 
Day 360/EOS for patients with Hurler syndrome only. 
 
7.4.4 
Laboratory Evaluations 
In the case where a laboratory assessment that is listed in the inclusion/exclusion criteria 
is outside of a protocol-specified range at screening and/or at the initial baseline, the 
assessment may be repeated prior to treatment number assignment. If the repeat value(s) 
remain outside of protocol-specified ranges, the patient will be excluded from the study. 
Clinically relevant deviations of laboratory test results should be evaluated for criteria 
defining an AE and reported as such. 
Guidance on maximum blood volume to be collected during the study are based on the 
recommendations of the USC/LA Children’s Hospital (World Health Organization 
[WHO] – Bulletin of WHO; Howie 2011) on blood volumes in child health research 
(review of safe limits) and WHO child growth standards. The estimated blood volume for 
safety and standard of care assessments are based on standard of care laboratory 
assessments obtained at the site. The recommended maximum daily blood volume is 
2 mL/kg/day. Considering the above recommendations, prioritization of sample 
collection will be needed in the pediatric population based on blood volume. Among 
protocol mandated research-related blood collections, only PK samples will be required 
to be collected on Day 0, because they are considered relevant for patient safety. The 


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remaining study specific samples will be prioritized as follows (highest priority first) and 
only be collected if considered to be safe by the Investigator: chimerism (CD3 T cell and 
CD33/66 [or CD15] myeloid chimerism, followed by CD19 and CD56), immune 
reconstitution, T cell repertoire, PK, and optional plasma biomarkers. Sample must be 
drawn prior to initiating conditioning regimen Lower priority research-related samples 
may be collected on a subsequent day as blood volume limitations permit (for details, 
refer to Appendix 1). 
 
7.4.4.1 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, 
platelet count, and ANC will be measured. 
7.4.4.2 
Clinical Chemistry 
Sodium, potassium, bicarbonate, phosphate, creatinine, uric acid, chloride, albumin, 
calcium, alkaline phosphatase, total bilirubin, lactate dehydrogenase (LDH), 
gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), ALT, glucose, 
and blood urea nitrogen (BUN). 
Direct and indirect reacting bilirubin should be differentiated as clinically indicated. 
 
7.4.4.3 
Viral Testing/Infection Surveillance 
All patients will be screened for hepatitis B surface antigen (HBsAg), hepatitis B core 
antibody (HBcAb), hepatitis C virus (HCV), herpes simplex virus (HSV), 
cytomegalovirus, (CMV), Epstein-Barr virus (EBV), and human T cell lymphotropic 
virus 1/2 (HTLV1/2) during their pre-transplant evaluation. 
Infection Surveillance of viral reactivation by quantitative PCR will be performed as 
detailed in Table 5. Testing will include CMV, EBV, and human herpesvirus (HHV-6) as 
deemed appropriate based on the standard of care at the Institution. 
 
7.4.5 
Electrocardiogram and Echocardiogram 
Electrocardiogram (ECG) and echocardiogram assessments will be conducted as detailed 
in Table 5 and clinically significant abnormalities should be evaluated for criteria 
defining an AE and reported as such. 
 
7.4.6 
Pregnancy Testing 
For all females of child bearing potential, serum pregnancy testing is required at 
Screening and end of study visit, regardless of reported reproductive status. 
7.4.7 
Pulmonary Function Tests (PFT) 
Pulmonary function tests (PFT) for assessing lung function should be performed in all 
patients capable of doing so (about age 6 years) at screening and Day 360/End of Study 
Visit. Otherwise oxygen saturation should be performed at screening and Day 360/End of 
Study Visit. 










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8. 
SAFETY MONITORING 
8.1 
Adverse Events 
An AE is any untoward medical occurrence (ie, any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a patient or clinical 
investigation patient after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the 
use of a medicinal (investigational) product. 
The occurrence of AEs should be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are 
volunteered by the patient or family during or between visits or through physical 
examination, laboratory test, or other assessments. 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one 
of the following criteria: 
• Induce clinical signs or symptoms 
• Are considered clinically significant 
• Require therapy 
Clinically significant abnormal laboratory values or test results should be identified 
through a review of values outside of normal ranges/clinically notable ranges, significant 
changes from baseline or the previous visit, or values which are considered to be non- 
typical in patients with underlying disease. Investigators have the responsibility for 
managing the safety of individual patient and identifying adverse events. 
AEs must be recorded on the AE eCRF for patients that meet eligibility and enroll in the 
study. The AEs should be reported per the signs, symptoms, or diagnosis associated with 
them, and accompanied by the following information: 
1.The Common Toxicity Criteria Adverse Event (CTCAE) grade (version 4.03) If 
CTCAE grading does not exist for an AE (and this is rare), use: 
• 1=mild, 
• 2=moderate, 
• 3=severe, 
• 4=life threatening. 
CTCAE Grade 5 (death) is not used. Fatal AEs will be collected in other eCRFs as 
per eCRF completion guidance. There may be cases where an AE with a Grade 4 
(life-threatening) may not necessarily be a serious AE (SAE) (e.g., certain lab 
abnormalities in the absence of meeting other seriousness criteria). 
2. Relationship to the study treatment (no/yes). 
3. Duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported. 


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4. Whether it constitutes an SAE (see Section 8.2 for definition of SAE). 
5. Action taken regarding study treatment. 
All AEs should be treated appropriately. Treatment may include one or more of the 
following: 
• No action taken (ie, further observation only) 
• Concomitant medication given 
• Non-drug therapy given 
• Patient hospitalized/patient’s hospitalization prolonged 
6. Outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
Once an AE is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can 
be found in the IB or will be communicated between IB updates in the form of 
Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 
The Investigator should also instruct each patient to report any new AE (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in 
the Investigator’s source documents and recorded on the patient eCRF are per the 
instructions below; however, if the AE meets the criteria of an SAE, it must be reported 
to Magenta. 
 
8.1.1 
Non-Serious AE Documentation 
Given the high number of non-serious AEs experienced in the patient population being 
studied, recording of non-serious AEs will be handled depending on when they occur. 
Recording of non-serious AEs will start on Day 0, the day of MGTA-456 transplant. All 
non-serious AEs occurring on Day 0 through 48 hours following infusion of MGTA-456 
will be recorded in the clinical database via eCRFs regardless of grade or expectedness. 
Between 48 hours after the infusion of MGTA-456 and up to Day 100, all non-serious 
AEs except for frequent and anticipated events related to the HSCT procedure itself, will 
be recorded in the clinical database. After Day 100, non-serious AEs will be collected as 
detailed in Table 8. 


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Table 8: 
Collection of Non-Serious Adverse Events 
 
Timepoint 
Criteria 
Day 0 to 
Hour 48 
Record all non-serious AEs on patient eCRF 
Hour 48 to 
Day 100 
Record all non-serious AEs on patient eCRF, except for those noted below. 
These AE are considered anticipated events that are caused by the HSCT 
procedure, primarily the preparative regimen. They are either anticipated low 
grade (Grade 1 or 2 per the CTCAE version 4.03) events or they are captured in 
the database separately (eg, vital sign pages, laboratory pages). 
The following will not be recorded as an AE in the clinical database: 
• 
All non-serious hematologic lab abnormalities AEs anticipated as part of 
the HSCT procedure, such as out of range absolute neutrophil or 
absolute lymphocyte counts, thrombocytopenia, anemia 
• 
Anticipated Grade 1 and 2 non-serious AEs related to the HSCT 
procedure including but not limited to: neutropenia, mucositis, 
gastrointestinal disorders such as vomiting, nausea, diarrhea, anorexia, 
hypertension, hypotension, electrolyte imbalance, alopecia, fatigue, 
weight gain or loss 
The following must be recorded as an AE in the clinical database: 
• 
Any other event not meeting the exception criteria above including 
 
All CTCAE Grade 3 or 4 AEs 
 
Any grade CTCAE AE that, in the Investigator’s clinical 
judgment, is not an anticipated result of standard HSCT 
procedures 
 
Any grade evidence for infection resulting in treatment of the 
patient 
 
Any grade GVHD 
 
Any evidence for malignancy 
 
Any grade pre-engraftment syndrome 
 
Non-serious AEs that may be anticipated, but continue after 
Day 100, should be recorded. 
Day 100 to 
end of 
study 
(+30d) 
All non-SAEs will be available in source documents but only documented 
infections, cases of GVHD and malignancy will be recorded in the eCRF 
 
8.2 
Serious Adverse Event Reporting 
8.2.1 
Definition of a Serious Adverse Event 
An SAE is defined as any appearance of or worsening of any pre-existing undesirable 
sign(s), symptom(s) or medical conditions(s) which meets any one of the following 
criteria: 
• Is fatal or life-threatening 


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• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
except: 
− Routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition 
− Elective or pre-planned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since the 
start of study drug 
− Treatment on an emergency outpatient basis for an event not fulfilling any 
of the definitions of a SAE given above and not resulting in hospital 
admission 
− Social reasons and respite care in the absence of any deterioration in the 
patient’s general condition 
• Is medically significant (ie., defined as an event that jeopardizes the patient or 
may require medical or surgical intervention) 
Life-threatening in the context of an SAE refers to a reaction in which the patient was at 
risk of death at the time of the reaction; it does not refer to a reaction that hypothetically 
might have caused death if more severe. 
All malignant neoplasms will be assessed as serious under ‘medically significant’ if other 
seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also 
considered an SAE. 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization, but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
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. 
Serious adverse events are monitored continuously and have also special reporting 
requirements; see Section 8.2.2. 
8.2.2 
SAE Reporting 
Every SAE, regardless of causality, occurring starting with initiation of the conditioning 
regimen (ie, Day -9) until 30 days after the last study visit (protocol period +30d) will be 
collected in the clinical database and must be reported to Magenta within 24 hours of 
learning of its occurrence as described below. Any SAEs experienced after this should 
only be reported to Magenta if the Investigator suspects a causal relationship to study 
treatment. 


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Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must 
be submitted within 24 hours of the Investigator receiving the follow-up information. An 
SAE that is considered completely unrelated to a previously reported one should be 
reported separately as a new event. 
SAEs (initial and follow-up) that are recorded electronically in the electronic data capture 
system should be entered, saved and e-signed within 24 hours of awareness of the SAE or 
changes to an existing SAE. 
In addition, SAEs (initial and follow-up) must be reported to the Magenta Drug Safety 
Department within 24 hours of awareness of the SAE or changes to an existing SAE. 
This should be done by emailing or faxing a signed copy of the SAE Report Form using 
the contact details below. 
 
Follow-up information provided should describe whether the event has resolved or 
continues, if and how it was treated, and whether the patient continued or withdrew from 
study participation. Each re-occurrence, complication, or progression of the original 
event should be reported as a follow-up to that event regardless of when it occurs. 
If the SAE is not previously documented in the IB or Package Insert (new occurrence) 
and is thought to be related to the investigational treatment, Magenta may urgently 
require further information from the Investigator for Health Authority reporting. Magenta 
may need to issue an Investigator Notification (IN) to inform all Investigators involved in 
any study with the same investigational treatment that this SAE has been reported. 
SUSARs will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries. 
 
8.3 
Pregnancy Reporting 
Every pregnancy occurring after the patient was administered MGTA-456 under this 
protocol and until 30 days after the patient has stopped study participation must be 
reported to Magenta within 24 hours of learning of its occurrence. The pregnancy should 
be followed to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. A pregnancy occurring after 
signing the informed consent and before the patient is enrolled will preclude study 
participation. 
Pregnancy should be recorded on a Pregnancy Report Form and reported by the 
Investigator to the Magenta Drug Safety Department using the contact information 
provided in Section 8.2.2. 


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If the father received study drug, consent to report information regarding pregnancy 
outcome needs to be obtained from the mother. 
Table 9 indicates the level of contraception (highly effective or effective) which is 
required during the compound clinical development in males and /or females of child 
bearing potential. This recommendation is made after consideration of the latest available 
information on clinical data. Since the immunosuppressive regimen and other frequently 
used co-medications include medications with teratogenic potential, women who can 
become pregnant must be made aware of the raised risk of first trimester pregnancy loss 
and must be counseled about pregnancy prevention and planning. 
Table 9: 
Contraception Requirements 
 
Gender 
Study Participation 
Need for 
Contraception 
Contraception 
Level/Method 
WOCBP 
Yes 
Yes 
Highly effective 
Male 
Yes 
Yes 
Effective 
WOCBP=women of child bearing potential 
 
8.4 
Prospective Suicidality Assessment 
There will be no prospective suicidality assessment. However, all SAEs relating to 
suicidal behavior will be reviewed by the Safety Management Team. 
 
8.5 
Early Phase Safety Monitoring 
The Investigator will monitor adverse events in an ongoing manner and inform Magenta 
of any clinically relevant observations. Any required safety reviews will be made jointly 
between medically qualified personnel representing Magenta and the Investigator. Such 
evaluations may occur verbally, but the outcome and key discussion points will be 
summarized in writing (e-mail) and made available to both Magenta and all 
Investigator(s). 
Criteria pertaining to stopping the study/treatment or adapting the study design are 
presented above. 
When 2 or more clinical site(s) are participating in the clinical study, Magenta will advise 
the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any 
new, clinically relevant safety information reported from another site during the conduct 
of the study in a timely manner. 


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9. 
DATA REVIEW AND DATABASE MANAGEMENT 
9.1 
Site Monitoring 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a Magenta 
representative will review the protocol and eCRFs with the Investigators and their staff. 
During the study, the Magenta representative or field monitor will visit the site regularly 
to check the completeness of patient records, the accuracy of entries on the eCRFs, the 
adherence to the protocol and to Good Clinical Practice, the progress of enrollment, and 
to ensure that study product is being stored, dispensed, and accounted for per 
specifications. Key study personnel must be available to assist the field monitor during 
these visits. 
The Investigator must maintain source documents for each patient in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and 
medical information, laboratory data, ECGs, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in 
the patient’s file. The Investigator must also keep the original informed consent form 
signed by the patient (a signed copy is given to the patient). 
The Investigator must give the monitor access to all relevant source documents to 
confirm their consistency with the eCRF entries. Magenta monitoring standards require 
full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria, documentation of SAEs, and the recording of data that will 
be used for all primary and safety variables. Additional checks of the consistency of the 
source data with the eCRFs are performed per the study-specific monitoring plan. No 
information in source documents about the identity of the patients will be disclosed. 
9.2 
Data Collection 
Designated Investigator staff will enter the data required by the protocol into the eCRFs 
using fully validated software that conforms to 21 CFR Part 11 requirements. Designated 
Investigator site staff will not be given access to the EDC system until they have been 
trained. Automatic validation programs check for data discrepancies and, by generating 
appropriate error messages, allow the data to be confirmed or corrected before transfer of 
the data to Magenta. The Investigator must certify that the data entered into the eCRFs 
are complete and accurate. After database lock, the Investigator will receive a CD-ROM 
or paper copies of the patient data for archiving at the investigational site. 
Data not requiring a separate written record will be defined in the Site Operations Manual 
and Assessment schedule and can be recorded directly on the eCRFs. All other data 
captured for this study will have an external originating source (either written or 
electronic) with the eCRF not being considered as source. 
9.3 
Database Management and Quality Control 
All data should be recorded, handled and stored in a way that allows its accurate 
reporting, interpretation, and verification. 


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Magenta or designee will review the data entered into the eCRFs by investigational staff 
for completeness and accuracy and instruct the site personnel to make any required 
corrections or additions. Queries are sent to the investigational site using an electronic 
data query. Designated Investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and 
fax it back to Magenta or designee who will make the correction to the database. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded 
using the Medical dictionary for regulatory activities (MedDRA) terminology. 
The occurrence of any protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be made available for data analysis. 
9.4 
Data Monitoring Committee 
An independent and external DMC will be instituted for this study to monitor the safety 
of patients. The membership of the DMC and the responsibilities of the DMC will be 
defined in a separate Data Monitoring Committee Charter document. The DMC Charter 
will include information about data flow, purpose and timing of DMC meetings, 
communication strategy, procedures for ensuring confidentiality, procedures to address 
conflicts of interest and statistical monitoring guidelines. 
Members of the committee will not otherwise be involved in the conduct of the study. 
Magenta personnel will support the smooth functioning of the committee. 
The DMC will assess the observed safety and clinical outcomes after the first 6 patients 
have reached Day 42 post-transplant and every approximately 6 months thereafter during 
the trial and will give a recommendation with respect to trial continuation. DMC 
members will be responsible for clinical interpretation of the results. At the DMC's 
discretion, more data and/or meetings may be requested and/or the timing of the meetings 
may be changed. 


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10. 
DATA ANALYSIS 
10.1 
Analysis Sets 
The full analysis set will include all patients that received MGTA-456. This analysis set 
will be used for all assessments of efficacy and safety. 
The PK analysis set will include all patients with available PK data and no major protocol 
deviations with relevant impact on PK data. 
The PD analysis set will include all patients with available PD data and no major protocol 
deviations with relevant impact on PD data. 
In general, data will be presented by cohort (ie, either fresh or cryopreserved HCS835 
product) and overall. 
 
10.2 
Patient Demographics and Other Baseline Characteristics 
All data for background and demographic variables will be listed by patient. Summary 
statistics will be provided. 
Relevant medical history, current medical conditions, results of laboratory screens, drug 
tests, and any other relevant information will be listed by patient. 
10.3 
Treatments - Study Drug, Rescue Medication, Other 
Concomitant Therapies, Compliance 
MGTA-456 infusions will be summarized as the number of each cell type per kilogram 
body weight. 
Concomitant treatments will be listed and summarized by time period to distinguish more 
easily between those given as part of the conditioning regimen, those given in the first 
weeks after transplantation, and those used at during other time periods. 
 
10.4 
Analysis of the Primary Variable(s) 
10.4.1 
Endpoints 
The primary endpoints are provided in Section 2. 
 
10.4.2 
Statistical Model, Hypothesis, and Methods of Analysis 
The incidence of each of the primary variables will be determined. The overall incidence 
will be presented together with the associated 95% confidence interval. 
10.4.3 
Handling of Missing Values, Censoring, and Discontinuations 
All available data will contribute to analyses of primary and secondary variables. 
Conventions for handling missing values, as applicable, will be further described in the 
Statistical Analysis Plan. 






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Figure 4 shows the probability of stopping for possible true event rates and for different 
sample sizes. 
Figure 4: 
Probability of Study Stopping Rules with Various Sample Sizes 
 


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11. 
ETHICAL CONSIDERATIONS 
11.1 
Regulatory and Ethical Compliance 
This clinical study was designed and shall be implemented and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US Code of 
Federal Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), and 
with the ethical principles laid down in the Declaration of Helsinki. 
11.2 
Responsibilities of the Investigator and IRB/IEC 
Before initiating a trial, the Investigator/institution should obtain approval/favorable 
opinion from the IRB/IEC for the trial protocol, written informed consent form, consent 
form updates, patient recruitment procedures (e.g., advertisements) and any other written 
information to be provided to patients. Prior to study start, the Investigator is required to 
sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Magenta monitors, auditors, 
Magenta Quality Assurance representatives, designated agents of Magenta, IRBs/IECs, 
and regulatory authorities as required. If an inspection of the clinical site is requested by a 
regulatory authority, the Investigator must inform Magenta immediately that this request 
has been made. 
For multi-center trials, a Coordinating Investigator will be selected by Magenta around 
the time of Last Patient Last Visit to be a reviewer and signatory for the clinical study 
report. 
 
11.3 
Publication of Study Protocol and Results 
Magenta assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for 
publication and/or posted in a publicly accessible database of clinical trial results. 


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12. 
PROTOCOL ADHERENCE 
This protocol defines the study objectives, the study procedures, and the data to be 
collected on study participants. Additional assessments required to ensure safety of 
patients should be administered as deemed necessary on a case by case basis. Under no 
circumstances should an Investigator collect additional data or conduct any additional 
procedures for any research related purpose involving any investigational drugs. 
Investigators must apply due diligence to avoid protocol deviations. If the Investigator 
feels a protocol deviation would improve the conduct of the study this must be considered 
a protocol amendment, and unless such an amendment is agreed upon by Magenta and 
approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the clinical study report. 
12.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol 
amendment that must be approved by Magenta, Health Authorities where required, and 
the IRB/IEC prior to implementation. 
Only amendments that are intended to eliminate an apparent immediate hazard to patients 
may be implemented, provided the Health Authorities and the reviewing IRB/IEC are 
subsequently notified by protocol amendment. 
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any patient included in 
this study, even if this action represents a deviation from the protocol. In such cases, the 
Clinical Leader should be informed and AE/SAE reporting requirements (Section 8) 
followed as appropriate. 


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Bartelink IH, Bredius RG, Ververs TT, et al (2008) Once-daily intravenous busulfan with 
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Beam D, Poe MD, Provenzale JM, et al (2007) Outcomes of unrelated umbilical cord 
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Boelens JJ, Aldenhoven M, Purtill D, et al (2013) Outcomes of transplantation using 
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Boelens JJ, Orchard PJ, Wynn RF (2014) Transplantation in inborn errors of metabolism: 
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Boucher AA, Miller W, Shanley R, et al. Long-term outcomes after allogeneic 
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Delaney C, Heimfeld S, Brashem-Stein C, et al (2010) Notch-mediated expansion of 
human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat Med; 
16:232-236. 
de Ru, M.H., Boelens, J.J., Das, A.M. et al. Enzyme replacement therapy and/or 
hematopoietic stem cell transplantation at diagnosis in patients with 
mucopolysaccharidosis type I: results of a European consensus procedure. Orphanet J 
Rare Dis 6, 55 (2011). 
Duffner PK, Barczykowski A, Kay DM, Jalal K, Yan L, Abdelhalim A, Gill S, Gill AL, 
Carter R. Later onset phenotypes of Krabbe disease: results of the world-wide registry. 
Pediatr Neurol. 2012 May;46(5):298-306. 
Eapen M, Klein JP, Ruggeri A, et al (2014) Impact of allele-level HLA matching on 
outcomes after myeloablative single unit umbilical cord blood transplantation for 
hematologic malignancy. Blood p. 133-40. 
Eisengart JB, Rudser KD, Xue Y, et al. Long-term outcomes of systemic therapies for 
Hurler syndrome: an international multicenter comparison. Genet Med. 
2018;20(11):1423–1429. 
Engelen M, Kemp S, de Visser M, et al. X-linked adrenoleukodystrophy (X-ALD): 
clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J 
Rare Dis. 2012;7:51. Published 2012 Aug 13. 
European School of Hematology, EBMT Handbook on Haematopoietic Stem Cell 
Transplantation (2008). 2012 revised edition. Editors: J. Apperley, E. Carreras, E. 
Gluckman, T. Masszi. Howie SRC (2011) Blood sample volumes in child health 
research: review of safe limits. Bulletin of the World Health Organization. Volume 89, 
Number 1, 46-53 
Harris AC, Boelens JJ, Ahn KW, et al (2018) Comparison of pediatric allogeneic 
transplant outcomes using myeloablative busulfan with cyclophosphamide or fludarabine. 
Blood Adv. 2(11):1198-1206. 


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Horwitz ME, Morris A, Gasparetto C, et al (2008) Myeloablative intravenous 
busulfan/fludarabine conditioning does not facilitate reliable engraftment of dual 
umbilical cord blood grafts in adult recipients. Biol. Blood Marrow Transplant. p. 591-4. 
Kanda J, Kaynar L, Kanda Y, et al (2013) Pre-engraftment syndrome after myeloablative 
dual umbilical cord blood transplantation: risk factors and response to treatment. Bone 
Marrow Transplantation; 48:926-931. 
Khalil A, Zaidman I, Bergman R, et al (2014) Autoimmune complications after 
hematopoietic stem cell transplantation in children with nonmalignant disorders. Sci 
World J; 2014:581657. 
Kharbanda S, Smith AR, Hutchinson SK, et al (2014) Unrelated donor allogeneic 
hematopoietic stem cell transplantation for patients with hemoglobinopathies using a 
reduced- intensity conditioning regimen and third-party mesenchymal stromal cells. Biol 
Blood Marrow Transplant; 20:581-586. 
Konuma T., et al. Cardiovascular toxicity of cryopreserved cord blood cell infusion, Bone 
Marrow Transplantation (2008), 41, 861-865 
Krivit W, Sung JH, Shapiro EG, et al (1995) Microglia: the effector cell for reconstitution 
of the central nervous system following bone marrow transplantation for lysosomal and 
peroxisomal storage diseases. Cell Transplant; 4(4):385-92. 
Kruizinga MD, van Tol MJD, Bekker V, et al (2018) Risk factors, treatment, and immune 
dysregulation in autoimmune cytopenia after allogeneic hematopoietic stem cell 
transplantation in pediatric patients. Biol Blood Marrow Transplant. 24(4):772-8. 
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Aubourg P, Köhler W, Arnold R. Long-term outcomes of allogeneic haematopoietic stem 
cell transplantation for adult cerebral X-linked adrenoleukodystrophy. Brain. 2017 Apr 
1;140(4):953-966. 
Kwon, J.M., Matern, D., Kurtzberg, J. et al. Consensus guidelines for newborn screening, 
diagnosis and treatment of infantile Krabbe disease. Orphanet J Rare Dis 13, 30 (2018). 
Laughlin MJ, Eapen M, Rubinstein P, et al (2004) Outcomes after transplantation of cord 
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2265-75. 
Lee JH, Joo YD, Kim H, et al (2013) Randomized trial of myeloablative conditioning 
regimens: busulfan plus cyclophosphamide versus busulfan plus fludarabine. J. Clin. 
Oncol. p. 701-9. 
Martin PL, Carter SL, Kernan NA, et al (2006) Results of the cord blood transplantation 
study (COBLT): outcomes of unrelated donor umbilical cord blood transplantation in 
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Transplant. p. 184-94. 
Martín-Henao GA, Resano PM, Villegas JM, et al (2010) Adverse reactions during 
transfusion of thawed haematopoietic progenitor cells from apheresis are closely related 
to the number of granulocyte cells in the leukapheresis product. Vox Sang; 99(3):267-73. 


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Miller WP, Rothman SM, Nascene S, et al (2011) Outcomes after allogeneic 
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disease. J Pediatr; 151(4):340-6. 
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hemolytic anemia and other autoimmune cytopenias are increased in very young infants 
undergoing unrelated donor umbilical cord blood transplantation. Biol Blood Marrow 
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Page KM, Stenger EO, Connelly JA, Shyr D, West T, Wood S, Case L, Kester M, Shim 
S, Hammond L, Hammond M, Webb C, Biffi A, Bambach B, Fatemi A, Kurtzberg J. 
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Transplant. 2019 Dec;25(12):e363-e374. 
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Przepiorka D, Weisdorf D, Martin P, et al (1995) 1994 Consensus Conference on acute 
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Raymond GV, Aubourg P, Paker A, Escolar M, Fischer A, Blanche S, Baruchel A, Dalle 
JH, Michel G, Prasad V, Miller W, Paadre S, Balser J, Kurtzberg J, Nascene DR, Orchard 
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Regan DM, Wofford JD, Wall DA (2010) Comparison of cord blood thawing methods on 
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Scarpa M, Orchard PJ, Schulz A, Dickson PI, Haskins ME, Escolar ML, Giugliani R. 
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Tolar J, Chap L, Jones J, Cooke MP, Bleul CC (2016) Phase I/II Trial of StemRegnin-1 
Expanded Umbilical Cord Blood Hematopoietic Stem Cells Supports Testing as a Stand 
Alone Graft.  Cell Stem Cell. 18(1): 144-155. 
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APPENDIX 2. DIAGNOSIS AND TREATMENT OF ACUTE GRAFT 
VERSUS HOST DISEASE 
Patients will be considered evaluable for aGVHD if they demonstrate donor cell engraftment and 
survive to Day 28. Organ involvement will be staged using the criteria outlined in Table 10. 
Biopsy of each organ site at diagnosis or major change in disease activity will be performed 
unless clinical circumstances make it impossible. 
Table 10: 
Staging and Grading aGVHD 
 
Site 
Stage 
Skin 
0. No rash 
1. MaculoPapular rash < 25% of body surface area 
2. MaculoPapular rash 25-50% of body surface area 
3. Generalized erythroderma 
4. Generalized erythroderma with bullous formation or desquamation 
Lower GI 
0. No diarrhea [peds = <281 mL/m2] (no change from baseline) 
1. 500-1000 cc [peds = 281-555 mL/m2] (3-4 loose stools/d, not interfering with ADL) 
2. 1001-1500 cc [peds = 556-833 mL/m2] (5-7 loose stools/d, not interfering with ADL, 
IV fluids <24 hrs) 
3. >1500 cc [peds = >833 mL/m2] (8+ loose stools/d, interfering with ADL, IV fluids 
>24 hours) 
4. Severe abdominal pain, +/- ileus, +/- frank blood 
Upper GI 
0. No prolonged nausea or vomiting 
1. Persistent nausea, vomiting, or anorexia 
Liver 
0. Bilirubin 2.0 mg/dL or less 
1. Bilirubin 2.1 - 3.0 mg/dL 
2. Bilirubin 3.1 - 6.0 mg/dL 
3. Bilirubin 6.1 - 15.0 mg/dL 
4. Bilirubin >15.1 mg/dL 
 
Overall GVHD Grading 
Overall Grade 
Organ Stage 
Skin 
Lower GI 
Upper GI 
Liver 
I 
1-2 
0 
0 
0 
II 
3 
1 
1 
1 
III 
- 
2-3 
- 
2-4 
IV 
4 
4 
- 
- 
Treatment 
Acute GVHD treatment may be by institutional guidelines. The recommended treatment for 
patients demonstrating moderate or severe GVHD (Grade II-IV) is methylprednisolone 
48 mg/m2/day or prednisone 60 mg/m2/day followed by a taper. Patients failing front line therapy 


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will follow the institutional treatment algorithm. Use of investigational agents will be reviewed 
with the Sponsor. 


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APPENDIX 3. NIH CONSENSUS CRITERIA FOR DIAGNOSIS AND 
GRADING OF SEVERITY OF CHRONIC GVHD 
Signs and symptoms of cGVHD are presented in Table 11. 
Table 11: 
Signs and Symptoms of Chronic GVHD 
 
Organ or site 
Diagnostic 
(Sufficient to 
establish the 
diagnosis of 
cGVHD) 
Distinctive (Seen in 
cGVHD, but 
insufficient alone to 
establish a diagnosis 
of cGVHD) 
Other features 
Common 
(Seen with 
both aGVHD 
and cGVHD) 
Skin 
Poikiloderma 
Depigmentation 
Sweat impairment 
Erythema 
Lichen 
planus-like 
features 
Ichthyosis 
Maculopapular 
rash 
Sclerotic 
features 
Keratosis pilaris 
Pruritus 
Morphea-like 
features 
Hypopigmentation 
Lichen 
sclerosus-like 
features 
Hyperpigmentation 
Nails 
Dystrophy 
Longitudinal ridging, 
splitting, or brittle 
features 
Onycholysis 
Pterygium unguis 
Nail loss (usually 
symmetric; affects 
most nails)† 
Scalp and body 
hair 
New onset of scarring 
or nonscarring scalp 
alopecia (after 
recovery from 
chemoradiotherapy) 
Scaling, 
papulosquamous 
lesions 
Thinning scalp hair, 
typically patchy, coarse, 
or dull (not explained by 
endocrine or other 
causes) 
Premature gray hair 


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Organ or site 
Diagnostic 
(Sufficient to 
establish the 
diagnosis of 
cGVHD) 
Distinctive (Seen in 
cGVHD, but 
insufficient alone to 
establish a diagnosis 
of cGVHD) 
Other features 
Common 
(Seen with 
both aGVHD 
and cGVHD) 
Mouth 
Lichen-type 
features 
Xerostomia 
Gingivitis 
Hyperkeratotic 
plaques 
Mucocele 
Mucositis 
Restriction of 
mouth opening 
from sclerosis 
Mucosal atrophy 
Pseudomembranes † 
Ulcers † 
Erythema 
Pain 
Eyes 
New onset dry, gritty, 
or painful eyes‡ 
Photophobia 
Cicatricial 
conjunctivitis 
Keratoconjunctivitis 
sicca ‡ 
Confluent areas of 
punctate keratopathy 
Periorbital 
hyperpigmentation 
Blepharitis (erythema of 
the eyelids with edema) 
Genitalia 
Lichen 
planus-like 
features 
Erosions† 
Vaginal 
scarring or 
stenosis 
Fissures† 
Ulcers† 
GI tract 
Esophageal 
web 
Strictures or 
stenosis in the 
upper to mid 
third of the 
esophagus † 
Exocrine pancreatic 
insufficiency 
Anorexia 
Nausea 
Vomiting 
Diarrhea 
Weight loss 
Failure to thrive 
(infants and 
children) 


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Organ or site 
Diagnostic 
(Sufficient to 
establish the 
diagnosis of 
cGVHD) 
Distinctive (Seen in 
cGVHD, but 
insufficient alone to 
establish a diagnosis 
of cGVHD) 
Other features 
Common 
(Seen with 
both aGVHD 
and cGVHD) 
Liver 
Total bilirubin, 
alkaline 
phosphatase 
>2×ULN† 
ALT or AST 
>2×ULN 
Lung 
Bronchiolitis 
obliterans 
diagnosed with 
lung biopsy 
Bronchiolitis 
obliterans diagnosed 
with PFTs and 
radiology‡ 
BOOP 
Muscles, fascia, 
joints 
Fasciitis 
Joint stiffness 
or contractures 
secondary to 
sclerosis 
Myositis or 
Polymositis 
Edema 
Muscle cramps 
Arthralgia or arthritis 
Hematopoietic 
and immune 
Thrombocytopenia 
Eosinophilia 
Lymphopenia 
Hypo- or 
hypergammaglobulinemi 
a 
Autoantibodies (AIHA 
and ITP) 
Other 
Pericardial or pleural 
effusions 
Ascites 
Peripheral neuropathy 
Nephrotic syndrome 
Myasthenia gravis 
Cardiac conduction 
abnormality or 
cardiomyopathy 
aGVHD=acute graft versus host disease; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
cGVHD=chronic graft versus host disease; PFT=pulmonary function test; ULN=upper limit of normal 
Can be acknowledged as part of the cGVHD symptomatology if the diagnosis is confirmed. 
† In all cases, infection, drug effects, malignancy, or other causes must be excluded. 
‡ Diagnosis of cGVHD requires biopsy or radiology confirmation (or Schirmer test for eyes). 


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The Working Group recommends that the diagnosis of cGVHD require at least 1 diagnostic 
manifestation of cGVHD or at least 1 distinctive manifestation, with the diagnosis confirmed by 
pertinent biopsy, laboratory tests, or radiology in the same or another organ. As in aGVHD, 
infection and other causes may confound or complicate the differential diagnosis of cGVHD 
(eg, nail dystrophies associated with onychomycosis, herpes simplex, or Candida albicans 
infections of the oral cavity; drug toxicity) and must be excluded. Diagnostic and distinctive 
manifestations of cGVHD can be found in the skin and appendages, mouth, eyes, female 
genitalia, esophagus, lungs, and connective tissues. Biopsy or other testing is always encouraged 
and often valuable to confirm the presence of cGVHD, but it is not always feasible and is not 
mandatory if the patient has at least 1 of the diagnostic findings of cGVHD (Table 11). Please 
note that an in-depth discussion of recommended terminology for histopathologic interpretation 
may be found in a forthcoming histopathology working group report. A biopsy read as 
“consistent with” or “unequivocal” cGVHD will be considered sufficient to establish the 
diagnosis of cGVHD if accompanied by at least 1 distinctive clinical manifestation. 
Characteristics that establish the diagnosis of cGVHD might not serve as the most appropriate 
parameters for assessing the severity of cGVHD. Valid and reliable diagnostic criteria might not 
be sufficiently sensitive to change to be useful as treatment-response criteria. Conversely, a 
sensitive measure of cGVHD response might not necessarily serve as an appropriate diagnostic 
and scoring tool. 
Organ-specific Manifestations of Chronic GVHD 
In all cases, drug reaction, infection, recurrent or new malignancy, and other causes must be 
excluded. Diagnostic clinical or laboratory features sufficient for the diagnosis of cGVHD are 
italicized in the sections below. 
Skin 
Diagnostic manifestations include poikiloderma (eg, atrophic and pigmentary changes), lichen 
planus-like eruption (eg, erythematous/violaceous flat-topped papules or plaques with or without 
surface reticulations or a silvery or shiny appearance on direct light), deep sclerotic features 
(eg, smooth, waxy, indurated skin “thickened or tight skin,” caused by deep and diffuse sclerosis 
over a wide area), morphea-like superficial sclerotic features (eg, localized patchy areas of 
moveable smooth or shiny skin with a leathery-like consistency, often with dyspigmentation), or 
lichen sclerosus-like lesions (eg, discrete to coalescent gray to white moveable papules or 
plaques, often with follicular plugs, with a shiny appearance and leathery consistency). Severe 
sclerotic features characterized by thickened, tight, and fragile skin are often associated with 
poor wound healing, inadequate lymphatic drainage, and skin ulcers from minor trauma. 
A distinctive feature for cGVHD (not seen in aGVHD, but not sufficiently unique to be 
considered diagnostic of cGVHD) is depigmentation. However, depigmentation would 
contribute to the diagnosis of cGVHD in combination with biopsy or laboratory confirmation of 
GVHD in skin or another organ. Sweat impairment and intolerance to temperature change from 
loss of sweat glands are seen in cGVHD. Other common, nondistinctive skin manifestations 
found with both aGVHD and cGVHD include erythema, maculopapular rash, and pruritus. 


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Nails 
Dystrophy consisting of longitudinal ridging, nail splitting or brittleness, onycholysis, pterygium 
unguis, and nail loss (usually symmetric and affecting most nails) are distinctive signs of 
cGVHD, but are not sufficient for diagnosis. 
Hair 
Distinctive features of cGVHD include new scarring and nonscarring scalp alopecia (after 
recovery from chemotherapy or radiotherapy) and loss of body hair. Other characteristics seen 
with cGVHD include premature graying, thinning, or brittleness, but these findings are not 
diagnostic. 
Mouth 
Diagnostic features of oral cGVHD include lichen planus-like changes (white lines and 
lacy-appearing lesions of the buccal mucosa, tongue, palate, or lips), hyperkeratotic plaques 
(leukoplakia), or decreased oral range of motion in patients with sclerotic features of skin 
GVHD. Distinctive features of cGVHD include xerostomia (dryness), mucoceles, mucosal 
atrophy, pseudomembranes, and ulcers (infectious pathogens such as yeast or herpes virus; 
secondary malignancy must be excluded). Manifestations common to both aGVHD and cGVHD 
include gingivitis, mucositis, erythema, and pain. 
Eyes 
Distinctive manifestations of cGVHD include new onset of dry, gritty, or painful eyes; cicatricial 
conjunctivitis; keratoconjunctivitis sicca; and confluent areas of punctate keratopathy. Other 
features include photophobia, periorbital hyperpigmentation, difficulty in opening the eyes in the 
morning because of mucoid secretions, and blepharitis (erythema of the eye lids with edema). 
New ocular sicca documented by low Schirmer test values with a mean value of both eyes 
≤5 mm at 5 minutes or a new onset of keratoconjunctivitis sicca by slit-lamp examination with 
mean values of 6 to 10 mm on the Schirmer test is sufficient for the diagnosis of cGVHD if 
accompanied by distinctive manifestations in at least 1 other organ. 
Genitalia 
Diagnostic features for the genitalia include lichen planus-like features and vaginal scarring or 
stenosis (often associated with oral GVHD). 
Gastrointestinal Tract 
Diagnostic features for the GI tract include esophageal web, stricture, or concentric rings 
documented by endoscopy or barium contrast radiograph. Chronic GVHD may be associated 
with pancreatic exocrine insufficiency, which often improves with enzyme supplementation. 
Manifestations common to both aGVHD and cGVHD (as well as other causes, such as drug side 
effects, motility disorders, infections, or malabsorption) include anorexia, nausea, vomiting, 
diarrhea, weight loss, and failure to thrive. Wasting syndrome may be a manifestation of 
cGVHD, but is often multifactorial (eg, decreased caloric intake, poor absorption, increased 
resting energy expenditures, and hypercatabolism). Endoscopic findings of mucosal edema and 
erythema or focal erosions with histologic changes of apoptotic epithelial cells and crypt cell 
dropout may be seen but are not considered diagnostic of cGVHD unless the patient also has 


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distinctive features in a non-GI system. Patients with unresolved aGVHD may have more severe 
intestinal mucosal lesions, including ulcers and mucosal sloughing. 
Liver 
Hepatic aGVHD and cGVHD typically presents as cholestasis, with increased bilirubin or 
alkaline phosphatase, but it may also present as acute hepatitis. Because of many possible 
alternative diagnoses, a liver biopsy is required to confirm GVHD involvement of the liver. Note 
that because of the histologic similarity between acute and chronic liver GVHD, the diagnosis of 
cGVHD cannot be made on the basis of liver biopsy alone, but requires a distinctive 
manifestation in at least 1 other organ system. 
Lungs 
The only diagnostic manifestation of cGVHD is biopsy-proven BO. BO diagnosed via 
pulmonary function and radiologic testing requires at least 1 other distinctive manifestation in a 
separate organ system to establish the diagnosis of cGVHD. BO is characterized by the new 
onset of an obstructive lung defect. Clinical manifestations may include dyspnea on exertion, 
cough, or wheezing. Some patients may be asymptomatic early in the disease process. 
Pneumothorax, pneumomediastinum, and subcutaneous emphysema are rare and often represent 
advanced disease. Restrictive pulmonary function abnormalities secondary to advanced sclerosis 
of the chest wall are attributable to skin GVHD. BO is clinically diagnosed when all of the 
following criteria are met: 
1. Forced expiratory volume in 1 second/forced vital capacity ratio <0.7 and forced expiratory 
volume in 1 second <75% of predicted. 
1. Evidence of air trapping or small airway thickening or bronchiectasis on high-resolution 
chest CT (with inspiratory and expiratory cuts), residual volume >120%, or pathologic 
confirmation of constrictive bronchiolitis. 
2. Absence of infection in the respiratory tract, documented with investigations directed by 
clinical symptoms, such as radiologic studies (radiographs or CT scans) or microbiologic 
cultures (sinus aspiration, upper respiratory tract viral screen, sputum culture, or 
bronchoalveolar lavage). 
3. BO-organizing pneumonia not due to infections may represent a manifestation of either 
aGVHD or cGVHD and is considered a common feature. 
Musculoskeletal System 
Diagnostic features include fascial involvement often affecting the forearms or legs and often 
associated with sclerosis of the overlying skin and subcutaneous tissue. Fascial involvement may 
develop without overlying sclerotic changes of the skin and can result in joint stiffness or 
contractures when present near joints. Fasciitis is detected on examination by stiffness, a 
restricted range of motion (eg, often decreased dorsal wrist flexion or inability to assume a 
Buddha prayer posture), edema of the extremities with or without erythema (early sign), peau 
d’orange (edematous skin with prominent pores resembling the surface of an orange), or joint 
contractures (late complications). Clinical myositis with tender muscles and increased muscle 
enzymes is a distinctive but nondiagnostic manifestation of cGVHD. Myositis may present as 
proximal myopathy, but this complication is rare and does not explain the frequent complaints of 
severe cramps. Evaluation of myositis involves electromyography and measurement of creatine 


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phosphokinase or aldolase. Arthralgia and arthritis are uncommon and are occasionally 
associated with the presence of autoantibodies. 
Hematopoietic and Immune Systems 
Abnormalities are common in cGVHD, but cannot be used to establish the diagnosis of cGVHD. 
Cytopenias may result from stromal damage or autoimmune processes. Lymphopenia (≤500/μL), 
eosinophilia (≥500/μL), hypogammaglobulinemia, or hypergammaglobulinemia may be present. 
Autoantibodies may develop with autoimmune hemolytic anemia and idiopathic 
thrombocytopenic purpura. Thrombocytopenia (<100,000/μL) at the time of cGVHD diagnosis 
has been associated with a poor prognosis. 
Other Findings 
Serositis (pericardial or pleural effusions or ascites), peripheral neuropathy, myasthenia gravis, 
nephrotic syndrome, and cardiac involvement have been attributed to cGVHD, but these 
manifestations are rare. For these manifestations, cGVHD is often a diagnosis of exclusion. 
Differential diagnosis between acute and chronic GVHD 
The Working Group recognized 2 main categories of GVHD, each with 2 subcategories 
(Table 12). The broad category of aGVHD includes: 
(1) classic aGVHD (maculopapular rash, nausea, vomiting, anorexia, profuse diarrhea, ileus, or 
cholestatic hepatitis) occurring within 100 days after transplantation or donor lymphocyte 
infusion (DLI; without diagnostic or distinctive signs of cGVHD); and 
(2) persistent, recurrent, or late aGVHD: features of classic aGVHD without diagnostic or 
distinctive manifestations of cGVHD occurring beyond 100 days of transplantation or DLI (often 
seen after withdrawal of immune suppression). 
The broad category of cGVHD includes: 
(1) classic cGVHD without features characteristic of aGVHD; and 
(2) an overlap syndrome in which features of cGVHD and aGVHD appear together. In the 
absence of histologic or clinical signs or symptoms of cGVHD, the persistence, recurrence, or 
new onset of characteristic skin, GI tract, or liver abnormalities should be classified as aGVHD 
regardless of the time after transplantation. 
With appropriate stratification, patients with persistent, recurrent, or late aGVHD or overlap 
syndrome can be included in clinical trials with patients who have cGVHD. 


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Table 12: 
Categories of Acute and Chronic GVHD 
 
Category 
Time of Symptoms 
after HCT or DLI 
Presence of Acute 
GVHD Features 
Presence of Chronic 
GVHD Features 
Acute GVHD 
Classic aGVHD 
≤100 days 
Yes 
No 
Persistent, recurrent, or 
late-onset aGVHD 
>100 days 
Yes 
No 
Chronic GVHD 
Classic cGVHD 
No time limit 
No 
Yes 
Overlap syndrome 
No time limit 
Yes 
Yes 
DLI=Donor lymphocyte infusion; GVHD=graft versus host disease; HCT=hematopoietic cell transplantation 
Table 13 presents calculations of mild, moderate, and severe global severity, with examples. If 
the entire abnormality in an organ is noted to be unequivocally explained by a non-GVHD 
documented cause, that organ is not included for calculation of the global severity. If the 
abnormality in an organ is attributed to multifactorial causes (GVHD plus other causes) the 
scored organ will be used for calculation of the global severity regardless of the contributing 
causes (no downgrading of organ severity score). 
Table 13: 
Calculation of Mild, Moderate, and Severe Global Severity of Chronic 
GVHD 
 
Severity 
Calculation (with Examples) 
Mild 
• 
1 or 2 organs or sites (except lung) with score 1 
− 
Mild oral symptoms, no decrease in oral intake 
− Mild dry eyes, lubricant eye drops ≤3x/day 
Moderate 
• 
3 or more organs with score 1 
• 
At least 1 organ or site with score 2 
− 
19% to 50% body surface area involved or superficial sclerosis 
− 
Moderate dry eyes, eye drops >3x/day or punctal plugs 
• 
Lung score 1 (FEV1 60% to 79% or dyspnea with stairs) 
Severe 
• 
A least 1 organ or site with score 3 
− 
>50% body surface area involved 
− 
Deep sclerosis, impaired mobility, or ulceration 
− 
Severe oral symptoms with major limitation in oral intake 
− 
Severe dry eyes affecting ADL 
• 
Lung score 2 (FEV1 40% to 59% or dyspnea walking on flat ground) 
FEV1=forced expiratory volume in 1 second; GVHD=graft versus host disease 





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SPONSOR: 
 
Magenta 
 
 
PROTOCOL NUMBER: 
 
IMD-001 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
 
 








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Table of Contents 
 
1 
Cover and signature pages ...................................................................................................... 2 
2 
List of Abbreviations and Definition of Terms ......................................................................... 7 
3 
Introduction ........................................................................................................................... 10 
4 
Study Objectives .................................................................................................................... 10 
5 
Study Design .......................................................................................................................... 11 
5.1 
STUDY DESIGN AND POPULATION ................................................................................ 11 
5.2 
STUDY TREATMENTS AND ASSESSMENTS ..................................................................... 12 
5.3 
RANDOMIZATION AND BLINDING ................................................................................. 13 
5.4 
SAMPLE SIZE JUSTIFICATION ......................................................................................... 13 
6 
Statistical Considerations ...................................................................................................... 14 
6.1 
MISSING DATA HANDLING ............................................................................................ 14 
6.2 
PARTIAL DATE IMPUTATION .......................................................................................... 14 
6.3 
BASELINE........................................................................................................................ 16 
6.4 
REPORTING GUDELINES ................................................................................................. 17 
7 
Analysis Sets .......................................................................................................................... 20 
7.1 
ANALYSIS SETS ............................................................................................................... 20 
7.2 
PROTOCOL DEVIATIONS ................................................................................................ 21 
8 
Methods of Analyses and Presentations ............................................................................... 22 
8.1 
SUBJECT DISPOSITION ................................................................................................... 22 
8.2 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ....................................................... 22 
8.3 
MEDICAL HISTORY ......................................................................................................... 23 
8.4 
PRIOR AND CONCOMITANT MEDICATION .................................................................... 24 
8.5 
CONDITIONING TREATMENT ......................................................................................... 24 
8.6 
STUDY DRUG EXPOSURE AND/OR COMPLIANCE .......................................................... 25 
8.7 
EFFICACY DATA ENDPOINTS AND ANALYSES ................................................................ 26 
8.7.1 
Primary Efficacy Endpoint and Analyses ............................................................... 26 
8.7.2 
Secondary Efficacy Endpoints and Analyses .......................................................... 28 
8.7.3 
Exploratory Efficacy Endpoints and Analyses ........................................................ 33 
8.7.4 
Subgroup Analysis ................................................................................................. 36 
8.8 
PHARMACOKINETIC ENDPOINTS AND ANALYSES ......................................................... 36 
8.9 
PHARMACODYNAMIC ENDPOINTS AND ANALYSES ...................................................... 37 
8.10 
QUALITY OF LIFE OR PHARMACOECONOMIC ENDPOINTS AND ANALYSES .................. 37 
8.11 
SAFETY DATA ENDPOINTS AND ANALYSES .................................................................... 37 
8.11.1 
Adverse Events (Aes) ............................................................................................. 37 
8.11.2 
Transplant-Related Mortality (TRM) ..................................................................... 39 
8.11.3 
Clinical Laboratory Evaluations ............................................................................. 39 
8.11.4 
Physical Examination ............................................................................................. 40 
8.11.5 
Vital Signs .............................................................................................................. 40 
8.11.6 
Echocardiogram (ECHO) and Electrocardiogram (ECG) ......................................... 42 
8.11.7 
Pulmonary Function Test (PFT).............................................................................. 42 
8.11.8 
Magnetic resonance imaging (MRI) and Chest X-ray ............................................ 42 


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9 
Interim Analyses and DMCs................................................................................................... 43 
10 
Annual safety report .......................................................................................................... 43 
11 
Changes to Planned Analyses ............................................................................................ 43 
12 
Document History.............................................................................................................. 44 
13 
References ......................................................................................................................... 46 
14 
Appendices ........................................................................................................................ 47 
14.1 
APPENDIX A – Study assessments ................................................................................. 47 
14.2 
APPENDIX B – Protocol amendment changes ............................................................... 48 
14.3 
APPENDIX C – Duration (total # of days) of neutropenia calculation examples ........... 50 
14.4 
APPENDIX D – Tables, Figures and Listing shells ........................................................... 52 
 


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2
List of Abbreviations and Definition of Terms 
ABC 
Adaptive Behavior Composite 
AE 
Adverse Event 
aGVHD 
Acute graft versus host disease 
ANC 
Absolute neutrophil count 
ALC 
Absolute lymphocyte count 
ASR 
Annual Safety Report 
ATC 
Anatomical Therapeutic Chemical 
ATG 
Antithymocyte globulin 
AUCinf 
Area under the plasma concentration-time curve from time zero to 
Infinity 
AUClast 
Area under the plasma concentration-time curve from time zero to time 
of last measurable concentration 
BU 
Busulfan 
cALD 
Cerebral adrenoleukodystrophy 
CBU 
Cord blood unit 
cGVHD 
Chronic graft versus host disease 
CRF 
Case Report Form 
CSF 
Cerebrospinal fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
CY 
Cyclophosphamide 
DLCO 
Diffusing capacity of lung for carbon monoxide 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCRF 
Electronic Case Report Form 
EFS 
Event free survival 
FAS 
Full analysis set 
FEV₁ 
Forced expiratory volume 
FLU 
Fludarabine 
FVC 
Forced vital capacity 


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G-CSF 
Granulocyte-colony stimulating factor 
GCP 
Good clinical practice 
GLD 
Globoid cell leukodystrophy 
GVHD 
Graft versus host disease 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
HSC 
Hematopoietic Stem Cell 
HSCT 
Hematopoietic Stem Cell Transplantation 
ICF 
Informed consent form 
ICH 
International Conference for Harmonisation 
IV 
Intravenous 
IMD 
Inherited Metabolic Disorders 
IND 
Investigational New Drug 
LLOQ 
Lower limit of quantification 
LVEF 
Left ventricular ejection fraction 
LVSF 
Left ventricular shortening fraction 
MAC 
Myeloablative conditioning 
Magenta 
Magenta Therapeutics, Inc. 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFI 
Mean fluorescence intensity 
MLD 
Metachromatic leukodystrophy 
MRI 
Magnetic resonance imaging 
MPS-HAQ Mucopolysaccharidosis-Health Assessment Questionnaire 
NFS 
Cerebral ALD Neurologic Function Scale Score 
OS 
Overall survival 
PD 
Pharmacodynamic 
PDCF 
Protocol deviation criteria form 
PDvs 
Protocol deviations 
PK 
Pharmacokinetic 
PT 
Preferred Term 
SAE 
Serious adverse event 


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SAP 
Statistical analysis plan 
SEM 
Standard error mean 
SI 
Système International 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TFL(s) 
Table(s), figure(s), listing(s) 
TNC 
Total nucleated cell 
TRM 
Transplant-related mortality 
UCB 
Umbilical cord blood 
UCBT 
Umbilical cord blood transplant 
VLCFA 
Very-long-chain fatty acid 
WAIS 
Wechsler Adult Intelligence Scale 
WHODDE 
World Health Organization drug dictionary 
WISC 
Wechsler Intelligence Score for Children 
WPPSI 
Wechsler Preschool and Primary Scale of Intelligence 


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3
Introduction 
The purpose of this document is to describe the statistical methods, data derivations and data 
summaries to be employed in the analysis of study IMD-001 for Magenta in MGTA-456 treatment 
in patients with selected inherited metabolic disorders (IMD) undergoing hematopoietic stem cell 
(HSC) transplantation (HSCT). 
The preparation of this statistical analysis plan (SAP) has been based on International Conference 
on Harmonisation (ICH) E3 and E9 Guidelines and in reference to Protocol IMD-001 Version 8.0 
(10 January 2020). 
4
Study Objectives 
PRIMARY OBJECTIVES 
To evaluate the effect of MGTA-456 on the rate and incidence of neutrophil recovery in patients 
with IMD undergoing HSCT. 
SECONDARY OBJECTIVES 
x
To evaluate the safety of MGTA-456 in patients with IMD undergoing HSCT; 
x
To characterize engraftment following transplantation with MGTA-456 and to evaluate 
the effect of MGTA-456 on chimerism in the CD3 and CD33/66 (or CD15) hematopoietic 
compartments; 
x
To assess the incidence of acute and chronic graft versus host disease (GVHD); 
x
To assess transplant-related mortality (the incidence of TRM). 
EXPLORATORY OBJECTIVES 
x
To assess disease-specific enzyme activity/protein level; 
x
To investigate plasma and cerebrospinal fluid (CSF) biomarkers for their potential 
predictive value for clinical outcome in IMD; 
x
To investigate immune reconstitution and immunoglobulin levels after transplantation 
with MGTA-456; 
x
To assess resource utilization; 
x
To assess the exposure to the manufacturing reagent LHD221 co-infused with the stem 
cells in this population; 
x
To assess neurodevelopment outcome; 
x
To assess peripheral neuropathy over time on patients with metachromatic 
leukodystrophy (MLD) and globoid cell leukodystrophy (GLD). 


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5
Study Design 
5.1
 STUDY DESIGN AND POPULATION 
This is a Phase 2, open-label, single-arm study in which patients with IMDs will receive MGTA-456 
as a stand-alone HSC graft after myeloablative conditioning (MAC). Approximately 12 patients will 
be enrolled into 1 of 2 sequential cohorts, with the option to include up to approximately 15 
additional patients in an expansion cohort following dosing of Cohort 2.  
The study population is children age < 2.5 years with Hurler syndrome, age 2-17 (inclusive) years 
with cerebral adrenoleukodystrophy (cALD), age <16 years with metachromatic leukodystrophy 
(MLD) and age ≤ 10 years with globoid cell leukodystrophy (GLD) (also referred to as Krabbe). Age 
ranges refer to time of consent. In addition: 
-
children (aged >6 months and <16 years) with IMD (Hurler syndrome, cALD, MLD or GLD) 
were eligible to enroll prior to Protocol Amendment 8 
-
children ≤6 months of age were eligible to enroll prior to Protocol Amendment 6 
and those patients will continue to be followed in the study. 
Cohort 1 will comprise ~6 patients who will receive MGTA-456 fresh expanded CD34+ cells and 
Cohort 2 will comprise ~6 patients who will receive MGTA-456 cryopreserved expanded CD34+ 
cells. The first 6 evaluable patients with IMD will be enrolled in Cohort 1, while the next 
approximately 6 patients with IMD will be enrolled in Cohort 2. For the study to proceed from 
Cohort 1 to Cohort 2, none of the stopping rules regarding excessive graft failure, TRM, or Grade 
3 to 4 acute GVHD (aGVHD) should be met (see Section 6.4 of the study protocol). Up to 
approximately 15 additional patients may be included in an expansion cohort following dosing of 
the initial 6 patients in Cohort 2, based on the recommendation of the Data Monitoring 
Committee (DMC). These patients will receive cryopreserved MGTA-456 product. 
All patients will be followed up to the end of study visit at 1 year after post-transplant.  
An overview of the study design is presented in Figure 1 below. 


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Figure 1. Study Design 
Note: Up to approximately 15 additional patients may be included in the study following dosing of Cohort 2 and will 
receive cryopreserved MGTA-456 product. 
After completing the study (end of study visit at 1 year after post-transplant), patients may be 
transferred to a separate long-term follow-up study, if eligible and willing (after signature of the 
specific study informed consent form (ICF)). The long-term follow-up study will be covered by a 
separate protocol and SAP. 
5.2
STUDY TREATMENTS AND ASSESSMENTS  
Each patient will undergo an approximate 50-day screening period (Day -60 to Day -10). The 
patient must meet all eligibility criteria before the expansion culture will be initiated. Following 
MGTA-456 manufacturing, patients will be admitted to begin the transplant conditioning regimen 
(Day -9 to Day -1).  
The schedule of assessments to be performed during the study is detailed in the schedule of 
assessments table of the study protocol (see Appendix A). 
MGTA-456 will be administrated only once during the study period. The day of MGTA-456 
administration will be considered Day 0 and will consist of the infusion of the expanded CD34+ 
fraction followed by the infusion of the CD34-depleted fraction of the cord blood unit (CBU). 
Infusional toxicity will be assessed within 48 hours after transplant. Each patient will remain 
hospitalized until neutrophil recovery is achieved. The patient will be monitored with protocol-
specific procedures for 1 year following transplant to assess engraftment, graft failure, and late 
hematological graft failure and other study endpoints. 
All eligible patients will have one of the two formulations of MGTA-456 administered, depending 
on the cohort to which they are enrolled to: 
x
Cohort 1 – Fresh MGTA-456 Cell Therapy Product: Patients with IMD will receive MGTA-
456 fresh expanded CD34+ cells.  
x
Cohort 2 – Cryopreserved MGTA-456 Cell Therapy Product: Patients with IMD will 


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receive cryopreserved MGTA-456 in a single umbilical cord blood transplant (UCBT) 
setting.  
x
Expansion cohort – Cryopreserved MGTA-456 Cell Therapy Product: Patients with IMD 
will receive cryopreserved MGTA-456 in a single umbilical cord blood transplant (UCBT) 
setting. This cohort is optional and has been added in Protocol Amendment 6. 
For all cohorts, starting on Day 0 of the study, 2 therapeutic cell preparations will be infused 
sequentially in the following order: 
1.
A minimal dose of 10 × 106 CD34+ cells per kg body weight within a range of 20 x 106 to 
270 × 106 total nucleated cell (TNC) per kg body weight will be administered. 
2.
The remaining and entire CD34-depleted fraction derived from the same UCB unit as the 
ex vivo expanded CD34+ cells (the CD34-depleted fraction). All available CD34-negative 
cells will be administered. 
 
5.3
RANDOMIZATION AND BLINDING 
Randomization will not be used in this study. Patients will be allocated to receive study treatment 
sequentially into 1 of the 2 cohorts, and potentially in the expansion cohort (with same treatment 
as patients from cohort 2). As this is an open-label study, blinding procedures are not applicable. 
 
5.4
SAMPLE SIZE JUSTIFICATION 
The study will consist of 2 cohorts each of approximately 6 patients, leading to a total sample size 
of ~12. The sample size is based on practical considerations considering the orphan patient 
population and expected rates of events leading to study cessation. 
The option to include up to approximately 15 additional patients in an expansion cohort following 
dosing of Cohort 2 was included in Protocol Amendment 6. However, this expansion cohort was 
not considered at study design stage, thus sample size calculation and corresponding stopping 
probability is based on the initial planned cohort 1 and cohort 2 patients. 
Figure 2 shows the probability of stopping for possible true event rates and for different sample 
sizes. 
 
 


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Figure 2. Probability of Study Stopping Rules with Various Sample Sizes 
 
6
Statistical Considerations 
The SAS system version 9.3 (or higher), will be used for all analysis, unless otherwise specified. 
6.1
MISSING DATA HANDLING 
No other imputation for missing data will be carried out other than to complete partial dates using 
standard imputation techniques as described below in section 6.2. 
For the time to event variables censoring rules will apply as defined in section 8.7, so there should 
be no missing data for these endpoints during the analyses. 
6.2
PARTIAL DATE IMPUTATION 
The following rules should be used when modifying partial or missing dates for reporting purposes 
such as defining on treatment flags.  
A permanent new date variable should be created if there is a requirement to be used in 
determining flags, sort orders and other derived variables needed for a table, listing or figure. 
Imputed date variable names will be defined in the derived dataset specifications. 


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Original (raw) date variables must not be overwritten. Imputed dates will not be displayed in the 
listings. 
General rules 
 
  
  
 
  
 
 
  
 
  
 
  
  
 
  
 
 
  
 
  
 
   
 
 
 
 
 
    




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If patient was not treated, then baseline assessment is considered as the last assessment result 
from screening. 
Change from baseline is defined as the difference between the post-baseline assessment value 
and the baseline value. 
6.4
REPORTING GUDELINES 
The following guidelines will be followed: 
x
Page Orientation: Landscape. 
x
Post-text tables and listings: will be generated in .lst and converted to rtf.  
x
Post-text figures: will be generated directly in .rtf. 
x
No in-text outputs are planned. 
x
Font: Courier New font with minimum of 8 point font size. 
x
Margins: Left: 3.8 cm, Right: 2 cm, Top: 3 cm, Bottom 2 cm on A4 paper. 
x
Columns header will be left aligned. 
x
Treatment labels will be the following and displayed in the following order, unless 
otherwise stated: 
o
Cohort 1 
o
Cohort 2 
o
Expansion cohort** 
o
Overall 
o
Screening only* 
o
Conditioning only* 
* In some cases, also a screening only column (including patients that discontinued or 
withdrawn before the conditioning regimen) and conditioning only column (including patients 
that discontinued or withdrawn between conditioning regimen and MGTA-456 infusion) will 
be considered. 
**To be displayed only if the expansion cohort will be included in the study. 
 
x
Visit labels: the visit labels displayed in Table 1 will be used as required. 




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x
N: The number of patients in the specified population and cohort.   
x
Continuous data will be summarized using number of patients (n), mean, standard 
deviation (SD), median, minimum value, maximum value and number of missing data (if 
there are any). For time to event summaries, median, quartiles (Q1 and Q3) and 
corresponding 95% confidence interval (CI) for the median will be presented. For PK 
summaries, geometric mean, coefficient of variation (arithmetic and geometric) will also 
be presented in addition to the arithmetic mean, SD, median, minimum value and 
maximum value. 
x
Categorical data will be summarized using n and percentage based on number of non-
missing data.   
o
All categories will be presented, even if no patients are counted in a particular 
category. 
o
In case 1 or more patients have missing data for the summary, the number of 
missing data will be presented as a separate category, labeled accordingly as 
‘Missing’, if not otherwise stated.   
o
Counts of zero in any category will be presented without percentage.  
o
All summaries percentages will be calculated using the number of patients with 
an assessment, unless otherwise stated. 
o
For AEs, medical history, prior and concomitant medications the counts are based 
on single counts of patients with multiple events/treatments under same 
category, while the percentages are calculated using N.  
x
Precision of summary statistics: 
o
Integer – Sample size (n, N) and number of missing data (if displayed); 
o
One additional decimal place than reported/collected – mean, median, other 
percentile, confidence interval; 
o
Two additional decimal places than reported/collected – standard deviation, 
standard error mean (SEM); 
o
Same number of decimal places as reported/collected – minimum, maximum; 
o
Percentages – one decimal place. 
x
Study day, as displayed in TFLs: Will be calculated with reference to MGTA-456 infusion 
start date as Day 0 for consistency with the protocol. This will be derived as: (assessment 
date – start date of MGTA-456 infusion). This will be the study day as presented in the 
TFLs. 
x
Study day, for inclusion in CDISC compliant datasets: Will be calculated with reference 
to MGTA-456 infusion start date as Day 1. It will be included in CDISC compliant datasets 
only and will not be displayed in TFLs. This will be calculated as (assessment date – start 


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date of MGTA-456 infusion)+1 if it’s on or after start of MGTA-456 infusion, or 
(assessment date – start date of MGTA-456 infusion) if it is prior to start of MGTA-456 
infusion. 
x
Data will be presented in listings by cohort and patient diagnosis. The order will be subject 
ID, visit, assessment date/time and assessment type/parameters (in order collected on 
eCRF, unless otherwise specified). In case of clinical laboratory results, the listings will be 
presented in order of cohort, diagnosis, subject ID, parameter, assessment date/time, 
visit. 
x
Dates will be presented in format YYYY-MM-DD. 
x
Version 4.03 of the NCI-CTC grading criteria (CTCAE v4) will be used for relevant tables.  
x
Latest version of the Medical Dictionary for Regulatory Activities (MedDRA) will be used 
for relevant tables. The version will be documented in the footnote of the corresponding 
TFLs. 
x
Latest version of the WHO Drug Global dictionary will be used for prior and concomitant 
medication coding. The version will be documented in the footnote of the corresponding 
TFLs. 
x
File naming: Each TFL output file will be named with a t, l or f to denote the output type 
and then according to its table numbering in the following way: Table 14.2-1.1 would be 
t14_2_1_1, Table 14.2-11 would be t14_2_11, Listing 16.2.7-1.1 would be l16_2_7_1_1, 
and Figure 14.2-2.1 would be f14_2_2_1.  
 
7
Analysis Sets 
7.1
ANALYSIS SETS 
Non-evaluable patients are defined as subjects that have major protocol deviations. Therefore, 
the non-evaluable patients will not be included in the analysis sets that require patients with no 
major protocol deviations as per their definitions from below.  
The following analysis sets are defined for this study: 
All patients 
“All patients” population consists of all patients who were enrolled regardless of whether they 
received MGTA-456 or not.  
Full analysis set (FAS) 
The full analysis set will include all patients that received MGTA-456. This analysis set will be used 
for all assessments of efficacy and safety. 


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Pharmacokinetic (PK) analysis set  
The PK analysis set will include all patients that received MGTA-456, with available PK data and 
no major protocol deviations with relevant impact on PK data. 
Pharmacodynamic (PD) analysis set  
The PD analysis set will include all patients that received MGTA-456, with available PD data and 
no major protocol deviations with relevant impact on PD data.  
According to protocol, PD data is referring to efficacy data. Therefore, the PD analysis set is 
equivalent to the standard Per-protocol analysis set.  
To note, in case two analysis sets are identical (same patients in both analysis sets) and TFLs are 
planned to be produced for both analysis sets (one being repeat of the other, the only difference 
being the analysis set) then only the TFLs planned for one of the two analysis sets will be produced. 
For example, if FAS and PD analysis set contains same patients, then only the outputs planned for 
FAS will be produced. 
7.2
PROTOCOL DEVIATIONS 
The full list of types of protocol deviations (PDvs) and their relation to the analysis sets, along with 
the method of identification of each protocol deviation, are detailed in the protocol deviation 
criteria form (PDCF) which is separate to this SAP.  This will be used as a basis for identifying 
patients with protocol deviations throughout the study. 
Protocol deviations noted during the trial by the Clinical Research Associates (CRAs), Medical 
Monitors or Data managers will be tracked throughout the study. In addition, some PDvs will be 
identified programmatically in SAS® using data from the clinical database. All PDvs will be read 
into SAS® prior to reporting. 
At the PDvs review meetings, a consolidated list of PDvs will be reviewed by the team. Prior to 
database lock, during a final review classification meeting, PDvs will be reviewed and agreement 
of the final analysis populations will be made. 
Major protocol deviations will be summarized by deviation category and corresponding protocol 
deviation coded terms. Also, minor protocol deviations will be presented in the summary table by 


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deviation category and corresponding protocol deviation coded terms.  A listing of all protocol 
deviations by patient will also be provided. 
8
Methods of Analyses and Presentations 
8.1
SUBJECT DISPOSITION  
The subject disposition summaries will be presented on the all patients population by cohort and 
overall. Overall will include all patients, including screen failures. Summaries for patients who 
underwent screening only and conditioning only will also be presented.   
The number and percentages of patients in each analysis population will be summarized. 
The summary of subject disposition will be showing the number and percentages of patients 
belonging to the following categories: 
x
Patients included in the study (i.e. signed informed consent); 
x
Patients started conditioning; 
x
Patients discontinued during conditioning; 
x
Patients completed conditioning; 
x
Patients completed conditioning but not continued with MGTA-456 infusion, along with 
the reasons for not continuing with MGTA-456 infusion; 
x
Patients completed MGTA-456 infusion but discontinued during follow-up, along with 
the reasons for discontinuation; 
x
Patients completed the study. 
Information on analysis populations, study completion and discontinuation will also be displayed 
in subject listings. 
8.2
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
The following demographic and baseline characteristics will be summarized on the FAS and on the 
PD analysis set, by cohort and overall: 


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x
Age, derived in years, with the tens place for decimal included, as the difference between 
the date of birth to MGTA-456 infusion start date: (MGTA-456 infusion start date – date 
of birth)/(12*30.4375). In case the patient discontinued or withdrawn before MGTA-456 
infusion then the age as collected on demographic CRF page will be reported. 
x
Gender; 
x
Child bearing status; 
x
Race; 
x
Ethnicity; 
x
Height; 
x
Weight; 
x
Lansky performance status at study entry. 
Separately the disease history of the corresponding IMD will be summarized on the FAS, by cohort 
and overall: 
x
Patients with the IMD included in the study; 
x
Time between diagnosis and parental consent, derived as number of months between 
the diagnosis date to parental consent date: (date of parental consent – date of 
diagnosis)/30.4375. 
In addition, listings of the above data will be produced for all patients.  
Furthermore, disease history details for each of the corresponding IMD will be presented for all 
patients in listings. 
8.3
MEDICAL HISTORY  
Medical histories and concomitant diseases will be coded using MedDRA. The version of the 
dictionary will be provided in the medical histories and concomitant diseases TFLs footnotes. 
Summaries of patient medical histories and concomitant diseases will be produced on the FAS, by 
cohort and overall, by system organ class (SOC) and preferred term (PT).  
Listing of medical history will be produced for all patients.  


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8.4
PRIOR AND CONCOMITANT MEDICATION 
Medications other than the conditioning treatment and MGTA-456 infusion will be coded using 
the WHO Drug Global dictionary. The version of the dictionary will be provided in the 
corresponding TFLs footnotes.   
To note, transfusions are collected on a separate CRF page, following PA6. 
Medications (including transfusions) will be defined as follows: 
x
Prior Medication: Any medication whose end date is before the MGTA-456 infusion date. 
x
Concomitant Medication: Any medication whose start or end date is either the same as 
or after the MGTA-456 infusion date. 
Any medication (including transfusions) with a missing medication end date will be assumed to 
be concomitant medication. Also, ongoing medications are considered as concomitant 
medications. 
Summaries of concomitant medications (including transfusions) will be produced on the FAS by 
cohort and overall, by Anatomical Therapeutic Chemical (ATC) class (level 1) and preferred term. 
An additional summary of concomitant medications will be produced by preferred term. 
In addition, a listing of prior and concomitant medications will be presented for all patients.  
A separate listing will be presented for all patients for the transfusions collected on the separate 
CRF page, following PA6. 
8.5
CONDITIONING TREATMENT  
A listing of conditioning treatment administration with Antithymocyte globulin (ATG), Fludarabine 
(FLU), Busulfan (BU) and Cyclophosphamide (CY) will be presented.  
To note, patients enrolled in the study before PA6 had the following conditioning treatment given: 
ATG given daily between Day -9 to Day -6; FLU and BU given daily between Day -5 to Day -2. The 
conditioning treatment changed in PA6, therefore all patients enrolled in the study following PA6 
had the following conditioning treatment given: BU given daily between Day -9 to Day -6; CY and 
ATG given daily between Day -5 to Day -2. Details are found in the study protocol and 
corresponding amendments. 


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8.6
STUDY DRUG EXPOSURE AND/OR COMPLIANCE 
Exposure to conditioning treatment (ATG, FLU, BU and CY) is assessed through duration of 
treatment which is defined in days as follows: 
Duration of conditioning ATG treatment (days) = [Date of last conditioning ATG treatment 
– Date of first conditioning ATG treatment] + 1; 
Duration of conditioning FLU treatment (days) = [Date of last conditioning FLU treatment 
– Date of first conditioning FLU treatment] + 1; 
Duration of conditioning BU treatment (days) = [Date of last conditioning BU treatment – 
Date of first conditioning BU treatment] + 1. 
Duration of conditioning CY treatment (days) = [Date of last conditioning CY treatment – 
Date of first conditioning CY treatment] + 1. 
To note, duration of conditioning CY treatment will be calculated only for patients enrolled in the 
study following PA6. 
All summaries for exposure to conditioning treatments will be presented by cohort on the FAS.  
MGTA-456 infusion exposure and compliance will be summarized by cell types (CD34enriched and 
CD34depleted) and for total TNC dose (=CD34enriched cells + CD34depleted cells) through 
volume of infusion and percentage of actual volume administered from the labeled volume which 
will be calculated for each cell type and for total TNC dose as follows: 
x
Total product volume administered (mL); 
x
Percentage of the actual volume administered from the labeled volume (%), derived as: 
[(Total product volume administered (mL)/Labeled volume (mL))*100].  
The amount of total product volume administered and percentage of the actual volume 
administered from the labeled volume will be calculated for each cell types (CD34enriched and 
CD34depleted) and for total TNC dose. For example, if patient has two bags of CD34enriched cell 
type then the total product volume administered and the corresponding percentages of actual 
from labeled volume will be considered based on the total amount of volume in both bags. 
In addition, actual CD34 dose, actual CD3 dose, actual TNC dose and corresponding percentages 


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of actual from planned dose will be calculated and summarized accordingly:  
x
Actual CD34 dose (x10^6/kg) = [(Total product volume administered (mL)/Labeled volume 
(mL))] * (Planned CD34 dose (x10^6/kg)); 
x
Percentage of the actual CD34 dose from the labeled CD34 dose (%), derived as: 
[(Actual CD34 dose (x10^6/kg)/ CD34 dose on label (x10^6/kg))*100].  
Similar calculations will be considered for the actual CD3 dose, percentage of the actual CD3 dose 
from the labeled CD3 dose, actual TNC dose and percentage of the actual TNC dose from the 
labeled TNC dose. 
To note, similarly as for the volume of product, the calculations for actual CD34 dose, actual CD3 
dose, actual TNC dose and corresponding percentages of actual from planned dose will be 
calculated for each cell types (CD34enriched and CD34depleted) and for total TNC dose. For 
example, if patient has two bags of CD34enriched cell type then the actual CD34 dose, actual CD3 
dose, actual TNC dose and corresponding percentages will be considered based on the total 
amount of cells in both bags. The calculated actual TNC dose for CD34enriched, CD34depleted 
and total TNC dose should be converted to x10^7/kg for the summary statistics and for presenting 
in the corresponding listing. 
All summaries for exposure and compliance of MGTA-456 infusion will be presented by cohort on 
the FAS.  
Details of MGTA-456 infusion administration and treatment exposure and compliance will be 
listed. 
8.7
 EFFICACY DATA ENDPOINTS AND ANALYSES  
All primary efficacy analyses and summaries will be presented by cohort, on the FAS and on the 
PD analysis set. All secondary and exploratory efficacy analyses and summaries will be presented 
by cohort, on the FAS, unless otherwise specified.  
All efficacy endpoints defined as below will be listed.  
8.7.1
Primary Efficacy Endpoint and Analyses 
Primary efficacy analysis is based on engraftment with MGTA-456 and the corresponding time to 


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neutrophil recovery.  
Engraftment with MGTA-456 is defined as achieving an absolute neutrophil count (ANC) ≥0.5 × 
10^9/L for 3 consecutive days.  
Incidence of engraftment with MGTA-456 will be presented by cohort. The associated two-sided 
95% Clopper-Pearson confidence intervals (Cis) and one-sided 95% Clopper-Pearson Cis will also 
be presented. 
Time to neutrophil recovery is defined as time from MGTA-456 infusion until the first day of 3 
consecutive days with an ANC ≥0.5 × 10^9/L. 
Time to neutrophil recovery (days) = (Date of first day of 3 consecutive days 
with an ANC ≥0.5 × 10^9/L – Date of MGTA-456 infusion) + 1 
Patients who reach the time point of analysis without an engraftment with MGTA-456 will have 
the time to neutrophil recovery censored at the date of last laboratory assessment with a ANC 
result.  
Time to neutrophil recovery (days) = (Date of last laboratory assessment with 
ANC result – Date of MGTA-456 infusion) + 1 
Patients discontinued the study and who are lost to follow-up will be censored at the date of last 
available assessment. 
Time to neutrophil recovery (days) = (Date of last available assessment – Date 
of MGTA-456 infusion) + 1 
Estimates of the survival function for time to neutrophil recovery (median [95% CI], Q1 and Q3) 
will be obtained using the Kaplan-Meier method. The CI for the median will be calculated using 
the Brookmeyer and Crowley method. Time to neutrophil recovery will also be presented 
graphically showing the number of patients at risk at relevant timepoints (day 30, day 42, day 60, 
day 100, day 180 etc as applicable). Time to neutrophil recovery summaries and graphical 
presentation will be presented by cohort. 
8.7.1.1
Supportive Analysis 1 
Duration (total # of days) of neutropenia (ANC<0.5 × 10^9/L) within 15, 28 and 42 days following 
MGTA-456 infusion will be determined for each patient. 
In addition, duration (total # of days) of neutropenia (ANC <0.5 × 10^9/L) from time of MGTA-456 
infusion to day of neutrophil recovery will be calculated for each patient.  


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The duration (total # of days) of neutropenia within 15, 28 and 42 days will be summarized by 
cohort.  
Summary statistics for the duration (total # of days) of neutropenia from time of MGTA-456 
infusion to day of neutrophil recovery will be presented on the FAS by cohort. 
Duration (total # of days) of neutropenia (ANC<0.5 × 10^9/L) within 15, 28 and 42 days following 
MGTA-456 infusion and duration (total # of days) of neutropenia (ANC <0.5 × 10^9/L) from time 
of MGTA-456 infusion to day of neutrophil recovery will be presented in a separate efficacy listing, 
for all subjects included in FAS. 
8.7.1.2
Supportive Analysis 2 
Daily ANC values from day of MGTA-456 infusion (day 0) to day 15 following MGTA-456 infusion 
will be summarized by each study day for each cohort, on the FAS. The SEM will be also presented 
for the summary statistics. A graph of mean (+/-SEM) will be presented by cohort and overall, on 
the FAS. 
 
8.7.2
Secondary Efficacy Endpoints and Analyses 
8.7.2.1
Late Hematological Graft Failure 
Late hematological graft failure is defined as meeting 1 of the following 3 criteria:  
1)
<5% donor whole blood or myeloid chimerism in peripheral blood or bone marrow 
beyond Day 42 post-transplant in patients with prior hematopoietic recovery with ≥5% 
donor cells by Day 42 post-transplant;  
2)
Sustained decline in the ANC to <500/mm^3 for 3 consecutive measurements on different 
days, unresponsive to growth factor therapy after initial hematopoietic recovery by Day 
42;  
3)
Subsequent bone marrow aplasia identified after initial hematopoietic recovery by Day 


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42  
Late hematological graft failure data will be analysed and presented as collected in the database. 
Incidence of late hematological graft failure will be presented by cohort. The associated two-sided 
95% Clopper-Pearson Cis and one-sided 95% Clopper-Pearson Cis will also be presented. 
 
8.7.2.2
Myeloid and Lymphoid Engraftment 
Contribution of MGTA-456 to myeloid and lymphoid engraftment as determined by percent 
chimerism in CD33/66 (or CD15), CD3, CD19 and CD56 cells will be summarized at relevant visits 
(Screening, Day 7, Day 14, Day 21, Day 28, Day 60, Day 84, Day 100, Day 180 and Day 360) by 
cohort. To note, following Protocol Amendment 6, chimerism is collected also at Day 84. 
All chimerism data (CD33/66, CD19+, CD3+, CD56+ and CD33/15 for both donor and recipient) will 
be presented in a separate listing. 
 
8.7.2.3
Platelet Recovery 
Platelet recovery is defined in 2 ways:  
[1] Platelet count ≥20 × 10^9/L for 3 consecutive laboratory measurements on different days 
without transfusion in the prior 7 days. 
[2] Platelet count ≥50 × 10^9/L for 3 consecutive laboratory measurements on different days 
without transfusion in the prior 7 days. 
For the platelet recovery analyses, the date of platelet recovery will be derived accordingly based 
on the corresponding data.  
To note, transfusions are collected on a separate CRF page, following PA6. All transfusions 
captured on both prior and concomitant medications and transfusion CRF pages will be 
considered for the derivation of the platelet recovery endpoints. 
Incidence of platelet recovery will be presented separately for platelet recovery definitions [1] 
and [2], by cohort. The associated two-sided 95% Clopper-Pearson Cis and one-sided 95% 
Clopper-Pearson Cis will also be presented.  
Time to platelet recovery is defined considering the two definitions of platelet recovery, as follows. 


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Separate analyses will be considered for each time to platelet recovery, based on the definitions 
[1] and [2].  
To note, all patients that have an event of platelet recovery based on definition [2] are fulfilling 
also definition [1] for platelet recovery, therefore will be included in both analyses accordingly. 
 
[1] Time to platelet recovery defined as platelet count ≥20 x 10^9/L for 3 consecutive laboratory 
measurements on different days without transfusion in the prior 7 days 
Time to platelet recovery is defined as time from MGTA-456 infusion until the first day of 3 
consecutive laboratory measurements on different days with a platelet count ≥20 x 10^9/L 
without transfusion in the prior 7 days. 
Time to platelet recovery [1] (days) = (Date of first day of 3 consecutive laboratory 
measurements on different days with a platelet count ≥20 x 10^9/L 
without transfusion in the prior 7 days – Date of MGTA-456 infusion) + 1 
Patients who reach the time point of analysis without having a date of platelet recovery as defined 
above, will have the time to platelet recovery censored at the date of last laboratory assessment 
with a platelet count result.  
Time to platelet recovery [1] (days) = (Date of last laboratory assessment with 
platelet count result – Date of MGTA-456 infusion) + 1 
Patients discontinued the study and who are lost to follow-up will be censored at the date of last 
available assessment. 
Time to platelet recovery [1] (days) = (Date of last available assessment – Date 
of MGTA-456 infusion) + 1 
 
[2] Time to platelet recovery defined as platelet count ≥50 x 10^9/L for 3 consecutive laboratory 
measurements on different days without transfusion in the prior 7 days 
Time to platelet recovery is defined as time from MGTA-456 infusion until the first day of 3 
consecutive laboratory measurements on different days with a platelet count ≥50 x 10^9/L 
without transfusion in the prior 7 days. 
Time to platelet recovery [2] (days) = (Date of first day of 3 consecutive laboratory 
measurements on different days with a platelet count ≥50 x 10^9/L 
without transfusion in the prior 7 days – Date of MGTA-456 infusion) + 1 


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Patients who reach the time point of analysis without having a date of platelet recovery as defined 
above, will have the time to platelet recovery censored at the date of last laboratory assessment 
with a platelet count result.  
Time to platelet recovery [2] (days) = (Date of last laboratory assessment with 
platelet count result – Date of MGTA-456 infusion) + 1 
Patients discontinued the study and who are lost to follow-up will be censored at the date of last 
available assessment. 
Time to platelet recovery [2] (days) = (Date of last available assessment – Date 
of MGTA-456 infusion) + 1 
Estimates for the survival function for time to platelet recovery will be summarized and presented 
graphically, similarly as the time to neutrophil recovery.  
 
8.7.2.4
Acute and Chronic GVHD 
GVHD will be collected weekly for all patients that underwent the MGTA-456 infusion, starting at 
Day 7 until hospital discharge, and then at every scheduled visit except Day 84. aGVHD will be 
collected until Day 100 and cGVHD will be collected at Day 100, Day 180 and Day 360/EOS. 
Incidence of grade II–IV aGVHD by visit and incidence of cGVHD by visit will be presented by cohort. 
The associated two-sided 95% Clopper-Pearson CIs will also be presented.  
All data collected for GVHD, including aGVHD and cGVHD will be listed in a separate listing. 
 
8.7.2.5
Overall Survival  
Overall survival (OS) is defined as the period from the date of MGTA-456 infusion up to the date 
of death, regardless of cause of death. 
OS (days)= (Date of death – Date of MGTA-456 infusion) + 1 
Patients alive at the time of the analysis will have the OS censored at the date of last assessment 


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when the patient was known alive. 
OS (days) = (Date of last assessment patient is known alive – Date of MGTA-456 infusion) 
+ 1 
Patients with no post-infusion assessments, will be censored at day 1. 
OS (days) = (Date of MGTA-456 infusion – Date of MGTA-456 infusion) + 1 (i.e. 
Day 1) 
Estimates for the survival function for OS will be summarized by cohort and presented graphically, 
similarly as the time to neutrophil recovery (section 8.7.1). 
 
8.7.2.6
Event Free Survival  
Event free survival (EFS) is defined as the period from the date of MGTA-456 infusion up to the 
date of graft failure (primary or late) or death (regardless of cause of death), whichever occurs 
first. 
To note, primary graft failure is defined as lack of engraftment with MGTA-456 by Day 42. Late 
graft failure is defined as late hematological graft failure in Section 8.7.2.1.  
EFS (days) = [Min (Date of primary graft failure, Date of late graft failure, Date of 
death) – Date of MGTA-456 infusion] + 1 
Patients that had engraftment with MGTA-456 by Day 42 and had no late graft failure and are 
alive at the time of the analysis will have the EFS censored at the date of last assessment or date 
of last contact, whichever occurs last. 
EFS (days)= [Max (Date of last assessment patient is known alive, Date of last contact) – 
Date of MGTA-456 infusion] + 1 
Patients with no post-infusion data, will be censored at day 1. 
EFS (days)= (Date of MGTA-456 infusion – Date of MGTA-456 infusion) + 1 (i.e. 
Day 1) 
Estimates for the survival function for EFS will be summarized by cohort and presented 
graphically, similarly as the time to neutrophil recovery (section 8.7.1). 


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8.7.3
Exploratory Efficacy Endpoints and Analyses  
8.7.3.1
Blood Enzyme Levels and ABCD1 Protein Level 
 
 
 
 
 
 
 
  
 
8.7.3.2
Plasma and CSF Biomarkers  
 
 
 
 
 
 
8.7.3.3
Immune Reconstitution and Immunoglobulin Levels 
 
 
 
 
 


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8.7.3.4
Resource utilization 
Resource utilization is evaluated through the duration of hospitalization after MGTA-456 infusion, 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






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PK concentrations will be plotted over time by cohort. Plots will also be produced for the mean 
PK concentrations over time by cohort with error bars to illustrate the standard deviation. If the 
data are sparse, this plot may not be presented. 
All PK concentration and corresponding sample details will be presented in a listing. 
If possible, the following PK parameters will be determined, by the PK vendor, using the actual 
recorded sampling times and non-compartmental method(s) with WinNonlin Pro (Version 5.2 or 
higher): Cmax, AUCinf, AUClast and others if available from the plasma concentration-time data. 
The PK parameters results will not be presented in a listing.  
In addition, ATG PK is evaluation following administration of ATG at scheduled timepoints as 
described in section 8.7.  All ATG PK details are presented in a listing.  
8.9
PHARMACODYNAMIC ENDPOINTS AND ANALYSES 
 
   
8.10
QUALITY OF LIFE OR PHARMACOECONOMIC ENDPOINTS AND ANALYSES 
 
 
 
 
 
 
8.11
SAFETY DATA ENDPOINTS AND ANALYSES 
8.11.1
Adverse Events (Aes)  
Serious adverse events (SAE) will be collected from time conditioning that is initiated at Day -9. 
Adverse events will be collected from day of transplant Day 0.  


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Adverse events will be coded using the MedDRA coding system. The version of the dictionary will 
be provided in the adverse events TFLs footnotes.   
Treatment-emergent adverse event (TEAE) is defined as any AE that occurs during or after MGTA-
456 infusion, or any event that is present at baseline and continues after the MGTA-456 infusion 
but increases in severity category. 
Any AE that is present at baseline but increases in severity category should be entered into the 
eCRF as different AE record with the differing grade recorded. 
The number and percentage of patients experiencing the following categories of Aes will be 
summarized by SOC and PT. Patients will be counted only once within each SOC and PT. SOCs will 
be presented by descending overall frequency, while PTs will be presented by descending overall 
frequency within each SOC. The following summaries will be presented: 
x
All Aes (*) 
x
All TEAEs 
x
TEAEs related to MGTA-456 infusion 
x
TEAEs related to MGTA-456 infusion that limit MGTA-456 administration 
x
Serious treatment-emergent adverse events 
x
All serious Aes (*) 
x
TEAEs from transplant to 48 hours after transplant  
x
TEAEs from day 3 to day 100 
x
TEAEs following day 100 to the end of the study  
 (*) All Aes and all serious Aes will be summarized on all patients population, by cohort and overall. 
Overall will include screening only and conditioning only patients. 
To note, in the TEAEs from transplant to 48 hours after transplant summary all TEAEs that 
occurred following MGTA-45 infusion to 2 days inclusive after MGTA-45 infusion are summarized. 
Similarly, in the TEAEs from day 3 to day 100 summary all TEAEs that occurred after 3 days and up 
to 100 days following MGTA-456 infusion are summarized.  
An overview of TEAE incidence rates by SOC, PT and maximum severity (as determined by the NCI 
CTCAE toxicity grading (CTCAE v4)) will be provided. Patients will be counted only once within 
each SOC, PT and severity.  
All summaries will be presented on the full analysis set, by cohort and overall, if not otherwise 
specified. 
All information on Aes will be listed. Separate listings of TEAEs related to MGTA-456 infusion that 
limit MGTA-456 administration, TEAEs (regardless of causality) from transplant to 48 hours after 
transplant and SAEs will be provided, on the FAS.  


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8.11.2
Transplant-Related Mortality (TRM)   
All patients who died, having a TRM in the opinion of the investigator, and the associated primary 
cause of death will be presented in the death listing. 
 
8.11.3
Clinical Laboratory Evaluations  
Blood samples for hematology and blood chemistry will be collected at each visit as outlined in 
the schedule of assessments (see Appendix A and study protocol).  
All laboratory parameters results will be converted to SI units in order to standardize the results. 
The summaries as mentioned below will be based on the standardized values.  
Also, clinical laboratory results will be assessed against the NCI-CTCAE v4.03 criteria (CTCAE v4). 
Shift tables to show the worst post-baseline NCI-CTCAE grade compared to baseline will be 
produced for each hematological parameter, by cohort on the FAS. In case of a Hypo/Hyper 
criteria consider both Hypo and Hyper shift tables for the corresponding parameter. All laboratory 
results (including results from unscheduled visit/repeat assessments) will be considered to 
determine the worst post-baseline NCI-CTCAE grade compared to baseline. 
Laboratory results will be listed in separate listings for all hematology and blood chemistry 
parameters, on all patients population. All results below/above the normal range will be flagged 
in accordingly.  
In addition, the following laboratory evaluations will be assessed: 
x
Viral testing 
x
Infection surveillance 
x
Human leukocyte antigen (HLA) typing 
x
Anti-HLA antibodies 
x
Urine substrate excretion (*) 
(*) Urine substrate excretion assessment is performed only for Hurler and MLD diagnosed patients.  
All the above laboratory evaluations details will be presented in listings, on all patients population. 


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Clinically relevant deviations of laboratory test results will be evaluated for criteria defining an AE 
by the investigator. In the case these events fulfil the criteria of Aes, these will be collected as Aes 
on the corresponding eCRF and will be presented and summarized as defined in section 8.11.1. 
In addition, pregnancy test results will be presented in a listing, on all patients population. 
 
8.11.4
Physical Examination 
A complete physical examination will be assessed during screening and include the examination 
of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, chest, heart, 
abdomen, back, lymph nodes, extremities, vascular and nervous system. 
Physical examination details will be listed, on the all patients population. 
Any significant findings that are present prior to MGTA-456 infusion may be recorded as medical 
history, and will be presented and summarized as defined in section 8.3. Significant findings 
observed after MGTA-456 administration which meet the definition of an AE will be appropriately 
recorded on the corresponding AE eCRF, and will be presented and summarized as defined in 
section 8.11.1. 
 
8.11.5
Vital Signs 
Height, head circumference, weight, temperature, oxygen saturation, systolic and diastolic blood 
pressure, pulse and respiratory rate will be assessed during vital signs assessment, at each visit as 
outlined in the schedule of assessments (see Appendix A and study protocol). Head circumference 
will be measured for patients with Hurler syndrome only. Oxygen saturation can be assessed 
separately on the corresponding eCRF page, but will be presented as part of vital signs data. On 
day of transplant/infusion (Day 0), vital signs will be assessed as follows: 
x
Before PA8: at pre-infusion (-1 hour), at time of MGTA-456 infusion, and 0.25, 0.5, 0.75, 
1, 2, 4, and 8 hours post-infusion after the complete dose of expanded product is given, 
except for weight which will be collected at pre-infusion only. For subsequent infusions 
of CD34-depleted fractions, vital signs should be collected prior to infusion, 0.25 hours 
during infusion and 0.25 and 1 hour post last infusion. 
x
From PA8 onwards: at pre-infusion (-1 hour), at time of 15 minutes after the infusion, of 
the first bag begins, prior to the infusion of the second bag and 15 minutes after the 
completion of the second bag, except for weight which will be collected at pre-infusion 
only. For subsequent infusions of CD34-depleted fractions, vital signs should be collected 
prior to infusion, 15 minutes after the infusion of the first bag begins, prior to the infusion 






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All MRI and chest X-ray assessment details will be listed, on the all patients population. 
9
Interim Analyses and DMCs 
No interim analyses are planned.  
A subset of the TFLs may be produced for publication purposes at agreed times with Magenta.  
In addition, there will be a review of safety data by an independent Data Monitoring Committee 
(DMC) at defined timepoints. Details regarding DMCs are contained in the DMC Charter. The DMC 
TFLs shells are flagged in accordingly in the TFL Shells document. 
 
10 Annual safety report 
Annual safety report (ASR) will include safety data. ASR is intended to serve as an annual report 
to regulatory authorities for US only studies as per US Investigational New Drug (IND) number at 
the IND birthdate. ASR requirements and corresponding outputs will be covered by a separate 
document. 
 
11 Changes to Planned Analyses 
The following are changes to the planned analyses from that stated in the protocol (Amendment 
8, 10 Jan 2020): 
x
An ‘All patients’ population set has also been defined. 
x
Defined a screening only and conditioning only group of patients. The screening only 
patients are patients that discontinued or withdrawn before the conditioning regimen, 
while the conditioning only patients are patients that discontinued or withdrawn between 
conditioning regimen and MGTA-456 infusion. 
x
Only patients receiving MGTA-456 infusion to be included in the PK analysis set and PD 
analysis set. Definition of PK analysis set and PD analysis set updated accordingly. 
x
Event free survival (EFS) efficacy endpoint has been also defined. 
After the decision to stop recruitment and prior to DBL it was decided that the following data 
would no longer be reported: 


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x
Plasma biomarker listing 
x
LHD221 PK parameter listing. 
12 Document History 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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13 References 
[1] (CTCAE v4)
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE 4.03 2010-06-14 QuickReference 5x7.pdf 
Brookmeyer, R. and Crowley, J. (1982), "A Confidence Interval for the Median Survival Time," 
Biometrics, 38, 29–41. 
Kaplan, E. L. and Meier, P. (1958), “Nonparametric Estimation from Incomplete Observations,” 
Journal of the American Statistical Association, 53, 457–481. 


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14 Appendices 
14.1
APPENDIX A – Study assessments 
  
 
 
  
 


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14.2
APPENDIX B – Protocol amendment changes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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14.4
APPENDIX D - Tables, Figures and Listing shells