A Study of EZN-2279 (Polyethylene Glycol Recombinant Adenosine Deaminase [PEG-rADA]) Administered as a Weekly Intramuscular Injection in Patients With Adenosine Deaminase (ADA)-Deficient Combined Immunodeficiency
Phase: PHASE3
Conditions: ADA-SCID, Adenosine Deaminase Deficiency, Severe Combined Immunodeficiency
Sponsor: Leadiant Biosciences, Inc.

Clinical Research Protocol Approval for Study STP2279-002 
August 23, 2017 
 
A Study of EZN-2279 (Polyethylene Glycol Recombinant Adenosine Deaminase [PEG-rADA]) 
Administered as a Weekly Intramuscular Injection in Patients with Adenosine Deaminase 
(ADA)-Deficient Combined Immunodeficiency 
 
NCT01420627 
 
 

 
 
 
 
CLINICAL RESEARCH PROTOCOL 
  
Sponsor:                       Leadiant Biosciences, Inc.  
9841 Washingtonian Blvd. 
Suite 500 
Gaithersburg, Maryland 20878 
(800) 447-0169 
 
IND Number:                 100,687 
 
Product Name:              EZN-2279 (PEG-rADA) 
 
 
Protocol Number:         STP-2279-002 
 
Protocol Title: 
A Study of EZN-2279 (Polyethylene Glycol 
 
Recombinant Adenosine Deaminase [PEG- 
 
rADA]) Administered as a Weekly Intramuscular 
Injection in Patients with Adenosine Deaminase 
(ADA)-Deficient Combined Immunodeficiency 
 
Version Number:          3.0 
 
 
 
Date:                              August 23, 2017 
 
 
STATEMENT OF CONFIDENTIALITY AND RESTRICTED DISTRIBUTION 
 
The information contained in this document, particularly unpublished data, is the property or under control 
of Leadiant Biosciences, Inc., and is provided to you in confidence as an investigator, potential 
investigator, or consultant, for review by you, your staff, and an applicable Institutional Review Board or 
Independent Ethics Committee.  The information is only to be used by you in connection with authorized 
clinical studies of the investigational drug described in the protocol.   You will not disclose any of the 
information to others without written authorization from Leadiant Biosciences, Inc., except to the extent 
necessary to obtain informed consent from those persons to whom the drug may be administered. 

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1. 
TABLE OF CONTENTS 
 
 
1. 
Table of Contents...................................................................................................................... 1 
2. 
Study Synopsis.......................................................................................................................... 5 
3. 
List of Abbreviations .............................................................................................................. 10 
4. 
General Study Information ..................................................................................................... 12 
5. 
Introduction............................................................................................................................. 13 
5.1. 
Disease Background ........................................................................................................ 13 
5.1.1. 
Treatment of ADA-Deficient Combined Immunodeficiency ................................. 14 
5.2. 
Description of Investigational Product ............................................................................ 18 
5.3. 
Investigational Product Background Information ........................................................... 18 
5.3.1. 
Non-Clinical Studies ............................................................................................... 18 
5.3.2. 
Clinical Studies ....................................................................................................... 21 
5.4. 
Target Population and Study Rationale ........................................................................... 21 
5.5. 
Potential Risks and Benefits ............................................................................................ 22 
6. 
Study Purpose, Objectives and Endpoints .............................................................................. 23 
6.1. 
Purpose ............................................................................................................................ 23 
6.2. 
Objectives ........................................................................................................................ 23 
6.2.1. 
Primary Objectives.................................................................................................. 23 
6.2.2. 
Secondary Objectives.............................................................................................. 23 
6.3. 
Endpoints......................................................................................................................... 24 
6.3.1. 
Primary Endpoint .................................................................................................... 24 
6.3.2. 
Secondary Endpoints .............................................................................................. 24 
6.3.3. 
Pharmacokinetic Endpoints .................................................................................... 25 
7. 
Study Design........................................................................................................................... 25 
7.1. 
Overview of Study Design .............................................................................................. 25 
7.1.1. 
Study Periods .......................................................................................................... 27 
7.1.2. 
Recruitment and Enrollment ................................................................................... 27 
7.2. 
Study Treatments............................................................................................................. 28 
7.2.1. 
Rationale for Dose Selection and Choice of Control Groups ................................. 28 
7.3. 
Assignment of Patients to Treatment .............................................................................. 28 
7.4. 
Study Duration ................................................................................................................ 28 
7.4.1. 
Duration of Treatment and Patient Participation .................................................... 28 
7.5. 
Methods Used to Minimize Bias ..................................................................................... 28 
7.6. 
Appropriateness of Study Measurements ........................................................................ 29 
7.7. 
Study Monitoring Committees ........................................................................................ 29 
8. 
Study Drug and treatments ..................................................................................................... 29 
8.1. 
Description of Study Drug(s) .......................................................................................... 29 
8.2. 
Supply and Labeling........................................................................................................ 29 
8.2.1. 
How Supplied.......................................................................................................... 29 
8.2.2. 
Labeling .................................................................................................................. 30 
8.3. 
Storage Conditions .......................................................................................................... 30 
8.3.1. 
EZN-2279 ............................................................................................................... 30 
8.3.2. 
Adagen® .................................................................................................................. 30 
8.4. 
Preparation for Administration ........................................................................................ 31 
8.4.1. 
EZN-2279 ............................................................................................................... 31 
8.4.2. 
Adagen® .................................................................................................................. 31 
8.5. 
Study Drug Accountability.............................................................................................. 31 
9. 
Study Population..................................................................................................................... 32 

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9.1. 
Number of Patients .......................................................................................................... 32 
9.2. 
Inclusion Criteria ............................................................................................................. 32 
9.3. 
Exclusion Criteria ............................................................................................................ 32 
9.4. 
Post-Enrollment Restrictions ........................................................................................... 33 
9.4.1. 
Concomitant Medications ....................................................................................... 33 
9.4.2. 
Concurrent Treatments............................................................................................ 33 
9.4.3. 
Dietary Restrictions ................................................................................................ 33 
9.5. 
Withdrawal of Enrolled Patients ..................................................................................... 33 
9.5.1. 
Withdrawal Criteria ................................................................................................ 34 
9.5.2. 
Withdrawal Procedures ........................................................................................... 34 
9.5.3. 
Replacement of Discontinued Patients ................................................................... 35 
10. 
Description of Study Procedures ......................................................................................... 35 
10.1. 
Informed Consent ........................................................................................................ 35 
10.2. 
Screening and Enrollment ........................................................................................... 35 
10.3. 
History and Baseline Characteristics ........................................................................... 36 
10.4. 
Safety Procedures ........................................................................................................ 36 
10.4.1. 
Physical Examination.............................................................................................. 36 
10.4.2. 
Vital Signs............................................................................................................... 36 
10.4.3. 
Laboratory Assessments ......................................................................................... 37 
10.4.4. 
Adverse Event Assessment ..................................................................................... 37 
10.5. 
Efficacy Procedures ..................................................................................................... 38 
10.5.1. 
Trough Plasma ADA Activity ................................................................................ 38 
10.5.2. 
Immune Status ........................................................................................................ 38 
10.5.3. 
Clinical Status ......................................................................................................... 39 
10.6. 
Pharmacokinetic and Pharmacodynamic Assessments ............................................... 39 
10.6.1. 
Pharmacokinetic Assessments ................................................................................ 39 
10.6.2. 
Pharmacodynamic Assessments ............................................................................. 40 
10.7. 
Study Medication Administration and Compliance .................................................... 40 
10.7.1. 
Dosage and Administration..................................................................................... 40 
10.7.2. 
Dose Adjustments ................................................................................................... 41 
10.7.3. 
Treatment Delays .................................................................................................... 41 
10.7.4. 
Assessment of Study Medication Compliance........................................................ 41 
10.8. 
Recording of Concomitant Medications ...................................................................... 41 
10.9. 
Compliance.................................................................................................................. 41 
11. 
Schedule of Study Procedures ............................................................................................. 42 
11.1. 
Screening ..................................................................................................................... 42 
11.2. 
Adagen® Lead -in ........................................................................................................ 43 
11.2.1. 
Adagen® Dosage and Schedule Adjustments.......................................................... 43 
11.2.2. 
Weekly Adagen Dosing .......................................................................................... 43 
11.2.3. 
Adagen® Pharmacokinetics..................................................................................... 43 
11.3. 
EZN-2279 Study Treatment Period ............................................................................. 44 
11.3.1. 
Day 1 (Week T-1) ................................................................................................... 44 
11.3.2. 
Day 8 (Week T-2) ................................................................................................... 45 
11.3.3. 
Day 15 (Week T-3) ................................................................................................. 45 
11.3.4. 
Day 22 (Week T-4) ................................................................................................. 45 
11.3.5. 
Day 29 (Week T-5) ................................................................................................. 45 
11.3.6. 
Day 36 (Week T-6) ................................................................................................. 46 
11.3.7. 
Day 43 (Week T-7) ................................................................................................. 46 
11.3.8. 
Day 50 (Week T-8) ................................................................................................. 46 
11.3.9. 
Day 57 (Week T-9) ................................................................................................. 47 
11.3.10.  Days 58 through 63 (Week T-9) ............................................................................. 47 

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11.3.11.  Day 64 (Week T-10) ............................................................................................... 48 
11.3.12.  Day 71 (Week T-11) ............................................................................................... 48 
11.3.13.  Day 78 (Week T-12) ............................................................................................... 48 
11.3.14.  Day 85 (Week T-13) ............................................................................................... 48 
11.3.15.  Day 92 (Week T-14) ............................................................................................... 49 
11.3.16.  Day 99 (Week T-15) ............................................................................................... 49 
11.3.17.  Day 106 (Week T-16) ............................................................................................. 49 
11.3.18.  Day 113 (Week T-17) ............................................................................................. 49 
11.3.19.  Day 120 (Week T-18) ............................................................................................. 50 
11.3.20.  Day 127 (Week T-19) ............................................................................................. 50 
11.3.21.  Day 134 (Week T-20) ............................................................................................. 50 
11.3.22.  Day 141 (Week T-21) ............................................................................................. 50 
11.4. 
EZN-2279 Maintenance Period ................................................................................... 51 
11.5. 
Study Completion: End-of Treatment, Completion of Maintenance or End of Study 52 
11.5.1. 
30-Day Early Discontinuation Follow-up ............................................................... 52 
12. 
Adverse Events .................................................................................................................... 53 
12.1. 
Assessment Period....................................................................................................... 53 
12.2. 
Definitions ................................................................................................................... 53 
12.2.1. 
Adverse Event ......................................................................................................... 53 
12.2.2. 
Unexpected Adverse Event ..................................................................................... 53 
12.2.3. 
Serious Adverse Event ............................................................................................ 53 
12.2.4. 
Relationship to Study Drug..................................................................................... 54 
12.2.5. 
Severity (Intensity).................................................................................................. 54 
12.3. 
Reporting Adverse Events ........................................................................................... 54 
12.4. 
Reporting Serious Adverse Events .............................................................................. 55 
12.4.1. 
Reporting of Other Non-serious Events.................................................................. 56 
12.5. 
Reporting of Pregnancy ............................................................................................... 56 
13. 
Statistics............................................................................................................................... 56 
13.1. 
Sample Size Determination ......................................................................................... 56 
13.2. 
Statistical Methodology ............................................................................................... 56 
13.2.1. 
Level of Significance .............................................................................................. 56 
13.2.2. 
Analysis Populations............................................................................................... 56 
13.2.3. 
Data Analysis .......................................................................................................... 57 
13.2.4. 
Handling Missing, Repeated, Unused and Spurious Data ...................................... 59 
13.2.5. 
Reporting of Deviations to Statistical Methodology............................................... 59 
13.3. 
Interim Analysis .......................................................................................................... 60 
13.4. 
Statistical Criteria for Termination of the Study ......................................................... 60 
14. 
Administrative ..................................................................................................................... 60 
14.1. 
Changes to Study Protocol .......................................................................................... 60 
14.1.1. 
Protocol Amendments............................................................................................. 60 
14.1.2. 
Protocol Deviations................................................................................................. 60 
14.2. 
Study Termination ....................................................................................................... 60 
14.3. 
Ethics ........................................................................................................................... 61 
14.3.1. 
Compliance Statement ............................................................................................ 61 
14.3.2. 
Institutional Review Board/Ethics Committee........................................................ 61 
14.3.3. 
Informed Consent.................................................................................................... 61 
14.3.4. 
Health Insurance Portability and Accountability Act ............................................. 62 
14.3.5. 
Confidentiality of Subject Records ......................................................................... 62 
14.3.6. 
Conflict of Interest .................................................................................................. 62 
14.4. 
Investigator Obligations .............................................................................................. 62 
14.5. 
Financial Disclosure .................................................................................................... 63 

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14.6. 
Quality Control and Quality Assurance of Study Data ............................................... 64 
14.6.1. 
Monitoring and Audits ............................................................................................ 64 
14.6.2. 
Data Processing and Data Quality Assurance ......................................................... 64 
14.7. 
Study Records.............................................................................................................. 64 
14.7.1. 
Regulatory Documentation ..................................................................................... 65 
14.7.2. 
Source Documents .................................................................................................. 65 
14.7.3. 
Case Report Forms.................................................................................................. 65 
14.7.4. 
Access to Study Records......................................................................................... 66 
14.7.5. 
Records Retention ................................................................................................... 66 
14.8. 
Publication Policy........................................................................................................ 66 
14.9. 
Financing and Insurance .............................................................................................. 66 
15. 
Investigator Agreement ....................................................................................................... 67 
16. 
References ........................................................................................................................... 68 

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2. 
STUDY SYNOPSIS 
 
 
Study Drug: EZN-2279 (Polyethylene Glycol Recombinant 
Adenosine Deaminase [PEG-rADA]) 
IND No.: 100,687 
Sponsor: Leadiant Biosciences, Inc. 
Protocol No.: 
STP-2279-002 
Development Phase:
3 
Indication: 
ADA-deficient combined immunodeficiency 
Protocol Title: A Study of EZN-2279 (Polyethylene Glycol Recombinant Adenosine Deaminase [PEG-
rADA]) Administered as a Weekly Intramuscular Injection in Patients with Adenosine Deaminase (ADA)- 
Deficient Combined Immunodeficiency 
Country: 
USA 
No. of centers: 
Up to 12 
Expected Study Duration: 
Approximately 48 Months 
Study Objectives: 
Primary Objective: The primary objective of the study is to evaluate whether therapy with EZN-2279 
achieves metabolic detoxification, as demonstrated by total erythrocyte dAXP concentration from a trough 
blood sample. 
Secondary Objective(s): The secondary objectives of the study are to: 
 
Evaluate the safety and tolerability of EZN-2279 
 
Assess   the   immunogenicity   to   EZN-2279   and   Adagen®,   including   binding   antibodies, 
neutralizing antibodies and anti-PEG antibodies 
 
Evaluate   whether   therapy   with   EZN-2279   maintains   the   trough   plasma   ADA   activity 
≥15 μmol/h/mL 
 
Determine the PK profile of EZN-2279 
 
Assess the effect of EZN-2279 on immune status as determined by ALC, lymphocyte subset (B, 
T, and NK) analysis, and immunoglobulin (Ig) concentration (IgA, IgG, IgM), 
 
Compare the clinical status (infections and hospitalizations) of the patients during the EZN-2279 
treatment period compared to the prior six months 
 
Assess the clinical growth status of the patients during the EZN-2279 treatment and maintenance 
periods 
Study Endpoints: 
Primary Endpoint: The primary endpoint is the percentage of patients achieving metabolic detoxification, 
assessed  from  trough  dAXP  samples  obtained  at  Weeks  T-15,  T-17,  T-19,  and  T-21. 
Metabolic 
detoxification will be defined as a trough dAXP concentration equal to or below 0.02 μmol/mL. 
 
Secondary Endpoint(s): 
The secondary endpoints for efficacy are: 
1) Trough Plasma ADA Activity - will be assessed from trough plasma ADA samples obtained at Weeks 
T-15,  T-17,  T-19,  and  T-21. 
Adequate  trough  ADA  activity  will  be  defined  as  ADA  activity 
≥15 μmol/h/mL. 
2) Maintenance phase trough plasma dAXP and ADA activity – will be assessed from trough plasma dAXP 
and  ADA  samples  obtained  during  the  maintenance  phase  of  the  study  through  completion  of 
EZN-2279 treatment. 
3) Immune status will be assessed through completion of the EZN-2279 maintenance period, through 
assessment of: 
 
Absolute lymphocyte count 
 
B-, T-, and NK-lymphocyte subset analysis by fluorescence-activated cell sorter (FACS) with 
monitoring of: 
o CD3+  (Mature T cells) - Percent and Absolute 
o CD3+ CD8+  (Suppressor T Cells) – Percent and Absolute 
o CD3+ CD4+  (Helper Cells) – Percent and Absolute 
o CD (16+56)+   (Natural Killer Cells) – Percent and Absolute 
o CD19+ (B Cells) – Percent and Absolute 
o Absolute Lymphocytes (CD45+) 

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Study Drug: EZN-2279 (Polyethylene Glycol Recombinant 
Adenosine Deaminase [PEG-rADA]) 
IND No.: 100,687 
Sponsor: Leadiant Biosciences, Inc. 
Protocol No.: 
STP-2279-002 
Development Phase: 
3 
Indication: 
ADA-deficient combined immunodeficiency 
Protocol Title: A Study of EZN-2279 (Polyethylene Glycol Recombinant Adenosine Deaminase [PEG-
rADA]) Administered as a Weekly Intramuscular Injection in Patients with Adenosine Deaminase (ADA)- 
Deficient Combined Immunodeficiency 
o %CD4 (Helper Cells) / %CD8 (Suppressor T Cells) 
 
Quantitative immunoglobulin concentration (IgA, IgG, IgM) 
 
4) Clinical Status – assessed by the following parameters: 
 
Infections: Clinically documented and microbiologically documented; 
 
Hospitalizations: Incidence and duration of hospitalizations through completion of the EZN-2279 
treatment period compared to the 6-month period prior to study entry; 
 
Growth: Height-for-age and weight-for-age Z-scores through completion of the EZN-2279 
maintenance period; 
 
Overall survival: will be assessed at the conclusion of the EZN-2279 treatment period though the 
end of EZN-2279 maintenance 
 
The secondary endpoints for assessment of safety are: 
1) Safety will be assessed through determination of adverse events (AEs), serious adverse events (SAEs), 
physical examinations, and laboratory evaluations through completion of the EZN-2279 maintenance 
period. 
2) Immunogenicity of EZN-2279 and Adagen® will be assessed through the end of the EZN-2279 
maintenance period by the evaluation of binding antibodies, neutralizing antibodies and anti-PEG 
antibodies. 
 
The pharmacokinetic endpoint is the PK profile of EZN-2279, as assessed by plasma ADA activity.  The 
following PK parameters will be computed from individual plasma concentrations collected during full PK 
sampling for Adagen® at the end of the Adagen® Lead-in period and for EZN-2279 during Week T-9 (after 
9th dose of EZN-2279): Cmax, Ctrough, tmax, AUC(0-t), Kel, and t½. 
Study Design and Methodology: 
Protocol STP-2279-002 is designed as an open-label, multicenter, single-arm, one way crossover study of 
EZN-2279 to determine the safety, efficacy, and PK of EZN-2279 in patients with ADA-SCID who are 
currently being treated with Adagen®.  Each patient will serve as his or her own control with respect to 
assessment of study endpoints.   The study will enroll enough patients to allow for up to six evaluable 
patients with ADA-deficient combined immunodeficiency and stable clinical status while currently 
receiving therapy with Adagen®  who meet all eligibility criteria and written informed consent/assent is 
obtained.  The initial three patients will be enrolled and complete through full EZN-2279 pharmacokinetic 
sampling (Week T-9).  An independent data and safety monitoring committee (DSMC) will review safety, 
PK (ADA activity), and erythrocyte dAXP data for the first three patients who complete through Week T- 
9.  If no concerns are noted, enrollment will continue for the remaining patients.  A similar DSMC review 
will occur after all patients complete through 9-weeks of EZN-2279 dosing. 
 
Patients for whom written informed consent/assent is obtained will be assigned a screening number and 
undergo screening procedures.   Patients completing screening assessments and meeting all eligibility criteria
will be enrolled in the study.   There are three periods to study treatment: the Adagen®  lead-in period,
the EZN-2279 treatment period (Weeks T-1 through T-21) and the EZN-2279 maintenance period. Patients
enrolled in the study will enter the Adagen® lead in phase of the study.  In this phase of the study, patients
will receive a single i.m. dose of Adagen® weekly and be assessed weekly for dAXP levels and ADA
activity. Patients receiving Adagen® more frequently than once a week will have his/her dose consolidated
to a once a week dose regimen during the Adagen Lead-in Phase of the study. Adagen® dose adjustments 
will be made if the patient does not meet criteria for trough dAXP levels (≤0.02 μmol/mL) and trough ADA
activity (15 μmol/h/mL) specified in the inclusion criteria. Once the patient meets protocol 

Leadiant Biosciences 
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Study Drug: EZN-2279 (Polyethylene Glycol Recombinant 
Adenosine Deaminase [PEG-rADA]) 
IND No.: 100,687 
Sponsor: Leadiant Biosciences, Inc. 
Protocol No.: 
STP-2279-002 
Development Phase: 
3 
Indication: 
ADA-deficient combined immunodeficiency 
Protocol Title: A Study of EZN-2279 (Polyethylene Glycol Recombinant Adenosine Deaminase [PEG-
rADA]) Administered as a Weekly Intramuscular Injection in Patients with Adenosine Deaminase (ADA)- 
Deficient Combined Immunodeficiency 
criteria for trough dAXP and ADA activity, he/she will have a full pharmacokinetic assessment performed 
on Adagen®. Prior to receiving the dose of Adagen® for pharmacokinetic assessment patients will have the 
following  baseline  procedures  performed:  physical  examination,  vital   signs,   growth  assessment, 
performance status, safety laboratory assessments (hematology, chemistry, urinalysis), and have blood 
samples  obtained  for  assessment  of  lymphocyte  subset  analysis,  quantitative  immunoglobulins  and 
Adagen®  antibody titers (for neutralizing and binding antibodies) and anti-PEG antibodies.    Following 
Adagen®  dosing, plasma ADA samples for full PK evaluation will be collected for 7 consecutive days 
following dosing. After completing Adagen® lead-in treatment and Pharmacokinetic assessments, patients 
will enter the EZN-2279 treatment phase (Weeks T-1 through T-21) of the study. 
 
Adagen® will be discontinued and therapy with an equivalent dose of EZN-2279 will be initiated.  In the 
EZN-2279 treatment phase of the study, patients will receive a single i.m. dose of EZN-2279 weekly for 
21 consecutive weeks. Prior to receiving the initial dose of EZN-2279, patients will have the following 
procedures performed: physical examination, vital signs, growth assessment, performance status, safety 
laboratory assessments (hematology, chemistry, urinalysis), and have blood samples obtained for assessment
of lymphocyte subset analysis, quantitative immunoglobulins,   EZN-2279 and Adagen® antibody titers
(neutralizing and binding antibodies) and anti-PEG antibodies.    Trough total erythrocyte dAXP
concentration and trough plasma ADA activity will be measured prior to dosing at weeks T-1, T-3, T-5, T-
7, T-8 and every other week from Week T-9 through Week T-21. At week T-8 the patient will have 
dAXP levels and ADA activity assessed to assure the dose of EZN-2279 administered maintains dAXP and 
ADA activity at protocol specified levels. If these levels are not met, the patient will undergo a dose 
adjustment and be reassessed prior to entering the EZN-2279 full PK sampling week (Week T-9).  Plasma 
ADA samples for full PK evaluation will be collected at Week T-9 (Days 58-63).  Physical examination 
and safety laboratory assessments will be performed every 4 weeks (Weeks T-5, T-9, T-13, T-17 and T- 
21).  Blood samples obtained for assessment of lymphocyte subset analysis, quantitative immunoglobulins, 
EZN-2279 antibody titers (i.e., neutralizing and binding antibodies) and anti-PEG antibodies will be obtained 
at selected timepoints during the EZN-2279 treatment period. 
 
Following completion of the EZN-2279 treatment period, patients may enter the EZN-2279 maintenance 
period.  During this phase of the study patients will continue to receive single i.m. doses of EZN -2279 
weekly.   The following assessments will be performed during study visits every 3 months: physical 
examination, vital signs, growth assessment, performance status, safety laboratory assessments (hematology, 
chemistry, urinalysis), and have blood samples obtained for assessment of trough ADA and dAXP levels,
lymphocyte subset analysis, quantitative immunoglobulins, antibody titers for EZN-2279 (i.e., neutralizing
and binding antibodies), anti-PEG antibodies and PEG.   The maintenance phase of the study will continue
until the study is concluded (i.e., full regulatory approval of EZN-2279 or early study termination). 
 
Throughout the duration of the study (i.e., Adagen®  lead-in, EZN-2279 treatment and EZN-2279 
maintenance) patients will continually be assessed for adverse events, infectious complications, 
hospitalizations, concomitant medications changes and concomitant procedures. 
 
The analysis of study endpoint data will occur after all patients complete the EZN-2279 treatment period 
(i.e., the primary endpoint analysis), at 6 months after the last patient enters the EZN-2279 maintenance 
phase, and annually thereafter. 
Sample Size: 
The study will enroll a sufficient number of patients with ADA-deficient combined immunodeficiency who 

Leadiant Biosciences 
Protocol STP-2279-002 
CONFIDENTIAL
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August 23, 2017 - FINAL 
 
 
 
Study Drug: EZN-2279 (Polyethylene Glycol Recombinant 
Adenosine Deaminase [PEG-rADA]) 
IND No.: 100,687 
Sponsor: Leadiant Biosciences, Inc. 
Protocol No.: 
STP-2279-002 
Development Phase: 
3 
Indication: 
ADA-deficient combined immunodeficiency 
Protocol Title: A Study of EZN-2279 (Polyethylene Glycol Recombinant Adenosine Deaminase [PEG-
rADA]) Administered as a Weekly Intramuscular Injection in Patients with Adenosine Deaminase (ADA)- 
Deficient Combined Immunodeficiency 
meet all study entry criteria described to assure six (6) patients are evaluable.
Subject Selection Criteria: 
Inclusion Criteria 
1. Diagnosis of ADA-deficient combined immunodeficiency 
2. Stable clinical status while receiving therapy with Adagen®.   Patients previously receiving gene 
therapy or undergoing hematopoietic stem cell transplantation who still require Adagen® treatment are 
eligible. The dose of Adagen® must be stable for at least 6 months prior to study entry. 
3. Have both of the following during the Adagen® Lead-in phase of the study in order to proceed with 
EZN-2279 dosing: 
a.   Trough plasma ADA activity 15 μmol/h/mL while receiving Adagen® and 
b.   Total erythrocyte dAXP ≤0.02 μmol/mL from a trough blood sample 
4. Patients or parent/guardian must be capable of understanding the protocol requirements and risks and 
providing written informed assent/consent. 
 
Exclusion Criteria 
1. Autoimmunity requiring immunosuppressive treatment. 
2. Patients with neutralizing anti-Adagen® antibodies at screening evaluation. 
3. Severe thrombocytopenia (platelet count <50  109/L). 
4. Current participation in other therapeutic protocols for ADA-deficient combined immunodeficiency. 
5. Current or prior participation in another clinical study with an investigational agent and/or use of an 
investigational drug in the 30 days before study entry. 
6. Known planned participation in a gene-therapy study for the planned duration of this study. 
7. Any condition that, in the opinion of the PI or Leadiant Biosciences, makes the patient unsuitable for the
study. 
8. Inability or unwillingness to administer Adagen® or EZN-2279 on a one time per week regimen. 
9. Inability to comply with the study protocol. 
10.  Female patients who are pregnant or lactating. 
11.  Female patients who are breast-feeding. 
Study Duration: 
All patients will receive a minimum of a 3-week Adagen® lead in followed by 21-weeks of study treatment 
with EZN-2279.   Patients will be given the opportunity to remain on EZN-2279 maintenance until the 
study is concluded (full regulatory approval of EZN-2279 or early study termination).     Assuming a 
12 month  enrollment  period  and  18  months  for  the  submission of  data  and  regulatory approval  of 
EZN-2279, the initial patient enrolled will receive study treatment for approximately 3 years and the last 
patient enrolled will receive study treatment for approximately 2 years.   Patient participation will be 
approximately 8-weeks longer than the treatment duration (4 week screening period and a 30-day post 
treatment safety follow-up of patients who discontinue study drug early). 
Reference Therapy, Dose Route of Administration and Duration of Treatment:
Adagen® by weekly i.m. injection; patients will be maintained on the same weekly Adagen® dose he/she 
was taking prior to study entry. Adagen® dose adjustments will be made during the Adagen® Lead-in 
phase of the study if the patient does not meet criteria for dAXP levels (≤0.02 μmol/mL) and ADA activity 
(15 μmol/h/mL) specified in the inclusion criteria. 
Study Drug, Dose, Route of Administration, and Duration of Treatment: 
EZN-2279 by weekly i.m. injection; patients will be transitioned to receive a dose of EZN-2279 equivalent 
to the Adagen®  dose received during the Adagen® Lead-in phase of the study.   As 1 mg of EZN-2279 
contains ADA enzymatic activity equivalent to 150 U of Adagen®, the equivalent dose will be calculated as 
follows: 

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Study Drug: EZN-2279 (Polyethylene Glycol Recombinant 
Adenosine Deaminase [PEG-rADA]) 
IND No.: 100,687 
Sponsor: Leadiant Biosciences, Inc. 
Protocol No.: 
STP-2279-002 
Development Phase: 
3 
Indication: 
ADA-deficient combined immunodeficiency 
Protocol Title: A Study of EZN-2279 (Polyethylene Glycol Recombinant Adenosine Deaminase [PEG-
rADA]) Administered as a Weekly Intramuscular Injection in Patients with Adenosine Deaminase (ADA)- 
Deficient Combined Immunodeficiency 
Adagen® dose (U/kg) x 1mg EZN-2279/150U Adagen® = EZN-2279 dose (mg/kg) 
Criteria for Evaluation: 
Safety Variables: AEs, SAEs, clinical signs and symptoms from physical examination, laboratory 
evaluations, and immunogenicity. 
 
Efficacy Variables: Total erythrocyte dAXP from a trough blood sample; trough plasma ADA activity, 
immune status (B-, T-, and NK-lymphocyte subset analysis, quantitative immunoglobulin concentration 
[IgA, IgG, IgM]), infections (clinically documented and microbiologically documented), incidence and 
duration of hospitalizations, growth (height-for-age and weight-for-age Z-scores), and overall survival. 
 
Pharmacokinetic Variables: Adagen® and EZN-2279 pharmacokinetics via assessment of plasma ADA 
activity. The following PK parameters will be computed: Cmax, Ctrough, tmax, AUC(0-t), Kel, and t½. 
Statistical Methodology: 
Each patient will serve as his/her own control based on the baseline assessment of each endpoint as 
appropriate. 
Safety Analysis: 
 
Adverse events will be coded according to MedDRA version 10.0 or later and will be summarized in 
frequency tables displaying counts and percentage by body system, preferred term, and treatment group. 
In addition, AEs will be summarized by relationship to study drug and by severity.   All Serious 
AEs will also be summarized in a frequency table. 
 
Laboratory parameters (Chemistry, Hematology, and Urinalysis) will be summarized descriptively at 
each timepoint and by treatment group. Out-of-normal range values will be listed. 
 
Immunogenicity - the results of antibodies (binding and neutralizing) against EZN-2279, Adagen® and 
anti-PEG antibodies will be summarized. The relationships between immunogenicity, PK, and the 
clinical toxicities will be examined as appropriate. 
 
Efficacy Analysis: 
The primary efficacy endpoint is the percentage of patients achieving metabolic detoxification, defined as 
achieving and maintaining the target trough total erythrocyte dAXP concentration of ≤0.02 μmol/mL while 
receiving EZN-2279. 
Analyses of the following secondary efficacy endpoints will be primarily descriptive, with data listings, 
graphical presentations, frequency tabulations, and summary statistics as appropriate: B-, T-, and NK- 
lymphocyte subset analysis; Quantitative immunoglobulin concentration; infection incidence; incidence 
and duration of hospitalizations ; growth; and overall survival. 
 
Pharmacokinetic Analysis: 
PK parameters (Cmax, Ctrough, tmax,  AUC(0-t), Kel, and t½)  and the plasma level-versus-time curves will be 
determined for each evaluable patient. Descriptive statistics including mean, standard deviation, coefficient 
of variation, median, minimum, maximum, mean and median plasma level graphs will be provided as 
appropriate. 

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3. 
LIST OF ABBREVIATIONS 
 
 
Abbreviation 
Term 
Ab 
Antibody 
ADA 
adenosine deaminase 
ADA+/+ mice 
mice heterozygous for the null Ada allele; ADA control 
ADA-/- mice 
mice homozygous for the null Ada allele; ADA-deficient mice 
Adagen® 
pegademase bovine, SS-PEG-ADA, PEG-ADA, PEGylated ADA 
ADA-SCID 
ADA-deficient SCID 
ADR 
adverse drug reaction 
AE 
adverse event/experience 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase
AUC 
area under the drug concentration-time curve
AUC(0-t) 
AUC from time zero to time t
BMT 
bone marrow transplantation
BUN 
blood urea nitrogen
C 
Celsius/Centigrade
C74S 
Cys74ser mutation
CBC 
complete blood count
CFR 
Code of Federal Regulations
Cmax 
maximum observed drug concentration.
cont’d 
Continued 
CRF 
case report form
Ct 
last measurable concentration
Ctrough 
concentration minimum before repeat dosing
CVs 
curriculum vitae
Cys74 
cysteine at position 74
d-adenosine 
2-deoxyadenosine 
d-ATP 
2'-deoxyadenosine 5'-triphosphate 
dAXP 
deoxyadenosine nucleotide 
dCydK 
deoxycytidine kinase 
d-inosine 
2-deoxyinosine 
DLT 
dose limiting toxicity
DNA 
deoxyribonucleic acid
DSMC 
Data and Safety Monitoring Committee
EDTA 
ethylenediaminetetraacetic acid
EZN-2279 
PEG-rADA; SC-PEG-rbADA-C74S
F 
Fahrenheit 
FACS 
fluorescence-activated cell sorter
FDA 
Food and Drug Administration
GCP 
Good Clinical Practices
HIPPA 
Health Insurance Portability and Accountability Act
HLA 
human leukocyte antigen
HPLC 
high-performance liquid chromatography
HSC 
hematopoietic stem cell
HSCT 
hematopoietic stem cell transplantation
ICH 
International Conference on Harmonization
IEC 
Independent Ethics Committee
Ig 
Immunoglobulin
IgA 
immunoglobulin A
IgG 
immunoglobulin G

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Abbreviation 
Term 
IgM 
immunoglobulin M
h 
Hour 
i.m. 
Intramuscular 
IND 
Investigational New Drug Application
IRB 
Institutional Review Board
i.v. 
Intravenous 
kg 
Kilogram 
Lead PI 
Lead Principal Investigator (study)
LFTs 
liver function tests
LLN 
lower limit of normal range
ln 
natural logarithm
MedDRA 
Medical Dictionary for Regulatory Activities
mL 
Milliliter 
mmHg 
millimeter of mercury
NA 
not applicable
NOAEL 
no-observed-adverse-effect level
PEG 
polyethylene glycol
PEG-ADA 
PEGylated ADA, Adagen® 
PEG-rADA 
PEGylated recombinant ADA, EZN-2279
pH 
negative logarithm of hydrogen ion concentration (“power of hydrogen”) 
PHI 
Protected Health Information
PI 
Principal Investigator (site)
PK 
pharmacokinetic(s)
rADA 
recombinant ADA
RBC 
red blood cell 
SAE 
serious adverse event/experience
SAP 
Statistical Analysis Plan
SAS 
Statistical Analysis Systems
SCID 
severe combined immunodeficiency
SC linker 
succinimidyl carbamate linker
ser 
Serine 
SS linker 
succinimidyl succinate linker
t1/2 
time of elimination half-life calculated as ln(2)/Kel
tmax 
time of the maximum drug concentration (obtained without interpolation) 
TSE 
transmissible spongiform encephalopathy
U 
Unit; amount of adenosine deaminase that converts 1 M of adenosine to 
inosine per minute at 25C and pH 7.4 
µL 
Microliter 
µmol 
Micromole 
U.S. 
United States (of America)
WBC 
white blood cell

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5.       INTRODUCTION 
Leadiant Biosciences, Inc. is developing EZN-2279 (Polyethylene Glycol Recombinant Adenosine 
Deaminase [PEG-rADA]) for the treatment of patients with ADA- deficient combined 
immunodeficiency (ADA-SCID). 
 
5.1.    Disease Background 
Adenosine deaminase-deficient combined immunodeficiency is a rare, inherited, and often fatal 
disease. It is characterized by severe and recurrent opportunistic infection, failure to thrive, profound 
lymphopenia with absent or severely impaired cellular and humoral immune function, and 
metabolic abnormalities [1,2]. These patients are lymphopenic at birth and predisposed to recurrent 
illnesses caused by pathogens and opportunistic organisms that often begin within a few weeks. The 
average age at diagnosis for patients with adenosine deaminase-deficient severe combined 
immunodeficiency (ADA-SCID) is 4.4 months [3,4]. 
 
The incidence of ADA deficiency is estimated to be between 1:200,000 and 1:1,000,000 live births 
[2,4]. ADA deficiency can be categorized into four phenotypes [1]: 
 
 
ADA-SCID: The largest number of patients with ADA deficiency (about 85% to 95%) present 
with ADA-SCID, which is the most severe form of the immunodeficiency. 
 
 
Delayed onset ADA deficiency has been identified in 10% to 15% of patients with ADA 
deficiency which presents after the first year of life and is most likely related to the specific ADA 
mutation that in such cases results in some residual ADA activity and less profound lymphopenia 
and immune function. 
 
     Late (or adult) onset ADA deficiency has been identified in a handful of individuals. 
 
 
Partial ADA deficiency can be an incidental finding in a healthy individual who has normal 
immune function and abnormal ADA expression in erythrocytes. Partial ADA deficiency is 
extremely rare. 
 
Patients with ADA-deficient combined immunodeficiency are unable to produce the ADA enzyme 
in their cells because of mutations in the ADA gene on chromosome 20q. ADA deficiency is a 
disorder of purine salvage [5]. In the absence of this enzyme, the purine substrates adenosine, 
2-deoxyadenosine, and their metabolites reach unusually high levels in cells and are toxic to 
lymphocytes (see Figure 1) [6]. Thus, deficiency of the ADA enzyme is the underlying defect that 
leads to the buildup of toxic metabolites, which in turn affect different organ systems, most 
notably the immune system [2]. It is still not entirely clear whether ADA-deficient patients have 
intrinsically abnormal lymphocytes or whether the defects seen are secondary to the effect of 
accumulation  of  2-deoxydenosine  and  adenosine  [2].  In  addition,  accumulation  of  toxic 
metabolites  also  may  interfere  with  thymic  stroma  development,  maturation,  and  function, 
resulting in impaired ability to support T-cell development [2]. 
 
Absence of the enzyme ADA allows accumulation of toxic metabolites, resulting in complete or 
partial deficiency of both cell-mediated and humoral immunity [1]. 

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Figure 1.      Biochemical defects in ADA deficiency 
 
 
 
ADA is expressed in all tissues of the body. In normal cells, DNA turnover is mediated by ADA 
catalyzing the deamination of d-adenosine to d-inosine. In ADA-deficient cells, there is an 
accumulation of d-adenosine, which is then converted by dCydK to d-ATP. The build-up of these 
two metabolites has profound effects on lymphocyte development and function – through effects 
on DNA synthesis, impaired cell division, and apoptosis – causing immunological defects. 
 
Source: Qasim et al 2004 [6]. 
 
Key: 
ADA = adenosine deaminase; d-adenosine = 2-deoxyadenosine; d-ATP = 2-deoxyadenosine 
5-triphosphate; dCydK = deoxycytidine kinase; d-inosine = 2-deoxyinosine; DNA = deoxyribonucleic 
acid. 
 
 
5.1.1. Treatment of ADA-Deficient Combined Immunodeficiency 
 
 
Without treatment, ADA-deficient combined immunodeficiency is fatal in the first years of life, 
and therefore early intervention is required [2]. Enzyme delivery is key to the successful 
detoxification of metabolic substrates and promotion of immune recovery in these patients [2]. The 
ADA enzyme can be delivered in the form of allogeneic wild-type cells, gene-modified autologous 
cells, or exogenous direct enzyme replacement therapy [2]. 
 
5.1.1.1.           Hematopoietic Stem Cell Transplantation (HSCT) 
Transplanting hematopoietic stem cells (HSCs) from a human leukocyte antigen (HLA)-identical 
sibling donor is well tolerated and results in long-term correction of the immunodeficiency in 
ADA deficiency; thus, HSCT is the treatment of choice for ADA-SCID [2,4]. If a genotypically 
matched family donor is available, bone marrow transplantation (BMT) is a highly successful 
procedure, with recent results indicating a long-term survival rate of approximately 90% for all 
forms of severe combined immunodeficiency (SCID) [7]. 
 
Since  the  first  transplantations  were  performed  nearly  40  years  ago,  an  increasing  number 
of procedures have been performed with significant improvement in survival rates over time [8]. 
In  2004,  Buckley  published  the  results  of  132  transplants  performed  over  21.3  years  at 
Duke University for various genetic types of SCID [9]. Twenty-two of the 132 patients had ADA- 
SCID. Eighteen of the ADA-deficient patients received T-celldepleted haploidentical marrows, and 
4 underwent HLA-identical transplantation. The 22 ADA-deficient patients did not receive pre-
transplant   chemotherapy   or   post-transplant   prophylaxis   for   graft-versus-host   disease. 
Seventeen (77%) of the ADA-deficient patients were reported as alive at 0.3-18.6 years after 
transplantation.  Five of the recipients of T-celldepleted haploidentical marrows died. One ADA- 
deficient patient, who was previously treated with Adagen®  for 18 years, died of pulmonary 

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hypertension.  Hematopoietic chimerism (T cell) was evident in 10 of the ADA-deficient patients. 
The number and function of natural killer cells normalized after transplantation. However, in most 
cases, the B cells were of recipient origin. 
 
Transplantation of parental or unrelated allogeneic hematopoietic stem cells in the approximately 
80% of infants with SCID who lack an HLA-matched sibling donor has success rates of 50% to 
85%, with a considerable number of patients dying from various complications [10]. 
 
Although haploidentical transplantation is a significant medical advance, it is not without 
complications. BMT from mismatched related donors has been associated with significantly delayed 
or incomplete immune reconstitution [7,11]. The delay in T-cell immune recovery may be 
6 months or more. During this period after mismatched related donor HSCT, infections remain a 
major cause of morbidity and mortality. 
 
Furthermore, neurologic abnormalities, mostly in association with infection or after bone marrow 
transplantation, occur in some ADA-deficient patients [12]; bilateral sensorineural deafness also 
has  been  reported  [13].  Hönig  et al  reported  a  high  rate  (50%)  of  neurologic  abnormalities 
observed in six patients with ADA deficiency surviving after HSCT [14]. The authors conclude 
that this high rate indicates that HSCT commonly fails to control central nervous system 
complications  in  this  metabolic  disease.  Recent  results  from  a  large  study  of  105  patients 
confirmed that children with severe immunodeficiency treated with HSCT have an increased risk 
of long-term cognitive difficulties and associated emotional and behavioral outcomes [8]. 
 
In summary, in patients with ADA-SCID use of HSCT from a matched related donor is associated 
with long-term survival and effective immune recovery in the majority of the patients, but does not 
prevent non immune complications of the disease [2]. However, in the absence of a suitable matched 
donor, parental haploidentical transplants are associated with greater complications and sometimes 
poorer long-term immune recovery [7]. The clinical status influences the risk of morbidity and 
mortality in the pre-transplant period, before effective immune reconstitution. This risk is greater 
when preconditioning is used to improve the chances of engraftment. In the absence of 
preconditioning there is less transplant-associated morbidity but a high rate of non-engraftment. 
Overall,  the  success  of  non-HLA  identical  transplantation  is  much  lower  for  patients  with 
ADA-SCID than for patients with SCID due to other gene defects. Patients whose transplants are 
successful demonstrate good immunologic recovery, with normal cellular and humoral function in 
most cases [5]. Completing a successful BMT depends upon finding a matched donor, but the 
probability  of  this  is  low.  ADA  enzyme  therapy  is  thus  considered  for  patients  lacking 
HLA-matched bone marrow donors and for patients whose clinical status places them at high risk 
for transplant-associated morbidity [15]. 
 
5.1.1.2.           Gene Therapy 
Gene   therapy   for   the   treatment   of   ADA-SCID   commonly   involves   gamma-retroviral 
mediated  introduction  of  the  human  ADA  gene  into  autologous  bone  marrow  progenitors 
and subsequent   infusion   of   cells   back   to   the   patient   following   mild   non-myeloablative 
chemotherapy [2]. Ex vivo gene therapy of hematopoietic cells with ADA does not correct the 
underlying ADA  mutation in  other  lineages,  such  as  neuronal cells [5]. To date,  more  than 
25 ADA-deficient patients have been treated with gene therapy. The treatment protocols vary 
between the different sites with respect to the specific retroviral constructs used for gene transfer and 
the conditioning protocols used. 
 
Trials of gene therapy for ADA-SCID were conducted starting in the early 1990s [16-21]. All of 
these studies used retroviral vectors to transfer normal human ADA deoxyribonucleic acid (DNA) 
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or cord blood. No serious adverse events were reported in these trials, but there also were no 
significant clinical benefits achieved [21]. While pilot trials have shown the safety and feasibility 
of gene therapy in patients with SCID due to ADA deficiency [16,17,22], all patients required 
maintenance  with  polyethylene  glycol  (PEG)-ADA  (see  Section  5.1.1.3  ),  and  the  ADA- 
transduced stem cells were unable to reconstitute the recipient’s immune system [23]. 
 
Starting in the late 1990s, a second generation of clinical trials evaluated gene therapy in patients 
with ADA-SCID or the X-linked form of SCID [10,24-26]. Although 18 of the 20 treated infants 
with X-linked SCID are alive and well with restored immunity, the use of gene therapy has been 
associated with the development of T-cell leukemia in five patients with X-linked SCID due to 
insertional  mutagenesis  caused  by  the  retroviral  vector  [7,10,23,27-31].  Molecular  studies 
indicated that three of the four leukemias in the French study [29] were caused by inadvertent 
activation of the proto-oncogene LMO2 due to vector integration in or around this gene [32]. 
Preliminary studies suggest a similar molecular etiology for the development of leukemia in the 
patient from the UK study [32]. The development of leukemia in patients with X-linked SCID is a 
concern for use of retroviruses in other types of HSC-directed gene transfer, including ADA-SCID 
[33]. A recent commentary in Human Gene Therapy concluded that SCID-X1 gene therapy using 
murine leukemia virus vectors with fully functional retroviral promoter/enhancer carries a high 
risk of leukemia insertion [34]. 
 
Since the design of the first gene-therapy trials, HSCs have been considered the optimal target 
cells for long-term, full correction of the ADA-SCID defect [35]. Aiuti et al first reported the 
restoration of immune function and correction of the metabolic defect by stem-cell gene therapy in 
two children with ADA-SCID [25,35]. Unlike all previous studies, these patients were not 
concurrently treated with Adagen® and received low-dose conditioning. Aiuti et al recently published 
results from the long-term follow-up of these two patients, as well as an additional eight patients 
treated with the same regimen [23]. All patients are alive after a median follow-up of 
4 years (range = 1.8 to 8.0 years). Nine patients had immune reconstitution with increases in T-cell 
counts (median count at 3 years = 1.07107/L) and normalization of T-cell function. No adverse 
events could be attributed to the ADA-transduced cells. The authors report that the use of 
nonmyeloablative  conditioning  and withdrawal  of  enzyme  replacement  therapy  were  crucial 
factors in the successful outcome of the trial; they conclude that gene therapy, combined with 
reduced-intensity conditioning, is a safe and effective option to be considered for SCID in patients 
with ADA deficiency who lack an HLA-identical sibling donor [23]. 
 
The sharp dichotomy between the absence of the T-cell lymphoproliferative syndrome in the patients 
with ADA-SCID [23] and its occurrence in 25% of the patients with X-linked SCID is important to 
understand if the therapeutic efficacy of gene therapy is to be retained while minimizing  its  risks  
[10].  The  time  to  immune  recovery  in the  patients  with  ADA-SCID  is markedly slower (6 to 
12 months) than the rapid development (3 to 6 months) of T cells in the patients with X-linked 
SCID who received gene therapy. This difference may reflect important biologic differences between 
the corrected hematopoietic stem cells in X-linked SCID and ADA- SCID [10]. The long-term 
follow-up reported by Aiuti [23] and the results of other trials of ADA- SCID  [21,22,36,37]  did  not  
reveal  the  leukemic  proliferation  complications  observed  in  the patients with X-linked SCID 
[23]. 
 
In summary, gene therapy with nonmyeloablative conditioning is associated with clinical benefit and 
is now an option to be considered for patients with ADA-SCID who lack an HLA-identical sibling 
[2]. In recent trials in Milan, London, and the United States, at least 20 patients who received 
gene therapy for ADA-SCID have been followed for longer than 1 year; all patients have survived, 
which compares favorably with HSCT data, and the majority of patients have near or full recovery 
of immune function [2]. Importantly, none of the patients showed clonal proliferation or 

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adverse events related to gene transfer, despite observation of integration of vector sequences into 
known oncogenes [2]. Results of molecular studies indicate that the retroviral integration profile after 
successful gene therapy did not cause selection or expansion of malignant cell clones in vivo [31,38]. 
In general, gene therapy poses minimal toxicity within the first year with a good chance of immune 
recovery; however, using current vector technology, the potential for long-term toxicity is retained 
[2]. The benefits and risks of gene therapy should be weighed carefully against the risks and efficacy 
of existing treatment [7,21,39]. Ongoing and upcoming clinical trials will use safer designs of 
retroviral vectors, newer types of vectors for viral gene delivery, and emerging methods for direct in 
situ gene repair [10]. 
 
5.1.1.3.           Enzyme Replacement Therapy with Adagen® 
Adagen®  (pegadamase bovine, PEG-ADA) provides specific and direct replacement of the ADA 
enzyme [40]. The active ingredient in Adagen® is a PEGylated adenosine deaminase. The enzyme 
in Adagen® is purified from the bovine intestine. The drug is then PEGylated. The PEGylation of 
the  molecule  is  critical  to  the  pharmacologic  activity  of  Adagen®   because  ADA  without 
PEGylation does not have a sufficient half-life to be efficacious. 
 
Adagen®  was approved in 1990 as enzyme replacement therapy for ADA deficiency in patients 
with SCID who are not suitable candidates for, or who have failed, bone marrow transplantation [40]. 
Since its approval in 1990, approximately 170 patients worldwide have been treated with Adagen® 
[Leadiant Biosciencesdata on file], and approximately 98 patients are currently receiving treatment 
with Adagen® [2]. PEGylated ADA is a life-saving product for these patients. Overall, 70% of 
patients treated with PEG-ADA had SCID and began enzyme replacement therapy at <1 year of 
age (50% were <6 months old); of the remaining patients, half started treatment at 1 to 3 years of 
age, and half started treatment at 3 to 34 years of age [2]. Studies have shown that upon initiation 
of Adagen® therapy, the absolute numbers of circulating T and B lymphocytes and NK cells increase, 
and protective immunity function develops [41]. Approximately two thirds of the patients who are 
currently receiving Adagen®  have been taking the drug for more than 5 years, and 20% have 
received the drug for 15 to 22 years [2]. The overall probability of surviving 20 years while 
receiving enzyme replacement therapy is estimated to be 78%, and a patient who is alive 6 months 
after starting Adagen® has about a 90% probability of surviving the next 12 years [2]. 
 
The mechanism of action of Adagen® is to correct the metabolic abnormalities associated with 
adenosine accumulation due to the absence of ADA and to detoxify the cells. Improvement in 
immune function and diminished frequency of opportunistic infections, compared with the natural 
history of ADA-SCID, occurs only after correction of the metabolic abnormalities. There is a lag 
between the correction of the metabolic abnormalities and improvement in immune function. This 
period of time for Adagen® to improve immune function is usually less than 6 months [40]. 
 
The rapid metabolic detoxification afforded by enzyme replacement allows clinical stabilization of 
patients and provides longer term treatment options when no suitable donor is available [1]. 
 
For patients scheduled to undergo HSCT, enzyme replacement may be important in stabilizing the 
child through metabolic detoxification before the transplant [1]. If a matched family donor is not 
available, most centers would start PEG-ADA to stabilize the child and to improve metabolic and 
immune recovery while initiating a search for an unrelated donor. 
 
Adagen® has been given as an adjunctive therapy in prior gene therapy trials, but it is recognized 
that enzyme replacement may blunt the survival advantage of gene-corrected cells [1]. Therefore, 
patients have received PEG-ADA as maintenance therapy until the time of gene therapy, at which 
point the enzyme replacement has been discontinued. The use of enzyme replacement therapy may 

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weights, correct immune deficiencies, resolve pulmonary abnormalities, and markedly extend the 
lifespan of such ADA-deficient mice. For example, ADA-/-  mice have been shown to accumulate 
adenosine in their lungs by postnatal Day 18. In such mice, administration of a single i.m. injection 
of 2.5 U of Adagen on Day 18 led to approximately a 10-fold reduction in lung adenosine levels 
by Day 21 (which was close to levels found in normal mice), as well as improvement in the lung 
phenotype and survival of these mice. Therefore, ADA-/-  mice are a relevant animal model to 
compare the efficacy of Adagen® and EZN-2279. 
 
In these experiments, ADA-/- mice were generated and genotyped. ADA-/- mice were injected i.m. 
or intraperitoneally (i.p.) in several dosing regimens with selected doses of Adagen® or EZN-2279. 
Compounds were given on the same schedule (once every 4 days  5 starting on postnatal Day 1 
until postnatal Day 21 followed, if needed, once each week until postnatal Day 42) and equivalent 
doses (5 U/mouse injected i.m. or i.p.). Doses and schedules of Adagen®  or EZN-2279 were 
chosen such that the peak and trough levels of ADA in the plasma were similar to what has been 
achieved in patients given therapeutic doses of Adagen®. In each experiment, groups of mice, 
including littermates, were left untreated for comparisons. Both untreated ADA+/+ and ADA-/- mice 
as well as ADA-/-  mice treated with EZN-2279 or Adagen®  were sacrificed 18 days to 6 weeks 
following injection. Bronchial alveolar lavage (BAL) fluid, thymus, and spleen were collected for 
the analysis of adenosine concentrations using RP-HPLC as well as for total cell counts and 
cellular differentials. Blood was obtained from the circulation or thoracic cavity at the time of 
sacrifice to measure ADA enzymatic activity using zymogram or spectrophotometric analysis, 
respectively. Survival and body weight also were assessed. 
 
Results of the pharmacology and PD studies performed in the ADA-/-   mouse model suggest 
EZN-2279  behaves  very  similarly  to  Adagen®   and  both  compounds  are  highly  effective. 
Consistent with this, when Adagen® and EZN-2279 were given at equivalent doses and schedules, 
both PEG-ADA compounds 1) were delivered to the circulatory system with equal efficiency in both 
ADA+/+  and ADA-/-  mice; 2) increased ADA plasma levels to similar, clinically relevant levels; 
3) decreased abnormally high adenosine levels found in the lung, spleen, or thymus to a similar 
extent; 4) maintained thymus and spleen cellularity, including total cell numbers and T- and B-
cell populations; and 5) promoted the survival of ADA-/-  mice. There is a suggestion that EZN-
2279 may be more efficacious than Adagen® in the ADA-/- mouse model. The results tended to show 
EZN-2279-treated ADA-/-  mice having statistically lower adenosine levels in the thymus compared 
with Adagen®, as well as a consistent trend toward better improvement of most PD endpoints (body 
weight, survival, and thymocyte and splenocyte cell number, as well as adenosine levels in spleen) 
when compared with Adagen®. These effects correlated with 35% higher plasma levels of ADA 
activity derived from EZN-2279 compared with Adagen® when analyzed either 24 or 72 hours after 
the last dose; the higher plasma levels of ADA activity are likely due to the longer half-life of 
EZN-2279. 
 
5.3.1.2.           Pharmacokinetics 
EZN-2279  demonstrated  improved  in  vitro  stability  in  human  plasma  in  comparison  with 
Adagen.  Two single-dose intravenous (i.v). studies in rats were conducted.  In these studies, PK 
parameters for ADA activity were markedly increased for EZN-2279 as compared with unPEGylated 
EZN-2279 and were equivalent to or slightly different than those for Adagen (i.e., in one 
experiment, EZN-2279 had lower clearance, longer half-life, and higher AUC compared to 
Adagen). 
 
Single i.m. doses of EZN-2279 or Adagen were given to rats or dogs at two dose levels (30 and 
150 U/kg). AUC and Cmax  values for ADA activity increased in proportion to dose for both rats 
and dogs. The AUC values for EZN-2279 were statistically significantly higher (approximately 

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45% in rats, 55% in dogs) compared with Adagen. Terminal elimination half-lives (t1/2) also were 
increased approximately 30% in rats and 80% in dogs when EZN-2279 was compared with Adagen. 
The calculated mean t1/2 in rats after a single dose was 49 to 61 hours for EZN-2279 and 
36 to 50 hours for Adagen. In dogs, these values were 128 to 154 hours for EZN-2279 and 68 to 
79 hours for Adagen. 
 
In multiple-dose studies, EZN-2279 was given every 3 to 4 days for 4 weeks (total of 9 doses) at 
three dose levels (30, 100, and 300 U/kg). These studies were conducted under GLP guidance. 
AUC and Cmax  values for ADA activity were higher on Day 29 as compared with Day 1 for rats 
that received 300 U/kg EZN-2279 and dogs that received 30, 100, or 300 U/kg EZN-2279. In 
contrast, likely due to detectable anti-drug antibodies, marked reductions in Day 29 exposure 
values for ADA activity occurred for male rats that received 30 U/kg EZN-2279 or 30 U/kg Adagen, 
female rats that received 30 U/kg EZN-2279, and male rats that received 100 U/kg EZN-2279. 
In dogs, Day 29 AUC values were markedly reduced for 1 of 5 males that received 
30 U/kg EZN-2279 and 1 of 5 females that received 100 U/kg EZN-2279. Anti-drug binding 
antibodies were present in the plasma of rats that received EZN-2279 or Adagen  and in most 
dogs that received EZN-2279 at the end of the 4-week treatment periods and/or recovery periods. 
In rare cases, neutralizing antibodies were detected that reduced the enzymatic activity of ADA in 
experimental assays. 
 
In conclusion, the PK (ADA activity) following single-dose i.m. administration to rats and dogs 
demonstrate that that AUC and t 1/2 were significantly higher for EZN-2279 compared to Adagen. 
Repeat doses of 30 U/kg EZN-2279 or 30 U/kg Adagen in rats, as well as 30 U/kg or 100 U/kg in 
dogs, resulted in the formation of anti-drug antibodies in some animals and markedly reduced 
exposure to ADA activity in comparison with single-dose administration. Despite the presence of 
anti-drug binding antibodies in rats and dogs in the repeat-dose studies, there was no evidence for 
clinical anaphylactic reactions to EZN-2279 or Adagen in either species. 
 
5.3.1.3.           Toxicology 
The single-dose studies of EZN-2279 and Adagen® in rats and dogs were conducted primarily for 
PK assessment. EZN-2279 and Adagen® were dosed intramuscularly. Toxicology evaluations 
including clinical signs, body weight, and food consumptions were done for up to 14 days after 
injection, after which animals were sacrificed. The experiments were performed under non-GLP 
conditions. 
 
The toxicity profile of EZN-2279 also was evaluated in Sprague-Dawley CD  rats and Beagle 
dogs in 4-week repeat-dose i.m. GLP toxicology studies. Animals were administered 30, 100, or 
300 U/kg of EZN-2279 every 3 or 4 days for 4 weeks (9 doses total) with a 4-week recovery 
period. Microscopic pathology evaluations were performed on approximately 40 tissues/animals. 
 
EZN-2279 given i.m. was well tolerated in rats and dogs in single- and repeat-dose studies. No 
mortality was observed in any of these studies, and no adverse effects on clinical condition, body 
weight, food consumption, electrocardiograms (dogs), or microscopic pathology were evident in 
either species at any dose. Adagen was similarly well tolerated in rats and dogs at single doses of 
30 and 150 U/kg and in rats at 30 U/kg given every 3 or 4 days for 4 weeks as part of a PK study. 
 
Compound-related findings were seen in the repeat-dose i.m. studies after 4 weeks of treatment 
(9 doses) and were limited to slight increases in MPV values (3% to 7%) for male rats that 
received 30, 100, or 300 U/kg EZN-2279; slightly prolonged mean values for aPTT for male and 
female rats that received 300 U/kg EZN-2279 (5 to 6 seconds); slightly prolonged aPTT for male 
dogs that received 30, 100, and 300 U/kg EZN-2279 (6 to 20 seconds) and female dogs that 

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patients, the following adverse reactions are reported in the Adagen® product label: pain at the 
injection site (two patients) and headache (one patient) [40]. 
 
In addition, during post-approval use of Adagen®, the following adverse reactions have been 
identified, regardless of relationship with the drug or the disease [40, Leadiant Biosciences data on 
file]: 
 
 
At least 5% of cases: Respiratory failure, failure to thrive, drug level decreased, respiratory 
tract infection, thrombocythemia, adverse reactions pertaining to an immune reaction (such as 
hemolytic anemia and neutralizing antibodies), infection, pneumonia, and death due to an 
unknown cause 
 
 
3% to 4% of cases: Autoimmune hemolytic anemia, drug-specific antibody present, injection- 
site erythema, urticaria, adenovirus infection, bovine tuberculosis, brain abscess, convulsion, 
developmental delay, drug ineffective, diarrhea, encephalitis, Epstein-Barr virus infection, 
erythema, hearing impairment, hepatoblastoma, Hodgkin’s disease, interstitial lung disease, lung  
disorder,  lymphocyte  count  decreased,  nervous  system  disorder,  sepsis, thrombocytopenia, 
and viral pneumonia 
 
Because Adagen®  is administered over extended periods, including life-time administration, and 
these reactions are reported voluntarily from a small population, it is not always possible to accurately 
estimate their frequency or establish a definitive causal relationship to drug exposure. 
 
In addition, the assessment of immune system function, which is part of the assessment of efficacy 
in this clinical study, also represents an important aspect of the assessment of safety. 
 
Refer to the EZN-2279 Investigator’s Brochure for additional information. 
 
6.       STUDY PURPOSE, OBJECTIVES AND ENDPOINTS 
 
6.1.    Purpose 
The purpose of this clinical study is to evaluate the safety and efficacy of EZN-2279 in patients 
with ADA-deficient combined immunodeficiency, with the goal of replacing PEGylated native 
bovine ADA   (Adagen®)   with   PEGylated   rADA   (EZN-2279).   The   EZN-2279   product   is 
manufactured using deoxyribonucleic acid (DNA) recombinant technology, with a more stable 
linker, which may potentially reduce immunogenicity and which will replace bovine protein with 
recombinant protein in patients with ADA-deficient combined immunodeficiency. 
 
6.2.    Objectives 
 
6.2.1. Primary Objectives 
The primary objective of this study is to evaluate whether therapy with EZN-2279 achieves metabolic 
detoxification, as demonstrated by total erythrocyte dAXP concentration from a trough blood sample. 
 
6.2.2. Secondary Objectives 
The secondary objectives of this study are to: 
    Evaluate the safety and tolerability of EZN-2279 
 
Assess  the  immunogenicity  to  EZN-2279  and  Adagen®,  including  binding  antibodies, 
neutralizing antibodies and anti-PEG antibodies 
    Evaluate   whether   therapy   with   EZN-2279   maintains   trough   plasma   ADA   activity 
≥15 μmol/h/mL 

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    Determine the PK profile of EZN-2279 
 
Assess the effect of EZN-2279 on immune status as determined by absolute lymphocyte count, 
lymphocyte subset (B, T, and NK) analysis, and immunoglobulin (Ig) concentration (IgG, IgA, 
IgM) 
    Compare  the  clinical  status  (infections  and  hospitalizations)  of  the  patients  during  the 
ENZ-2279 treatment period compared to the prior six months 
 
Assess  the  clinical  growth  status  of  the  patients  during  the  EZN-2279  treatment  and 
maintenance periods 
 
6.3.    Endpoints 
EZN-2279 treatment will occur in 2 distinct study phases, an EZN-2279 treatment phase (i.e., the 
initial 21 weeks of EZN-2279 treatment) and a long term EZN-2279 maintenance phase (see 
Section 7.1.1). 
 
The procedures used to collect study data for the assessment of study endpoints are described in 
Section 10. 
 
The analysis of study endpoint data will occur after all patients complete the EZN-2279 treatment 
period (i.e., the primary endpoint analysis), at 6 months after the last patient enters the EZN-2279 
maintenance phase and annually thereafter (see Section 13.2.3). 
 
6.3.1. Primary Endpoint 
The primary endpoint is the percentage of patients achieving metabolic detoxification, assessed from 
trough dAXP samples obtained at Weeks T-15, T-17, T-19, and T-21. Metabolic detoxification will 
be defined as a trough dAXP concentration equal to or below 0.02 μmol/mL. 
 
6.3.2. Secondary Endpoints 
The secondary endpoints for efficacy are: 
 
Trough Plasma ADA Activity - will be assessed from trough plasma ADA samples obtained at 
Weeks T-15, T-17, T-19, and T-21.  Adequate trough ADA activity will be defined as ADA 
activity ≥15 μmol/h/mL. 
 
Maintenance phase trough plasma dAXP and ADA activity - will be assessed from trough 
plasma dAXP and ADA samples obtained during the maintenance phase of the study through 
completion of EZN-2279 treatment 
 
Immune Status – will be assessed through completion of the EZN-2279 maintenance period, 
through assessment of: 
 
Absolute lymphocyte count 
 
B-, T-, and NK-lymphocyte subset analysis: The number of cells for each subset will be 
determined by FACS using the following panel: 
 
CD3+   (Mature T cells) 
o Percent and Absolute 
 
CD3+ CD8+   (Suppressor T Cells) 
o Percent and Absolute 
 
CD3+ CD4+   (Helper Cells) 
o Percent and Absolute 
 
CD (16+56)+ (Natural Killer Cells) 
o Percent and Absolute 
 
CD19+  (B Cells) 
o Percent and Absolute 

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 
Absolute Lymphocytes (CD45+) 
 
%CD4 (Helper Cells) / %CD8 (Suppressor T Cells) 
 
Quantitative immunoglobulin concentration (IgG, IgA, IgM) 
    Clinical status – will be assessed through determination of the following parameters 
 
Infections through completion of the EZN-2279 treatment period will be determined and 
defined as either: 
 
Clinically documented – patients with documented signs and symptoms of infection 
without positive microbiologic cultures 
 
Microbiologically documented – patients with documented signs and symptoms of 
infection and with positive viral or bacterial cultures 
 
Hospitalizations – Incidence and duration of hospitalizations through completion of the 
EZN-2279 treatment period compared to the 6-month period prior to study entry 
 
Growth – height, weight and growth curve determinations through completion of the 
EZN-2279 maintenance period 
 
Overall survival – will be assessed at the conclusion of the EZN-2279 treatment period 
through the end of  EZN-2279 maintenance 
The secondary endpoints for safety are: 
 
Safety – will be assessed through determination of adverse events (AEs), serious adverse 
events (SAEs), physical examinations, laboratory evaluations, and immunogenicity through 
completion of the EZN-2279 maintenance period. 
 
Immunogenicity of EZN-2279 and Adagen® will be assessed through the end of the EZN-2279 
maintenance period by the evaluation of binding antibodies, neutralizing antibodies and anti- 
PEG antibodies. 
 
 
6.3.3. Pharmacokinetic Endpoints 
Pharmacokinetics of EZN-2279 and Adagen® will be based on plasma concentrations of ADA 
activity.  The concentration of ADA activity in all collected samples will be determined by a 
validated assay.   The following PK parameters will be computed from individual plasma 
concentrations collected during full PK sampling for Adagen® at the end of the Adagen® Lead-in 
period and for EZN-2279 during Week 13 (after 9th dose of EZN-2279): Cmax, Ctrough, tmax, AUC(0-t), 
Kel, and t½. 
 
For pediatric patients < 10 years of age, full PK sampling will not be done in an effort to minimize 
blood collection volumes to ensure the safety of the patients. 
 
7.       STUDY DESIGN 
 
7.1.    Overview of Study Design 
Protocol STP-2279-002 is designed as an open-label, multicenter, single-arm, one way crossover 
study of  EZN-2279  to determine  the  safety,  efficacy,  and  PK  of  EZN-2279  in  patients  with 
ADA-SCID who are currently being treated with Adagen®.  Each patient will serve as his or her 
own control with respect to assessment of study endpoints. 
 
The  study  will  enroll  enough  patients  to  ensure  six  evaluable  patients  with  ADA-deficient 
combined immunodeficiency and stable clinical status while currently receiving therapy with 
Adagen®  who meet all eligibility criteria and written informed consent/assent is obtained.   The 
initial three patients will be enrolled and complete through full EZN-2279 pharmacokinetic sampling 
(Week T-9).  An independent data and safety monitoring committee (DSMC) will review safety, PK 
(ADA activity), and erythrocyte dAXP data.  If no concerns are noted, enrollment will 

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continue for the remaining patients.  A similar DSMC review will occur after all six patients 
complete through 9-weeks of EZN-2279 dosing. 
 
Patients  for  whom  written  informed  consent/assent  is  obtained  will  be  assigned  a  screening 
number  and  undergo  screening  procedures.    Patients  completing  screening  assessments  and 
meeting all eligibility criteria will be enrolled in the study.  There are three periods to study treatment: 
the Adagen® lead-in period, the EZN-2279 treatment period (Weeks T-1 through T-21) and the 
EZN-2279 maintenance period. Patients enrolled in the study will enter the Adagen® lead- in phase 
of the study.   In this phase of the study, patients will receive a single i.m. dose of Adagen®  
weekly and be assessed weekly for dAXP levels and ADA activity. Patients receiving Adagen® 
more frequently than once a week will have his/her dose consolidated to a once a week dose regimen 
during the Adagen Lead-in Phase of the study.  Adagen®  dose adjustments will be made if the 
patient does not meet criteria for trough dAXP levels (≤0.02 μmol/mL) and trough ADA activity 
(15 μmol/h/mL) specified in the inclusion criteria. Once the patient meets protocol criteria for 
trough dAXP and ADA activity, and is considered to be fully detoxified, he/she will have a full 
pharmacokinetic assessment performed if equal to or older than 10 years of age. Prior to receiving 
the dose of Adagen® for pharmacokinetic assessment, patients will have the following baseline 
procedures performed: physical examination, vital signs, growth assessment, performance status, 
safety laboratory assessments (hematology, chemistry, urinalysis), and have blood samples obtained  
for  assessment  of  lymphocyte  subset  analysis,  quantitative  immunoglobulins  and Adagen®  
antibody titers (for neutralizing and binding antibodies) and anti-PEG antibodies. Following 
Adagen®  dosing, plasma ADA samples for full PK evaluation will be collected for 7 consecutive 
days following dosing. After completing Adagen® lead-in treatment and pharmacokinetic 
assessments as indicated, patients will enter the EZN-2279 treatment phase (Weeks T-1 through T-
21) of the study. 
 
Adagen® will be discontinued and therapy with an equivalent dose of EZN-2279 will be initiated. 
In  the  EZN-2279  treatment  phase  of  the  study,  patients  will  receive  a  single  i.m.  dose  of 
EZN-2279 weekly for 21 consecutive weeks. Prior to receiving the initial dose of EZN-2279, 
patients will have the following procedures performed: physical examination, vital signs, growth 
assessment, performance status, safety laboratory assessments (hematology, chemistry, urinalysis), 
and have blood samples obtained for assessment of lymphocyte subset analysis, quantitative 
immunoglobulins, EZN-2279 and Adagen®  antibody titers (neutralizing and binding antibodies) 
and anti-PEG antibodies.  Trough total erythrocyte dAXP concentration and trough plasma ADA 
activity will be measured prior to dosing at weeks T-1, T-3, T-5, T-7, T-8 and every other week 
from Week T-9 through Week T-21.  At week T-8 the patient will have dAXP levels and ADA 
activity assessed to assure the dose of EZN-2279 administered maintains dAXP and ADA activity 
at protocol specified levels. If these levels are not met and the patient is not considered fully 
detoxified, the patient will undergo a dose adjustment and be reassessed prior to entering the EZN- 
2279 full PK sampling week (Week T-9).  During study week T-9, plasma ADA samples for full 
PK evaluation will be collected at Week T-9 (Days 58-63).   Physical examination and safety 
laboratory assessments will be performed every 4 weeks (Weeks T-5, T-9, T-13, T-17 and T-21). 
Blood samples obtained for assessment of lymphocyte subset analysis, quantitative 
immunoglobulins, EZN-2279 antibody titers (i.e., neutralizing and binding antibodies) and anti-PEG 
antibodies will be obtained at selected timepoints during the EZN-2279 treatment period. 
 
Following completion of the EZN-2279 treatment period, patients may enter the EZN-2279 
maintenance period.  During this phase of the study patients will continue to receive single i.m. 
doses of EZN-2279 weekly.   The following assessments will be performed during study visits 
every 3 months: physical examination, vital signs, growth assessment, performance status, safety 
laboratory assessments (hematology, chemistry, urinalysis), and have blood samples obtained for 

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assessment of trough ADA and dAXP levels, lymphocyte subset analysis, quantitative 
immunoglobulins, EZN-2279 antibody titers (for neutralizing and binding antibodies), and anti- 
PEG antibodies.   The maintenance phase of the study will continue until the study is concluded 
(i.e., full regulatory approval of EZN-2279 or early study termination). 
 
Throughout the duration of the study (i.e., Adagen®  lead-in, EZN-2279 treatment and EZN-2279 
maintenance) patients will continually be assessed for adverse events, infectious complications, 
hospitalizations, concomitant medications changes and concomitant procedures. 
 
The analysis of study endpoint data will occur after all patients complete the EZN-2279 treatment 
period (i.e., the primary endpoint analysis), at 6 months after the last patient enters the EZN-2279 
maintenance phase, and annually thereafter (see Section 13.2.3). 
 
7.1.1. Study Periods 
Patient participation in the study will be defined by the four distinct study periods defined below: 
 
Screening (up to 28-days prior to start of Adagen® Lead in dosing)  – This period starts at 
the time of the initial screening procedure through administration of the first dose of Adagen®  
in the lead in period. Note: patients will continue to receive his/her prescribed dose of 
Adagen® during this period. 
 
Adagen®  Lead-in – This period starts with the initial dose of study-required Adagen® 
dosing through the start of EZN-2279 study treatment.  This period will be a minimum of 
3 weeks. 
 
EZN-2279 Study Treatment – This period starts with the initial dose of EZN-2279 through 
completion of at least 21 weeks of EZN-2279 dosing. 
 
EZN-2279 Maintenance – This period begins after completion of the EZN-2279 study 
period and continues until the end of the study (full regulatory approval of EZN-2279 or 
early study termination). 
 
7.1.2. Recruitment and Enrollment 
It is anticipated that patients will be enrolled in the study within approximately 12-months. 
 
7.1.2.1.           Recruitment Definitions 
 
Screening Failure – Patients who provide informed consent and do not proceed to study treatment 
(e.g.,  subject  withdrawals  consent,  does  not  meet  entry  criteria).    Screening  data  will  be 
documented on the study specific Screening Log.   Reasons for screen failure will be documented 
in the subject’s source documents and on the Screening Log. 
 
Enrolled Subject – Patients who pass pre-study (screening) evaluations and are assigned to study 
treatment. 
 
Treated Subject – Patients who are enrolled and receive at least one dose of Adagen®  during the 
Adagen Lead-In period. 
 
Discontinued Subject  – Patients who are treated but fail to complete through the end of the 
21-week EZN-2279 treatment period. 
 
Completed Subject – Patients who are treated and complete through the end of the 21-week 
EZN-2279 treatment period. 

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7.2.    Study Treatments 
 
7.2.1. Rationale for Dose Selection and Choice of Control Groups 
Patients enrolled in this study will have ADA-SCID and be well-controlled on a weekly dose regimen 
of Adagen®.  Patients will be maintained on the same weekly Adagen®  dose during the Adagen®   
lead-in  period  but  will  be  switched  to  a  once  weekly  dosing  regimen  to  permit assessment 
of Adagen® and EZN-2279 pharmacokinetics (only for patients ≥ 10 years of age) and trough levels.  
During the Adagen Lead-in Phase, Adagen®  dose adjustments will be made if the patient  does  
not  meet  criteria  for  dAXP  levels  (≤0.02 μmol/mL)  and  ADA  activity  (15 μmol/h/mL) 
specified in the inclusion criteria and the patient is considered to not be fully detoxified. 
 
Following the Adagen® lead in phase, patients will be transitioned to receive an equivalent dose of 
EZN-2279.   As 1 mg of EZN-2279 contains ADA enzymatic activity equivalent to 150 U of 
Adagen®, the equivalent dose will be calculated as follows: 
 
Adagen® dose (U/kg) x 1mg EZN-2279/150U Adagen® = EZN-2279 dose (mg/kg) 
 
 
7.3.    Assignment of Patients to Treatment 
This is a non-randomized study. Each patient who completes the study screening assessments, meets 
all eligibility criteria, and is accepted for study participation will be assigned a unique patient 
number and begin Adagen® lead-in treatment followed by EZN-2279 treatment and maintenance 
periods. 
 
7.4.    Study Duration 
The primary analysis of data for efficacy, PK, immunogenicity, clinical status, and safety will be 
performed when the Week T-21 (at least 21 weeks of EZN-2279 treatment) data is available for the 
last patient enrolled in the study. 
 
7.4.1. Duration of Treatment and Patient Participation 
All patients will receive a minimum of a 3-week Adagen® lead-in followed by 21-weeks of study 
treatment with EZN-2279.   Patients will be given the opportunity to remain on EZN-2279 
maintenance until the study is concluded (full regulatory approval of EZN-2279 or early study 
termination).   Assuming a 12 month enrollment period and 18 months for the submission of data 
and regulatory approval of EZN-2279, the initial patient enrolled will receive study treatment for 
approximately 3 years and the last patient enrolled will receive study treatment for approximately 
2 years. 
 
Patient participation will be approximately 8-weeks longer than the treatment duration (4 week 
screening period and a 30-day post treatment safety follow-up of patients who discontinue study drug 
early). 
 
7.5.    Methods Used to Minimize Bias 
Due to the single-arm, one way crossover study design used, blinding is not possible. 
 
Laboratory assessments performed for pharmacokinetics (only for patients ≥ 10 years of age), 
safety and efficacy are objective data provided by central laboratories and are not subject to bias. 

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Physical examination and adverse event assessments are subjective assessments that are subject to 
bias due to the inability to blind study staff to the identity of study treatments administered. 
 
7.6.    Appropriateness of Study Measurements 
In this study, for patients ≥ 10 years of age, pharmacokinetics will be assessed by repeated 
sampling  for  ADA  activity  following  a  dose  and  pharmacodynamics  will  be  assessed  by 
monitoring dAXP levels. These are assessments that are commonly used to monitor patients 
treated with Adagen®. 
 
Safety in this study will be assessed by monitoring adverse events, laboratory parameters (serum 
chemistry, hematology, and urinalysis), physical examination changes and vital signs. These are 
standard assessments for monitoring safety in clinical trials.  In addition, monitoring of binding 
and neutralizing antibodies is commonly used to monitor patients treated with Adagen®. 
 
In addition to pharmacodynamics, efficacy will be assessed by monitoring trough ADA activity, 
immune status (ALC, lymphocyte subset analysis, quantitative immunoglobulins) and clinical 
evaluations (growth, incidence of infections and hospitalizations).  These are assessments that are 
commonly used to monitor patients treated with Adagen®. 
 
7.7.    Study Monitoring Committees 
An independent Data and Safety Monitoring Committee (DSMC) will be set up to monitor the 
conduct of the study. The DSMC will review the safety information after the initial three patients 
have been treated with weekly administrations of EZN-2279 through completion of the full PK 
sampling assessments (Week T-9), after all 6 patients have been treated with weekly administrations 
of EZN-2279 through completion of Week T-9, after all patients complete the EZN-2279 
Treatment Phase (i.e., Week T-21) and when all patients completed 1 year (i.e, 2 maintenance cycles) 
of treatment with EZN-2279. At minimum, the DSMC will review safety, PK (ADA activity), and 
erythrocyte dAXP data during the study. 
 
A Charter for the DSMC will be written as an independent document. 
 
8.       STUDY DRUG AND TREATMENTS 
 
8.1.    Description of Study Drug(s) 
EZN-2279 and Adagen® are isotonic, pyrogen-free, sterile solutions in phosphate-buffered saline. 
Adagen pH is 7.2 to 7.4.   EZN-2279 pH is 6.7 to 7.1., both solutions are clear and colorless, 
contain no preservatives and designed for i.m. injection only. 
 
Both drug products (EZN-2279 and Adagen®) are manufactured by L e a d i a n t  B i o s c i e n c e s ,  
I n c . ., Indianapolis, IN. 
 
8.2.    Supply and Labeling 
 
8.2.1.       How Supplied 
Leadiant Biosciences will supply sufficient quantities of EZN-2279 and lead-in Adagen® for 
the study. 
 
8.2.1.1.           EZN-2279 
EZN-2279  will  be  supplied  in  1.5  mL  single-use  vials  containing  2.4  mg  of  EZN-2279 
(1.6 mg/mL). Vials of EZN-2279 will be boxed individually. 

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8.2.1.2.           Adagen® 
Adagen®  will be supplied in boxes of four 1.5 mL single-use vials (NDC-57665-001-01). Each 
vial contains 375 units of Adagen® (250 units/mL). 
 
8.2.2.       Labeling 
 
8.2.2.1.           EZN-2279 
EZN-2279 will be labeled in accordance with FDA requirements for a clinical investigational 
study. 
 
Each vial of EZN-2279 provided to the study site will contain a label with the wording as noted in 
the example below on both the box and vial; however, the layout of the wording and the size of the 
label affixed to the drug vial may be different. 
 
 
Protocol STP-2279-002 
Contents:    EZN-2279  SterileFor intramuscular use only.  Each 1.5-mL single-dose vial 
contains 2.4 mg (1.6 mg/mL). 
Storage: 
+2ºC to +8ºC (36ºF to 46ºF) Protect from light REFRIGERATE - DO NOT FREEZE 
Caution: 
New Drug - Limited by Federal (United States) law to investigational use. 
Lot No.: 
Manufactured 
 
Manufactured for:  Leadiant Biosciences, Inc., Gaithersburg, MD 20878 
 
8.2.2.2. 
Adagen® 
Adagen® will be labeled with the standard labeling of the commercially available product. 
 
For inventory control purposes, a secondary label will be added to  each box of Adagen®  to 
designate Adagen® supplied by Leadiant Biosciences only for study use. 
 
A sample label is provided below. 
 
 
Protocol STP-2279-002 
Only for use for patients enrolled in Protocol STP-2279-002 
 
 
 
8.3.    Storage Conditions 
 
8.3.1. EZN-2279 
EZN-2279 should be stored refrigerated at +2°C to +8ºC (36°F to 46°F). Do not freeze. EZN-2279 
should not be stored at room temperature. EZN-2279 should not be administered if it has been 
shaken or vigorously agitated. EZN-2279 should not be used if there are any indications that it 
may have been frozen. 
 
EZN-2279 should be protected from light. Avoid excessive or prolonged light exposure when storing 
EZN-2279. 
 
8.3.2. Adagen® 
Adagen®  should be stored refrigerated at +2°C to +8ºC (36°F to 46°F). Do not freeze.  Adagen® 
should not be stored at room temperature. Adagen®  should not be administered if it has been 
shaken or vigorously agitated. Adagen® should not be used if there are any indications that it may 
have been frozen. 

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8.4.    Preparation for Administration 
 
8.4.1. EZN-2279 
As with all parenteral drug products, aseptic technique should be used during administration of 
EZN-2279. EZN-2279 should not be shaken or vigorously agitated. EZN-2279 should not be 
administered if there are any indications that it may have been frozen. 
 
Before administration of EZN-2279, the solution should be inspected visually for particulate 
matter and discoloration. The solution should be clear and free of particulates. EZN-2279 should 
not be diluted nor mixed with any other drug before administration. 
 
Use only one dose per vial; do not re-enter the vial. Discard unused portions. Do not save unused 
drug for later administration. 
 
Note: All vials of EZN-2279 used for one dose must be from the same lot. 
 
8.4.2. Adagen® 
As with all parenteral drug products, aseptic technique should be used during administration of 
Adagen®.   Adagen®  should not be shaken or vigorously agitated. Adagen®  should not be 
administered if there are any indications that it may have been frozen. 
 
Before administration of Adagen®, the solution should be inspected visually for particulate matter 
and discoloration. The solution should be clear and free of particulates. Adagen®  should not be 
diluted nor mixed with any other drug before administration. 
 
Use only one dose per vial; do not re-enter the vial. Discard unused portions. Do not save unused 
drug for later administration. 
 
Note: All vials of Adagen® used for one dose must be from the same lot. 
 
8.5.    Study Drug Accountability 
The Food and Drug Administration requires accounting for the disposition of all study drugs 
(active or placebo).  The Investigator at each study site is responsible for ensuring that a current 
record of study drug disposition is maintained and dispensed only at an official study site by 
authorized personnel as required by applicable regulations and guidelines.  Records of product 
disposition as required by federal law consist of the date received, date dispensed/administered, 
quantity dispensed/administered, and the subject to whom the drug was dispensed/administered. 
 
The Investigator or designee authorized by the Investigator will be responsible for maintaining 
accurate records of the shipment, dispensing/return of the study drug by the study site, and return 
of used/undispensed study drug to Leadiant Biosciences.  Drug accountability records must be 
available for inspection by Leadiant Biosciences or its representative and is subject to inspection by 
a regulatory agency (e.g., FDA, EMEA) at any time.  Copies of the records will be provided to 
Leadiant Biosciences at the conclusion of the study.   Product accountability records will be reviewed 
by the Leadiant Biosciences Monitor. 
 
During the study, all opened and partially used investigational product and containers should be 
disposed of by the investigational site or designee in accordance with their institutional policies. The 
Leadiant Biosciences monitor or designee will verify drug inventory and dispensing/accountability 
records.    At  the  end  of  the  study,  all  investigational  product  distributed  to  the  Investigator, 

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including unassigned, unused, and partially used investigational product and containers, must be 
removed from the study site or destroyed as directed by Leadiant Biosciences. The disposal of the 
investigational product must be in accordance with institutional, local, and federal guidelines. 
 
A written explanation will be required for any product not returned to Leadiant Biosciences or 
documented as destroyed by the site(s).  All Clinical supply return, destruction, and accountability 
forms must be maintained in either the pharmacy or in another approved area. 
 
The lot numbers of EZN-2279 and Adagen®  used in this study will be documented in the site’s 
study record (e.g., the Drug Accountability Log or similar record). Details regarding the receipt 
and dispensing of the study drug will be recorded in the study records. At the conclusion of the study, 
any unused EZN-2279 or Adagen®  will be returned to L e a d i a n t  B i o s c i e n c e s  or its 
designee. If no EZN-2279 or Adagen®  supplies remain, this fact will be indicated on the Drug 
Accountability Log. 
 
9.       STUDY POPULATION 
 
9.1.    Number of Patients 
The study will enroll a sufficient number of patients who meet all study entry criteria described in 
Sections 9.2 and 9.3, respectively to assure 6 evaluable patients.   More than 6 patients may be 
enrolled to achieve the required number of evaluable patients.  It is expected that up to 12 study 
centers will participate in the study.  There are no restrictions on the number of patients a single 
study center may enroll. 
 
9.2.    Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for enrollment into the study. 
 
1.   Diagnosis of ADA-deficient combined immunodeficiency 
2.   Stable clinical status while receiving therapy with Adagen®.   Patients previously receiving 
gene therapy or undergoing hematopoietic stem cell transplantation who still require Adagen® 
treatment are eligible.  The dose of Adagen® must be stable for at least 6 months prior to study 
entry. 
3.   Have both of the following during the Adagen® Lead-in phase of the study prior to EZN-2279 
transition: 
a.   Trough plasma ADA activity 15 μmol/h/mL while receiving Adagen® and 
b.   Total erythrocyte dAXP ≤0.02 μmol/mL from a trough blood sample 
 
4.   Patients or parent/guardian must be capable of understanding the protocol requirements and 
risks and providing written informed assent/consent. 
 
9.3.    Exclusion Criteria 
Patients meeting any of the following exclusion criteria will not be eligible for enrollment. 
 
1.   Autoimmunity requiring immunosuppressive treatment. 
2.   Patients with detectable neutralizing anti-Adagen® antibodies at screening evaluation. 
3.   Severe thrombocytopenia (platelet count <50  109/L). 
 
4.   Current participation in other therapeutic protocols for ADA-deficient combined 
immunodeficiency. 

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5.   Current or prior participation in another clinical study with an investigational agent and/or use 
of an investigational drug in the 30 days before study entry. 
6.   Known planned participation in a gene-therapy study for the planned duration of this study. 
 
7.   Any condition that, in the opinion of the PI, makes the patient unsuitable for the study. 
 
8.   Inability or unwillingness to administer Adagen® or EZN-2279 on a one time per week 
regimen. 
9.   Inability to comply with the study protocol. 
10. Female patients who are pregnant or lactating. 
11. Female patients who are breast-feeding. 
12. Female patients of childbearing potential who are not using an FDA approved birth control 
method. 
 
9.4.    Post-Enrollment Restrictions 
 
9.4.1. Concomitant Medications 
There are no known drug interactions with EZN-2279 or Adagen®.  However, vidarabine is a 
substrate for ADA, and 2'-deoxycoformycin is a potent inhibitor of ADA. Thus, the activities of these 
drugs and EZN-2279 or Adagen®  could be substantially altered if they are used in combination 
with one another. 
 
Investigational  agents,  including  those  intended  to  treat  the  patient’s  disease,  are  disallowed 
concomitant to study conduct. 
 
9.4.2. Concurrent Treatments 
Concurrent treatments intended to directly treat the patient’s disease are disallowed. 
 
Concurrent treatments intended to prevent or treat complications associated with ADA-SCID 
(e.g., antibiotics, antifungal agents, intravenous immunoglobulins) are permitted. 
 
9.4.3. Dietary Restrictions 
There are no dietary restrictions for patients enrolled in the study. 
 
9.5.    Withdrawal of Enrolled Patients 
In the absence of a medical contraindication or significant protocol violation, every effort will be 
made by the Principal Investigator to keep subject in the study.  The primary reason for a subject 
withdrawing prematurely should be selected from the following standard categories: 
 
 
Adverse  Event  –  clinical  or  laboratory  events  that  in  the  judgment  of  the  Principal 
Investigator require discontinuation of study medication in the best interests of subject. 
 
Death – death of the subject, whether study related or not. 
 
Withdrawal of Consent – subject desires to withdraw from further participation in the 
study  in  the  absence  of  a  medical  need  to  withdraw  determined  by  the  Principal 
Investigator. 
 
Lost to follow-up – the subject did not return for one or more follow-up visit(s) following 
the start of study treatment. 

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 
Protocol Non-compliance – the subject’s participation in the study failed to meet protocol 
requirements which had a direct impact on subject safety and evaluability of the subject’s 
data. The violation necessitated premature termination from the study. 
 
Subject  meets  withdrawal  criteria  –  the  subject’s  condition  meets  the  criteria  for 
withdrawal from the study (Section 9.5.1). 
 
Other  –  causes  of  premature  termination  from  the  study  other  than  the  above  (e.g., 
termination of study by Leadiant Biosciences, subject relocated). 
 
9.5.1. Withdrawal Criteria 
Reasons  for  patient  withdrawal  or  completion  of  the  maintenance  period  may  include  the 
following: 
 
Adverse event requiring the discontinuation of EZN-2279 treatment 
 
Death 
 
Protocol violation requiring the discontinuation of EZN-2279 treatment 
 
Loss to follow-up 
 
Withdrawal of consent 
 
Investigator’s decision, e.g., PI believes it is no longer in the patient’s best interest to 
remain in the study 
 
Sponsor’s decision to discontinue the study 
 
Lack of efficacy 
 
Study completion (only applies to patients in the maintenance period) 
 
Other reason - causes of premature termination from the study other than the above (e.g., 
subject relocated) 
 
The reason for study discontinuation must be documented in the patient’s source documents and in 
the CRF. 
 
The study will end upon full regulatory approval of EZN-2279 or early study termination of the 
study by Leadiant Biosciences. 
 
As required, a patient will be followed up after the day of withdrawal, as described below in this 
section, in Section 11.5, Section 11.5.1 and Section 10.4.4. 
 
Patients are free to withdraw from the study at any time for any reason. Leadiant Biosciences 
reserves the right to discontinue this study at any time. 
 
The reasons for patient withdrawal or study completion, as well as details relevant to the patient 
withdrawal or study completion, shall be recorded in the CRF. Patients withdrawn before their 
completion of the study will undergo all procedures scheduled for study completion as outlined in 
Section 11.5. 
 
Any patient withdrawn due to any AE (whether serious or non-serious) or clinically significant 
abnormal laboratory test values will be evaluated by the PI or his/her designee, or a monitoring 
physician, and will be treated and/or followed up until the symptoms or values return to normal or 
acceptable levels, as judged by the Investigator (see Section 10.4.4). 
 
9.5.2. Withdrawal Procedures 
Under any circumstance, a final physical examination of each patient must be performed at the 
time of study discontinuation. See Section 11.5 for procedures related to the discontinuation of 
treatment, the completion of maintenance, or the end of the study. 

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Should a subject be withdrawn from the study, all efforts will be made to complete and report the 
observations as thoroughly as possible, including a complete final evaluation at the time of the 
patient’s withdrawal with an explanation of the reason subject was withdrawn from the study. 
 
9.5.3. Replacement of Discontinued Patients 
Patients who do not complete through EZN-2279 Week T-9 will be replaced.  Additionally, any 
patient not completing the EZN-2279 treatment phase of the protocol (i.e. completion of Week T- 
21) will be considered unevaluable and will need to be replaced to achieve 6 evaluable patients. 
 
10.     DESCRIPTION OF STUDY PROCEDURES 
 
10.1.  Informed Consent 
Patients or the legally authorized representative of eligible patients who express interest in 
participating in the study must sign an IRB/IEC-approved Informed Consent form that conforms to 
the Elements of the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule 
Authorization (see Sections 14.3.3 and 14.3.4) before initiation of any study activities. 
Documentation of consent must be completed by the Investigator or his/her designee. 
 
The PI and other members of the study site’s treating team will review the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits, and 
alternative therapies including best supportive care. Patients must be informed that participation in 
the study is voluntary, he/she may withdraw from the study at any time, and withdrawal from the 
study will not affect his/her subsequent medical treatment or relationship with the treating physician. 
Patients will also be informed of any financial costs that the patient will or may incur as a result of 
participation in the study, and that their study record and medical records/documents that pertain 
directly to the study will be reviewed and possibly copied by  Leadiant Biosciences or its 
designee, or a governmental agency (such as the FDA), and that every effort will be made to maintain 
patient confidentiality. 
 
The Informed Consent must be witnessed and dated by the PI or his/her designee, and the original 
retained by the PI/Study Site as part of the patient’s study record. 
 
For patients under 18 years of age, Assent of the minor child must be obtained in accordance with 
Good Clinical Practices and the requirements of the reviewing Institutional Review Board (IRB) 
 
A copy of the fully executed/signed Informed Consent form and Assent form (if applicable) must 
be given to the patient. In the event the patient is re-screened, the patient is not required to sign 
another Informed Consent form unless the patient is re-screened more than 30 days from the 
previous Informed Consent form’s signature date. 
 
10.2.  Screening and Enrollment 
The  Investigator  or  his/her  designee  will  obtain  a  signed  Informed  Consent  and  Assent  (if 
required) before initiating any study-specific procedures. Each patient that is consented will be given 
a 3-digit sequential patient number, beginning with 001 at each study site. 
 
Leadiant Biosciences will track enrollment and notify participating study sites when the target total 
enrollment has been attained and enrollment closed. 

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10.3.  History and Baseline Characteristics 
The following history and demographic data will be collected: 
 
Demographics – age, gender, race, and ethnicity 
 
Disease background and history: 
o Date of diagnosis 
o Prior treatments for SCID, including dates and results 
o Adagen® treatment dates and current dose and regimen of Adagen® 
o Adagen®  toxicities experienced – including the name of the toxicity, the date it last 
occurred, and status (i.e., resolved or ongoing) 
o History of hospitalizations and infectious complications over the past year 
o Other significant disease-related medical history 
 
Medical  History  –  in  addition  to  the  disease  background  and  history,  a  complete 
evaluation of history of disorders of the following systems – cardiovascular, pulmonary, 
gastrointestinal, 
urologic, 
hematologic, 
neurologic, 
ophthalmologic, 
otolaryngeal, 
musculoskeletal,  endocrine,  and  psychosocial;  Note:  any  medications  being  taken  for 
active conditions and include in medication history; prior surgical procedures; allergies to 
medications, including medication and reaction. 
 
Medication History – all prescription and non-prescription medications (including blood 
products, use of vitamins, supplements and herbal remedies) taken within 60 days of 
enrollment (i.e., start of Adagen®  lead-in period) will be recorded.  Information recorded 
includes the medication name, dose, dose regimen, route of administration, start and stop 
(if applicable) dates, and indication for use.  Note if a product is being taken for the 
prevention of a condition, “prophylaxis for” or “prevention of” should be included in the 
description of indication. 
 
10.4.  Safety Procedures 
 
10.4.1.          Physical Examination 
Physical examination will include an examination of general appearance, skin, neck (including 
thyroid),  eyes,  ears,  nose, throat,  lungs,  heart,  abdomen,  back,  lymph  nodes,  extremities,  and 
nervous system, and include a performance status evaluation (see Appendix 3). 
 
A  physical  examination  will  be  performed  as  indicated  in  Sections  11.1  through  11.5  and 
Appendix 1. 
 
Height   and   weight   will   be   collected   as   part   of   growth   assessments   as   indicated   in 
Sections 10.5.3.3, and 11.1 through 11.5 and Appendix 1. 
 
Changes in physical examination findings (e.g., new findings, changes in status of previous findings) 
will be documented. Findings made after the start of study drug administration that meet the 
definition of an AE (see Section 12.2.1) must be recorded on the Adverse Event CRF. 
 
10.4.2.          Vital Signs 
Vital signs will include sitting systolic and diastolic blood pressure, pulse rate, respirations, and 
temperature. Blood pressure will be measured and recorded to the nearest millimeter of mercury 
(mmHg). 
 
Clinically meaningful changes in vital signs made after the start of study drug, which meet the 
definition of an AE, must be recorded on the Adverse Event CRF. 

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10.4.3. 
Laboratory Assessments 
The following laboratory evaluations will be performed by the site’s local laboratory as indicated 
in Sections 11.1 through 11.5 and Appendix 1. 
 
 
Hematology:  Hemoglobin,  hematocrit,  WBC  count,  differential  (includes  at  least: 
neutrophils [include bands], lymphocytes, monocytes, eosinophils, and basophils), and 
platelet count. 
 
Serum chemistry: Bicarbonate, blood urea nitrogen (BUN), calcium, chloride, creatinine, 
glucose, magnesium, phosphate, potassium, sodium, and total protein, albumin, alkaline 
phosphatase, ALT, AST, and total bilirubin. 
 
Urinalysis: Macroscopic (bilirubin, blood, glucose, ketones, leukocyte esterase, nitrite, pH, 
protein, specific gravity, and urobilinogen). Microscopic examination will include red 
blood cells (RBCs), WBCs, bacteria, and casts. 
 
Serum or urine pregnancy test: Only for female patients of child-bearing potential. 
 
 
If a laboratory assessment has been performed within the specified protocol window as part of 
standard of care by a laboratory listed on the FDA 1572 form, it does not need to be repeated for 
the purpose of the protocol.  The laboratory assessment result will be included on the CRF for the 
study. 
 
Following the start of study treatment clinically meaningful laboratory abnormalities will be 
reported as an adverse event. 
 
10.4.3.1.         Immunogenicity 
Venous blood samples for determination of anti-EZN-2279 and anti-Adagen® binding and 
neutralizing antibodies, and anti-PEG antibodies will be collected in 2mL 
ethylenediaminetetraacetic acid (EDTA) tubes at the timepoints listed in Appendix 2. 
 
If the results of ADA activity indicate an unexpected reduction in activity from previous sampling 
timepoints, and if there is an adequate amount of sample remaining for analysis, assay for binding, 
neutralizing, and  anti-PEG antibodies will be performed 
 
Samples will be collected, processed and shipped to the central laboratory for analysis as described 
in the laboratory manual for the study. 
 
10.4.4.           Adverse Event Assessment 
The patients will be instructed to inform the PI or his/her designee of any AEs occurring during 
the study. All AEs whether observed by the PI or his/her designee, elicited by the PI or his/her 
designee (e.g., via physical examination findings or review of laboratory results), or spontaneously 
reported by the patient will be documented in the patient’s medical record/chart. 
 
Patients will be questioned in an open manner (e.g., “how do you feel?”, “any changes since your 
last visit?”) regarding any new adverse events that may have occurred.  Patients will also be 
specifically questioned regarding the status of ongoing adverse events.  For each adverse event the 
following information will be recorded: 
 
Onset date and time 
 
Resolution date and time 
 
Severity/intensity (see section 12.2.5) 
 
Relationship to study drug (see section 12.2.4) 
 
Serious or non-serious (see section 12.2.3) 

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 
Actions taken to manage/treat the event 
 
Outcome of the event - resolved, resolved with sequalae, ongoing, death 
All AEs should be followed until they are resolved or until a stable clinical endpoint is reached. Any  
SAE  should  be  reported  to  Leadiant Biosciences  Drug  Safety  Surveillance  (see  Study  
Reference 
Manual for contact information). 
 
Any patient withdrawn due to any AE (whether serious or non-serious) or clinically significant 
abnormal laboratory test value will be evaluated by the PI or his/her designee, or a monitoring 
physician, and will be treated and/or followed up until the symptom(s) or value(s) return to 
normal/Baseline or acceptable levels, as judged by the PI. 
 
10.5.  Efficacy Procedures 
 
10.5.1.          Trough Plasma ADA Activity 
Venous blood samples for the determination of ADA activity will be collected in a 2mL EDTA 
collection tube at the timepoints listed in Appendix 2.  Samples will be collected, processed and 
shipped to the central laboratory for analysis as described in the laboratory manual for the study. 
 
10.5.2.          Immune Status 
 
10.5.2.1.         Lymphocyte Subset Analysis 
Blood samples (4 mL) will be collected into a lavender-top collection tube containing EDTA for 
lymphocyte subset analysis as described below. 
 
Samples will be collected, processed and shipped to the central laboratory for analysis as described 
in the laboratory manual for the study.  The blood sample must be kept at room temperature; do 
not freeze or refrigerate. 
 
CD3+   (Mature T cells) 
o Percent and Absolute 
 
CD3+ CD8+   (Suppressor T Cells) 
o Percent and Absolute 
 
CD3+ CD4+   (Helper Cells) 
o Percent and Absolute 
 
CD (16+56)+ (Natural Killer Cells) 
o Percent and Absolute 
 
CD19+  (B Cells) 
o Percent and Absolute 
 
Absolute Lymphocytes (CD45+) 
 
%CD4 (Helper Cells) / %CD8 (Suppressor T Cells) 
 
10.5.2.2.         Quantitative immunoglobulin concentration 
Blood for assessments of serum IgG, IgA, and IgM will be collected in 3.5mL gold top serum 
separator tube (SST) at the timepoints listed in Appendix 2.  Blood samples will be collected, 
processed and shipped to the central laboratory for analysis as described in the laboratory manual for 
the study. 

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10.5.3.          Clinical Status 
 
10.5.3.1.         Infections 
Patients suspected of having an infection will have signs and symptoms of the suspected infection 
evaluated.  Appropriate cultures will be obtained based upon clinical presentation. 
 
All infections will be classified by the PI as clinically or microbiologically documented as described 
below: 
 
Clinically  documented  –  patients  with  documented  signs  and  symptoms  of  infection 
without positive cultures 
 
Microbiologically  documented  –  patients  with  documented  signs  and  symptoms  of 
infection and with positive cultures 
 
10.5.3.2.         Hospitalizations 
If a patient is hospitalized, the reason for and the duration of each hospitalization will be recorded. 
 
All  hospitalizations  should  be  reported  to  Leadiant Biosciences  Drug  Safety  Surveillance  
(see  Study 
Reference Manual for contact information). 
 
10.5.3.3.         Growth 
Height (in cm) and weight (in kg) will be obtained for determination of height-for-age and weight- 
for-age Z-scores. 
 
 
10.5.3.4.         Overall Survival 
Patient survival will be recorded throughout the patient’s participation in the study.   If death is 
reported during the study, the date of death and reason for the patient death will be documented 
and recorded. 
 
All patient deaths should be reported immediately (see Section 12.4) to Leadiant Biosciences 
Drug Safety 
Surveillance (see Study Reference Manual for contact information). 
 
10.6.  Pharmacokinetic and Pharmacodynamic Assessments 
 
10.6.1.          Pharmacokinetic Assessments 
Only patients ≥ 10 years of age will undergo full PK assessments due to blood volume restrictions 
in pediatric patients.  All patients < 10 years of age will have the same assessments and in lieu of 
full PK sampling will have limited PK sampling done.  Only trough samples along with 48 hours 
post dose during Adagen Lead In Week T-5 and EZN-2279 Week T-9 will be collected. 
 
Venous blood samples (EDTA tube, up to 2 mL per timepoint) for the determination of the PK 
profile of EZN-2279 will be collected at Week L-4, after the Adagen® lead-in, and Week T-9 after 
initiation of EZN-2279 therapy (see Appendix 2).  Note: If the dose of EZN-2279 is altered, the 
full PK profile should be repeated not earlier than  4 weeks after adjustment of the dose of 
EZN-2279. 
 
Note: The site should calculate sample collection dates and times in advance of scheduling a patient’s 
first day of administration, so as to avoid sample collections during non-routine times such as 
evenings, holidays, etc. 

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It is extremely important to collect all samples at the times specified. Both the scheduled and 
actual times of sample collection should appear on the sample collection record used in the clinic. In 
addition, the actual times at which the infusion is started and stopped must be recorded. 
 
10.6.2.          Pharmacodynamic Assessments 
 
10.6.2.1.         dAXP 
Venous blood samples for the determination of total erythrocyte dAXP (EDTA tube, 2 mL per 
timepoint) will be collected at the timepoints listed in Appendix 2.   Samples will be collected, 
processed and shipped to the central laboratory for analysis as described in the laboratory manual 
for the study. 
 
10.6.2.2.         Maximum Total Blood Collection Volume 
During  a  patient’s  study  participation,  the  maximum  amounts  of  venous  blood  that  will  be 
collected are listed in Appendix 2.  Note: there is limited PK sampling for patients < 10 years of 
age. 
 
10.7.  Study Medication Administration and Compliance 
 
10.7.1.          Dosage and Administration 
 
10.7.1.1.         Adagen® 
Adagen®  will be administered during the Adagen®  Lead-in phase of the study.   Patients will 
remain on his/her weekly Adagen®  dose. The total weekly dosage will be consolidated to a once 
weekly dose regimen.   This phase of the study will continue until the patient meets protocol 
criteria for dAXP levels and ADA activity. 
 
For example, a 50kg patient on a dose of 15U/kg twice a week will have his/her dose consolidated 
to 30U/kg once weekly.  The dose volume will be calculated as follows: 
 
50 kg x 30U/kg x 1 mL/250 U = 6.0 mL (1500 U) 
 
The date and time of each dose administered will be recorded. 
 
10.7.1.2.         EZN-2279 
EZN-2279 will be administered starting after completion of the Adagen®  Lead-in phase. Patients 
will be transitioned to receive an equivalent dose of EZN-2279 as a weekly i.m. injection.  Based 
upon 1 mg EZN-2279 containing ADA enzymatic activity of 150 U of Adagen®, the equivalent 
dose of EZN-2279 will be calculated as follows: 
 
Adagen® dose (U/kg) x 1mg EZN-2279/150U Adagen® = EZN-2279 dose (mg/kg) 
 
For example, for a 50 kg patient on a dose of 30 U/kg of Adagen®: 
 
Adagen® 30 U/kg x  1 mg EZN-2279 = 0.2 mg/kg EZN-2279 
150 U Adagen® 
 
 
50 kg x 0.2mg/kg x 1 mL/1.6 mg = 6.25 mL (10 mg) 
 
The date and time of each dose administered will be recorded. 

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All patients will be observed for at least 1 hour after administration of EZN-2279 for doses 
administered at the study site through study Week T-9. 
 
10.7.2.          Dose Adjustments 
Adjustments of the dose and/or schedule of EZN-2279 or Adagen® may be required if a patient’s 
trough plasma ADA activity is less than 15 μmol/h/mL and/or the trough dAXP level is greater 
than 0.02 μmol/mL for two or more consecutive assessments and compliance with the study drug 
regimen is confirmed and the patient is not considered fully detoxified. The Investigator, the sponsor, 
and Lead PI must agree upon all modifications in the dosing regimen for each patient before any 
changes are instituted. 
 
The  dose  of  Adagen®  should  not  be  adjusted  more  than  once  every  2  weeks  and  the  dose 
EZN-2279 should not be adjusted more than once every 4 weeks to allow the effect of these changes 
on trough level of ADA to be manifested. 
 
10.7.3.          Treatment Delays 
EZN-2279 or Adagen® will be administered weekly ± 1 day.  The PI, after upon consultation with 
Leadiant Biosciences and Lead PI, may elect to delay or withhold a dose if the clinical condition 
of the patient warrants such action. The PI, Leadiant Biosciences, and Lead PI must agree upon all 
modifications in the dosing regimen for each patient before any changes are instituted. 
 
10.7.4.          Assessment of Study Medication Compliance 
Compliance will be assured by having the study drug administered under the supervision of the PI 
and/or designated site staff members while the patient is at the clinic/study site during the visit(s). 
Administration  of  the  study  drug  must  be  recorded  in  source  documents.    For  EZN-2279 
Treatment Week 12, the patient is permitted to self dose at home, but enough drug will be 
dispensed along with diary cards which become part of the patient source documentation. 
 
10.8.  Recording of Concomitant Medications 
All changes in prior and new prescription and non-prescription medications (including i.v. 
immunoglobulins, blood products, use of vitamins, supplements and herbal remedies) from the 
start of screening through the final study visit are to be recorded.  For each change in prior medication 
and new medication the following will be recorded: 
    Name of the medication 
    Total daily dose 
    Route of administration 
    The start and stop dates 
    The indication for use 
o If  a  product  is  being  taken  for  the  prevention  of  a  condition,  “prophylaxis  for”  or 
“prevention of ”should be included in the description of indication 
o If a product is being taken for an active condition, a corresponding medical condition must 
be included in the medical history 
 
10.9.  Compliance 
This study is to be conducted according to: 
 
 
United States (U.S.) and international standards of Good Clinical Practices (GCP) as defined 
in the U.S. Food and Drug Administration (FDA) Code of Federal Regulations (CFR), and 
International Conference on Harmonization (ICH) guidances, 
    Applicable government regulations, 

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    Institutional Review Board(s) (IRB)/Independent Ethics Committee(s) (IEC), and 
    Institutional (study site) research policies and procedures. 
 
 
The Principal Investigator and the study personnel will verify patient compliance with the study 
requirements,  procedures  and  schedule  of  events.    The  Principal  Investigator  or  physician 
Sub-Investigator (listed on Form FDA 1572) will be present for the initial dose administration of 
Adagen®  during the Lead-In phase and EZN-2279 (Week T-1) and for the post-dose monitoring 
and evaluation for all patients.   The Principal Investigator or physician sub-investigator will be 
available and accessible at all other times throughout the study for the management of the patients 
enrolled in this clinical trial.    Non-compliance with any study evaluations/procedures will be 
documented in the patient’s source documents and case report forms (CRFs). 
 
11.     SCHEDULE OF STUDY PROCEDURES 
Study activities are listed in Appendix 1. 
 
11.1.  Screening 
Patients who fulfill all of the inclusion criteria and none of the exclusion criteria may be entered into 
the study. 
 
The following evaluations are to be performed within 28 days before start of the Adagen® Lead-in 
period unless otherwise indicated. 
 
 
Informed assent/consent 
 
Obtain patient history and baseline characteristics 
o Demographics 
o Disease background and history 
o Assessment of AEs/toxicities the patient has experienced while on Adagen® treatment 
o Assessment of infectious complications and hospitalizations within the past 12 months 
o Medical history 
o Medication history 
 Physical examination 
 Vital signs 
 Height and weight for growth assessment 
 Performance status score 
 
Urine or serum pregnancy test for females of childbearing potential must be performed 
within 7-days before starting Adagen® Lead-in. 
 
Safety Lab 
o Hematology 
o Serum chemistry 
o Urinalysis 
 
Immunogenicity - Adagen®  antibody titers (i.e., neutralizing and binding antibodies) and 
anti-PEG antibodies 
 
Patients passing screening assessment will enter the Adagen Lead-in phase of the study. 
 
For  patients  currently  maintained  with  Adagen®   on  a  1  time  per  week  dosage  regimen,  the 
following additional laboratory assessments will be performed to determine whether an Adagen® 
dosage adjustment when entering the Adagen® Lead-in phase is required: 
 
Total erythrocyte dAXP from a trough blood sample 
 
Trough plasma ADA activity 

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11.2.  Adagen® Lead -in 
 
11.2.1. 
Adagen® Dosage and Schedule Adjustments 
Patients entering the Lead-in phase will have Adagen®  dose/dose schedule changes implemented 
prior to the first Adagen lead-in dose as described below: 
 
Patients on once weekly Adagen® dosing and meet entry criteria for dAXP level and ADA 
activity – these patients will enter Adagen®  Lead-in on the dose and regimen he/she was 
taking prior to study entry 
 
Patients on once weekly Adagen®  dosing and do not meet entry criteria for dAXP levels 
and ADA activity – these patients should have his/her dosage adjusted (see Section 10.7.2) 
 
Patients on two or more weekly doses of Adagen® – these patients will have his/her dose 
regimen of Adagen® consolidated into a single weekly dose.  For example, a patient 
receiving 20U/kg twice weekly will have his/her dose regimen consolidated to a dose of 
40U/kg once weekly. 
 
11.2.2. 
Weekly Adagen Dosing 
Patients will have weekly study visits (± 1 day).  For each visit, the patient will return to the study 
site have the following procedures performed: 
 
Adverse event assessment 
 
Assessment of infectious complications and hospitalizations 
 
Assessment of concomitant medications and procedures since last study visit 
 
Trough blood samples will be obtained 15 to 30 minutes prior to Adagen® dosing for: 
o dAXP 
o ADA activity 
 
The patient will receive his/her dose of Adagen®. 
 
Patients will be followed weekly for dAXP and ADA activity. 
 
If the results of these tests indicate a dAXP level ≤ 0.02 μmol/mL and a trough ADA 
activity level ≥ 15 μmol/h/mL for two consecutive weekly measurements and all other 
section criteria are still met the patient will be able to proceed to the Adagen® 
Pharmacokinetic assessment (see Section 11.2.3). 
 
If the dAXP and trough ADA activity levels do not meet protocol selection criteria for two 
consecutive weeks and the patient is not considered fully detoxified, the patient should 
have his/her dosage re-adjusted (see Section 10.7.2).  This process may be repeated until 
the patient meets the ADA activity and dAXP levels and is considered fully detoxified for 
study inclusion. 
 
A  schematic  diagram  of  procedures  for  dose  adjustment  and  consolidation  is  provided  in 
Appendix 4. 
 
11.2.3. 
Adagen® Pharmacokinetics 
 
11.2.3.1. 
Day 1 
Day 1 is the day of the first administration of Adagen®  on study.   Prior to administration of 
Adagen® the following baseline procedures will be performed: 
 
Update medical history 
 
Physical examination 
 
Height and weight  for growth assessment 

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 
Performance status 
 
Vital Signs 
 
Safety Lab 
o Hematology 
o Chemistry 
o Urinalysis 
 
Other labs – blood samples will be obtained 15 to 30 minutes prior to dosing for: 
o dAXP 
o Trough ADA activity 
o B-, T-, and NK-lymphocyte subset analysis 
o Quantitative immunoglobulins 
o Adagen®   antibody  titers  (i.e.,  neutralizing  and  binding  antibodies)  and  anti-PEG 
antibodies 
 
Assessment of concomitant medications and procedures since last study visit 
 
Following completion of the above procedures, the patient will receive Adagen® at his/her current 
weekly dose administered as a single weekly injection. 
 
11.2.3.2.         Days 2 through 8 
Blood samples for ADA activity will be obtained at 24, 48, 72, 96, 120, 144, and 168 hours following 
Day 1 PK dose.   All blood samples will be obtained ± 4 hours of the scheduled collection 
time. Note: the 168 hour post-dose sample will be obtained immediately prior to the initial dose 
of EZN-2279. 
 
For patients < 10 years of age, PK sampling will be limited to trough samples and at 48 hours post 
dose for monitoring of ADA activity and Cmax timepoint. 
 
11.3.  EZN-2279 Study Treatment Period 
 
11.3.1.          Day 1 (Week T-1) 
Prior to administration of EZN-2279 the following procedures will be performed: 
 
Physical examination 
 
Height and weight  for growth assessment 
 
Performance status 
 
Vital Signs 
 
Safety Lab 
o Hematology 
o Chemistry 
o Urinalysis 
 
Other labs – blood samples will be obtained 15 to 30 minutes prior to dosing for: 
o dAXP 
o Trough ADA activity (168 hours following Day 1 Adagen® PK dose) 
o B-, T-, and NK-lymphocyte subset analysis 
o Quantitative immunoglobulins 
o EZN-2279 and Adagen® antibody titers (neutralizing and binding antibodies) and anti- 
PEG antibodies 
 
Adverse event assessment 
 
Assessment of infectious complications and hospitalizations 
 
Assessment of concomitant medications and procedures since last study visit 

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Following completion of the above procedures, the patient will receive EZN-2279.  The equivalent 
dose of EZN-2279 will be calculated as described in Sections 7.2.1 and 10.7.1. 
 
11.3.2. 
Day 8 (Week T-2) 
On Day 8 (± 1 day) the patient will return to the study site and have the following procedures 
performed: 
 
Adverse event assessment 
 
Assessment of infectious complications and hospitalizations 
 
Assessment of concomitant medications and procedures since last study visit 
 
The patient will receive his/her dose of EZN-2279 after all procedures have been completed. 
 
11.3.3. 
Day 15 (Week T-3) 
On Day 15 (± 1 day) the patient will return to the study site and have the following procedures 
performed: 
 
Adverse event assessment 
 
Assessment of infectious complications and hospitalizations 
 
Assessment of concomitant medications and procedures since last study visit 
 
Blood samples will be obtained 15 to 30 minutes prior to administration of EZN-2279 for: 
 
dAXP 
 
Trough ADA activity 
 
EZN-2279  antibody  titers  (i.e.,  neutralizing  and  binding  antibodies)  and  anti-PEG 
antibodies 
 
The patient will receive his/her dose of EZN-2279 after all procedures and laboratory blood draws 
have been completed. 
 
11.3.4. 
Day 22 (Week T-4) 
On Day 22 (± 1 day) the patient will return to the study site and have the following procedures 
performed: 
 
Adverse event assessment 
 
Assessment of infectious complications and hospitalizations 
 
Assessment of concomitant medications and procedures since last study visit 
 
The patient will receive his/her dose of EZN-2279 after all procedures have been completed. 
 
11.3.5. 
Day 29 (Week T-5) 
On Day 29 (± 1 day) the patient will return to the study site and have the following procedures 
performed: 
 
Physical examination 
 
Height and weight for growth assessment 
 
Performance status 
 
Vital Signs 
 
Safety Lab 
o Hematology 
o Chemistry 
 
Adverse event assessment 

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 
Assessment of infectious complications and hospitalizations 
 
Assessment of concomitant medications and procedures since last study visit 
 
Blood samples will be obtained 15 to 30 minutes prior to administration of EZN-2279 for: 
 
dAXP 
 
Trough ADA activity 
 
The patient will receive his/her dose of EZN-2279 after all procedures and laboratory blood draws 
have been completed. 
 
11.3.6. 
Day 36 (Week T-6) 
On Day 36 (± 1 day) the patient will return to the study site and have the following procedures 
performed: 
 
Adverse event assessment 
 
Assessment of infectious complications and hospitalizations 
 
Assessment of concomitant medications and procedures since last study visit 
 
The patient will receive his/her dose of EZN-2279 after all procedures and laboratory blood draws 
have been completed. 
 
11.3.7. 
Day 43 (Week T-7) 
On Day 43 (± 1 day) the patient will return to the study site and have the following procedures 
performed: 
 
Adverse event assessment 
 
Assessment of infectious complications and hospitalizations 
 
Assessment of concomitant medications and procedures since last study visit 
 
Blood samples will be obtained 15 to 30 minutes prior to administration of EZN-2279 for: 
 
dAXP 
 
Trough ADA activity 
 
The patient will receive his/her dose of EZN-2279 after all procedures and laboratory blood draws 
have been completed. 
 
 
11.3.8. 
Day 50 (Week T-8) 
On Day 50 (± 1 day) the patient will return to the study site and have the following procedures 
performed: 
 
Adverse event assessment 
 
Assessment of infectious complications and hospitalizations 
 
Assessment of concomitant medications and procedures since last study visit 
 
Blood samples will be obtained 15 to 30 minutes prior to administration of EZN-2279 for: 
 
dAXP 
 
Trough ADA activity 
 
The patient will receive his/her dose of EZN-2279 after all procedures and laboratory blood draws 
have been completed. 

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11.3.8.1. 
EZN-2279 Dose Evaluation for Adjustment 
 
The results from trough ADA activity and dAXP will be reviewed to assess whether patients have 
a dAXP level ≤ 0.02 μmol/mL and a trough ADA activity level ≥ 15 μmol/h/mL. 
 
Based upon this review: 
 
If the Week T-7 and T-8 values for ADA activity and dAXP levels meet the established 
values, the patient will proceed to Day 57 (Week T-9) and begin full PK sampling 
 
If  the Week T-7 and T-8 values for ADA activity and dAXP levels DO NOT meet the 
established values and the patient is not considered fully detoxified: 
o The patient will have his/her dosage of EZN-2279 adjusted.  Dose adjustments will be 
based upon dAXP and ADA values and agreed upon by the PI, Sponsor and Lead PI 
o Return to Week T-5 (Section 11.3.5) and continue through weekly dosing for 4 weeks 
(T-5 through T-8) and be re-assessed  as described in this section 
 
11.3.9.          Day 57 (Week T-9) 
On Day 57 (± 1 day) the patient will return to the study site and have the following procedures 
performed: 
 
Physical examination 
 
Height and weight for growth assessment 
 
Performance status 
 
Vital Signs 
 
Safety Lab 
o Hematology 
o Chemistry 
 
Adverse event assessment 
 
Assessment of infectious complications and hospitalizations 
 
Assessment of concomitant medications and procedures since last study visit 
 
Blood samples will be obtained 15 to 30 minutes prior to administration of EZN-2279 for: 
 
dAXP 
 
Trough ADA activity 
 
B-, T-, and NK-lymphocyte subset analysis 
 
Quantitative immunoglobulins 
 
The patient will receive his/her dose of EZN-2279 after all procedures and laboratory blood draws 
have been completed. 
 
This is the first day of the full PK sampling for EZN-2279.   Note: If the dose or schedule of 
EZN-2279  is  altered,  the  full  PK  profile  should  be  repeated  not  earlier  than  9  weeks  after 
adjustment of the dose/schedule of EZN-2279. 
 
11.3.10.        Days 58 through 63 (Week T-9) 
The patient will return to the study site each day for blood sampling (only for patients ≥ 10 years 
of age). Blood samples for ADA activity will be obtained at 24, 48, 72, 96, 120, 144, and 168 
hours following Day 29 dose. All blood samples will be obtained ± 4 hours of the scheduled 
collection time. Note: the 168 hour post-dose sample will be obtained immediately prior to the 
Week T-10 dose of EZN-2279. 

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For patients < 10 years of age, PK sampling will be limited to trough samples and at 48 hours post 
dose for monitoring of ADA activity and Cmax timepoint. 
 
11.3.11. 
Day 64 (Week T-10) 
On Day 64 (± 1 day) the patient will return to the study site and have the following procedures 
performed: 
 
Adverse event assessment 
 
Assessment of infectious complications and hospitalizations 
 
Assessment of concomitant medications and procedures since last study visit 
 
Blood samples will be obtained 15 to 30 minutes prior to administration of EZN-2279 for: 
 
dAXP 
 
Trough ADA activity (168 hours following Day 57 EZN-2279 dose) 
 
EZN-2279  antibody  titers  (i.e.,  neutralizing  and  binding  antibodies)  and  anti-PEG 
antibodies 
 
The patient will receive his/her dose of EZN-2279 after all procedures and laboratory blood draws 
have been completed. 
 
11.3.12. 
Day 71 (Week T-11) 
On Day 71 (± 1 day) the patient will receive EZN-2279 at a dose of 0.2 mg/kg and have the 
following procedures performed: 
 
Adverse event assessment 
 
Assessment of infectious complications and hospitalizations 
 
Assessment of concomitant medications and procedures since last study visit 
 
Blood samples will be obtained 15 to 30 minutes prior to administration of EZN-2279 for: 
 
dAXP 
 
Trough ADA activity 
 
The patient will receive his/her dose of EZN-2279 after all procedures and laboratory blood draws 
have been completed. 
 
If the patient will self-administer the Week T-12 dose of EZN-2279, the dose will be dispensed 
with a dosing diary card and administration instructions. 
 
11.3.13. 
Day 78 (Week T-12) 
On Day 78 (± 1 day) the patient will receive his/her dose of EZN-2279.  The dose may be given at 
the study site or self-administered by the patient. 
 
11.3.14. 
Day 85 (Week T-13) 
On Day 85 (± 1 day) the patient will return to the study site and have the following procedures 
performed: 
 
Physical examination 
 
Height and weight for growth assessment 
 
Performance status 
 
Vital Signs 
 
Safety Lab 
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o Chemistry 
 
Adverse event assessment 
 
Assessment of infectious complications and hospitalizations 
 
Assessment of concomitant medications and procedures since last study visit 
 
Blood samples will be obtained 15 to 30 minutes prior to administration of EZN-2279 for: 
 
dAXP 
 
Trough ADA activity 
 
The patient will receive his/her dose of EZN-2279 after all procedures and laboratory blood draws 
have been completed. 
 
If the patient will self-administer the Week T-14 dose of EZN-2279, the dose will be dispensed 
with a dosing diary card and administration instructions. 
 
11.3.15. 
Day 92 (Week T-14) 
On Day 92 (± 1 day) the patient will receive his/her dose of EZN-2279.  The dose may be given at 
the study site or self-administered by the patient. 
 
11.3.16. 
Day 99 (Week T-15) 
On Day 99 (± 1 day) the patient will return to the study site and have the following procedures 
performed prior: 
 
Adverse event assessment 
 
Assessment of infectious complications and hospitalizations 
 
Assessment of concomitant medications and procedures since last study visit 
 
Blood samples will be obtained 15 to 30 minutes prior to administration of EZN-2279 for: 
 
dAXP 
 
Trough ADA activity 
 
The patient will receive his/her dose of EZN-2279 after all procedures and laboratory blood draws 
have been completed. 
 
If the patient will self-administer the Week T-16 dose of EZN-2279, the dose will be dispensed 
with a dosing diary card and administration instructions. 
 
11.3.17. 
Day 106 (Week T-16) 
On Day 106 (± 1 day) the patient will receive his/her dose of EZN-2279.  The dose may be given 
at the study site or self-administered by the patient. 
 
11.3.18. 
Day 113 (Week T-17) 
On Day 113 (± 1 day) the patient will return to the study site and have the following procedures 
performed: 
 
Physical examination 
 
Height and weight for growth assessment 
 
Performance status 
 
Vital Signs 
 
Safety Lab 
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o Chemistry 
 
Adverse event assessment 
 
Assessment of infectious complications and hospitalizations 
 
Assessment of concomitant medications and procedures since last study visit 
 
Blood samples will be obtained 15 to 30 minutes prior to administration of EZN-2279 for: 
 
dAXP 
 
Trough ADA activity 
 
The patient will receive his/her dose of EZN-2279 after all procedures and laboratory blood draws 
have been completed. 
 
If the patient will self-administer the Week T-18 dose of EZN-2279, the dose will be dispensed 
with a dosing diary card and administration instructions. 
 
11.3.19. 
Day 120 (Week T-18) 
On Day 120 (± 1 day) the patient will receive his/her dose of EZN-2279.  The dose may be given 
at the study site or self-administered by the patient. 
 
11.3.20. 
Day 127 (Week T-19) 
On Day 127 (± 1 day) the patient will return to the study site and have the following procedures 
performed: 
 
Adverse event assessment 
 
Assessment of infectious complications and hospitalizations 
 
Assessment of concomitant medications and procedures since last study visit 
 
Blood samples will be obtained 15 to 30 minutes prior to administration of EZN-2279 for: 
 
dAXP 
 
Trough ADA activity 
 
The patient will receive his/her dose of EZN-2279 after all procedures and laboratory blood draws 
have been completed. 
 
If the patient will self-administer the Week T-20 dose of EZN-2279, the dose will be dispensed 
with a dosing diary card and administration instructions. 
 
11.3.21. 
Day 134 (Week T-20) 
On Day 134 (± 1 day) the patient will receive his/her dose of EZN-2279.  The dose may be given 
at the study site or self-administered by the patient. 
 
11.3.22. 
Day 141 (Week T-21) 
On Day 141 (± 1 day) the patient will return to the study site and have the following procedures 
performed: 
 
Physical examination 
 
Height and weight for growth assessment 
 
Performance status 
 
Vital Signs 
 
Safety Lab 
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o Chemistry 
o Urinalysis 
 
Other labs – obtained 15 to 30 minutes prior to dosing 
o dAXP 
o Trough ADA activity 
o B-, T-, and NK-lymphocyte subset analysis 
o Quantitative immunoglobulins 
o EZN-2279 antibody titers (i.e., neutralizing and binding antibodies)  and anti-PEG 
antibodies 
 
Adverse event assessment 
 
Assessment of infectious complications and hospitalizations 
 
Assessment of concomitant medications and procedures since last study visit 
 
Assessment of overall survival 
 
The patient will receive his/her dose of EZN-2279 after all procedures and laboratory blood draws 
have been completed. 
 
Following  completion  of  assessments  and  dosing  at  Week  T-21  the  patient  will  enter  the 
EZN-2279 maintenance period. 
 
11.4.  EZN-2279 Maintenance Period 
As part of standard clinical care, the following evaluations will be performed during visits 
approximately every 3 months (13 weeks 3 weeks) until study completion.  For example, based 
upon the start of EZN-2279 treatment (Day 1, Week T-1), maintenance visits would be scheduled 
to occur on Weeks 34 (Cycle 1), 47 (Cycle 2), 60 (Cycle 3), 73 (Cycle 4 ), 86 (Cycle 5), 99 (Cycle 
6), 112 (Cycle 7), 125 (Cycle 8), 138 (Cycle 9), 151 (Cycle 10), 164 (Cycle 11), 177 (Cycle 12), 
190 (Cycle 13) ±3 weeks from start of EZN-2279 treatment. 
 
The patient will have the following procedures performed at each maintenance visit prior to 
EZN-2279 dosing: 
 
Physical examination 
 
Height and weight for growth assessment 
 
Performance status 
 
Vital Signs 
 
Safety Lab 
o Hematology 
o Chemistry 
o Urinalysis 
 
Other labs – blood samples will be obtained 15 to 30 minutes prior to dosing for: 
o dAXP 
o Trough ADA activity 
o B-, T-, and NK-lymphocyte subset analysis 
o Quantitative immunoglobulins 
o EZN-2279 antibody titers (i.e., neutralizing and binding antibodies) and  anti-PEG 
antibodies 
 
Adverse event assessment 
 
Assessment of infectious complications and hospitalizations 
 
Review  of  EZN-2279  administration  diary  card  and  returned  vials  for  assessment  of 
treatment compliance 
 
Assessment of concomitant medications and procedures since last study visit 

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 
Assessment of overall survival 
 
An appropriate supply of EZN-2279 will be dispensed along with a medication compliance diary 
card.  Note that it is not necessary to dispense a full 13 week supply during a maintenance visit; 
quantities of EZN-2279 dispensed will be at the discretion of the Investigator based upon the patient’s 
proximity to the study site and medication compliance. 
 
11.5.  Study Completion: End-of Treatment, Completion of Maintenance or 
End of Study 
At the time of study discontinuation, the following evaluations should be repeated: 
 
Physical examination 
 
Height and weight for growth assessment 
 
Performance status 
 
Vital Signs 
 
Safety Lab 
o Hematology 
o Chemistry 
o Urinalysis 
 
Other labs – blood samples will be obtained for: 
o dAXP 
o Trough ADA activity 
o B-, T-, and NK-lymphocyte subset analysis 
o Quantitative immunoglobulins 
o EZN-2279 antibody titers (i.e., neutralizing and binding antibodies) and  anti-PEG 
antibodies 
 
Adverse event assessment 
 
Assessment of infectious complications and hospitalizations 
 
Assessment of concomitant medications and procedures since last study visit 
 
Assessment of overall survival 
 
All patients, regardless of the reason for study discontinuation (see Section 9.5.1), should have the 
above evaluations at the time of study discontinuation, whenever possible. All reasons for 
discontinuation of study treatment must be documented. 
 
11.5.1.          30-Day Early Discontinuation Follow-up 
For patients who discontinue treatment and the study prior to study completion, the following 
evaluations for safety will occur at least 30 days after the last dose of study drug (EZN-2279 or 
Adagen®): 
 
Physical examination 
 
Height and weight for growth assessment 
 
Performance status 
 
Vital Signs 
 
Safety Lab 
o Hematology 
o Chemistry 
o Urinalysis 
 
Adverse event assessment 
 
Assessment of concomitant medications 

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Any ongoing drug-related toxicities noted will be followed until a stable clinical endpoint is 
reached (see Section 10.4.4). 
 
12.     ADVERSE EVENTS 
 
12.1.  Assessment Period 
The AE reporting period for this study begins with the first lead-in dose of Adagen®  and ends 
30 days after the final dose of EZN-2279 (or, for patients who are withdrawn before switching 
treatment to EZN-2279, 30 days after the final dose of Adagen®). 
 
12.2.  Definitions 
 
12.2.1.          Adverse Event 
An adverse event is any untoward medical event associated with the use of a drug in humans, whether 
or not considered drug related.     An adverse event can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a drug and does not imply any judgment about causality. 
An  untoward  medical  event  which  occurs outside  the  period  of  follow-up  as  defined in  the 
protocol will not be considered an adverse event.  Worsening of a medical condition for which the 
efficacy of the study drug is being evaluated will not be considered an adverse event. 
 
12.2.2.          Unexpected Adverse Event 
An unexpected adverse event is one that is not listed in the Investigator Brochure or is not 
listed at the specificity or severity that has been observed. 
 
For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the investigator brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, 
cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the investigator brochure listed only cerebral vascular accidents. “Unexpected,”  as  
used  in  this  definition,  also  refers  to  adverse  events  or  suspected  adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
 
12.2.3.          Serious Adverse Event 
 
A serious adverse event is an adverse event that in the view of either the investigator or 
sponsor, results in any of the following outcomes: Results in death 
 
Is  life-threatening  (an  event  that  in  the  view  of  either  the  investigator  or  sponsor,  its 
occurrence places the patient or subject at immediate risk of death; it does not include an event 
that had it occurred in a more severe form, might have caused death) 
 
Requires in-patient hospitalization or prolongation of existing hospitalization 
 
Results  in  persistent  or  significant  disability/incapacity  or  substantial  disruption  of  the 
ability to conduct normal life functions 
 
Is a congenital anomaly or birth defect 
 
Is another important medical event that may not be immediately life-threatening or result in 
death or hospitalization but based upon appropriate medical judgment, may jeopardize the 
patient or may require medical or surgical intervention to prevent one of the other outcomes 
listed above.  Examples of such events are intensive treatment in an emergency room for 

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allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
 
The term “severe” is often used to describe the intensity (severity) of an event; the event itself may 
be of relatively minor medical significance (such as a severe headache).  This is not the same as 
“serious”, which is based on patient/event outcome or action criteria usually associated with events 
that pose a threat to a patient’s life or functioning. 
 
12.2.4.          Relationship to Study Drug 
The Investigator must attempt to determine if an adverse event is in some way related to the use of 
the study drug. This relationship should be described based upon the following definitions: 
 
Unrelated: The adverse event is clearly due to causes distinct from the use of the study drug, 
such as a documented pre-existing condition, the patient’s clinical state,   environmental 
factors, the effect of other concomitant medications or treatments administered. 
 
Unlikely:  The  adverse  event  does  not  follow  a  reasonable  temporal  sequence  from 
administration of the study drug, does not follow a known response pattern to the study 
drug, and could readily have been due to other causes such as the patient’s clinical state, 
environmental factors, the effect of other concomitant medications or treatments administered. 
 
Possible:  The adverse event follows a reasonable temporal sequence from administration of 
the study drug and follows a known response pattern to the study drug, BUT, the adverse 
event could readily have been produced by the patient’s clinical state, environmental factors, 
the effect of other concomitant medications or treatments administered. 
 
Probable: The adverse event follows a reasonable temporal sequence from administration of 
the study drug and follows a known response pattern to the study drug, AND cannot be 
reasonably explained the patient’s clinical state, environmental factors, the effect of other 
concomitant medications or treatments administered.    The event improves upon 
discontinuation of the study drug. 
 
Definite:  The adverse event follows a reasonable temporal sequence from administration of 
the study drug and follows a known response pattern to the study drug.  Based on the known 
pharmacology of the study drug, the event is clearly related to the effect of the study drug. 
The adverse event improves upon discontinuation of the study drug and reappears upon 
repeat exposure. 
 
12.2.5.          Severity (Intensity) 
The Investigator will assess the severity (intensity) of all AEs according to the following grading 
system: 
 
 
Mild AE- awareness of the event but is easily tolerated 
 
Moderate AE – interferes with activities of daily living 
 
Severe AE – incapacitating and causes inability to perform activities of daily living 
 
12.3.  Reporting Adverse Events 
All new events, as well as those that worsen in intensity or frequency relative to baseline, which 
occur must be captured.  The Investigator or his/her staff should elicit information regarding the 
occurrence of adverse events through information volunteered by the patient, open-ended 
questioning of the patient, physical examination results and review of laboratory results. 
 
Information to be recorded for each AE includes: 

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 
A medical diagnosis of the event (if a medical diagnosis cannot be determined, a description 
of each sign or symptom characterizing the event should be recorded) 
 
The date and time of onset of the event 
 
The date and time of resolution of the event 
 
Assessments of  severity,  causal  relationship, and  seriousness  of  the  adverse event  (see 
definitions in Section 12.2.1 through 12.2.4) 
 
Action(s) taken (if any) for management of the adverse event, including but not limited to 
change  in  the  study  drug  administration  (e.g.,  temporary  interruption  in  dosing,  dose 
reduction); drug treatment; non-drug treatment; diagnostic procedures performed 
 
Outcome of the adverse event:  e.g., patient recovered without sequelae; patient recovered 
with sequelae; event ongoing; patient died 
 
If a medical condition is known to have caused the injury or accident (e.g., a fall secondary to 
dizziness), the medical condition (dizziness) and the medical condition resultant to the fall (hip 
fracture) should be reported as two separate AEs. The act of falling (i.e., fall) should be recorded 
as part of the event term in the CRF. 
 
All adverse events will be followed until resolution, stabilization, or for 30 days after last dose of 
study drug, whichever occurs first. 
 
12.4.  Reporting Serious Adverse Events 
All serious adverse events (SAEs), regardless of relationship to study drug, must be reported to 
Leadiant 
Biosciences 
as 
described below. 
 
 
Serious adverse events that are fatal or life–threatening must be reported to Leadiant 
Biosciences or their designee by telephone immediately after site personnel first become 
aware of the event.  Within 24 hours, the Leadiant Biosciences Serious Adverse Event Form 
must be faxed to the medical monitor or designee regardless of whether full information 
regarding the event is known or not.  If full information is not known, additional follow-up 
by the Investigator will be required. 
 
 
All other serious adverse events must be reported to the Lead ian t Bioscien ces 
medical monitor or designee within 24 hours by phone, e-mail or fax after becoming 
aware of the event. Within  48  hours,  the  Leadiant Biosciences  Serious  Adverse Event  
Form must  be  faxed  to  the medical monitor or designee regardless of whether full 
information regarding the event is known or not.  If full information is not known, 
additional follow-up by the Investigator will be required. 
 
Report all SAEs to the Leadiant Biosciences safety representative listed in the Study Reference 
Manual. 
 
All SAEs will be evaluated by the Leadiant Biosciences Medical Monitor or designee.  If meeting 
the requirements for expedited reporting (i.e., serious, unexpected and related), Leadiant Biosciences 
will so report the adverse event to all regulatory authorities with jurisdiction over ongoing trials with 
the study drug and to all other investigators involved in clinical trials with EZN-2279. 
 
The Investigator must report all SAEs reported by Leadiant Biosciences to regulatory authorities in 
an expedited manner to the reviewing IRB.   For all other SAEs, the Investigator must report 
all serious adverse events in accordance with the requirements of the reviewing IRB. 
 
 

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Leadiant Biosciences will forward all reports of SAEs to the DSMC and the 
Lead PI. 
 
 
12.4.1.          Reporting of Other Non-serious Events 
In addition to reporting of SAEs, the following are specific conditions defined by Leadiant 
Biosciences for this study, which may or may not be SAEs (i.e., as defined above [Section 12.2.3). 
These conditions, whether serious or not, are to be reported to Leadiant Biosciences within 48-hours 
using the Leadiant Biosciences Serious Adverse Event Form: 
 
     All signs and symptoms of an allergic reaction that may not necessarily be deemed serious. 
For example: urticaria, facial swelling, lip swelling, orbital swelling, rash, pruritus, nasal 
congestion, injection site reaction, etc., should be reported to Leadiant Biosciences as “Special 
AE Report.”   Note:  An  anaphylactic  reaction  meets  the  definition  of  “serious”  and  
would, therefore, be reported as an SAE. 
 
12.5.  Reporting of Pregnancy 
If a patient becomes pregnant or is found to be pregnant while on the study, the Leadiant 
Biosciences medical monitor or designee will be contacted to discuss the management of the 
patient, which may include discontinuation of study drug. 
 
Although pregnancy is not a serious adverse event all pregnancies occurring during this study will 
be reported to the Leadiant Biosciences Drug Safety within 48 hours of becoming aware of the 
pregnancy and complete and submit a pregnancy report form. 
 
All pregnancies will be followed until delivery or pregnancy termination for maternal and fetal 
outcomes. 
 
13.     STATISTICS 
 
13.1.  Sample Size Determination 
The sample size of six patients accounts for more than 5% of the entire eligible patient population 
worldwide and 10% of the entire eligible patient population in the United States. 
 
The study will enroll a sufficient number of patients with ADA-SCID who meet all study entry 
criteria to assure six (6) patients are evaluable, where evaluable is defined as completing the EZN- 
2279 treatment period and providing primary study endpoint data. 
 
The patients enrolled in this study all will have achieved metabolic detoxification with Adagen® 
prior to initiating EZN-2279 treatment. Patients are expected to maintain the target trough total 
erythrocyte dAXP concentration with EZN-2279 at a planned success rate of 100%. Therefore, the 
usual statistical sample size calculations using precision analysis, power analysis, or probability 
are not applicable due to zero variability. 
 
13.2.  Statistical Methodology 
 
13.2.1.          Level of Significance 
If applicable, hypotheses will be tested at a two-sided statistical significance level of 0.05. 
 
13.2.2.          Analysis Populations 
The as-treated population, defined as all patients who are enrolled and receive at least one dose of  
 

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study drug (EZN-2279 or Adagen®) will be the primary analysis set in evaluating patient 
characteristics, treatment administration/compliance and safety. 
 
The primary efficacy endpoint, the percentage of patients achieving metabolic detoxification, will be 
determined for patients who achieve or who do not achieve metabolic detoxification while receiving  
EZN-2279  per  protocol.  Metabolic  detoxification  is  defined  as  achieving  and maintaining 
the target trough total erythrocyte dAXP concentration of ≤0.020 μmol/mL while receiving EZN-
2279. 
 
The PK evaluable population, defined as all patients who have received EZN-2279 for at least 
9 weeks (i.e., through at least Week 13) and who have sufficient PK data at Weeks 5 and 13 (or 
later, if the dose or schedule of EZN-2279 was altered before Week 13) to indicate exposure, will be 
the analysis set for evaluating PK parameters. 
 
Patients < 10 years of age will not have full PK sampling done due to the blood volume requirements 
and will only have limited sampling done. 
 
13.2.3.          Data Analysis 
Statistical analysis will be conducted by Leadiant Biosciences, or its designee.  The primary analysis 
of study data will be performed after the last patient has completed through the EZN-2279 treatment 
phase (Study Week T-21). Once the last patient enters the EZN-2279 maintenance phase, data 
will be analyzed after all patients complete 6-months of EZN-2279 maintenance (EZN-2279 
treatment week 47) and annually thereafter. The analysis of study data will be repeated upon study 
completion. 
 
Efficacy  and  safety  analyses  will  be  performed  using  Statistical  Analysis  Systems®   (SAS®) 
Version 9 or later (SAS Institute, Cary, NC), or comparable software. 
 
A complete description of data handling rules and planned statistical analyses is detailed in a separate 
Statistical Analysis Plan (SAP). Unless otherwise specified in this document or in the SAP, 
baseline is defined as the last measurement for a variable before the initial dose of study drug (EZN-
2279 or Adagen®), and missing data will generally not be imputed. If applicable, hypotheses will be 
tested at a two-sided statistical significance level of 0.05. 
 
Analyses will be primarily descriptive, with data listings, graphical presentations, frequency 
tabulations, and summary statistics as appropriate. 
 
Each patient will serve as his/her own control based on the baseline assessment of each endpoint 
as appropriate, including changes in body weight as percentile on the growth curve, antibody 
formation, etc. 
 
Additional statistical analyses, other than those described in this section, may be performed if deemed 
appropriate to further explore the study data. 
 
13.2.3.1.         Study Conduct and Patient Disposition 
The number of patients treated will be tabulated. Patients not meeting the eligibility criteria will be 
documented. Protocol violations will be reviewed. Reasons for study discontinuation and time of 
withdrawal from study will be summarized. 
 
13.2.3.2.         Baseline Characteristics 
Patient characteristics at study entry will be summarized in frequency tables, and descriptive 
statistics will be provided for quantitative variables. 

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13.2.3.3.         Study Drug Administration 
Study drug administration will be summarized for EZN-2279 and Adagen®. The total number of 
doses administered; the median (range) of doses administered; the median (range) treatment duration; 
dose modifications, dose delays, and dose omissions; and reasons for deviations from planned 
therapy will be described. 
 
13.2.3.4.         Efficacy Data Analysis 
 
Primary Efficacy Endpoint  – the  primary efficacy endpoint is the percentage  of  patients 
achieving metabolic detoxification, defined as achieving and maintaining the target trough 
total erythrocyte dAXP concentration of ≤0.020 μmol/mL while receiving EZN-2279. Total 
erythrocyte dAXP from a trough blood sample will be evaluated at various timepoints (see 
Appendix 2 for collection schedule). 
 
 
Secondary Efficacy Endpoints – Analyses of the following secondary efficacy endpoints will 
be primarily descriptive, with data listings, graphical presentations, frequency tabulations, and 
summary statistics as appropriate. 
 
 
Trough plasma ADA activity: the percentage of patients achieving and maintaining the 
target trough plasma ADA activity of 15 mol/h/mL while receiving EZN-2279 
 
Immune function status: 
o Absolute Lymphocyte count 
o B-, T-, and NK-lymphocyte subset analysis: the number of cells for each subset will 
be determined by FACS. The following subsets will be assessed: 
 
CD3+   (Mature T cells) - Percent and Absolute 
 
CD3+ CD8+   (Suppressor T Cells) - Percent and Absolute 
 
CD3+ CD4+   (Helper Cells) - Percent and Absolute 
 
CD (16+56)+ (Natural Killer Cells) - Percent and Absolute 
 
CD19+  (B Cells) - Percent and Absolute 
 
Absolute Lymphocytes (CD45+) 
 
%CD4 (Helper Cells) / %CD8 (Suppressor T Cells) 
o Quantitative immunoglobulin concentration (IgA, IgG, IgM) 
 
Infections: Clinically documented and microbiologically documented 
 
Incidence and duration of hospitalizations 
 
Growth: Height-for-age and weight-for-age Z-scores 
 
Overall survival 
 
13.2.3.5. 
Safety Data Analysis 
Adverse Events and Serious Adverse Events – AEs will be categorized using Medical Dictionary 
for Regulatory Activities (MedDRA) Version 10.0 or later. The intensity of toxicities will be 
graded by the Investigator as mild, moderate, or severe as described in Section 12.2.5. 
Serious Adverse Events (SAEs) will be a subset of the overall AE analysis and may be analyzed 
in a similar manner. 
 
The calculation of AE incidence will be based on the number of patients per AE category. For 
each  patient  who  has  multiple  AEs  classified  to  the  same  category,  that  patient  will  be 
tabulated under the maximum toxicity intensity for that AE category. The incidence of AEs 
will be tabulated by MedDRA system organ class and preferred term, as well as by treatment 
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An AE onset between the date of the first dose of study drug and 30 days after the last dose of 
study drug is considered as a treatment-emergent AE. 
 
 
Laboratory Safety Data – Hematology, chemistry, and urinalysis data will be summarized 
by timepoint of collection and by treatment group. In addition, out-of-normal range values 
will be listed. 
 
 
Other  Safety  Data  –  the  results  of  antibodies  against  EZN-2279,  antibodies  against 
Adagen®, and antibodies against PEG will be summarized. The relationships between 
immunogenicity, PK, and the clinical toxicities will be examined as appropriate. 
 
Concomitant medications and findings in physical examinations will be described textually as 
recorded in the CRF. 
 
Descriptive statistics of vital signs measurements as well as changes from baseline will be 
tabulated. 
 
13.2.3.6.         Pharmacokinetic Data Analysis 
Pharmacokinetics of EZN-2279 and Adagen® will be based on plasma concentrations of ADA 
activity. The concentration of ADA activity in all collected samples will be determined by a validated 
assay. The following PK parameters (secondary endpoints) will be computed from individual plasma 
concentrations using appropriate validated PK software. 
 
 
Cmax 
Maximum observed drug concentration 
 
Ctrough 
Concentration minimum before repeat dosing
 
tmax 
Time of the maximum drug concentration (obtained without interpolation)
 
AUC(0-t) 
AUC calculated using linear trapezoidal summation from time zero to time
t, where t is the time of the last measurable concentration (Ct) 
 
Kel 
Terminal elimination rate constant calculated by linear regression of the
terminal linear portion of the log concentration versus time curve 
 
t1/2 
Apparent terminal half-life calculated as ln(2)/Kel
 
PK parameters and the plasma level-versus-time curves will be determined for each evaluable 
patient. Descriptive statistics including mean, standard deviation, coefficient of variation, median, 
minimum, maximum, mean and median plasma level graphs will be provided as appropriate. 
 
13.2.3.7. 
Linkage Between Pharmacologic Effects and Clinical Effectiveness 
The linkage between the pharmacologic effects of EZN-2279 and any measured or anticipated 
evidence of clinical effectiveness will be explored and summarized. 
 
13.2.4. 
Handling Missing, Repeated, Unused and Spurious Data 
The handling of missing, repeated, unused and spurious data will be described in the statistical 
analysis plan for the study. 
 
13.2.5. 
Reporting of Deviations to Statistical Methodology 
The methods for documenting deviations to the statistical methodology will be described in the 
statistical analysis plan for the study.   These deviations will be described in the clinical study 
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13.3.  Interim Analysis 
An interim analysis is planned to occur for all available data after the third patient completes the 
primary endpoint.   The interim analysis will include all data available at the time, but at a 
minimum the first three patients data completing through 21 weeks of EZN-2279 dosing. 
 
13.4.  Statistical Criteria for Termination of the Study 
There are no statistical criteria for the termination of the study. 
 
14.     ADMINISTRATIVE 
 
14.1.  Changes to Study Protocol 
 
14.1.1.          Protocol Amendments 
Protocol changes must be in the form of a written amendment approved by Leadiant 
Biosciences. 
 
Protocol amendments and necessary revisions to the informed consent form must be submitted by 
the Investigator to the local IRB and such amendments will only be implemented after written 
approval of the requisite IRB.   Protocol changes to eliminate an immediate hazard to a study 
patient may, at the direction of Leadiant Biosciences, be implemented immediately by the 
Investigator.  The Investigator must then immediately inform the IRB and obtain required approvals. 
 
If a protocol amendment requires revision to the informed consent form, the revised IRB-approved 
form must be used to re-consent patients currently enrolled in the study and the new form must be 
used to obtain consent from new patients prior to enrollment. 
 
All amendments will be submitted to local regulatory authorities by Leadiant Biosciences as 
required by local regulation. 
 
14.1.2.          Protocol Deviations 
Deviations to the protocol will not be permitted without the prior approval of Leadiant Biosciences.  
All departures from this protocol will be recorded as protocol deviations, independent of whether the 
deviation was approved by Leadiant Biosciences.  If Leadiant Biosciences approves a protocol 
deviation, a written waiver will be provided to the Investigator.  The original waiver will be filed in 
the site regulatory files and a copy filed with the study records for the patient. 
 
Departures from the protocol involving informed consent, eligibility criteria, study drug 
administration and the administration of prohibited treatments will require written IRB notification 
by the Investigator. 
 
14.2.  Study Termination 
Leadiant Biosciences reserves the right to temporarily or permanently discontinue the study at any 
site and at any time.  Reasons for study discontinuation may include, but are not limited to, the 
following: 
 
 
Investigator non-compliance with the protocol, Good Clinical Practice guidelines or regulatory 
requirements 
    Insufficient enrollment to complete the study within the prescribed timeframe 
    Safety concerns 
    Drug supply issues 
    Discontinuation of the study protocol and/or all studies with EZN-2279 

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    Request to discontinue the study by a regulatory or health authority 
 
Leadiant Biosciences will promptly inform all Investigators and the requisite regulatory authorities 
if the study is suspended or terminated for safety reasons.  In the case of such suspension or 
termination, Leadiant Biosciences will provide the Investigator with instructions regarding the 
disposition of patients (e.g., termination of treatment, patient follow-up) currently on the study.  The 
Investigator will promptly notify the IRB and implement patient disposition instructions. 
 
Should the study be terminated prematurely, all unused study drug(s), unused case report forms 
and any other investigational study material will be returned to the Sponsor. 
 
14.3.  Ethics 
 
14.3.1.          Compliance Statement 
This study will be conducted in accordance the principles of the Declaration of Helsinki, the 
International Conference on Harmonization Guidance on Good Clinical Practice and the 
requirements of federal regulatory authorities regarding the conduct of clinical trials and the 
protection of human subjects. 
 
14.3.2.          Institutional Review Board/Ethics Committee 
The  Investigator  will  submit  the  protocol  and  subsequent  amendments,  the  Investigator’s 
Brochure and subsequent revisions, the informed consent and any other material used to inform 
patients/subjects  about  the  study  to  the  local  IRB  for  approval  prior  to  enrolling  any 
patient/subject into the study.   The IRB should be duly constituted according to applicable 
regulatory requirements.  Approval must be in the form of a letter signed by the Chairperson of 
the IRB or the Chairperson’s designee, must be on IRB stationary and must include the protocol 
by name and/or designated number.  IRB approval of the informed consent form must be clearly 
indicated in the IRB approval letter (indicating version/date of the version approved) or by other 
means utilized by the IRB (e.g., IRB approval stamp on the approved version of the form).  If an 
Investigator is a member of the IRB, the approval letter must stipulate that the Investigator did 
not participate in the final vote, although the Investigator may participate in the discussion of the 
study. 
 
The Investigator will also report the progress of the study to the IRB on an annual basis or more 
frequently as required by the IRB.  The Investigator will also promptly inform the IRB of: 
 
Serious adverse events that the Sponsor reports to regulatory authorities in an expedited 
manner 
 
All changes in research activity 
 
Protocol deviations, as required by Leadiant Biosciences or the IRB 
 
Other reports as required by the IRB 
 
The completion, termination, or discontinuation of the study, and 
 
A final summary of the final results at the conclusion of the study as required by the IRB 
Copies of all correspondence between the Investigator and the IRB will be provided to Leadiant 
Biosciences. 
14.3.3.          Informed Consent 
The Investigator will obtain written informed consent from each patient or the patient’s legal 
representative  prior  to  performing  any  study-related  procedures.    The  consent  form  used  to 

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document informed consent from study participants must contain the elements of informed consent 
as described in 21 CFR, Part 50. 
 
The study records (i.e., patient source documents and applicable study logs) will document that 
informed consent was obtained prior to patient participation in the study. 
 
14.3.4.          Health Insurance Portability and Accountability Act 
The Investigator must obtain authorization from the patient to use and/or disclose protected heath 
information (PHI) in compliance with the Health Insurance Portability and Accountability Act of 
1996 (HIPAA).  HIPAA authorization may be included in the informed consent form or a separate 
document. 
 
HIPAA authorization may be obtained as part of the informed consent form or in a separate document 
and will include: 
 
Identification of the parties that can use and disclose PHI 
 
Identification of the parties to whom PHI may be disclosed 
 
A description of the PHI 
 
A description of the purpose for use and disclosure 
 
Information pertaining to the patient’s rights related to authorization 
 
Information about the expiration of the authorization and how to revoke authorization 
 
A statement about what may happen if authorization is not provided 
 
A statement that once information has been disclosed, it may be disclosed again without 
further authorization. 
 
14.3.5.          Confidentiality of Subject Records 
It is the responsibility of the Investigator to insure that the confidentiality of all patients participating 
in the study and all of their medical information is maintained.  Case report forms (CRFs) and 
other documents submitted to Leadiant Biosciences must not contain the name of a study participant.  
Each patient in the study will be identified by a unique identifier that will be used on all CRF’s and 
any other material submitted to Leadiant Biosciences.   All CRFs and any identifying information 
must be kept in a secure location with access limited to the study staff directly participating in the 
study. 
 
Personal medical information may be reviewed by representatives of Leadiant Biosciences, of the 
IRB or of regulatory authorities in the course of monitoring the progress of the study.   Every 
reasonable effort will be made to maintain such information as confidential. 
 
The results of the study may be presented in reports, published in scientific journals or presented at 
medical meetings; however, patient names will never be used in any reports about the study. 
 
14.3.6.          Conflict of Interest 
The Investigator shall acknowledge, by signing the Investigator’s Statement/ Signature Page (Section 
15),  that  the  participation  in  this  clinical  study  by  the  Investigator  and  his/her sub-
investigators presents no conflict of interest with the study. 
 
14.4.  Investigator Obligations 
The Investigator is responsible to meet the obligations of clinical investigators as described in ICH 
GCP guidelines, the Declaration of Helsinki and U.S. federal regulations as defined in 21 CFR 
Parts 50, 54, 56, and 312. These obligations include, but are not limited to: 

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 
Protect the rights, safety and welfare of patients under the Investigator’s care 
 
Conduct the study in accordance with the approved study protocol 
 
Conduct the study in accordance with GCP guidelines and applicable federal, state and 
local regulations and laws 
 
Ensure that the staff involved with the conduct of the study are knowledgeable on the 
study agents used, the study protocol, study procedures, and reporting requirements 
 
Properly obtain   informed consent and HIPAA authorization from all patients enrolled 
using the current IRB-approved forms 
 
Supply study drug only to those patients who are participating in the study and are under 
the direct supervision of the Investigator or an authorized sub-investigator.   The Investigator 
must not supply the study drug to any person not authorized to receive it. 
 
Prepare and maintain accurate and complete case histories for all patients participating in 
this trail that document all study procedures performed and record all data required for this 
study protocol 
 
Report  all  serious  adverse  events  to  the  sponsor  and  IRB  (as  necessary)  within  the 
timeframes described in this protocol 
 
Report any changes in research activity and unanticipated problems involving risk to study 
participants promptly to the IRB 
 
Report all protocol deviations promptly to Leadiant Biosciences.  Significant deviations will 
require prompt notification to the IRB. 
 
Provide the IRB with copies of reports of serious adverse events submitted by Leadiant 
Biosciences to regulatory authorities in an expedited manner (e.g., IND Safety Reports) 
 
Provide Leadiant Biosciences with complete and accurate financial information to allow 
submission of complete and accurate certification and disclosure statements to FDA as 
required. 
 
The Investigator, or a licensed physician sub-investigator to which the Investigator has delegated 
responsibility, is required to administer or oversee the care of study patients/subjects and review 
study data (e.g., adverse events, laboratory data, treatment response data, etc.) in a timely manner. 
 
14.5.  Financial Disclosure 
All Investigators and sub-investigators listed on any FDA 1572 form supplied by the Investigator 
will disclose the following information as required by 21 CFR, Part 54: 
 
Any financial arrangement  entered into between  Leadiant Biosciences  and the  
Investigator/sub- investigator whereby the value of the compensation to the Investigator/sub-
investigator for conducting the study could be influenced by the outcome of the study. 
 
Any significant payments totaling more than $25,000 USD, exclusive of the costs of 
conducting this or other clinical studies, from Leadiant Biosciences, such as a grant to fund 
ongoing 
research, compensation in the form of equipment, retainer for ongoing consultation, or 
honoraria. 
 
Any proprietary interest in the test product. 
 
Any significant equity interest in Leadiant Biosciences in excess of $50,000 USD. 
 
The Investigator/sub-investigator shall promptly update financial disclosure information if any 
changes occur during the course of the study and for 1-year following completion of this study. 
This financial disclosure requirement includes the spouse and the dependent children of the 
Investigator/sub-investigator. 

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14.6.  Quality Control and Quality Assurance of Study Data 
 
14.6.1.          Monitoring and Audits 
During the course of the study, a clinical monitor assigned by Leadiant Biosciences will make 
regularly scheduled visits to the investigational site to review the progress of the study.  The 
frequency of monitoring visits will depend on the enrollment rate and performance at each site.  
During each visit, the monitor will review various aspects of the study including, but not limited to: 
 
Compliance with the protocol 
 
Compliance with the principles of Good Clinical Practice and regulatory requirements 
 
Review of written informed consent forms for patients enrolled 
 
Comparison of source documentation to data recorded on case report forms to assure the 
completeness and accuracy of data collected 
 
Continued acceptability of facilities and staff 
 
Assessment of proper study drug accountability and storage 
 
During scheduled monitoring visits, the Investigator and the investigational site staff must be 
available to meet with the study monitor in order to discuss the progress of the study, make necessary 
corrections to case report form entries, respond to data clarification requests and respond to any other 
study-related inquiries of the monitor. 
 
 
In addition to the above, representatives of Leadiant Biosciences’ auditing staff or government 
inspectors may review the conduct/results of the study at the investigational site.  The Investigator 
must promptly notify Leadiant Biosciences of any audit requests by regulatory authorities.  The 
Investigator will cooperate with the auditor(s), make available to the auditor all requested 
documentation, and ensure that issues detected during the course of these audits are satisfactorily 
resolved.    The Investigator will supply Leadiant Biosciences with copies of all documentation 
and correspondence related to regulatory agency audits as outlined in the Clinical Study Agreement 
between Leadiant Biosciences and the Investigator and/or Institution.  If the results of the audit 
result in an FDA-483 (or similar document from another regulatory agency), the Investigator will 
promptly provide a copy to Leadiant Biosciences and will provide a copy of the draft response to 
Leadiant Biosciences prior to submission to the regulatory agency. 
 
14.6.2.          Data Processing and Data Quality Assurance 
Case report form/electronic case report form entries will be reviewed for correctness against 
source document data by Leadiant Biosciences’ monitor.   If any entries into the CRF are incorrect, 
incomplete or illegible, the monitor will request the Investigator or the study site staff to make 
appropriate corrections.  Once the CRF/eCRF page is complete, it will be processed as described 
in the data management plan (DMP) for the study.  Data edit and consistency checks will be 
performed to review for missing, out of range, or inconsistent data. 
 
A quality control (QC) audit of the database will be performed to assure accuracy of the electronic 
database prior to database lock.   Discrepancies noted during the audit will be corrected.   Error 
rates determined during the QC audit must be within the acceptable error rate defined by the DMP 
prior to lock of the database. 
 
14.7.  Study Records 
The Investigator is responsible for preparing and maintaining adequate records to enable the conduct 
of the study to be documented.  Study records include, but are not limited to, regulatory 
documentation (Section 14.7.1) and patient records (Sections 14.7.2 and 14.7.3). 

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14.7.1.          Regulatory Documentation 
Prior to initiating the study, the Investigator will provide Leadiant Biosciences the following 
documents: 
    A signed FDA Form 1572 
    A current curriculum vitae for the Principal Investigator and each sub-investigator listed on the 
FDA Form 1572 
    Copy of the current medical licenses for the Investigator and physician sub-investigators 
 
Written IRB approval of the protocol, informed consent form and any other material provided 
to potential study participants with information about the study (e.g., advertisements) 
    A copy of the IRB-approved informed consent document and HIPAA authorization 
 
Current IRB membership list for the reviewing IRB and/or multiple project assurance number 
or an    IRB    organization    number    under    the    Federal    Wide    Assurance    program 
(www.ohrp.osophs.dhhs.gov) 
    A signed Investigator Protocol Agreement (Section 15 of study protocol) 
    Completed financial disclosure form for the Investigator and all sub-investigators 
 
Local reference laboratory documentation, including current laboratory certification, current 
laboratory normal values, and directors CV 
 
During the course of the study, the Investigator will maintain current records to document regulatory 
compliance with the study including: the study protocol and amendments, all versions of the 
Investigators Brochure in effect during study conduct, signed Investigator Agreement protocol 
page(s),  FDA 1572 forms, curricula vitae of the Investigator and sub-investigators, medical licenses 
of the Investigator and physician sub-investigators, financial disclosure of the Investigator  and  sub-
investigators,  IRB  approvals  of  the  protocol,  protocol  amendment(s), informed consent form(s), 
IRB membership list, IRB-approved informed consent form(s), IRB correspondence, protocol 
deviations, study logs (as provided by Leadiant Biosciences), drug dispensing and accountability 
records, safety reports, and all correspondence pertaining to the conduct of the study.  Regulatory 
documentation will be reviewed by Leadiant Biosciences or its representatives during monitoring 
visits to assure regulatory compliance. 
 
14.7.2.          Source Documents 
The Investigator will maintain records separate from the case report forms in the form of clinical 
charts, medical records, original laboratory, radiology and pathology reports, pharmacy records, 
patient diary cards, etc.  The Investigator will document in the clinic chart or medical record the 
name and number of the study and the date on which the patient signed informed consent prior to 
the patient’s participation in the study.  Source documents must completely reflect the nature and 
extent of the patient’s medical care, and must be available for verification against case report form 
entries when the Leadiant Biosciences or its representatives visit the investigational site.   All 
information obtained from source documents will be kept in strict confidentiality. 
 
14.7.3.          Case Report Forms 
All site-generated study data will be entered either onto case report forms (CRFs) supplied by 
Leadiant Biosciences or into an electronic Case Report Form (eCRF) via an electronic data capture 
(EDC) system.  The CRFs/eCRFs are not to be used as the primary method for collection of study 
data (unless otherwise described in this section of the study protocol) and CRF/eCRF entries must 
be supported by source documents maintained by the Investigator.  Only those site staff so authorized 
at the initiation of the study may enter data onto the case report forms or into an EDC system. 
 
For those studies using paper CRFs, all entries must be legible and made in black pen.  If an entry 
error is made, a single line will be placed through the incorrect entry.  The correct entry will then 

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be made, with the correction dated and initialed by the person making the entry.  Any corrections 
to data entered into the CRF must be made in such a way that the original entry is not obscured. 
Resolutions to data clarification forms (DCFs) issued by Leadiant Biosciences or its designated data 
management contractor will be maintained with the CRFs for each patient. 
 
The  Investigator  is responsible  for the  completeness  and accuracy of all  CRF/eCRF  data  as 
certified by the Investigator’s dated signature on designated CRF/eCRF pages. 
 
14.7.4.          Access to Study Records 
The Investigator will make available all records pertaining to the conduct of this study to Leadiant 
Biosciences and its representatives, and auditors from domestic and foreign regulatory authorities to 
facilitate monitoring visits and study audits. 
 
14.7.5.          Records Retention 
The Investigator will retain the records of the study for 15 years, or for 2 years following the date 
that a marketing application for the study drug is approved, or if no marketing application is filed, or 
if such an application is not approved, for 2 years after the IND has been closed.  Leadiant 
Biosciences will notify Investigators when retention of study records is no longer required.  All study 
records must be maintained in a safe and secure location that allows for timely retrieval, if needed. 
 
Study records that must be retained include copies of case report forms, signed informed consents, 
regulatory documentation, source documents, clinic charts, medical records, laboratory results, 
radiographic reports, and other study-specific documentation. 
 
Should the Investigator relocate or retire, or should there be any changes in the archival arrangements  
for  the  study  records,  Leadiant Biosciences  must  be  notified.     The  responsibility  for 
maintaining the study records may be transferred to another suitable individual, but Leadiant 
Biosciences must be notified of the identity of the individual assuming responsibility for maintaining 
the study records and the location of their storage.  If no other individual at the investigational site is 
willing to assume this responsibility, Leadiant Biosciences will assume responsibility for 
maintaining the study records. 
 
14.8.  Publication Policy 
Publication of study data is addressed in the Clinical Study Agreement between Leadiant 
Biosciences and the Investigator and/or Institution. 
 
14.9.  Financing and Insurance 
Financing and Insurance are addressed in the Clinical Study Agreement between Leadiant 
Biosciences and the Investigator and/or Institution. 

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15.     INVESTIGATOR AGREEMENT 
 
 
I  have  reviewed  Leadiant Biosciences’  Protocol  STP-2279-002,  entitled  “A  Study  of EZN-
2279 (Polyethylene Glycol Recombinant Adenosine Deaminase [PEG-rADA]) Administered as a 
Weekly Intramuscular Injection in Patients with Adenosine Deaminase (ADA)-Deficient Combined 
Immunodeficiency” and agree that it contains all the information necessary to conduct the study as 
required.   I will conduct the trial in accordance with the principles of ICH Good Clinical Practice 
and the Declaration of Helsinki. 
 
I will maintain as confidential all written and verbal information provided to me by Leadiant 
Biosciences, including but not limited to, the protocol, case report forms, Investigators’ Brochure,  
material  supplied  at  investigator  meetings,  minutes  of  teleconferences,  etc.    Such material will 
only be provided as necessary to site personnel involved in the conduct of the trial, the IRB or IEC, 
or local regulatory authorities. 
 
I will obtain written informed consent from each prospective trial patient or each prospective trial 
patient’s legal representative prior to conducting any protocol-specified procedures.  The consent 
form used will have the approval of the local IRB or IEC. 
 
I will maintain adequate source documents and record all observations, treatments and procedures 
pertinent to trial patients in their medical records.  I will accurately complete the case report forms 
supplied by Leadiant Biosciences in a timely manner.  I will ensure that my facilities and records 
will be available for inspection by representatives of Leadiant Biosciences, the local IRB or IEC or 
local regulatory authorities.  I will ensure that I and my staff are available to meet with 
representatives of Leadiant Biosciences during regularly scheduled monitoring visits. 
 
I will notify Leadiant Biosciences, or its designated representative, within 24 hours of any serious 
adverse events.  Following this notification, a written report describing the serious adverse event will 
be provided to Leadiant Biosciences, or its designated representative, as soon as possible, but no later 
than three days following the initial notification. 
 
My signature below indicates that my participation in this clinical study presents no conflict of 
interest for me or my sub-investigators with the study. 
 
 
 
 
 
Investigator’s Name (Print) 
 
 
 
 
Investigator’s Signature 
Date 

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16. 
REFERENCES 
1.   Booth  C,  Gaspar  HB.  Pegademase  bovine  (PEG-ADA)  for  the  treatment  of  infants  and 
children   with   severe   combined   immunodeficiency   (SCID).   Biologics   Targets   Ther. 
2009;3:349-358. 
 
2.   Gaspar HB, Aiuti A, Porta F, Candotti F, Hershfield MS, Notarangelo LD. How I treat ADA 
deficiency. Blood. 2009;114:3524-3532. 
 
3.   Arredondo-Vega  FX,  Santisteban  I,  Daniels  S,  Toutain  S,  Hershfield  MS.  Adenosine 
deaminase  deficiency:  genotype-phenotype  correlations  based  on  expressed  activity  of 
29 mutant alleles. Am J Hum Genet. 1998;63:1049-1059. 
 
4.   Hershfield 
MS. 
Immunodeficiency 
caused 
by 
adenosine 
deaminase 
deficiency. 
Immunol Allergy Clin North Am. 2000;20:161-175. 
 
5.   Booth C, Hershfield M, Notarangelo L, et al. Management options for adenosine deaminase 
deficiency;   proceedings   of   the   EBMT   satellite   workshop   (Hamburg,   March   2006). 
Clin Immunol. 2007;123:139-147. 
 
6.   Qasim W, Gaspar HB, Thrasher AJ. Gene therapy for severe combined immune deficiency. 
Expert Rev Mol Med. 2004;6:1-15. 
 
7.   Gaspar HB, Thrasher AJ. Gene therapy for severe combined immunodeficiencies. Expert Opin 
Biol Ther. 2005;5:1175-1182. 
 
8.   Titman P, Pink E, Skucek E, et al. Cognitive and behavioral abnormalities in children after 
hematopoietic   stem   cell   transplantation   for   severe   congenital   abnormalities.   Blood. 
2008;112:3907-3913. 
 
9.   Buckley RH. Molecular defects in human severe combined immunodeficiency and approaches 
to immune reconstitution. Annu Rev Immunol. 2004;22:625-655. 
 
10. Kohn DB, Candotti F. Gene therapy fulfilling its promise. N Engl J Med. 2009;360:518-521. 
 
11. Notarangelo   LD,   Forino   C,   Mazzolari   E.   Stem   cell   transplantation   in   primary 
immunodeficiencies. Curr Opin Allergy Clin Immunol. 2006;6:443-448. 
 
12. Nofech-Mozes  Y,  Blaser  SI,  Kobayashi  J,  Grunebaum  E,  Roifman  CM.  Neurologic 
abnormalities in patients with adenosine deaminase deficiency. Pediatr Neurol. 2007;37:218- 
221. 
 
13. Albuquerque  W,  Gaspar  HB.  Bilateral  sensorineural  deafness  in  adenosine  deaminase- 
deficient severe combined immunodeficiency. J Pediatr. 2004;144:278-280. 
 
14. Hönig M, Albert MH, Schulz A, et al. Patients with adenosine deaminase deficiency surviving 
after hematopoietic stem cell transplantation are at high risk of CNS complications. Blood. 
2007;109:3595-3602. 
 
15. Taupin P. Drug evaluation: ADA-transduced hematopoietic stem cell therapy for ADA-SCID. 
IDrugs. 2006;9:423-430. 
 
16. Blaese RM, Culver KW, Miller AD, et al. T lymphocytedirected gene therapy for ADA
SCID: Initial trial results after 4 years. Science. 1995;270:475-480. 

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17. Bordignon C, Notarangelo LD, Nobili N, et al. Gene therapy in peripheral blood lymphocytes 
and bone marrow for ADA- immunodeficient patients. Science. 1995;270:470-475. 
 
18. Hoogerbrugge PM, van Beusechem VW, Fischer A, et al. Bone marrow gene transfer in three 
patients with adenosine deaminase deficiency. Gene Ther. 1996;3:179-183. 
 
19. Kohn DB, Weinberg KI, Nolta JA, et al. Engraftment of gene-modified umbilical cord blood 
cells in neonates with adenosine deaminase deficiency. Nat Med. 1995;1:1017-1023. 
 
20. Onodera M, Ariga T, Kawamura N, et al. Successful peripheral T-lymphocytedirected gene 
transfer for a patient with severe combined immune deficiency caused by adenosine deaminase 
deficiency. Blood. 1998;91:30-36. 
 
21. Kohn DB. Gene therapy for childhood immunological diseases. Bone Marrow Transplant. 
2008;41:199-205. 
 
22. Kohn DB, Hershfield MS, Carbonaro D, et al. T lymphocytes with a normal ADA gene 
accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in 
ADA-deficient SCID neonates. Nat Med. 1998;4:775-780. 
 
23. Aiuti A, Cattaneo F, Galimberti S, et al. Gene therapy for immunodeficiency due to adenosine 
deaminase deficiency. N Engl J Med. 2009;360:447-458. 
 
24. Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, et al. Gene therapy of human severe 
combined immunodeficiency (SCID)-X1 disease. Science. 2000;288:669-672. 
 
25. Aiuti  A,  Slavin  S,  Aker  M,  et  al.  Correction  of  ADA-SCID  by  stem cell  gene  therapy 
combined with nonmyeloablative conditioning. Science. 2002;296:2410-2413. 
 
26. Gaspar HB,  Parsley KL, Howe  S, et al.  Gene therapy of X-linked  severe  combined 
immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet. 2004;364:2181- 
2187. 
 
27. McCormack MP, Rabbitts T. Activation of the T-cell oncogene LMO2 after gene therapy for 
X-linked severe combined immunodeficiency. N Engl J Med. 2004;350:913-922. 
 
28. Hacein-Bey-Abina S, Le Deist F, Carlier F, et al. Sustained correction of X-linked severe 
combined immunodeficiency by ex vivo gene therapy. N Engl J Med. 2002;346:1185-1193. 
 
29. Hacein-Bey-Abina S, Garrigue A, Wang GP, et al. Insertional oncogenesis in 4 patients after 
retrovirus-mediated gene therapy of SCID-X1. J Clin Invest. 2008;118:3132-3142. 
 
30. Howe SJ, Mansour MR, Schwarzwaelder K, et al. Insertional mutagenesis combined with 
acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. 
J Clin Invest. 2008;118:3143-3150. 
 
31. Qasim W, Gaspar HB, Thrasher AJ. Progress and prospects: gene therapy for inherited 
immunodeficiencies. Gene Ther. 2009;1-7. (Epub ahead of print) 
 
32. Wilson JM. Adverse events in gene transfer trials and an agenda for the new year. Human 
Gene Ther. 2008;19:1-2. (editorial) 
 
33. Puck JM, Malech HL. Gene therapy for immune disorders: good news tempered by bad news. 
J Allergy Clin Immunol. 2006;117:865-869. 

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34. Board of the European Society of Gene and Cell Therapy, Executive Committee of the 
Clinigene Network of Excellence, Executive of the Consert Integrated Project. Case of leukaemia 
associated with X-linked severe combined immunodeficiency gene therapy trial in London. 
Human Gene Ther. 2008;19:3-4. (commentary) 
 
35. Aiuti A, Ficara F, Cattaneo F, Bordignon C, Roncarolo MG. Gene therapy for adenosine 
deaminase deficiency. Curr Opin Allergy Clin Immunol. 2003;3:461-466. 
 
36. Gaspar HB, Bjorkegren E, Parsley K, et al. Successful reconstitution of immunity in ADA- 
SCID by stem cell gene therapy following cessation of PEG-ADA and use of mild 
preconditioning. Mol Ther. 2006;14:505-513. 
 
37. Muul LM, Tuschong LM, Soenen SL, et al. Persistence and expression of the adenosine 
deaminase gene for 12 years and immune reaction to gene transfer components: long-term results 
of the first clinical gene therapy trial. Blood. 2003;101:2563-2569. 
 
38. Sauer AV, Aiuti A. New insights into the pathogenesis of adenosine deaminase-severe 
combined immunodeficiency and progress in gene therapy. Curr Opin Allergy Clin Immunol. 
2009;1-7. (Epub ahead of print) 
 
39. MacLaren RE, Ali RR, Thrasher AJ. Risks of gene therapy should be weighed against lack of 
alternatives for many disease. Br Med J. 2005;330:791. (letter) 
 
40. ADAGEN® 
(pegademase 
bovine) 
Injection 
package 
insert, 
2008. Available 
at: 
http://www.access 
data.fda.gov/drugsatfda_docs/label/2008/019818s042lbl.pdf. Accessed 2 September 2009. 
 
41. Hershfield MS. Combined immune deficiencies due to purine enzyme defects. In: Stiehm ER, 
Ochs HD, Winkelstein JA (eds). Immunologic Disorders in Infants & Children. 5th ed. 
Philadelphia: Elsevier Saunders; 2004:480-504. 

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Appendix 1  Study Activities 
 
 
 
Procedure 
 
 
Screening
Adagen® Lead-In Period 
Week 1
Week 2 
Week 3 
Weeks 4+
Adagen® Pharmacokinetics 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Informed assent/consent 
X 
Demographics 
X 
Disease background/history (Prior 
Treatments, Adagen® Dose Adagen® 
AEs, Infectious complications, and 
Hospitalizations) 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Medical history 
X 
X 
 
Medication history 
X 
Physical examination 
X 
X 
Vital signs 
X 
X 
Performance status 
X 
X 
Height, weight, growth curve 
X 
X 
Pregnancy test 
X 
Serum chemistry 
X 
X 
Hematology 
X 
X 
 
Urinalysis 
X 
X 
Total trough erythrocyte dAXP 
Xa 
X 
X 
X 
X 
X 
Trough ADA activity 
Xa 
X 
X 
X 
X 
X 
Full PK profilej 
X 
X 
X 
X 
X 
X 
B-/T-/NK-lymphocyte subset 
X 
Quantitative immunoglobulins 
X 
Antibody titers (binding, 
neutralizing), anti-PEG antibodies 
X 
X 
 
 
 
X 
 
 
 
 
 
 
Clinical status 
Infectious complications 
Hospitalizations 
 
 
 
 
 
X 
 
 
 
 
 
 
Adverse Events 
 
Concomitant medications/procedures 
X 
X 
Adagen® administration (± 1 day) 
X 
X 
X 
X 
X 
Adagen® dose/regimen adjustment 
X 
Xb 
Xc 
Xc 
 
EZN-2279 administration (± 1 day) 
a – if necessary, only for patients maintained on a once weekly dose regimen;  b – if necessary, only patients on a twice weekly or greater dose regimen; c – if necessary based upon  meeting inclusion 
criteria for trough dAXP and ADA activity; patient requires trough dAXP ≤ 0.02 μmol/mL and trough ADA activity  15 μmol/h/mL on 2 consecutive weekly measurements to proceed to Adagen 
®pharmacokinetics; j- full PK profile conducted only on patients ≥ 10 years of age.  Patients < 10 years of age will have limited PK sampling of trough and 48 hour post dosing only. 

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Procedure 
EZN-2279 Treatment Period (Weeks 1 through 8) 
 
Week T-1 
(Day1) 
Week T-2 
(Day 8) 
Week T-3 
(Day 15) 
Week T-4 
(Day 22) 
Week T-5 
(Day 29) 
 
Week T-6 
(Day 36) 
Week T-7 
(Day 43) 
Week T-8 
(Day 50) 
EZN-2279 
Dose 
Adjustmente 
Informed assent/consent 
Demographics 
Disease background/history 
Prior Treatments 
Adagen® Dose 
Adagen® AEs 
Infectious complications 
Hospitalizations 
 
 
 
 
 
 
 
 
 
Medical history 
Medication history 
 
 
Physical examination 
X 
X 
Vital signs 
X 
X 
Performance status 
X 
X 
Height, weight, growth curve 
X 
X 
 
Pregnancy test 
Serum chemistry 
X 
X 
Hematology 
X 
X 
 
Urinalysis 
X 
Total trough erythrocyte dAXP 
X 
X 
X 
X 
X 
Trough ADA activity 
Xd 
X 
X 
X 
X 
Full PK profilej 
B-/T-/NK-lymphocyte subset 
X 
Quantitative immunoglobulins 
X 
Antibody titers (binding, neutralizing), 
anti-PEG antibodies 
 
X 
 
X 
 
 
 
 
 
 
Clinical status 
Infectious complications 
Hospitalizations 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Adverse Events 
Concomitant medications/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
Adagen® administration (± 1 day) 
EZN-2279 administration (± 1 day) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
d – trough sample for ADA activity is also the 168 hour full PK sample 
e – prior to week T-9  if necessary based upon dAXP and ADA results from weeks T-7 and T-8; if adjustment made, patients return to week T-5 

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Procedure 
EZN-2279 Treatment Period (Weeks 9 through 13) 
Week T-9
Week T-10
Week T-11
Week T-12
Week T-13
Day 57
Day 58
Day 59
Day 60
Day 61
Day 62
Day 63 
Day 64
Day 71
Day 78
Day 85
Informed assent/consent 
Demographics 
Disease background/history 
Prior Treatments 
Adagen® Dose 
Adagen® AEs 
Infectious complications 
Hospitalizations 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
Medication history 
Physical examination 
X 
X 
Vital signs 
X 
 
X 
Performance status 
X 
X 
Height, weight, growth curve 
X 
X 
Pregnancy test 
Serum chemistry 
X 
X 
Hematology 
X 
X 
Urinalysis 
Total trough erythrocyte dAXP 
X 
X 
X 
X 
Trough ADA activity 
X 
Xf 
X 
X 
Full PK profilej 
X 
X 
X 
X 
X 
X 
X 
B-/T-/NK-lymphocyte subset 
X 
Quantitative immunoglobulins 
X 
Antibody titers (binding, neutralizing), 
anti-PEG antibodies 
 
 
 
 
 
 
 
X 
 
 
 
Clinical status 
Infectious complications 
Hospitalizations 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
Adverse Events 
Concomitant medications/procedures 
X 
X 
X 
X 
Adagen® administration (± 1 day) 
EZN-2279 administration (± 1 day) 
X 
X 
X 
X 
X 
f – trough sample for ADA activity is also the 168 hour full PK sample 
j – Full PK profile conducted only on patients ≥ 10 years of age.  Patients < 10 years of age will have limited PK sampling of trough and 48 hour post dosing only. 

Leadiant Biosciences, Inc. 
Protocol STP-2279-002 
CONFIDENTIAL
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Procedure 
EZN-2279 Treatment Period (Weeks 14 through 21) 
 
EZN-2279 
Maintenanceg 
End of 
Study/Early 
Discontinuation
30-Day Early 
Discontinuation 
Follow-upi 
Week 
T-14 
Week
T-15
Week
T-16
Week
T-17
Week
T-18
Week 
T-19 
Week
T-20
Week 
T-21
Day 92 
Day 99 
Day 106 
Day 113 
Day 120 
Day 127 
Day 134 
Day 141 
Informed assent/consent 
Demographics 
 
 
Disease background/history 
Prior Treatments 
Adagen® Dose 
Adagen® AEs 
Infectious complications 
Hospitalizations 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
 
Medication history 
Physical examination 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
X 
Height, weight, growth curve 
X 
X 
X 
X 
X 
Pregnancy test 
Serum chemistry 
 
X 
 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
Urinalysis 
 
 
X 
X 
X 
X 
Total trough erythrocyte dAXP 
X 
X 
X 
X 
X 
X 
Trough ADA activity 
X 
X 
X 
X 
X 
X 
Full PK profilej 
 
 
B-/T-/NK-lymphocyte subset 
X 
X 
X 
Quantitative immunoglobulins 
X 
X 
X 
Antibody titers (binding, 
neutralizing), anti-PEG antibodies 
 
 
 
 
 
 
 
X 
X 
X 
 
Clinical status 
Infectious complications 
Hospitalizations 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Overall Survival 
 
 
X 
X 
X 
Adverse Events 
----------------------------------------------------------------------------------------------------------------------------------------------------
Concomitant medications/procedures  
X 
X 
X 
 
X 
X 
X 
X 
Adagen® administration (± 1 day) 
 
 
EZN-2279 administration (± 1 day) 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
g - assessments every 13 weeks ± 3 weeks; h – dosing of EZN -2279 continues once a week ± 1 day; i – only for patients who discontinue the study early 

Leadiant Biosciences, Inc. 
Protocol STP-2279-002 
CONFIDENTIAL
75 of 80
Version 3.0 
August 23, 2017 – FINAL 
 
 
 
 
Appendix 2. Blood Sampling Schedule and Collection Volumes 
 
 
Routine Safety 
Study Assessments 
 
 
Total* 
 
Test: 
Hematology 
(incl. ALC) 
Chemistry 
dAXP* 
Trough 
ADA* 
Full PK 
ADA 
 
Immunogenicity* 
Quant. 
Ig 
Lymph 
subset 
 
 
 
Volume per Sample (mL) 
 
 
 
3 
 
 
4 
 
 
2 
 
 
2 
 
 
2 
 
 
 
2 
 
 
3.5 
 
 
4 
Patient
s ≥ 10 
years 
of age 
Patient
s < 10 
years 
of age 
 
 
Tube Type 
 
EDTA 
(lavender) 
Gel 
separator 
(tiger top) 
EDTA 
(lavender) 
EDTA 
(lavender) 
EDTA 
(lavender) 
 
EDTA 
(lavender) 
Gold top 
SST 
EDTA 
(lavender) 
 
 
Study Days 
 
 
 
 
 
 
 
 
 
 
Screening 
3 
4 
 
 
 
2 
 
 
9 
9 
Adagen® Patients on 1x 
week dosing only 
 
 
2 
2 
 
 
 
 
4 
4 
Adagen® Lead-in Week -1 
 
 
2 
2 
 
 
 
 
4 
4 
Adagen® Lead-in Week -2 
 
 
2 
2 
 
 
 
 
4 
4 
Adagen® Dose Adjustment 
(if necessary) 
 
 
 
 
 
 
 
 
0 
0 
Adagen® Lead-in Week -3 
(if necessary) 
 
 
2 
2 
 
 
 
 
4 
4 
Adagen® Lead-in Week -4 
(if necessary) 
 
 
2 
2 
 
 
 
 
4 
4 
Adagen® PK - Day 1 (0 hrs) 
3 
4 
2 
2 
 
2 
3.5 
4 
20.5 
20.5 
Adagen® PK - Day 2 (24 hrs) 
 
 
 
 
2 
 
 
 
2 
0 
Adagen® PK - Day 3 (48 hrs)  
 
 
 
2 
 
 
 
2 
2 
Adagen® PK - Day 4 (72 hrs) 
 
 
 
 
2 
 
 
 
2 
0 
Adagen® PK - Day 5(96 hrs) 
 
 
 
 
2 
 
 
 
2 
0 
Adagen® PK - Day 6 (120 hrs)  
 
 
 
2 
 
 
 
2 
0 
Adagen® PK - Day 7 (144 hrs)  
 
 
 
2 
 
 
 
2 
0 
Week T-1 (168 hrs) 
3 
4 
2 
2 
 
2 
3.5 
4 
20.5 
20.5 

Leadiant Biosciences, Inc. 
Protocol STP-2279-002 
CONFIDENTIAL
76 of 80
Version 3.0 
August 23, 2017 – FINAL 
 
 
 
 
 
Routine Safety 
Study Assessments 
 
 
Total* 
 
Test: 
Hematology 
(incl. ALC) 
Chemistry 
dAXP* 
Trough 
ADA* 
Full PK 
ADA 
 
Immunogenicity* 
Quant. 
Ig 
Lymph 
subset 
 
 
 
Volume per Sample (mL) 
 
 
 
3 
 
 
4 
 
 
2 
 
 
2 
 
 
2 
 
 
 
2 
 
 
3.5 
 
 
4 
Patient
s ≥ 10 
years 
of age 
Patient
s < 10 
years 
of age 
 
 
Tube Type 
 
EDTA 
(lavender) 
Gel 
separator 
(tiger top) 
EDTA 
(lavender) 
EDTA 
(lavender) 
EDTA 
(lavender) 
 
EDTA 
(lavender) 
Gold top 
SST 
EDTA 
(lavender) 
 
 
Week T-2 
 
 
 
 
 
 
 
 
0 
0 
Week T-3 
 
 
2 
2 
 
2 
 
 
6 
6 
Week T-4 
 
 
 
 
 
 
 
 
0 
0 
Week T-5 
3 
4 
2 
2 
 
 
 
 
11 
11 
Week T-6 
 
 
 
 
 
 
 
 
0 
0 
Week T-7 
 
 
2 
2 
 
 
 
 
4 
4 
Week T-8 
 
 
2 
2 
 
 
 
 
4 
4 
EZN-2279 Dose Adjustment 
(if necessary) 
 
 
Repeat Weeks T-5
through T-8 sampling 
 
 
 
 
 
 
Week T-9 - Day 57 (0 hrs) 
3 
4 
2 
2 
 
 
3.5 
4 
18.5 
18.5 
Week T-9 - Day 58 (24 hrs) 
 
 
 
 
2 
 
 
 
2 
0 
Week T-9 - Day 59 (48 hrs) 
 
 
 
 
2 
 
 
 
2 
2 
Week T-9 - Day 60 (72 hrs) 
 
 
 
 
2 
 
 
 
2 
0 
Week T-9- Day 61 (96 hrs) 
 
 
 
 
2 
 
 
 
2 
0 
Week T-9 - Day 62 (120 hrs)  
 
 
 
2 
 
 
 
2 
0 
Week T-9 - Day 63 (144 hrs)  
 
 
 
2 
 
 
 
2 
0 
Week T-10 (168 hrs) 
 
 
2 
2 
 
2 
 
 
6 
6 
Week T-11 
 
 
2 
2 
 
 
 
 
4 
4 
Week T-12 
 
 
 
 
 
 
 
 
0 
0 
Week T-13 
3 
4 
2 
2 
 
 
 
 
11 
11 

Leadiant Biosciences, Inc. 
Protocol STP-2279-002 
CONFIDENTIAL
77 of 80
Version 3.0 
August 23, 2017 – FINAL 
 
 
 
 
 
Routine Safety 
Study Assessments 
 
 
Total* 
 
Test: 
Hematology 
(incl. ALC) 
Chemistry 
dAXP* 
Trough 
ADA* 
Full PK 
ADA 
 
Immunogenicity* 
Quant. 
Ig 
Lymph 
subset 
 
 
 
Volume per Sample (mL) 
 
 
 
3 
 
 
4 
 
 
2 
 
 
2 
 
 
2 
 
 
 
2 
 
 
3.5 
 
 
4 
Patient
s ≥ 10 
years 
of age 
Patient
s < 10 
years 
of age 
 
 
Tube Type 
 
EDTA 
(lavender) 
Gel 
separator 
(tiger top) 
EDTA 
(lavender) 
EDTA 
(lavender) 
EDTA 
(lavender) 
 
EDTA 
(lavender) 
Gold top 
SST 
EDTA 
(lavender) 
 
 
Week T-14 
 
 
 
 
 
 
 
 
0 
0 
Week T-15 
 
 
2 
2 
 
 
 
 
4 
4 
Week T-16 
 
 
 
 
 
 
 
 
0 
0 
Week T-17 
3 
4 
2 
2 
 
 
 
 
11 
11 
Week T-18 
 
 
 
 
 
 
 
 
0 
0 
Week T-19 
 
 
2 
2 
 
 
 
 
4 
4 
Week T-20 
 
 
 
 
 
 
 
 
0 
0 
Week T-21 
3 
4 
2 
2 
 
2 
3.5 
4 
20.5 
20.5 
TOTAL 
 
 
 
 
 
 
 
 
244 
178 
Maintenance 
(Every 13 weeks) 
 
3 
4 
2 
2 
 
 
2 
3.5 
4 
20.5 
20.5 
* at timepoints when immunogenicity, dAXP and ADA activity sampling is performed, only 2 x 2mL EDTA tubes will need to be collected 

Leadiant Biosciences, Inc. 
Protocol STP-2279-002 
CONFIDENTIAL
Version 3.0 
August 23, 2017 - FINAL 
78 of 80
 
 
 
Appendix 3  Performance Status Criteria 
 
Karnofsky (≥16 years old) 
Lansky (<16 years old) 
Score 
Description 
Score
Description
100 
Normal, no complaints, no 
evidence of disease 
100
Fully active, normal
90 
Able to carry on normal activity,
minor signs or symptoms of 
disease 
90
Minor restrictions in physically 
strenuous activity 
80 
Normal activity with effort; some
signs or symptoms of disease 
80
Active, but tires more quickly 
70 
Cares for self, unable to carry on
normal activity or do active work 
70
Both greater restriction of and less 
time spent in play activity 
60 
Required occasional assistance, 
but is able to care for most of 
his/her needs 
60 
Up and around, but minimal active 
play; keeps busy with quieter activities 
50 
Requires considerable assistance
and frequent medical care 
50
Gets dressed, but lies around much of 
the day; no active play, able to 
participate in all quiet play and 
activities 
40 
Disabled, requires special care
and assistance 
40
Mostly in bed; participates in quiet 
activities 
30 
Severely disabled, hospitalization
indicated. Death not imminent. 
30
In bed; needs assistance even for quiet 
play 
20 
Very sick, hospitalization 
indicated; death not imminent 
20
Often sleeping; play entirely limited to 
very passive activities 
10 
Moribund, fatal processes 
progressing rapidly 
10
No play; does not get out of bed 
0 
Dead 
0
Dead

Leadiant Biosciences, Inc. 
Protocol STP-2279-002 
CONFIDENTIAL
Version 3.0 
August 23, 2017 - FINAL 
79 of 80
 
 
 
Appendix 4  Adagen® Lead-in Dose Consolidation/Adjustment Schematic 
 
 

Leadiant Biosciences, Inc. 
Protocol STP-2279-002 
CONFIDENTIAL
Version 3.0 
August 23, 2017 - FINAL 
80 of 80
 
 
 
Appendix 5  EZN-2279 Dose Adjustment Schematic