Gene Transfer For Patients With Sickle Cell Disease Using A Gamma Globin Lentivirus Vector: An Open-Label Phase 1 / 2 Pilot Study
Phase: PHASE1
Conditions: Anemia, Sickle Cell
Sponsor: Children's Hospital Medical Center, Cincinnati

Title:  
Gene Transfer for Patients With Sickle Cell Disease Using a Gamma Globin Lentivirus Vector: An 
Open-Label Phase 1/2 Pilot Study PROTOCOL NO.: ARU-1801  Phl  01 
 
Protocol version 13(13-Aug-2021)   
 
NCT Number: 
02186418 
 
IRB approval: 
30-Sep-2021 

 
 
 
 
CLINICAL STUDY PROTOCOL 
IND: 15832 
 
Gene Transfer for Patients With Sickle Cell Disease Using a Gamma 
Globin Lentivirus Vector: An Open-Label Phase 1/2 Pilot Study 
PROTOCOL NO.: ARU-1801_Ph1_01 
Sponsor: 
Aruvant Sciences, GmbH 
Viaduktstrasse 8, 4051 
Basel, Switzerland 
Sponsor Contact: 
Will Chou, MD 
Chief Executive Officer 
Aruvant Sciences, Inc. 
151 West 42nd Street, 14th Floor 
New York, NY 10036 
Medical Monitor: 
Cynthia Gonzales, MD 
PPD 
Medical Director, Pharmacovigilance 
Wilmington, NC 28401-3331 USA 
Telephone: +1 800-201-8725 
Version of Protocol:  
Version 13.0 
Date of Protocol:  
13 Aug 2021 

 
 
 
 
Previous Date and Version: 
Version 12.0 (17 May 2021) 
Version 11.0 (10 March 2021) 
Version 10.0 (21 September 2020) 
Version 9.0 (11 August 2020) 
Version 8.0 (10 October 2019) 
Version 7.0 (01 October 2019) 
Version 6.0 (22 May 2019) 
Version 5.0 (19 March 2019) 
Version 4.1 (16 January 2019) 
Version 4.0 (17 August 2017) 
Version 3.0 (16 June 2017 
Version 2.9 (06 December 2016) 
Version 2.8 (06 October 2016) 
Version 2.7 (21 April 2016) 
Version 2.6 (06 August 2015) 
Version 2.5 (16 June 2015) 
Version 2.5 (16 April 2015) 
Version 2.4 (03 March 2015) 
Version 2.3 (31 December 2014) 
Version 2.2 (25 September 2014) 
Version 2.1 (10 July 2014) 
Version 2.0 (21 April 2014) 
Version 1.0 (30 January 2014) 

 
 
 
 
Aruvant Sciences, GmbH (ASG), a Swiss limited liability company, is the Sponsor of this 
study. Aruvant Sciences, Inc, a Delaware corporation and an affiliate of ASG, has been 
engaged by ASG to manage the day-to-day operations of the study. All references to Sponsor, 
as defined herein, shall refer to Aruvant Sciences, Inc, acting pursuant to a services 
agreement with ASG. 
CONFIDENTIAL  
All financial and nonfinancial support for this study will be provided by Aruvant Sciences. 
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed, 
written consent of Aruvant Sciences. 
The study will be conducted according to the International Council for Harmonisation 
harmonised tripartite guideline E6: Good Clinical Practice.  
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8/20/2021

Aruvant Sciences, GmbH 
ARU-1801 
Protocol: ARU-1801_Ph1_01 (Version 13.0) 
13 August2021 
Page 5 
Declaration of Investigator 
I have read and understood all sections of the protocol entitled “Gene Transfer for Patients 
With Sickle Cell Disease Using a Gamma Globin Lentivirus Vector: An Open-Label 
Phase 1/2 Pilot Study” and the accompanying investigator’s brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 13.0, 13 Aug 2021, the International Council for 
Harmonisation harmonised tripartite guideline E6: Good Clinical Practice and all applicable 
government regulations. I will not make changes to the protocol before consulting with 
Aruvant Sciences or implement protocol changes without independent ethics committee 
approval except to eliminate an immediate risk to subjects. I agree to administer study 
treatment only to subjects under my personal supervision or the supervision of a 
subinvestigator. 
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Subject identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Aruvant Sciences. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 

Aruvant Sciences, GmbH 
ARU-1801 
Protocol: ARU-1801_Ph1_01 (Version 13.0) 
13 August2021 
Page 6 
Protocol Amendment Summary of Changes 
Protocol Version 13.0 (13 Aug 2021) 
Summary of Change 
Rationale 
Protocol Sections 
Affected 
Test Melphalan Dose 
• 
Removed optional test dose of 
melphalan. 
• 
The test dose is no longer needed 
to inform melphalan 
pharmacokinetics because 
predictive modeling will now be 
used. 
Sections 2.1.3, 3.1, 6.1, 
6.6, 7.5, 7.6.3, and the 
Schedule of Events 
(Table 13-1 and 
Table 13-1 footnote x) 
Exploratory Objectives 
• 
Clarified the objective regarding 
melphalan pharmacokinetics in 
patients with SCD. 
• 
The wording of this objective was 
revised to reflect removal of 
melphalan test dose. 
Section 2.1.3 
Melphalan Dosing 
• 
For all subjects receiving 
melphalan, changed melphalan 
dosing from a dose of 140 mg/m2 
of body surface area to model-
informed precise dosing for 
subjects with a predicted 
melphalan AUC <8 μg.h/mL and 
added supportive rationale. 
• 
Patients with SCD may have 
higher than normal renal GFR, 
which can result in suboptimal 
exposure to melphalan 
conditioning. Proposed model 
informed dosing is based on a 
published model, as well as 
melphalan PK, and engraftment 
data from the first 4 subjects 
treated with ARU-1801.  
Sections 3.1, 3.1.1, 5.5.3, 
6.6 and the Schedule of 
Events (Table 13-1), 
References, and 
Appendices 5 and 6 
CD34+ Kinetics Visit 
• 
The CD34+ Kinetics Clearance 
and Kinetics visits have been 
removed  
• 
The plerixafor mobilization 
without apheresis is no longer 
necessary to understand subject’s 
mobilization pattern. CD34+ 
counts from peripheral blood will 
continue to be measured as part of 
Days 1 and 2 of HSC Collection 
Section 3.1.1, 5.5.1, 6.1, 
6.3.3, and 6.5.3 and the 
Schedule of Events 
(Table 13-1) 
Neutrophil and Platelet Recovery 
• 
Adjusted the definition of 
neutrophil and platelet recovery 
• 
Modified to align with more 
broadly accepted definitions. 
Section 2.2.1 
Feasibility Endpoints 
• 
Clarified that optional leukopack 
collection for research purposes is 
not included in the feasibility 
endpoint on CD34+ cell 
collection. 
• 
Administrative clarifications. 
Section 2.2.1 

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Protocol: ARU-1801_Ph1_01 (Version 13.0) 
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Summary of Change 
Rationale 
Protocol Sections 
Affected 
• 
Clarified that subjects must have 
an average VCN of >0.01 copies 
per cell for the feasibility endpoint 
on gene-marked cells 
Proportion Anti-sickling Hemoglobin 
• 
Changed the endpoint on 
proportion anti-sickling 
hemoglobin from Month 6-12 to 
Month 6-24 
• 
Sustained levels of anti-sickling 
hemoglobin are of clinical 
relevance 
Sections 2.2.2 and 7.2 
Opioid Use 
• 
Removed secondary endpoint of 
change in disease severity from 
baseline as measured by opioid 
use 
• 
Added an exploratory endpoint on 
change in VOEs requiring 
parenteral opoids 
• 
Updated wording “opiate” to 
“opioid” for consistent word use 
throughout 
• 
At home opioid use has proven 
difficult to accurately capture. 
• 
Data were captured in different 
ways in the pre-treatment and 
post-treatment periods, resulting 
in the information being captured 
not being comparable. 
• 
VOEs requiring parenteral opioid 
use can be captured accurately and 
are of clinical relevance. 
Sections 2.2.2, 2.2.3, 
6.5.3, 7.2, 7.3, 7.6.2, 
7.6.4, and the Schedule 
of Events (Table 13-1) 
Breastfeeding and Pregnancy 
• 
Clarified that subjects should not 
become pregnant or breastfeed 
from the time of consent through 1 
year after ARU-1801 
• 
The previous exclusion criteria did 
not specify restrictions in the pre-
treatment period. 
Section 4.1.2 
Transfusion Withdrawal 
• 
Revised guidance on transfusion 
withdrawal to wean transfusions 
beginning at Month 3 and to 
conclude transfusion support 
between Months 4 and 5 
• 
Revised to permit earlier cessation 
of transfusions. 
Section 5.7 
Prior Medications and Procedures 
• 
Clarified that all disease-
modifying therapies should be 
discontinued when the subject 
initiates HbS reductive 
transfusions at least 2 months 
before HSC collection, not just 
hydroxyurea. 
• 
Clarification was needed to 
address newly approved 
medications. 
Section 5.10.1 
Enrollment Definition and Number of Subjects 
• 
Provided a clear definition of 
“Enrolled”. 
• 
Enrollment was not previously 
defined, and this is needed to 
Sections 6.1 and 7 

Aruvant Sciences, GmbH 
ARU-1801 
Protocol: ARU-1801_Ph1_01 (Version 13.0) 
13 August2021 
Page 8 
Summary of Change 
Rationale 
Protocol Sections 
Affected 
avoid any confusion in providing 
study results. 
Laboratory Tests 
• 
Added blood smear to list of 
laboratory tests. 
• 
This is an added safety test. 
Section 6.3.2 
Efficacy Assessments 
• 
Clarified wording on efficacy 
assessments. 
• 
Revised to more clearly describe 
the tests being performed. 
Section 6.5.2 
Bone Marrow Gene Transfer Testing 
• 
Removed burst forming unit 
erythroid (pooled) for RNA from 
bone marrow gene transfer testing. 
• 
This test is no longer needed to 
evaluate ARU-1801. 
Section 6.5.2.3 
Vaso-occlusive Episode Definition 
• 
Removed myocardial infarction, 
renal infarction, bone infarction, 
and venous thromboembolism 
from the definition of vaso-
occlusive episode. 
• 
Provided definition of splenic 
sequestration. 
• 
The listed events can be the result 
of different etiologies than vaso-
occlusion due to sickling. 
• 
Splenic sequestration was 
previously not defined and open 
for interpretation. 
Section 6.5.3 
 
 
Protocol Version 12.0 (16 May 2020) 
Summary of Change 
Rationale 
Protocol Sections 
Affected 
Withdrawal of Subjects From Study Treatment and/or the Study 
• 
Added the specific chromosomal 
abnormalities or genetic mutations 
that would result in subject 
withdrawal. 
• 
Deleted text about the evaluation 
of somatic mutations.  
• 
To clarify the course of action for 
any positive findings of 
chromosomal abnormalities or 
genetic mutations. 
Section 4.2 and 
Section 6.1 
Study Visits 
• 
Added that the baseline bone 
marrow collection and testing 
must be completed after 
enrollment and prior to initiation 
of additional research procedures. 
• 
To clarify the timing of the 
baseline bone marrow collection, 
to ensure genetic testing is 
completed before the subjects 
receive any study intervention. 
Section 6.1 and the 
Schedule of Events 
(Table 13-1 and 
Table 13-1 footnote v) 

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Protocol: ARU-1801_Ph1_01 (Version 13.0) 
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Summary of Change 
Rationale 
Protocol Sections 
Affected 
• 
In the Schedule of Events, added 
an “X” in the column for the HbS 
Reductive Visit and deleted the 
“(X)” in the columns for CD34+ 
Kinetics Clearance Visit and Stem 
Cell Clearance Visit, for bone 
marrow morphology, flow 
cytometry, genomic evaluation for 
myeloid malignancy, and sample 
for gene transfer testing 
• 
Added footnote v to the “X” in the 
column for the HbS Reductive 
Visit. Footnote v states that the 
baseline bone marrow testing must 
be completed after enrollment and 
prior to initiation of additional 
research procedures such as 
central line placement or RBC 
transfusions. 
• 
Added subject counseling for the 
baseline bone marrow genomic 
evaluation. 
• 
To ensure subjects are informed of 
any positive genetic findings and 
are offered genetic counseling to 
understand the implications of 
these findings. 
Section 6.1 
 
Protocol Version 11.0 (10 March 2021) 
Summary of Change 
Rationale 
Protocol Sections 
Affected 
Introduction 
• 
Provided most up to date 
information on clinical experience 
with lentiviral gene therapy 
• 
Added section on risk of 
hematologic malignancy 
• 
Information updated to reflect 
most up-to-date safety information 
in trials of lentiviral gene therapy 
for SCD. 
Sections 1.2, 1.3 and 1.4 
Withdrawal of Subjects From Study Treatment and/or the Study 
• 
Added increased risk for 
hematologic malignancy based 
upon baseline NGS or cytogenetic 
findings 
• 
Prevents additional risk to 
subjects with cytogenetic 
abnormalities or mutations that 
are associated with a high risk for 
development of malignancy.  
Section 4.2 

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Protocol: ARU-1801_Ph1_01 (Version 13.0) 
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Summary of Change 
Rationale 
Protocol Sections 
Affected 
Study Procedures 
• 
Revised schedule and timepoints 
for peripheral blood CD34+ 
kinetics 
• 
Data for first 2 days of HSC 
collection is required to 
understand CD34+ kinetics 
• 
CD34+ kinetics from subsequent 
collection days are not required as 
they are no longer informative. 
o 
The 10-12 and 24 hour 
timepoints are not needed 
to understand plerixafor 
mobilization kinetics.  
Section 5.5.1.2 
• 
Removed bone marrow harvest as 
source for CD34+ cells to 
manufacture ARU-1801 
• 
Peripheral blood stem cell 
collection is the safest and most 
feasible method for collecting 
CD34+ cells. 
Synopsis and Sections 
1.3.2, 3, 5.5.1 5.5.2, 
5.10.2, and 6.1 
• 
Added radioactive GFR to be 
done within 30 days of planned 
chemotherapy 
• 
This test measures true renal 
filtration, which is impaired in 
SCD. This will generate data to 
evaluate the relationship between 
renal filtration and exposure to 
melphalan. 
Section 5.5.3 and Section 
6.3.6.3 
• 
Added NGS and cytogenetic 
evaluation of bone marrow as 
safety test 
• 
NGS and cytogenetics will be 
done on all collected bone marrow 
samples to more closely evaluate 
for possible indicators of potential 
hematologic malignancy. 
 
Sections 6.1, 6.3.2, and 
6.4.2.1 
Schedule of Events 
• 
Added genetic evaluation of bone marrow for myeloid malignancy to all 
timepoints when bone marrow is collected: pre-ARU-1801, Months 6, 12, 
18, 24 and Year 3 visits 
• 
Revised CD34+ kinetics schedule 
• 
Modified pregnancy testing schedule so that repeat testing is not needed if 
test result is available within 48 hours; reduced testing timepoints in follow-
up 
• 
Added radioactive GFR to chemotherapy clearance visit with footnote that 
may be performed within 30 days of chemotherapy 
Appendix 1. Tables 13-1, 
13-2 and 13-3 
 

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Protocol: ARU-1801_Ph1_01 (Version 13.0) 
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Protocol Version 10.0 (21 September 2020) 
Summary of Change 
Rationale 
Protocol Sections 
Affected 
Schedule of Events  
• 
Additional timepoints were added for the following assessments: F-RBCs 
and F-retics, Complete Blood Count w/reticulocytes, and Hemoglobin 
Electrophoresis  
Appendix 1. Tables 13-2 
and 13-3 
 
 
Protocol Version 9.0 (11 August 2020) 
Summary of Change 
Rationale 
Protocol Sections 
Affected 
Hematopoietic Stem and Progenitor Cell Collection 
Add an additional optional HSC 
collection visit and remove the total Hb 
requirements for the Stem Cell 
Collection Visit 
HSC are required for research 
purposes to develop ARU-1801 drug 
product manufacturing process 
Section 3.1.1, Section 
5.5.1 and Section 5.5.1.2 
Exclusion Criteria 
Add wording on male contraception 
requirements 
As melphalan is teratogenic, 
contraception is required for male 
subjects for 1-year post- infusion 
Section 4.1.2 
Pregnancy 
Add wording on collection of pregnancy 
safety information on partners of male 
subjects 
To ensure safety information is 
collected from pregnant partners of 
male subjects 
Section 6.7 
Administrative  
• 
Clarify language around Cohort 2 enrollment and dosing 
• 
Clarification of types of research material to include manufacturing 
intermediates and RBCs 
 
Section 3.1 
Section 6.8 
 
 
Protocol Version 8.0 (10 October 2019) 
Summary of Change 
Rationale 
Protocol Sections 
Affected 
Endpoints 
Added primary safety endpoints for the 
time required for neutrophil and platelet 
recovery  
Added safety endpoints for 
laboratory parameters already being 
measured  
Synopsis; Sections 2.2.1 
and 7  

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Protocol: ARU-1801_Ph1_01 (Version 13.0) 
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Page 12 
Summary of Change 
Rationale 
Protocol Sections 
Affected 
Inclusion/Exclusion Criteria 
Revised upper age limit from 35 to 
45 years old 
Broaden pool of eligible subjects 
with adequate functional status and 
organ function 
Synopsis; Sections 3.1, 
4.1.1, 7, and 7.6 
Revised exclusion criterion to exclude 
subjects with a history of stroke or at 
moderate to high risk of stroke 
Exclude subjects who may be 
candidates for alternative therapies 
(eg, hydroxyurea or chronic 
treatment with blood transfusions) 
for the primary or secondary 
prevention of stroke  
Synopsis, Section 4.1.2 
Study Procedures 
• 
Added screening electrocardiogram 
(ECG) 
• 
Added screening brain magnetic 
resonance imaging and angiography  
• 
Added new study visit to assess 
CD34+ kinetics after plerixafor 
injection without stem cell 
collection 
• 
Modified language related to 
hematopoietic stem cell (HSC) 
collection 
• 
Removed option for ARU-1801 
administration via intra-bone 
marrow infusion 
• 
Evaluate for baseline ECG 
abnormalities 
• 
Assess risk of stroke 
• 
Identify time window for 
subsequent HSC collection to 
minimize the number of 
apheresis procedures  
• 
Provide flexibility to alter 
apheresis parameters to improve 
HSC collection  
 
• 
ARU-1801 will be administered 
intravenously. Current data do 
not support improved efficacy 
with intra-bone marrow infusion. 
Synopsis; Sections 3.1, 
3.1.1, 5.5.1, 5.5.1.1 
(new), 5.5.1.2, 6.1, 6.2, 
6.3.4, and 6.3.6; 
Table 13-1 
 
 
 
 
 
 
 
Synopsis; Sections 3.1, 
5.2, 5.5.3, 5.5.5, and 
5.10.2 
• 
Adjusted melphalan dose calculation 
for subjects weighing >130% of 
ideal body weight (rather than 
>125%) 
• 
Updated pharmacokinetic (PK) 
endpoint analysis, including PK 
parameters 
• 
Updated per current prescribing 
information 
• 
Allow for comprehensive 
characterization of melphalan 
PK 
Synopsis; Sections 5.5.3, 
6.6, 7.3, 7.5, and 7.7.3; 
Table 13-1 

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Protocol: ARU-1801_Ph1_01 (Version 13.0) 
13 August2021 
Page 13 
Summary of Change 
Rationale 
Protocol Sections 
Affected 
Adverse Event Monitoring and Reporting 
• 
Revised adverse event (AE) 
collection to include all AEs up to 
2 years after ARU-1801 infusion 
and a more limited collection from 
Years 2 through 15  
• 
Provided additional clarifications on 
AE and sickle cell disease (SCD)-
related event definitions  
• 
Added retrospective AE and 
SCD-related event collection (only 
for subjects who enrolled before 
protocol Version 8.0) 
• 
Allow for a more comprehensive 
collection of safety data  
• 
Provide additional investigator 
guidance for AE monitoring,  
• 
Allow capture of all AEs 
recorded on source 
documentation 
Sections 6.3.1.1, 6.3.1.2, 
6.3.1.3, 6.3.1.4, 6.3.1.6, 
6.3.1.8, 6.3.1.10, and 
6.5.3; Tables 13-2 and 
13-3 
Other Study Changes 
Allow for outpatient monitoring after 
ARU-1801 infusion for compliant 
subjects and per investigator’s discretion 
Provide flexibility to investigator to 
individualize subject monitoring plan 
after chemotherapy 
Figure 1; Section 5.5.3; 
Table 13-1 
Clarified study duration and transition to 
separate long-term follow-up (LTFU) 
study 
Provide information on transition to 
anticipated LTFU study after Year 2 
once study is active and has received 
site IRB/IEC/REB approval 
Synopsis; Sections 3.1 
and 6.1; Tables 13-1, 
13-2, and 13-3 
Revised ARU-1801 description, 
identification, packaging, and storage 
Align with 2019 Investigator's 
Brochure 
Sections 5.2, 5.3, and 
5.4.1 
Modified language regarding subject 
withdrawal  
Provide guidance to investigator to 
encourage subject follow-up 
Section 4.2.2 
Added reproductive health history 
collection 
Data needed to understand effects of 
treatment on reproductive health  
Sections 6.2.1 and 6.3.4; 
Tables 13-1, 13-2, and 
13-3 
Removed standard of care imaging 
assessments  
Remove collection of data not used 
for study analyses 
Synopsis; Sections 6.3 
and 6.3.6; Tables 13-2 
and 13-3 
Added future testing of blood samples  
Allow collection of additional 
plasma and serum for future 
biomedical research purposes 
Section 6.8; Tables 13-1 
and 13-2 
Minor revisions to schedules of events 
Align with modifications in study 
procedures 
Tables 13-1, 13-2, and 
13-3 

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Summary of Change 
Rationale 
Protocol Sections 
Affected 
Administrative  
The following changes were made for administrative purposes: 
• 
Definition of Sponsor 
• 
Updates to introduction per 2019 investigator’s brochure  
• 
Principal investigator roles and responsibilities 
• 
Study schematic revisions 
• 
Listing screening procedures  
• 
Central laboratory responsibilities 
• 
Rearranging safety versus efficacy gene therapy testing and assessments for 
feasibility 
 
Title page; Protocol 
Approval – Sponsor 
Signatory page; Synopsis 
Sections 1.3, 3.1, 6.2, 
6.3, 6.3.2, 6.3.3 (new), 
6.5.1, 6.5.2, 6.5.2.3, 9.1, 
and 10 
 
Protocol Version 7.0 (01 October 2019) 
Summary of Change 
Rationale 
Protocol Sections 
Affected 
Study Population 
• 
Age range for subject enrollment 
changed to 18 to 35 years 
• 
Reference to future enrollment of 
pediatric subjects was removed 
Provide clarification to investigators 
that subject enrollment is limited to 
adult subjects  
Synopsis; Sections 2.2.2, 
3.1, 3.1.1, 4.1.1, 4.1.2, 
4.2.1, 4.2.2, 5.4.3, 5.5.5, 
5.10.1, 6, 6.3.1.3, 6.4.3, 
6.5.5, 6.5.6, 7, 7.2, 7.4, 
7.6.1, 7.6.2, 7.6.4, 9.1, 
9.3, 10.1, and 10.3; 
Tables 13-1, 13-2, and 
13-3; Appendix 2 and 4 
 
 

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Page 15 
Table of Contents 
Protocol Amendment Summary of Changes ..............................................................................6 
Table of Contents .....................................................................................................................15 
List of Tables ............................................................................................................................20 
List of Figures ..........................................................................................................................20 
Protocol Synopsis.....................................................................................................................21 
List of Abbreviations................................................................................................................30 
1 
Introduction ......................................................................................................................33 
1.1 
Sickle Cell Disease .................................................................................................33 
1.2 
Current Therapies for Sickle Cell Disease ..............................................................33 
1.3 
Study Intervention ...................................................................................................35 
1.3.1 
Nonclinical Experience ............................................................................37 
1.3.2 
Clinical Experience ..................................................................................38 
1.4 
Benefit-Risk Assessment ........................................................................................38 
1.4.1 
Hematologic Malignancy Risks ...............................................................39 
2 
Study Objectives and Endpoints ......................................................................................43 
2.1 
Objectives ...............................................................................................................43 
2.1.1 
Primary Objectives ..................................................................................43 
2.1.2 
Secondary Objectives ..............................................................................43 
2.1.3 
Exploratory Objectives ............................................................................43 
2.2 
Endpoints ................................................................................................................44 
2.2.1 
Primary Endpoints ...................................................................................44 
2.2.2 
Secondary Endpoints ...............................................................................45 
2.2.3 
Exploratory Endpoints .............................................................................46 
3 
Investigational Plan ..........................................................................................................47 
3.1 
Study Design ...........................................................................................................47 
3.1.1 
Rationale of Study Design .......................................................................50 
4 
Subject Selection and Withdrawal Criteria ......................................................................56 
4.1 
Selection of Study Population .................................................................................56 
4.1.1 
Inclusion Criteria .....................................................................................56 

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4.1.2 
Exclusion Criteria ....................................................................................57 
4.2 
Withdrawal of Subjects From Study Treatment and/or the Study ..........................59 
4.2.1 
Reasons for Withdrawal/Discontinuation ................................................59 
4.2.2 
Handling of Withdrawals .........................................................................62 
4.2.3 
Replacements ...........................................................................................63 
5 
Study Treatments ..............................................................................................................64 
5.1 
Method of Assigning Subjects to Treatment Groups ..............................................64 
5.2 
Treatments Administered ........................................................................................64 
5.3 
Identity of Investigational Product..........................................................................64 
5.4 
Management of Clinical Supplies ...........................................................................64 
5.4.1 
Investigational Product Packaging and Storage.......................................64 
5.4.2 
Test Article Accountability ......................................................................65 
5.4.3 
Other Supplies..........................................................................................65 
5.5 
Study Treatment Procedures and Administration ...................................................66 
5.5.1 
Hematopoietic Stem and Progenitor Cell Collection ...............................66 
5.5.1.1 
Plerixafor-Mobilized Peripheral Blood Collection ..................................67 
5.5.1.2 
HSC Collection Target .............................................................................68 
5.5.2 
CD34+ Cell Isolation ...............................................................................69 
5.5.3 
Chemotherapy Conditioning With Melphalan .........................................69 
5.5.4 
Transduction of CD34+ Cells ..................................................................71 
5.5.4.1 
Safety and Efficacy Testing of Transduced Cells ....................................72 
5.5.4.2 
Positive Microbial Culture Results ..........................................................72 
5.5.5 
Infusion of ARU-1801 .............................................................................72 
5.6 
Other Treatments: Supportive Care ........................................................................73 
5.6.1 
Infectious Disease Prophylaxis ................................................................73 
5.6.2 
Blood Product Support.............................................................................73 
5.6.3 
Management of ARU-1801 Infusion-Related Toxicities .........................74 
5.6.4 
Fertility Preservation................................................................................74 
5.7 
Transfusion Withdrawal ..........................................................................................75 
5.8 
Blinding...................................................................................................................75 
5.9 
Treatment Compliance ............................................................................................75 
5.10 Prior and Concomitant Therapy ..............................................................................76 
5.10.1 
Prior Medications and Procedures ...........................................................76 

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5.10.2 
Concomitant Medications and Procedures ..............................................76 
5.10.3 
Medications and Procedures After Treatment ..........................................77 
6 
Study Assessments and Procedures ..................................................................................78 
6.1 
Study Visits .............................................................................................................78 
6.2 
Screening Assessments ...........................................................................................80 
6.2.1 
Demographics and Baseline Medical History .........................................81 
6.3 
Safety Assessments .................................................................................................82 
6.3.1 
Adverse Events ........................................................................................82 
6.3.1.1 
Definitions of Adverse Events .................................................................82 
6.3.1.2 
Serious Adverse Events ...........................................................................84 
6.3.1.3 
Eliciting and Documenting Adverse Events ............................................84 
6.3.1.4 
Reporting Adverse Events .......................................................................85 
6.3.1.5 
Reporting Serious Adverse Events ..........................................................86 
6.3.1.6 
Sickle Cell-Related Events ......................................................................87 
6.3.1.7 
Adverse Events of Special Interest ..........................................................88 
6.3.1.8 
Suspected Unexpected Serious Adverse Reactions and Nonserious 
Adverse Events of Special Interest ..........................................................89 
6.3.1.9 
Assessment of Severity ............................................................................89 
6.3.1.10 Assessment of Causality ..........................................................................90 
6.3.1.11 Follow-up of Subjects Reporting Adverse Events ...................................91 
6.3.2 
Safety Laboratory Tests ...........................................................................91 
6.3.2.1 
Gene Transfer Safety Testing ...................................................................93 
6.3.3 
Physical Examinations .............................................................................93 
6.3.4 
Vital Sign Measurements .........................................................................94 
6.3.5 
Imaging ....................................................................................................94 
6.3.6 
Other Assessments ...................................................................................95 
6.3.6.1 
Pulmonary Function Tests........................................................................95 
6.3.6.2 
Iron Overload Status ................................................................................95 
6.3.6.3 
Nuclear Medicine GFR ............................................................................95 
6.4 
Safety Monitoring ...................................................................................................95 
6.4.1 
Data Safety Monitoring Board .................................................................95 
6.4.2 
Safety and Feasibility Criteria .................................................................96 
6.4.2.1 
Safety Criteria: Toxicity ...........................................................................96 
6.4.2.2 
Feasibility Criteria ...................................................................................97 

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6.4.3 
Early Study Stopping Rules .....................................................................98 
6.5 
Feasibility and Efficacy Assessments .....................................................................99 
6.5.1 
Feasibility Assessments ...........................................................................99 
6.5.2 
Efficacy Assessments .............................................................................100 
6.5.2.1 
Hemoglobin Electrophoresis..................................................................100 
6.5.2.2 
Peripheral Blood Gene Transfer Testing ................................................100 
6.5.2.3 
Bone Marrow Gene Transfer Testing .....................................................101 
6.5.3 
Incidence of SCD-Related Events and Parental Opioid Use .................101 
6.5.4 
Performance Status ................................................................................102 
6.5.5 
Patient-Reported Outcomes: ASCQ-Me System ...................................102 
6.6 
Pharmacokinetic Assessments ..............................................................................103 
6.7 
Pregnancy ..............................................................................................................104 
6.8 
Future Testing .......................................................................................................104 
7 
Statistical and Analytical Plan ........................................................................................106 
7.1 
Primary Safety and Feasibility Endpoints.............................................................106 
7.2 
Secondary Efficacy Endpoints ..............................................................................106 
7.3 
Exploratory Endpoints ..........................................................................................107 
7.4 
Sample Size Calculations ......................................................................................107 
7.5 
Analysis Sets .........................................................................................................108 
7.6 
Statistical Analysis Methodology .........................................................................108 
7.6.1 
Analysis of Primary Safety and Feasibility Endpoints ..........................109 
7.6.2 
Analysis of Secondary Efficacy Endpoints ...........................................109 
7.6.3 
Analysis of Exploratory Pharmacokinetic Endpoint .............................109 
7.6.4 
Exploratory and Other Analyses ............................................................ 110 
7.6.5 
Interim Analyses .................................................................................... 111 
8 
Data Quality Assurance .................................................................................................. 112 
8.1 
Data Management ................................................................................................. 112 
9 
Ethics .............................................................................................................................. 113 
9.1 
Institutional Review Board ................................................................................... 113 
9.2 
Ethical Conduct of the Study ................................................................................ 113 
9.3 
Subject Information and Consent.......................................................................... 113 
10 Investigator’s Obligations .............................................................................................. 115 

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10.1 Confidentiality ...................................................................................................... 115 
10.2 Financial Disclosure and Obligations ................................................................... 116 
10.3 Investigator Documentation .................................................................................. 116 
10.4 Study Conduct ....................................................................................................... 117 
10.5 Adherence to Protocol........................................................................................... 117 
10.6 Adverse Events and Study Report Requirements ................................................. 117 
10.7 Investigator’s Final Report ................................................................................... 117 
10.8 Records Retention ................................................................................................. 117 
10.9 Publications ........................................................................................................... 118 
11 Study Management ......................................................................................................... 119 
11.1 Monitoring ............................................................................................................ 119 
11.1.1 
External Data Monitoring Committee ................................................... 119 
11.1.2 
Monitoring of the Study ......................................................................... 119 
11.1.3 
Inspection of Records ............................................................................ 119 
11.2 Management of Protocol Amendments and Deviations........................................120 
11.2.1 
Modification of the Protocol ..................................................................120 
11.2.2 
Protocol Deviations................................................................................120 
11.3 Study Termination .................................................................................................120 
11.4 Final Report ..........................................................................................................121 
12 Reference List.................................................................................................................122 
13 Appendices .....................................................................................................................130 
13.1 Appendix 1: Schedules of Events (Screening and Study Treatment Visits, 
Post-infusion Visits, and Long-term Follow-up Visits) .................................130 
13.2 Appendix 2: Karnofsky Scores .............................................................................147 
13.3 Appendix 3: Side Effects Related to Melphalan Chemotherapy ..........................148 
13.4 Appendix 4: Adult Sickle Cell Quality-of-Life Measurement (ASCQ-Me) .........149 
13.5 Appendix 5: Formulas and Methods for Melphalan Dosing ................................159 
13.6 Appendix 6: Flow Chart for Melphalan Dosing ...................................................161 
 
 

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List of Tables 
Table 3-1 
Cystatin C eGFR and Melphalan AUC in Subjects Treated with ARU-1801 52 
Table 6-1 
Acute and Chronic Conditions Associated With Sickle Cell Disease ............. 88 
Table 6-2 
Severity Grading for Events not Listed in the Common Terminology Criteria 
for Adverse Events Version 5.0 ....................................................................... 90 
Table 6-3 
Probability of Early Termination in the First Stage of the Initial Cohort (6 
Subjects) .......................................................................................................... 99 
Table 13-1 
Schedule of Events: Screening and Study Treatment Visits ......................... 131 
Table 13-2 
Schedule of Events: Post-infusion Visits (Day 7 Through Year 2) ............... 139 
Table 13-3 
Schedule of Events: Long-term Follow-up Visits (Month 30 Through Year 15)
....................................................................................................................... 144 
Table 13-4 
Karnofsky Scores (Age 10 and Older) .......................................................... 147 
Table 13-5 
Risks and Side Effects Related to Melphalan ............................................... 148 
  
List of Figures 
Figure 1 
Study Design Schema ..................................................................................... 49 
Figure 2 
Engraftment versus AUC ................................................................................ 52 
Figure 3 
Observed and Predicted AUC ......................................................................... 53 
 

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Protocol Synopsis 
Protocol Number: 
ARU-1801_Ph1_01 
Title: 
Gene Transfer for Patients With Sickle Cell Disease Using a 
Gamma Globin Lentivirus Vector: An Open-Label Phase 1/2 
Pilot Study 
Sponsor: 
Aruvant Sciences, GmbH 
Viaduktstrasse 8, 4051 
Basel, Switzerland 
Study Phase: 
½ 
Indication: 
Sickle cell disease (SCD) 
Rationale: 
This Phase 1/2 study will use a novel therapy, ARU-1801, for 
SCD using gene transfer of recombinant γ-globin lentivirus (LV) 
vector (pseudotyped with a vesicular stomatitis virus G 
[VSV-G]) with a point mutation at codon 16 (sGbGM) into 
CD34+ cells (from human bone marrow [BM] or mobilized 
peripheral blood) followed by autologous transplant after 
reduced intensity conditioning with single-dose melphalan. 
Current therapies for symptomatic and supportive care for 
patients with SCD include anti-inflammatories and analgesics to 
treat pain from episodic sickling, iron chelation to mitigate iron 
overload from frequent transfusions, infection prevention using 
penicillin prophylaxis, early immunizations against encapsulated 
bacteria, and aggressive parenteral antibiotic therapy for 
presumed bacteremia. Efficacy of these therapies is variable, and 
indefinite treatment is needed. 
Hydroxyurea, an approved treatment for SCD, induces fetal 
hemoglobin (HbF) and reduces SCD complications; however, 
close medical monitoring and daily lifelong intake and 
compliance are required, which are the main deterrents to its 
effectiveness. Another approved treatment, L-glutamine, 
significantly reduced the number of pain crises and 
hospitalizations compared with the control group. L-glutamine 
treatment also requires daily lifelong intake and is limited by 
cost and availability and therefore has not been widely used. 
Patients with severe SCD may be offered an allogeneic 
hematopoietic stem cell (HSC) transplant, which is curative but 
requires a matched related donor, is often limited to children due 
to increased toxicities in older SCD patients, and is associated 
with complications, such as graft-versus-host disease, graft 

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rejection, and late effects, such as sterility and secondary 
malignancy from high-dose chemotherapy. 
There continues to be an unmet need for SCD therapy that has 
durable effects, would not rely on donor availability, has fewer 
complications than are associated with allogeneic, unrelated, or 
haplo-identical HSC transplant, and would not require intense 
induction. 
This Phase 1/2 gene transfer study is designed to evaluate the 
safety, feasibility, and efficacy of 1) obtaining sufficient CD34+ 
cells via plerixafor-mobilized peripheral blood (P-MPB) in 
subjects with SCD; 2) ex vivo gene transfer of the γ-globin LV 
vector into the sickle CD34+ cells; 3) reduced intensity 
conditioning; and 4) engraftment and efficacy of autologous 
gene-modified CD34+ cells, when transplanted back into 
subjects with SCD. 
Objectives: 
Primary Objectives: 
The following are the primary objectives: 
• To evaluate the safety of: 
• Stem cell collection from subjects with SCD 
• Infusion of CD34+ cells transduced with sGbGM 
vector into subjects with SCD 
• Chemotherapy conditioning with melphalan in 
subjects with SCD 
• To evaluate the feasibility of: 
• Obtaining clinically sufficient number of CD34+ 
cells for gene transfer  
• Ex vivo manipulation of CD34+ cells and gene 
transfer 
• Engraftment of ex vivo manipulated gene-modified 
stem cells 
Secondary Objectives: 
The following are the secondary objectives: 
• To evaluate the efficacy of genetic correction via 
determination of the following: 
• Percentage of gene-marked cells  
• Contribution of gene-modified cells to multilineage 
hematopoiesis and circulating red blood cells (RBCs) 
• Hematological and functional correction of sickling 
in SCD  

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• To evaluate subjects for change in disease severity from 
baseline 
• To evaluate subjects for change in quality of life from 
baseline  
Exploratory Objectives: 
The following is the exploratory objective: 
• To characterize the pharmacokinetics (PK) of melphalan 
in patients with SCD 
• To characterize the relationship between the PK of 
melphalan and engraftment of ARU-1801 
Study Population: 
Subjects enrolled in this study must be from 18 to 45 years of 
age with a confirmed diagnosis of severe SCD (as defined in 
protocol), have adequate functional status and organ function, 
and either failed, were unable to tolerate, or chose not to have 
hydroxyurea therapy. Subjects must be capable of understanding 
the written informed consent, provide signed and witnessed 
written informed consent, and agree to comply with protocol 
requirements.  
Subjects will not be allowed to enroll if they have active 
malignant disease; have a current diagnosis of human 
immunodeficiency virus; have abnormal pulmonary function 
tests; have evidence of uncontrolled bacterial, viral, or fungal 
infections; have a history of stroke or are at moderate to high 
risk of primary stroke; have αthalassemia (2 or more gene 
deletions or any αglobin structural variants) SCD; have previous 
documented liver biopsy result showing cirrhosis, bridging 
hepatic fibrosis, or active hepatitis; have previous documented 
evidence of iron overload; have documented matched sibling 
donors and have not declined HSC transplant; have a medical 
history of pulmonary hypertension; or have any condition, 
screening laboratory or diagnostic test, or chronic physical or 
mental illness that, in the opinion of the investigator, makes 
participation ill advised. Female subjects cannot be pregnant or 
lactating/breastfeeding and must be either surgically sterile, 
postmenopausal (no menses for the previous 12 months), or 
must agree to practice an effective method of birth control as 
determined by the investigator from time of consent through at 
least 1 year post ARU-1801 infusion. Male subjects must agree 
to practice an effective method of birth control as determined by 
the investigator for a minimum of 1 year after ARU-1801 
infusion. 

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Study Design: 
The study is an open-label Phase 1/2 study in adult subjects aged 
18 to 45 years with severe SCD completed in 2 stages. In the 
first stage, a cohort of subjects will be enrolled in a staggered 
manner until a total of 6 subjects are enrolled. Specifically, in 
the first stage, approximately 30 days must elapse after the 
infusion of 1 subject before the next subject can undergo 
infusion of ARU-1801. The independent Data Safety Monitoring 
Board (DSMB) will review the safety data from each subject 
before treating the next subject, although the DSMB may 
propose to alter this requirement as detailed in the DSMB 
charter. 
After 6 subjects in the first stage are evaluable, the DSMB will 
review the safety and feasibility of the procedure in this cohort 
and make a recommendation regarding dosing 4 additional 
subjects, for a total enrollment of 10 subjects in this study.  
After providing informed consent, potential subjects will 
undergo screening procedures and be evaluated for inclusion 
into the study. If all inclusion and no exclusion criteria are met, 
the subject will be allowed to enroll in the study. The principal 
investigator at each site will be responsible for all treatment and 
care the subject receives at the site during the study. Enrolled 
subjects will have sickle hemoglobin (HbS) reduced via 
erythrocytapheresis or transfusions with a goal of achieving a 
HbS level of ≤30% for at least 2 months before HSC collection 
and ≤20% within 7 days before HSC collection by P-MPB. 
Chronic transfusions are continued through treatment with 
ARU-1801 and should begin to be weaned starting at Month 3 
after infusion. The overall goal of HSC collection is to collect 
≥8×106 CD34+ cells/kg body weight. At least 2 weeks before 
HSC collection, serial sampling of peripheral blood CD34+ 
concentration will be assessed after plerixafor administration but 
without apheresis to understand CD34+ kinetics and guide the 
subsequent timing and duration of apheresis for each individual 
subject. Collection of HSCs via PMPB may be repeated to 
obtain sufficient HSCs. For subjects who provide separate 
consent, additional HSC collection will be performed to obtain 
additional HSCs for research purposes. The HSCs are enriched 
for CD34+ cells and then transduced ex vivo with the sGbGM 
LV vector. Subjects will undergo chemotherapy conditioning 
with a single intravenous (IV) dose of melphalan. The melphalan 
dose will be identified via predictive modeling but will not 
exceed 200 mg/m2 of body surface area. All subjects will have 

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melphalan PK evaluated after administration of the conditioning 
dose. At least 36 hours after the melphalan conditioning dose, 
ARU-1801 (the transduced CD34+ cells) are prepared for 
autologous IV infusion. The goal is to infuse 4×106 CD34+ 
cells/kg body weight or higher to the subject.  
Subjects will return to the study site at regular intervals for 
follow-up for 2 years after the ARU-1801 infusion. It is 
anticipated that a separate long-term follow-up (LTFU) clinical 
study will be initiated. Once the LTFU study is approved at the 
site, all subjects who complete the Year 2 study visit in this 
study will be asked to consent and enroll into the LTFU study 
and will be followed for a total of 15 years after the ARU-1801 
infusion. Long-term follow-up after Year 2 will continue in this 
Phase 1/2 study until subjects have transitioned into the LTFU 
study.  
The independent DSMB will review safety data on an ongoing 
basis throughout the study. Predefined safety criteria toxicities, 
feasibility criteria, and early study stopping criteria will be 
monitored by the investigator(s) and Sponsor and reviewed on 
an ongoing basis by the DSMB. Subjects are free to withdraw 
from the study at any time. At the time of consent withdrawal, 
the subject will be asked to provide permission for collection of 
relevant source documentation from clinical records to ascertain 
the subject’s health status. 
The duration of the study is defined for each subject as the date 
signed written informed consent is provided through the last 
follow-up visit. 
Estimated Study 
Duration: 
Before subjects receive ARU-1801 infusion on Day 0, subjects 
will undergo screening and have visits for HbS reduction (in the 
months before stem cell collection), stem cell clearance, stem 
cell collection, chemotherapy clearance, and chemotherapy (at 
least 36 hours before infusion). Subjects will be followed in this 
study and/or in the LTFU study for a total follow-up period of 
15 years after the ARU-1801 infusion.  

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Safety Assessments: 
Safety will be assessed in this study through the assessment of 
adverse events (AEs) and serious AEs (SAEs), chronic 
conditions related to SCD, laboratory test results (including 
assessment of neutrophil and platelet recovery), physical 
examination findings, and vital sign measurements. Pulmonary 
function tests will be performed at screening. Peripheral blood 
gene transfer safety testing will include replication competent 
LV assay and vector insertion site analysis, and BM samples will 
be tested for standard morphology, flow cytometry for leukemia 
panel, genomic evaluation, and vector insertion site analysis. 
Efficacy Assessments: 
Peripheral blood testing will include the following: 
• Vector copy number analysis (VCN) analysis by 
quantitative polymerase chain reaction (qPCR) on DNA 
from white blood cell (WBC) fraction 
• VCN analysis (qPCR) on DNA from sorted cell 
subpopulations of erythroid, myeloid and B and T cells   
• HbF content in RBC (F-RBC) and  in reticulocytes (F-
retics) by flow cytometry  
• RBC testing (P50 [partial pressure of oxygen in the 
blood at which hemoglobin is 50% saturated] and 
ektacytometry with Oxygenscan) 
• Mononuclear cells and plasma for archiving 
• Capillary zone electrophoresis (CZE) analysis for HbF 
and variants 
Bone marrow aspirates will be performed at baseline (at some 
timepoint prior to ARU-1801 infusion), and then at Months 6, 
12, 18, 24 and Year 3 and will include the following (if there is 
clinical or laboratory indication of a clonal dominance or 
oligoclonality, BM aspirates may also be obtained during LTFU 
as indicated): 
• VCN analysis by qPCR on DNA isolated from BM 
mononuclear cells and sorted myeloid, T, B and 
precursor erythroid hematopoietic lineages 
• Colony-forming unit cells (CFU-c) assay for vector 
copies by qPCR on individual CFU-c 
Disease severity will be assessed through the incidence of vaso-
occlusive episodes (pre-transplant versus post-transplant).  
Patient-reported outcomes will be assessed using the adult sickle 
cell quality of life measurement (ASCQ-Me®). A modified 
Karnofsky Performance Status Scale, designed for recipients 

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aged ≥10 years will used to determine the score (10-100) that 
best represents the subject’s activity status at the requested time 
point. 
Pharmacokinetic 
Assessments: 
Blood samples will be collected for analysis of melphalan PK 
for all subjects. 
Blood samples for quantification of melphalan concentration in 
plasma will be collected at pre-dose (within 60 minutes before 
the start of the melphalan infusion), immediately at the end of 
the melphalan infusion, and approximately 5 minutes, 
15 minutes, 1 hour, 2 hours, 4 hours, and 6 hours after the end of 
the infusion. 
Study Drug, Dosage, 
and Route of 
Administration: 
The investigational product, ARU-1801, consists of the CD34+ 
cells transduced with the -globin (sGbGM) LV vector. It may be 
given as a fresh infusion or cryopreserved for later 
administration. The product for fresh infusion is formulated in 
<10 mL/kg volume of Plasmalyte-A® supplemented with 1% 
human serum albumin and filled into a syringe. The 
cryopreserved product is formulated in a cryopreservation 
medium containing 10% dimethyl sulfoxide and filled into a 
bag. The investigational product, ARU-1801, is administered via 
IV infusion. Cells will be suspended and intravenously infused 
over a period no longer than 15 minutes, followed by an IV 
infusion of 10 mL/kg bolus of saline over approximately 
30 minutes. The goal is to infuse the subject with 4×106 CD34+ 
cells/kg body weight or higher. 
Sample Size: 
A sample size of 10 subjects is planned to obtain initial data on 
the safety and feasibility of γ-globin gene transfer in subjects 
with SCD. 
Early stopping rules are in place for this study. Accrual of 
subjects will be suspended pending DSMB review if 1 or more 
of the first 3 subjects do not meet the safety criteria or 3 or more 
of 6 subjects do not meet either the safety or the feasibility 
criteria. The study will be stopped if 2 of the first 3 subjects fail 
to meet the safety criteria or at least 4 subjects (of 6 subjects) 
fail to meet both the safety and feasibility criteria.  
According to the study stopping criteria and assuming the 
probability of being both safe and feasible to be 0.64 (64%), the 
study will terminate at or before 3 subjects with a probability of 
0.104, and at or before 6 subjects with a probability of 0.122. 
Statistical Methods: 
Statistical analysis will be performed using SAS software (SAS 
Institute, Inc, Cary, North Carolina) Version 9.3 or later. 

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Continuous variables (absolute values and change from baseline 
values) will be summarized using the mean, standard deviation, 
median, minimum value, and maximum value. Categorical 
variables will be summarized using frequency counts and 
percentages. Shift tables from baseline to post-infusion visits 
may be provided. Data will be listed in data listings. 
Given the small sample size and single-arm design of the study, 
the focus of the statistical analysis will be on the provision of 
point estimates with 2-sided 95% confidence intervals. In 
addition, some exploratory informal testing analyses will be 
performed, using a 2-sided significance level of 0.15 (15%) for 
informational purposes only. 
Primary Safety and Feasibility 
Summary statistics of the number of subjects that failed the 
safety, feasibility, or both safety and feasibility criteria will be 
provided. For each of the safety and feasibility endpoints, 
summary statistics will be provided. The incidence of AEs and 
SAEs will also be provided. 
Moreover, the summary of the safety endpoints will be broken 
down into the following 3 distinct parts: 
• Part 1 will include those events from study entry to the 
recovery from the stem cell collections.  
• Part 2 will include those events from immediately before 
administration (baseline) through 30 days after gene 
transfer infusion.  
• Part 3 will include capturing subject status at Day +30 
post infusion, defined as baseline through the remainder 
of the study. 
Secondary Efficacy 
The secondary efficacy endpoints related to gene transfer will be 
measured by the following: 
• Quantification of HbFG16D (γ-globin gene with point 
mutation at codon 16) and other hemoglobin subtypes, 
including HbF (endogenous), HbS, adult Hb (HbA), 
HbA2 and, if applicable, HbC and HbE by CZE 
• Change in the proportion of anti-sickling/sickling 
hemoglobin (HbF+HbFG16D+HbA2/HbS) in Months 6-
24 post-transplantation compared with baseline by CZE 
• Flow cytometry for percentage of F-RBC and F-retics in 
peripheral blood 

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• Determining vector copies in the WBC fraction by qPCR 
• Determining gene transfer in BM based on the following: 
• Vector copies by qPCR 
• CFU-c analysis for gene-marked CFU-c by qPCR 
For each of the secondary gene transfer efficacy endpoints, 
summary statistics will be provided. 
Summary statistics will be presented for changes from baseline 
in disease severity (eg, annualized vaso-occlusive episode 
pre-transplant versus post-transplant). Baseline disease severity 
will be determined from a retrospective review of the subject’s 
medical records for the last 2 years before the screening visit. 
Summary statistics will be presented for ASCQ-Me scores at 
baseline and by post-baseline time points. 
Exploratory PK 
Individual plasma concentration of melphalan will be listed for 
each sampling time point and summarized using descriptive 
statistics. Plasma PK parameters for melphalan including, but 
not limited to, area under the plasma concentration versus time 
curve (AUC) from time zero (pre-dose) to time of last 
quantifiable concentration (AUC[0-t]), AUC from time zero 
(pre-dose) extrapolated to infinite time (AUC[0-∞]), maximum 
observed plasma concentration, clearance, and volume of 
distribution will be listed individually for each subject and 
summarized using descriptive statistics. Individual and mean 
plasma concentration versus time profiles for melphalan will be 
plotted. 
The relationship between melphalan AUC and safety and 
efficacy endpoints will be explored using descriptive statistics. 
Correlation coefficients will be generated between PK versus 
pharmacodynamic parameters. 
Version and Date of 
Protocol: 
Version 13 (13 Aug 2021) 

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List of Abbreviations 
Abbreviation 
Definition 
ACS 
acute chest syndrome 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCQ-Me® 
adult sickle cell quality-of-life measurement 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUC(0-t) 
area under the plasma concentration versus time curve from time zero 
(pre-dose) to time of last quantifiable concentration 
AUC(0-∞) 
area under the plasma concentration versus time curve from time zero 
(pre-dose) extrapolated to infinite time 
BM 
bone marrow 
BMH 
bone marrow harvest 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CFU-c 
colony-forming unit cells 
Cmax 
maximum observed plasma concentration 
CTCAE v5.0 
Common Terminology Criteria for Adverse Events Version 5.0 
DLCO 
diffusing capacity of carbon monoxide 
DMSO 
dimethyl sulfoxide 
DP 
drug product 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
FAS 
full-analysis set 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
F-RBC 
HbF content in RBC 
F-retics 
HbF content in reticulocytes 
FVC 
forced vital capacity 

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Abbreviation 
Definition 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulating factor 
GFR 
Glomerular filtration rate 
GI 
Gastrointestinal 
Hb 
Hemoglobin 
HbA 
adult hemoglobin  
HbA2 
adult hemoglobin 2 
HbF 
fetal hemoglobin  
HbFG16D 
γ-globin gene with point mutation at codon 16 
HbS 
sickle hemoglobin  
HIV 
human immunodeficiency virus 
HSC 
hematopoietic stem cell  
HSCT 
hematopoietic stem cell transplant  
IB 
investigator’s brochure  
ICF 
informed consent form  
ICH 
International Council for Harmonisation  
IEC 
independent ethics committee  
IRB 
institutional review board 
IV 
Intravenous 
LTFU 
long-term follow-up 
LTR 
long terminal repeat  
LV 
Lentivirus 
MedDRA 
Medical Dictionary for Regulatory Activities  
MRI 
magnetic resonance imaging  
NGS 
Next Generation Sequencing 
PFT 
pulmonary function tests 
PK 
pharmacokinetic(s)  
PKS 
pharmacokinetic set 
P-MPB 
plerixafor-mobilized peripheral blood  
PRBC 
packed red blood cells 
PRO 
patient-reported outcome 
QoL 
quality of life 

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Abbreviation 
Definition 
qPCR 
quantitative polymerase chain reaction  
RBC 
red blood cell  
RCL 
replication competent lentivirus 
REB 
research ethics board 
RIC 
reduced intensity conditioning  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCD 
sickle cell disease  
sGbGM 
vesicular stomatitis virus G with a point mutation at codon 16  
SUSAR 
suspected unexpected serious adverse reaction  
ULN 
upper limit of normal 
VCN 
vector copy number 
VOE 
vaso-occlusive episode  
VSV-G 
vesicular stomatitis virus G  
WBC 
white blood cell 
WHODrug 
World Health Organization Drug Dictionary  
 

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1 
Introduction 
1.1 Sickle Cell Disease 
Sickle cell disease (SCD) is a common monogenic blood disorder caused by an A→T 
transversion in the sixth codon of the β-globin gene that affects approximately 100,000 
Americans (NHGRI 2016). Because of the abnormality, hemoglobin forms long fibers upon 
deoxygenation (sickle hemoglobin [HbS]), resulting in red blood cells (RBCs) that are rigid 
and sickle-shaped rather than flexible and disc-shaped. This is reversible upon reoxygenation, 
but repeated cycles of sickling cause damage to RBC membranes and results in dense, poorly 
deformable RBCs that have difficulty traversing the microvasculature and are hemolyzed or 
removed by the reticuloendothelial system. Chronic hemolytic anemia and shortened RBC 
lifespan are hallmarks of the disease; the lifespan of a sickle RBC is approximately 14 days 
(as compared with approximately 120 days in a normal RBC). Patients with SCD have 
accelerated erythropoiesis and reticulocyte counts elevated to nearly 10 times normal.  
The clinical consequences of these RBC abnormalities include chronic anemia, severe pain, 
and organ damage caused by occlusion of veins. Episodic vascular occlusions can severely 
diminish quality of life (QoL) and life expectancy (Platt et al 1994), and cumulative organ 
damage eventually results in organ failure. Health care costs for treating patients with SCD 
exceed 1.1 billion dollars annually in the United States alone (Kauf et al 2009). In addition, 
despite the genetic homogeneity of the SCD mutation, there is substantial phenotypic 
diversity and research is ongoing into how to predict disease severity so that early aggressive 
therapeutic modalities might be applied to the appropriate population.  
1.2 Current Therapies for Sickle Cell Disease 
Current therapies for symptomatic and supportive care for patients with SCD include 
anti-inflammatories and analgesics to treat pain from episodic sickling, iron chelation to 
mitigate iron overload from frequent transfusions, infection prevention using penicillin 
prophylaxis, early immunizations against encapsulated bacteria, and aggressive parenteral 
antibiotic therapy for presumed bacteremia. Efficacy of these therapies is variable and 
indefinite treatment is needed.  
Hydroxyurea, an approved therapy for SCD, induces fetal hemoglobin (HbF), which is more 
effective than adult hemoglobin in binding and transporting oxygen. The therapy reduces but 
does not eliminate complications from SCD, requires close monitoring, and is associated 

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with side effects from marrow suppression (Charache et al 1995; Steinberg et al 2003; 
Brawley et al 2008). Additionally, SCD patients are reluctant to choose hydroxyurea therapy 
due to required daily, lifelong compliance and close monitoring (Brawley et al 2008).  
In 2018 the US Food and Drug Administration (FDA) approved L-glutamine for the 
treatment of SCD. Patients receiving L-glutamine showed a significant reduction in the 
number of pain crises and hospitalizations compared with the control group (Niihara et al 
2018). L-glutamine treatment also requires daily lifelong intake and is limited by cost and 
availability and therefore has not been widely used. 
Crizanlizumab was approved by the US FDA in 2019 to reduce the frequency of vaso-
occlusive crises in adults and pediatric patients aged 16 years and older with SCD. 
Crizanlizumab does not treat the underlying cause of SCD but rather the mechanism in which 
vaso-occlusive crises occur, which is ischemia through vascular occlusion caused by sickled 
RBC adhesion to endothelial cells mediated through p-selection. Crizanlizumab must be 
administered IV every 4 weeks, therefore this treatment is not accessible to all patients. 
Voxelotor was approved by the US FDA in 2019 in adults and pediatric patients 12 years of 
age and older with SCD. Voxelotor is an HbS polymerization inhibitor, which works by 
increasing the oxygen affinity of Hb and stabilizing RBCs in an oxygenated stage, and thus 
preventing Hb polymerization of HbS. The efficacy of voxelotor was demonstrated in a 
randomized, double-blind, placebo-controlled, multicenter study that included 2 doses of 
voxelotor (1500 mg and 900 mg) taken once daily. The study showed statistically significant 
improvements in total Hb and markers of hemolysis.  
Despite voxelotor’s clinically significant improvement in Hb and hemolysis, no meaningful 
decrease in vaso-occlusive crises was observed. Thus, voxelotor treatment response is limited 
to partial correction of anemia and hemolysis in SCD, and voxelotor does not address the 
clinical manifestation of vaso-occlusive crises, which is arguably the most clinically 
important outcome in SCD. 
Patients with severe SCD may be offered an allogeneic hematopoietic stem cell (HSC) 
transplant (HSCT), which is curative but requires a suitable donor. The outcomes of HSCT 
are heavily dependent upon the degree of human leukocyte antigen (HLA) matching between 
the donor and the patient. Event-free survival (survival without graft failure) is highest in 
patients who receive HSCT from a matched sibling donor and is significantly worse in 

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patients who receive an HSCT from a matched unrelated donor or haploidentical donor 
(Eapen et al 2019). Myeloablative conditioning regimens are common before HSCT 
(Brazauskas et al 2020) and carry their own safety risks such as prolonged neutropenia and 
thrombocytopenia, organ toxicity, and infertility. HSCT carries long-term risks of graft versus 
host disease (GVHD), which greatly contributes to the morbidity of HSCT. Acute GVHD 
occurs in 10% to 21% of patients with SCD after allogeneic HSCT, and chronic GVHD 
occurs in 5% to 20% (Gluckman 2013, Walters 2015, Gluckman et al 2017). Prophylaxis for 
GVHD can cause additional adverse effects. HSCT has a significant mortality risk. HSCT for 
SCD is a viable treatment option for the few patients who have a matched sibling donor 
where outcomes are improved and mortality is as low as 5% (Khoury and Abboud 2011). 
However, at increasing ages, and with less optimal HLA-matched graft sources, the risks of 
HSCT begin to increase, with mortality as high as 29% (Brazauskas et al 2020). 
There continues to be an unmet need for SCD therapy that has durable effects, is not limited 
by donor availability, has fewer complications than are associated with allogeneic, unrelated, 
or haplo-identical HSCT, and does not require intense induction. The experience with 
hydroxyurea for SCD has shown the beneficial effects of increased HbF. Increased 
endogenous levels of HbF can ameliorate the clinical course of inherited disorders of 
-globin gene expression, such as -thalassemia and sickle cell anemia (Forget 1998). The 
experience with HSCT for SCD has shown that eliminating the βS-globin gene and replacing 
sickle RBC with those that produce normal β-globin is curative when the graft is stable, 
Furthermore, it has been shown that a limited number of engrafted normal (or genetically 
corrected) donor stem cells can repopulate nearly the entire peripheral RBC compartment. 
Prevention of sickling with the addition of an anti-sickling -globin gene to autologous HSCs 
is possible via gene therapy, which eliminates the need for a matched donor, eliminates the 
high risk of graft rejection, and allows the use of reduced intensity conditioning (RIC) and 
thus reducing morbidity related to immunosuppression and also preserving fertility. Unlike 
hydroxyurea and L-glutamine treatment, gene therapy could be a one-time treatment. 
1.3 Study Intervention 
The Sponsor proposes ARU-1801 as a novel therapy for SCD using gene transfer of 
recombinant γ-globin lentivirus (LV) vector (pseudotyped with a vesicular stomatitis virus G 
[VSV-G]) with a point mutation at codon 16 (sGbGM) into CD34+ cells (from human bone 

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marrow [BM] or mobilized peripheral blood) followed by autologous transplant after RIC 
with single-dose melphalan.  
The transgene is a recombinant human β-globin gene with human Aγ-globin exons and a 
point mutation in the γ-globin exon to improve affinity to α-globin. The transgene is driven 
by the β-globin gene promoter and carries the β-globin 3’ enhancer and the hypersensitive 
sites 2, 3, and 4 of the locus control region of the β-globin locus, an erythroid-specific 
enhancer. Further details about the gene mutation are provided in the investigator’s brochure 
(IB).  
Lentiviral vectors based on human immunodeficiency virus type 1 (HIV-1) are retroviruses 
that share the long terminal repeat (LTR)-Gag-Pol-Env-LTR genome common to all 
retroviruses but have additional genes that modulate viral replication and facilitate entry 
through the intact nuclear membrane of nondividing cells; LV vectors integrate into 
nondividing HSCs with high efficiency (Naldini et al 1996; Naldini and Verma 2000; Case et 
al 1999). This allows transduction in as little as 18 to 20 hours while achieving a high level 
of correction of human hematopoietic stem and progenitor cells. The HIV-based LV vectors 
confer several advantages over conventional LTR-driven -retroviral vectors. While 
-retroviral vectors have shown success in X-linked severe combined immunodeficiency 
(Gaspar et al 2004; Cavazzana-Calvo et al 2000), chronic granulomatous disease (Ott et al 
2006), adenosine deaminase deficiency (Aiuti et al 2009), and Wiscott-Aldrich syndrome 
(Aiuti et al 2013), they have been associated with severe adverse events (AEs) in X-linked 
severe combined immunodeficiency and chronic granulomatous disease, including T-cell 
acute lymphoblastic and T-cell leukemia as well as myelodysplastic syndrome and 
monosomy 7 (Thrasher et al 2006; Hacein-Bey-Abina et al 2008; Howe et al 2008). The 
self-inactivating design of LV vectors mitigates such risks and allows for efficient 
concentration without significant loss in titers, which is important for globin vectors that are 
typically produced at very low titers. In addition, development of LV vectors has minimized 
the possibility that replication competent LV could be generated (Recombinant DNA 
Advisory Committee, 2015). The integration profile of LV vectors is different from 
-retroviral vectors, which improves their safety. In addition, because the LV vector can 
accommodate the large globin gene and associated regulatory elements, the sGbGM LV 
vector expresses a high level of HbF in postnatal RBC after gene transfer into HSCs. The 
safety of vectors derived from the HIV virus has been rigorously demonstrated in preclinical 
studies (Kaner et al 2016). Furthermore, studies in over 250 patients who have received gene 

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therapy using LV vectors have been published to date, with no evidence of insertional 
oncogenesis (Tucci et al 2020). Details of vector development are provided in the IB.  
The sGbGM LV vector is pseudotyped with the VSV-G envelope generated for the 
transduction of HSCs from patients with hemoglobinopathies. The virus reverse transcribes 
and integrates into the CD34+ cell genome following cell entry. The final product consists of 
autologous CD34+ cells, from peripheral blood or BM, transduced with the sGbGM LV 
vector; the final product is referred to as ARU-1801. 
Development of ARU-1801 began at Cincinnati Children’s Hospital Medical Center, and an 
investigator-initiated US investigational new drug application was submitted to the FDA in 
November 2013. This study originally began as Protocol 2010-2588. In February 2019, the 
Sponsor (Aruvant) submitted documentation to the FDA initiating the transfer of the 
investigational new drug from Cincinnati Children’s Hospital Medical Center to Aruvant. As 
of April 2019, 4 subjects with severe SCD have been enrolled in the study. Two subjects were 
withdrawn from the study before administration of the gene-modified cell product 
(1 withdrew consent during screening and 1 was withdrawn due to inability to comply with 
study procedure), and 2 subjects had completed treatment under the protocol and at least 
15 months of follow-up.  
1.3.1 
Nonclinical Experience 
A number of nonclinical studies have been undertaken in mice to explore the pharmacology 
and toxicity of the prototype sGbG LV vector. A safety study was also conducted in 
macaques with this vector. During the nonclinical development, the HbF gene was modified 
to optimize oxygen carrying capacity and anti-sickling properties. Corroborative studies 
using an in vitro immortalization assay further confirmed the safety of the test vector, which 
showed a nearly 200-fold lower genotoxicity of the sGbG vector backbone. A subsequent 
toxicology study was performed with the sGbGM LV vector in mice. The results of these 
studies demonstrated the long-term safety of the sGbG and sGbGM LV vectors and did not 
provide any indication of insertional mutagenesis in vivo or in vitro or evidence of 
donor-derived tumors.  
In vivo nonclinical studies using the prototype sGbG LV vector demonstrated complete 
correction of the hematological, and functional RBC parameters and inflammation and organ 
pathology were seen in sickle mice following myeloablative-conditioning and transplant. 

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Correction was sustained long term in primary and secondary transplant recipients with a 
6-month survival rate of 100% in genetically corrected mice compared with a 20% survival 
rate in mock-transplanted mice.  
Comparative studies between sGbG and sGbGM LV vector have been performed in 2 sickle 
mouse models that demonstrated the superior ability of the sGbGM LV vector to form HbF 
compared with sGbG, resulting in correction of sickling, a superior reduction in 
reticulocytosis, and a rise in Hb in both types of sickle mice. 
Refer to the ARU-1801 IB for detailed summaries of nonclinical studies. 
1.3.2 
Clinical Experience 
The use of LV vectors in humans has not been associated with adverse effects from gene 
transfer or from the viral vector in HIV-positive subjects (Humeau et al 2004; Manilla et al 
2005; Levine et al 2006; Wang et al 2009), subjects with -thalassemia (Cavazzana-Calvo et 
al 2010; Thompson et al 2018), subjects with adrenoleukodystrophy (Cartier et al 2009; 
Eichler et al 2017), and in other indications. Potential safety concerns with genotoxicity are 
well documented in the literature. 
The proposed LV gene therapeutic approach has been used in at least 50 patients with SCD 
and over 100 patients with transfusion-dependent beta thalassemia. These trials have shown 
significant clinical improvement and promising expression of the target globin (Thompson et 
al 2018; Thompson et al 2020).  
This Phase 1/2 gene transfer study is designed to evaluate the safety, feasibility, and efficacy 
of 1) obtaining sufficient CD34+ cells via plerixafor-mobilized peripheral blood (P-MPB) in 
subjects with SCD; 2) ex vivo gene transfer of the γ-globin LV vector into the sickle CD34+ 
cells; 3) reduced intensity of conditioning; and 4) engraftment and efficacy of autologous 
gene-modified CD34+ cells, when transplanted back into subjects with SCD.  
1.4 Benefit-Risk Assessment 
The potential benefits of gene therapy for SCD include the possibility of cure with a single 
treatment using autologous HSC, which obviates the need for a matched related donor, 
reduces the risk of graft rejection even with reduced-intensity myeloablative conditioning, 
reduces immunological toxicities, and may preserve fertility. 

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The potential risks of this therapy include inadvertent generation of replication competent LV 
(of which there are no reports to date) and insertional mutagenesis. Insertional mutagenesis is 
less likely with the proposed LV vector than with retrovirus vectors (Montini et al 2006; 
Arumugam et al 2009; Modlich et al 2009; Montini et al 2009; Milone and O’Doherty 2018 
[review]). In addition, the LV vector used for the proposed procedure has the following 
characteristics to enhance safety: a self-inactivating vector design, a relatively 
lineage-restricted enhancer that is transcriptionally inactive, and a transgene (γ-globin) that 
cannot alter cellular proliferation. Nonclinical testing of the vector has not shown evidence of 
γ-globin vector-derived malignancy in any animal or development of clonal dominance 
attributable to the γ-globin vector. Furthermore, there are no reported cases of 
leukemogenesis in gene therapy trials that involve modification of HSCs or nondividing 
T cells (Milone and O’Doherty 2018 [review]).  
Immune responses to the transgene may be minimal with the approach of expressing the 
naturally occurring HbF via gene transfer into HSC (Perumbeti et al 2009). While the 
immunological effects of expressing altered β-globin or γ-globin chains in humans cannot be 
predicted, the long history of chronic transfusions in patients with SCD and thalassemia 
suggests that globin proteins have low immunogenicity. 
Potential procedural risks include infusion-related toxicity, the risks of stem cell harvesting, 
and the toxicity of chemotherapy conditioning. The potential for infusion-related toxicity is 
reduced by procedures to minimize contamination and by pre-infusion testing for microbial 
contamination and endotoxin. Furthermore, initial nonclinical and clinical experience has not 
shown significant reactions from cultured- and gene-altered autologous blood progenitors. 
The recommended procedure for stem cell harvesting is P-MPB, which can be performed 
without anesthesia and is associated with less morbidity than bone marrow harvest (BMH) of 
the pelvis, which also entails the risks of general anesthesia. Adverse effects of melphalan 
conditioning are well known and include anorexia, vomiting, hyponatremia, 
myelosuppression, mucositis, diarrhea, alopecia, and cytopenias. Blood counts will be 
monitored.  
1.4.1 
Hematologic Malignancy Risks 
Secondary malignancy is a known risk of both allogeneic and autologous HSCT, even for 
non-malignant hemoglobinopathies such as SCD. The pathogenesis of secondary malignancy 
is multifactorial, including host susceptibility and damage to residual and persistent HSCs 

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from alkylating chemotherapy, which is necessary to clear the native stem cell niche and 
allow engraftment of the therapeutic cells.  
Risk of Hematologic Malignancy in SCD 
Multiple studies have concluded that patients with SCD have an underlying increased risk of 
leukemia compared with the general population. A population-based retrospective study of 
patients from England concluded that patients with SCD have 11 times higher rates of 
developing acute myelogenous leukemia (AML) than patients hospitalized for other 
conditions (Seminog et al 2016).  Another study performed in California analyzed 27 years of 
population-based data and found a 3.37 times higher incidence of leukemia in patients with 
SCD aged 15-39 years and a 2.6 times higher incidence in patients with SCD over 40 years 
of age. In this study, the median age of first primary cancer was 46 years (n=115 patients 
with malignancy in the SCD group) (Brunson et al 2017). Similar results were found in a 
study at University of Illinois at Chicago, which identified 8 cases of hematologic 
malignancies in 1,327 patients with SCD from 2010 to 2015 by manually verifying cases per 
ICD-9-CM codes (0.12% per patient-year) versus 12 cases in 5,295 matched control 
individuals, which is a 2.66 times higher incidence in patients with SCD (Jain et al 2018).  
While these studies were limited by retrospective design, all three have concluded that 
patients with SCD carry an increased burden of risk for the development of hematologic 
malignancies, likely due to chronic lifelong stress erythropoiesis and inflammation which 
could lead to development of genetic aberrations within HSCs and premature stem cell aging. 
In the general population, the median age at diagnosis of myelodysplastic syndrome (MDS) 
is >70 years (Sallman and Padron 2017), and only 6% of cases are diagnosed in persons 
younger than 50 years old (Ma 2012). Incidence rates of MDS/AML in the general 
population are provided by SEER, which shows rates increase with age (National Cancer 
Institute). The findings of the UK and California studies of hematologic malignancies in 
adolescents and young adults with SCD demonstrate a much earlier median age of onset of 
malignancy than the general population. These data validate the idea that BM in SCD 
patients sustains more damage, experiencing premature aging, which results in a higher and 
earlier risk of malignancy than the general population. 

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Risk of Secondary Malignancy in Autologous Gene Therapy for SCD 
As of March 2021, 4 subjects have undergone melphalan conditioning and ARU-1801 
infusion, with a median follow-up of 26.5 months (the shortest follow-up is 6 months). There 
have been no reported cases of hematologic malignancy in the ARU-1801_Ph1_01 trial. 
The most extensive experience of autologous gene therapy for SCD is with BB1111, a LV 
gene therapy approach being developed by Bluebird Bio. BB1111 has been administered to 
47 patients with SCD since approximately 2015. To date, a total of 3 patients with SCD who 
have received BB1111 have developed leukemia or MDS. The first case was a patient who 
developed MDS 36 months after BB1111 infusion, which later evolved into AML. After 
extensive evaluation, the investigators were able to exclude insertional oncogenesis as the 
cause and attributed the malignancy to the combination of underlying patient predisposition 
and exposure to myeloablative chemotherapy (Hseih et al 2020). Bluebird Bio has recently 
reported 2 additional cases of hematologic malignancy within the SCD cohort: one case of 
AML 5.5 years after drug product (DP) infusion and one case of suspected MDS 6 months 
after DP infusion. Bluebird Bio has performed an extensive evaluation in the case of AML 
and was able to conclude that the vector was not integrated into a gene that affects cellular 
proliferation and had not impacted expression of the surrounding genes. The case of 
suspected MDS was reported based on clinical evidence of prolonged anemia after 
conditioning and presence of trisomy 8 in a small fraction of cells in the BM. It is unclear if 
the trisomy 8 existed before therapy. Of note, this patient has only 6 months of follow-up. In 
all the known cases of leukemia after gene therapy with more oncogenic gamma retroviral 
vectors, onset of malignancy occurred from 16 to 60 months (Hacein-Bey-Abina et al 2003; 
Hacein-Bey-Abina et al 2008; Howe et al 2008; Braun et al 2014; Stein et al 2010; Siler et al 
2015; Uchiyama et al 2019; Gaspar 2011). Furthermore, a case report of trisomy 8-related 
pancytopenia and MDS after gene therapy for ADA-SCID showed that trisomy 8 was pre-
existing, having predated gene therapy infusion based on cryopreserved BM and fluorescence 
in situ hybridization analysis (Engel et al 2007). Another study of patients with ADA-SCID 
later demonstrated dysplasia in patients’ marrow before chemotherapy and peripheral blood 
abnormalities in 7 patients who had undergone neither chemotherapy nor gene therapy, 
indicating that the risk for MDS is often a primary problem of the underlying disease (ADA-
SCID), unrelated to chemotherapy or gene therapy (Sokolic et al 2011). Given that the 
suspected MDS case occurred within 6 months of treatment and was preceded by prolonged 
anemia after busulfan, there is a good possibility that this patient had pre-existing risk factors 

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for developing MDS at baseline, which highlights the need for more thorough screening for 
MDS risk factors before treatment. 
There have been no reported cases of hematologic malignancy in over 100 patients treated 
with transfusion-dependent beta thalassemia (Hseih et al 2020). Notably, all trials of BB1111 
utilize myeloablative doses of busulfan administered IV over 4 days as the stem cell 
conditioning agent before DP infusion. While this is not dissimilar from conditioning 
regimens used for allogeneic HSCT in SCD patients, the relative rate of malignancy in 
Bluebird’s trials is higher than expected (3 of 47 patients or 6.4% compared with 
approximately 1% in allogeneic HSCT) (Eapen et al 2019; Kahn et al 2020). 
Risk of Secondary Malignancy in Allogeneic HSCT for SCD 
The overall incidence of secondary malignancy after allogeneic HSCT for SCD is low across 
a variety of different conditioning regimens. In one large study that included 294 patients 
with SCD, 3 patients developed malignancy after HSCT, representing an incidence of 1% 
(Kahn et al 2020). In another large study that included 910 patients with SCD, 6 developed 
malignancy after HSCT, for an incidence of 0.7% (Eapen et al 2019). This evidence 
establishes that the only currently available curative therapy for SCD has a 1% risk of 
secondary malignancy.  
A RIC regimen has been studied in allogeneic HSCT for SCD with good results. In a study of 
43 patients treated, no cases of hematologic malignancy have been reported after a median 
follow-up of 3.4 years (King et al 2015). These findings suggest that the risk of secondary 
malignancy might be lower in the setting of RIC with a melphalan-based regimen. 
Given the potential for curative therapy, the favorable preliminary experience with gene 
therapeutic approaches to hematologic diseases, and the known, monitorable, and 
manageable potential risks of the therapeutic procedure, the benefit-risk assessment supports 
the conduct of this study.  

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2 
Study Objectives and Endpoints 
2.1 Objectives 
2.1.1 
Primary Objectives 
The following are the primary objectives: 
• To evaluate the safety of: 
• Stem cell collection from subjects with SCD 
• Infusion of CD34+ cells transduced with sGbGM vector into subjects with SCD 
• Chemotherapy conditioning with melphalan in subjects with SCD 
• To evaluate the feasibility of: 
• Obtaining clinically sufficient number of CD34+ cells for gene transfer  
• Ex vivo manipulation of CD34+ cells and gene transfer 
• Engraftment of ex vivo manipulated gene-modified stem cells 
2.1.2 
Secondary Objectives 
The following are the secondary objectives: 
• To evaluate the efficacy of genetic correction via determination of the following:  
• Percentage of gene-marked cells  
• Contribution of gene-modified cells to multilineage hematopoiesis and circulating 
RBCs 
• Hematological and functional correction of sickling in SCD  
• To evaluate subjects for change in disease severity from baseline 
• To evaluate subjects for change in QoL from baseline 
2.1.3 
Exploratory Objectives 
The following is the exploratory objective: 
• To characterize the pharmacokinetics (PK) of melphalan in patients with SCD 

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• To characterize the relationship between the PK of melphalan and engraftment of 
ARU-1801. 
2.2 Endpoints 
2.2.1 
Primary Endpoints 
The following are the primary safety endpoints: 
• The incidence of: 
• Grade 3 allergic reaction associated with infusion of the transduced cell product  
• Grade 4 infection following infusion of the transduced cell product uncontrolled 
for >14 days 
• Grade 4 neutropenia lasting >1 month following melphalan  
• Grade 3 or 4 irreversible organ toxicity–neurologic, pulmonary, cardiac, 
gastrointestinal (GI), genitourinary, hepatic, or cutaneous–that is attributable to 
the study procedures 
• AEs and serious adverse events (SAEs) graded per the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 5.0 (v5.0) 
• Death due to study procedures 
• Hematological malignancy due to vector insertion 
• Hematological cancer related to the investigational product or study 
medications/procedures 
• Duration of neutropenia following conditioning (defined as the time from first 
measurement where absolute neutrophil count (ANC) < 500 cells/µL to first of 3 
consecutive absolute neutrophil count measurements on 3 consecutive days with ANC 
≥500 cells/µL) 
• Duration of thrombocytopenia following conditioning (defined as the time from first 
measurement where platelet count < 50,000 cells/µL to the first of 3 consecutive 
platelet counts on 3 consecutive days 50,000 cells/µL and independent of platelet 
transfusion for ≥7 days consecutive days) 

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The following are the primary feasibility endpoints: 
• Number of subjects with a total number of CD34+ cells recovered from all collections 
combined (mobilized peripheral blood and BM) of at least 8106/kg viable CD34+ 
cells (excluding the optional leukopack collection for research purposes) 
• Proportion of subjects for which a minimum of 4106 CD34+ cells/kg body weight 
from all collections combined have been successfully transduced  
• Number of subjects with BM aspirates at 1-year post-infusion with ≥1% gene-marked 
cells (with an average vector copy number [VCN] of > 0.01 copies per cell). 
2.2.2 
Secondary Endpoints 
The following are the secondary efficacy endpoints: 
• Quantification of HbFG16D (γ-globin gene with point mutation at codon 16) and other 
Hb subtypes, including HbF (endogenous), HbS, adult Hb (HbA), HbA2 and, if 
applicable, HbC and HbE by capillary zone electrophoresis (CZE) 
• Change in the proportion of antisickling/sickling hemoglobin 
(HbF+HbFG16D+HbA2/HbS) in Months 6-24 post-transplantation compared with 
baseline by CZE 
• Flow cytometry for percentage of HbF-containing RBC (F-RBC) and HbF content in 
reticulocytes (F-retics) in peripheral blood 
• Determining vector copies in the white blood cell (WBC) fraction 
• Determining gene transfer in BM based on the following: 
• Vector copies 
• Colony-forming unit cells (CFU-c) analysis for gene-marked CFU-c 
• Change in disease severity from baseline as measured by: 
• Annualized vaso-occlusive episodes (VOEs) pre-transplant versus post-transplant 
• Change in QoL from baseline as measured by the adult sickle cell quality-of-life 
measurement (ASCQ-Me®) 

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2.2.3 
Exploratory Endpoints 
The following are the exploratory endpoints: 
• Plasma PK parameters of melphalan including, but not limited to, area under the 
plasma concentration versus time curve (AUC), maximum observed plasma 
concentration (Cmax), clearance, and volume of distribution 
• Change in VOEs requiring parenteral opioids 

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3 
Investigational Plan 
3.1 Study Design 
The study is an open-label Phase 1/2 study in adult subjects aged 18 to 45 years with severe 
SCD completed in 2 stages. In the first stage, a cohort of subjects will be enrolled in a 
staggered manner until a total of 6 subjects are enrolled. Specifically, approximately 30 days 
must elapse after the infusion of 1 subject before the next subject can undergo infusion of 
ARU-1801. The independent Data Safety Monitoring Board (DSMB) will review the safety 
data from each subject before treating the next subject, although the DSMB may propose to 
alter this requirement as detailed in the DSMB charter. 
After 6 subjects in the first stage are evaluable, the DSMB will review the safety and 
feasibility of the procedure in this cohort and make a recommendation regarding treating 
4 additional subjects, for a total enrollment of 10 evaluable subjects in this study.  
After providing informed consent, potential subjects will undergo screening procedures and 
be evaluated for inclusion into the study. If all inclusion and no exclusion criteria are met, the 
subject will be allowed to enroll in the study. The principal investigator at each site will be 
responsible for all treatment and care the subject receives at the site during the study 
(Section 10). Enrolled subjects will have HbS reduced via erythrocytapheresis or transfusions 
with a goal of achieving a HbS ≤30% for at least 2 months before HSC collection and ≤20% 
within 7 days before HSC collection by P-MPB. Minor deviations of these HbS target goals 
for a given subject may be made at the investigator’s discretion based upon consideration of 
safety and feasibility. The minimum 2-month requirement for HbS reduction may incorporate 
time required to receive erythrocytapheresis or transfusions just before screening as long as a 
HbS ≤30% over time is documented in the subject's medical records. Subjects may be treated 
with erythrocytapheresis or transfusions to maintain a HbS ≤30% for longer periods of time 
(eg, 6 months) before HSC collection at the investigator’s discretion. The overall goal of 
HSC collection is to collect ≥8×106 CD34+ cells/kg body weight. Collection of HSCs via P-
MPB may be repeated to obtain sufficient HSCs. For subjects who provide separate consent, 
additional HSC collection will be performed to obtain HSCs for research purposes. These 
will be primarily used for ARU-1801 DP manufacturing process improvements. 
The HSCs are enriched for CD34+ cells and then transduced ex vivo with the sGbGM LV 
vector. Subjects will undergo chemotherapy conditioning with RIC melphalan. Melphalan 

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dosing details are provided in Section 5.5.3.At least 36 hours after melphalan conditioning, 
ARU-1801 (the transduced CD34+ cells) are prepared for autologous IV infusion. 
ARU-1801 (the gene-modified CD34+ cells) are suspended in <10 mL/kg volume of 
Plasmalyte-A® supplemented with 1% human serum albumin and given to the subject as a 
single IV infusion and followed by a normal saline bolus (Section 5.2). The goal is to infuse 
4×106 CD34+ cells/kg body weight or higher to the subject.  
Subjects will return to the study site at regular intervals for follow-up for 2 years after the 
ARU-1801 infusion. It is anticipated that a separate long-term follow-up (LTFU) clinical 
study will be initiated. Once the LTFU study is approved at the site, all subjects who 
complete the Year 2 study visit in this study will be asked to consent and enroll into the 
LTFU study and will be followed for a total of 15 years after the ARU-1801 infusion. 
Long-term follow-up after Year 2 will continue in this Phase 1/2 study until subjects have 
transitioned into the LTFU study.  
Patient reported outcomes (PROs) will be assessed using the ASCQ-Me. The independent 
DSMB will monitor safety data throughout the study (Section 6.4.1). Predefined safety 
criteria toxicities (Section 6.4.2.1), feasibility criteria (Section 6.4.2.2), and early study 
stopping criteria (Section 6.4.3) will be monitored by the investigator(s) and Sponsor and 
reviewed on an ongoing basis by the DSMB. Subjects are free to withdraw from the study at 
any time (Section 4.2). At the time of consent withdrawal, the subject will be asked to 
provide permission for collection of relevant source documentation from clinical records to 
ascertain the subject’s health status (Section 4.2.2). 
The duration of the study is defined for each subject as the date signed written informed 
consent is provided through the last follow-up visit.  
The study design schema is presented in Figure 1.  

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Figure 1 
Study Design Schema 
 
Abbreviations: HbS, sickle hemoglobin; HSC, hematopoietic stem cell; PK, pharmacokinetic; P-MPB, 
plerixafor-mobilized peripheral blood; SCD, sickle cell disease. 
a. 
At investigator’s discretion and based on the subject’s compliance, subjects may complete clinical 
monitoring assessments as an outpatient (Section 5.5.3). 

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3.1.1 
Rationale of Study Design 
The scientific grounds for important aspects of the study design are described as follows: 
• Subject Population: Although gene therapy is predicted to have greatest efficacy 
when given to younger patients (before the onset of organ damage), safety and 
feasibility will be assessed in adult subjects in this study.  
• HSC Collection: The planned method for HSC collection is plerixafor followed by 
apheresis. Plerixafor is approved for use in the stimulation of stem cell release from 
the BM in preparation for autologous transplant in subjects with lymphoma and 
multiple myeloma. Plerixafor has been used successfully in gene therapy protocols 
for thalassemia and SCD (bluebirdbio Protocols HGB-205 and HGB-206). Plerixafor 
has been administered to patients with SCD in dose-escalation studies, without gene 
therapy, and to assess the kinetics of CD34+ mobilization into peripheral blood in 
settings when apheresis is not subsequently performed (Boulad et al 2018; Esrick et al 
2018; King AA, Kamani N, Bunin N, et al. Successful matched sibling donor marrow 
transplantation following reduced intensity conditioning in children with 
hemoglobinopathies. Am J Hematol. 2015;90(12):1093-8. 
• Lagresle-Peyrou et al 2018). The use of plerixafor with apheresis is preferred because 
it may supplant multiple BMH procedures and avoid the accompanying pain, risks, 
and morbidity associated with multiple surgical procedures under anesthesia.  
• There is limited information on the kinetics of CD34+ mobilization and the optimal 
time window for CD34+ apheresis collection among individual subjects with SCD 
(Boulad et al 2018; Esrick et al 2018; King AA, Kamani N, Bunin N, et al. Successful 
matched sibling donor marrow transplantation following reduced intensity 
conditioning in children with hemoglobinopathies. Am J Hematol. 2015;90(12):1093-
8. 

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• Lagresle-Peyrou et al 2018). Based upon published data on CD34+ kinetics after 
plerixafor administration in a small number of subjects with SCD, the peak 
concentration of peripheral blood CD34+ cells appears to occur within the first 
6 hours after plerixafor administration and with considerable variability in peak CD34 
concentration and area under the time-concentration curve (Boulad et al 2018; Esrick 
et al 2018; King AA, Kamani N, Bunin N, et al. Successful matched sibling donor 
marrow transplantation following reduced intensity conditioning in children with 
hemoglobinopathies. Am J Hematol. 2015;90(12):1093-8. 
Lagresle-Peyrou et al 2018). Therefore, in the current study, serial sampling of 
peripheral blood CD34+ concentration will be assessed after plerixafor administration 
and the individualized mobilization pattern may be used to guide the subsequent 
timing and duration of apheresis for each individual subject. 
• Conditioning Regimen: The benefit-risk profile of melphalan for pretransplant 
conditioning has been well characterized after clinical experience with transplantation 
and with gene therapy for adenosine deaminase deficiency (Gaspar et al 2006) and for 
SCD (Shenoy 2007). Based on previous clinical experience with melphalan, this 
study will include RIC with a single dose of melphalan. An advantage of RIC is that 
autologous recovery occurs within 3 to 4 weeks of the conditioning regimen, which 
means that it is not necessary to collect and store BM as a backup for potential 
reinfusion. In the present study, this means that after adequate CD34+ cells have been 
collected for gene therapy, no further HSC collection is needed. This RIC has not 
been associated with ovarian failure, delayed puberty, or other endocrine dysfunction 
(Blood and Marrow Transplant Clinical Trials Network Protocol 0601).  
Patients with SCD typically have altered kidney function, including renal 
hyperfiltration. The median glomerular filtration rate (GFR) in patients with SCD is 
137-154 mL/min with ranges reported of 132-176 mL/min (95% CI). (Marouf et al 
2006; Niss et al 2020). Because of the renal contribution to melphalan clearance, 
renal hyperfiltration can result in reduced melphalan exposure in some patients with 
SCD. Successful engraftment of ARU-1801 is key to ensure sustained production of 
HbFG16D and continued clinical benefits. Reduced melphalan AUC and subsequent 
lower ARU-1801 engraftment were observed in one of the first 4 subjects treated with 
ARU-1801. Before chemotherapy, this subject had renal hyperfiltration according to 

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cystatin C estimated glomerular filtration rate (eGFR) (Subject 004, Table 3-1, 
Figure 2). 
Table 3-1 
Cystatin C eGFR and Melphalan AUC in Subjects Treated with 
ARU-1801 
 
Subject 
Parameter 
002 
004 
006 
008 
Cystatin C eGFR (mL/min/1.73m2) 
78 
200 
108 
126 
Melphalan AUC (μg.h/mL) 
8.27 
5.73 
8.52 
6.78 
Abbreviations: AUC, area under the plasma concentration versus time curve; eGFR, estimated glomerular 
filtration rate. 
Figure 2 
Engraftment versus AUC 
  
Abbreviations: AUC, area under the plasma concentration versus time curve; DP, drug product; PB, peripheral 
blood; VCN, vector copy number. 
To lower the probability for reduced engraftment of ARU-1801 in subsequent 
subjects enrolled in this study, the exact dose of melphalan given to a subject will be 
based on predictive modeling (Section 5.5.3). 
002
004
006
008
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
5.0
5.5
6.0
6.5
7.0
7.5
8.0
8.5
9.0
PB VCN as % of DP VCN
Melphalan AUC (mg.h/L)
Engraftment vs Melphalan AUC

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o Based on a study of 100 patients treated with melphalan prior to stem cell 
transplant for multiple myeloma, Nath et al in 2010 developed a predictive 
model for melphalan AUC based on the 3 covariates GFR, lean body mass, 
and hematocrit. Using the Nath model, simulations comparing patients with 
multiple myeloma and patients with SCD predict a shift towards lower 
exposures for patients with SCD, with an AUC <7 μg.h/mL for approximately 
1 in 4 patients with SCD (vs 1 in 10 patients with multiple myeloma) 
(InsightRx).  
o Individual PK results from the first 4 subjects treated with ARU-1801 were 
compared with modeled PK using each subject’s individual covariates. The 
modeled exposure was calculated using a modified version of that published 
by Nath et al in 2010 (substituting estimated eGFR using Cystatin C for 
creatinine clearance) and highly correlated to the measured exposure via PK 
in all 4 subjects (Figure 3). Therefore, the modified Nath model will be used 
to predict melphalan AUC in all subjects.  
Figure 3 
Observed and Predicted AUC 
 
 
Abbreviation: AUC, area under the plasma concentration versus time curve. 
o The target range for melphalan AUC will be 7.0 – 13.0 μg.h/mL.  

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o The lower bound of the AUC target range of 7 μg.h/mL was selected based on 
analysis of the relationship between melphalan AUC and ARU-1801 
engraftment (as measured by ratio of most recent peripheral blood VCN/ Drug 
Product VCN) in the first 4 subjects with SCD treated with ARU-1801. This 
analysis demonstrated that the 3 subjects with a melphalan AUC 
> 6.7 μg.h/mL had peripheral blood VCN / Drug Product VCN ratios >50%. 
The one subject with an AUC < 6.7 μg.h/mL had a peripheral blood/DP VCN 
of only 10%, evidence of poor engraftment (Figure 2). 
o The upper bound of the AUC target range of 13.0 μg.h/mL was selected based 
on a simulation of predicted AUC in 10,000 patients with multiple myeloma 
given a conventional BSA-based dose of melphalan 140 mg/m2, using the 
Nath model and model covariates based on NHANES 2017-18 and Nath et al 
2010. In this simulation, the 25th percentile AUC was 8.6 μg.h/mL, and the 
75th percentile AUC was 13.0 μg.h/mL (InsightRx). The results of this 
simulation are similar to the actual values found in patients with multiple 
myeloma who received a median dose of melphalan 192 mg/m2 and had an 
AUC range of 10.8 - 15.1 μg.h/mL (25th, 75th percentiles). The goal of 
selecting an upper bound of a target AUC range that is at the 75th percentile of 
the expected AUC for a reduced intensity melphalan dose of 140 mg/m2 is to 
maintain the expected adverse event profile of a RIC dose of melphalan. 
Melphalan exposures with median AUCs of 13.4 and 14.1 μg.h/mL have been 
associated with either no or low-grade AEs (Nath et al 2010; Cho et al 2017). 
o Subjects with a model-predicted melphalan AUC ≥ 8.0 μg.h/mL for a 
140 mg/m2 melphalan dose will receive a conventional body-surface area-
based dose of melphalan 140 mg/m2.  
o Subjects with a model-predicted melphalan AUC < 8.0 μg.h/mL for a 
140 mg/m2 melphalan dose will receive a model-informed dose of melphalan 
to target achieving a melphalan AUC of 10.4 μg.h/mL. The model-informed 
dose to achieve a target AUC of 10.4 μg.h/mL will be limited to a maximum 
of 200 mg/m2, which was chosen to minimize toxicity.  
o This dosing strategy balanced the percentage of subjects below and above the 
target melphalan AUC (7.0– 13.0 μg.h/mL), with simulations showing 11% 
above target and 17% below target (Insight Rx). Previous studies have shown 

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that the toxicity of melphalan is related to the AUC achieved (Shaw et al 2014 
Table 2). In one study, Grade 3-4 mucositis was associated with a median 
melphalan AUC of 16.9 ug.h/mL, whereas Grade 0-2 mucositis was 
associated with a median AUC of 13.4 ug.h/mL (Nath et al 2010 Table 9). 
Similarly, in a different study, Grade 2-3 mucositis was associated with an 
AUC of 16.1 ug.h/mL, whereas Grade 0-1 mucositis was associated with an 
AUC of 14.1 ug.h/mL (Cho et al 2017). Accordingly, the upper AUC limit 
represents a low risk of melphalan toxicity, and the selective dose increase is 
not expected to significantly increase subject exposure to this low risk. 
o The higher doses administered to these subjects (many of whom will have 
renal hyperfiltration) will achieve an AUC that is similar to an expected AUC 
with a 140 mg/m2 melphalan dose in patients with normal renal function. 
Thus, in these subjects, the toxicity profile of higher doses of melphalan is 
expected to mirror a RIC 140 mg/m2 dose. 
• Premedication: Subjects will receive premedication with acetaminophen, 
diphenhydramine, and hydrocortisone before infusion of ARU-1801 to prevent or 
mitigate systemic reactions to infusions (see Section 5.4.3).  
• Long-term Toxicity Monitoring Related to Gene Transfer: Peripheral blood 
samples from enrolled subjects will be analyzed regularly to monitor for abnormal 
morphology, replication competent LV, and for clonality of insertion sites as evidence 
of a monoclonal population indicating malignant transformation. This is consistent 
with regulatory guidelines for viral vector-based human gene therapy products.   

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4 
Subject Selection and Withdrawal Criteria 
4.1 Selection of Study Population 
Adult subjects with severe SCD will be enrolled until a total of 10 subjects have received 
ARU-1801. Subjects will receive study treatment only if they meet all of the inclusion 
criteria and none of the exclusion criteria. 
Deviations from the inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability, or subject 
safety. Therefore, adherence to the criteria as specified in the protocol is essential. 
4.1.1 
Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in this study: 
1. Is 18 to 45 years old.  
2. Is capable of understanding the written informed consent, provides signed and 
witnessed written informed consent, and agrees to comply with protocol requirements 
(Section 9.3). 
3. Has confirmed diagnosis of SCD (genotype HbS-β0-thalassemia or HbS-β+ 
thalassemia disease or HbSS, confirmed by β-globin gene analysis and a hemoglobin 
separation method).  
4. Has severe SCD, defined as 1 or more of the following: 
a. Minimum of 2 episodes of clinically diagnosed acute chest syndrome (ACS) 
requiring hospital admission, or 1 life-threatening episode of ACS requiring 
intensive care unit admission for exchange transfusion and/or intubation, or 
frequent ACS episodes, which necessitate treatment with chronic transfusion 
therapy. 
b. Frequent painful VOEs that significantly interfere with normal life activities, 
defined as a history of 2 or more severe acute sickle pain events per year requiring 
additional treatment at a medical facility outside of home pain management over 
the preceding 2-year period prior to study enrollment, or that necessitate chronic 
transfusion therapy. 

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c. Subjects on chronic transfusion therapy for severe disease symptoms other than 
those previously listed, and which interfere with normal life activities. 
5. Has failed hydroxyurea therapy, was unable to tolerate hydroxyurea therapy, or has 
actively made the choice to not take the recommended daily hydroxyurea advised for 
severe disease (note: must be off hydroxyurea therapy for 2 months prior to stem cell 
collection). If refusing hydroxyurea, the subject must document that he/she has been 
educated about the benefits and continues to refuse the treatment. Subjects who were 
placed on chronic transfusion therapy instead of hydroxyurea for severe disease are 
eligible. Subjects who are unable to take hydroxyurea due to financial or safety 
monitoring constraints are eligible.  
6. Has adequate functional status and organ function as defined by the following: 
a. Karnofsky performance score ≥60. 
b. Ability to undergo general or regional (spinal or epidural) anesthesia as per 
standard institutional practice. 
c. Adequate renal function: defined as a cystatin C estimated glomerular filtration 
rate (eGFR) >60 mL/min/1.73 m2. 
d. Adequate liver function as defined by a serum conjugated (direct) bilirubin 
<2.5× the upper limit of normal (ULN) for age; aspartate aminotransferase (AST) 
and alanine aminotransferase (ALT) <5×ULN for age as per local laboratory. 
e. Adequate cardiac function, defined as left ventricular ejection fraction >40%. 
4.1.2 
Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study: 
1. All participants of reproductive potential must agree to use an effective method of 
birth control as determined by the investigator for a period of no less than 1 year after 
the ARU-1801 infusion.  
a. Female subjects cannot be pregnant or lactating/breastfeeding and must be either 
surgically sterile, postmenopausal (no menses for the previous 12 months),or must 
be practicing an effective method of birth control as determined by the 
investigator (eg, oral contraceptives, double barrier methods, hormonal injectable 
or implanted contraceptives, tubal ligation, or partner with vasectomy). Women 

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must agree not to breastfeed from consent through at least 1 year after the ARU-
1801 infusion as stipulated in the informed consent document. 
b. Male subjects agree to use an effective method of birth control as determined by 
the investigator for a minimum of 1 year after ARU-1801 infusion. 
2. Has active malignant disease or is receiving treatment for any type of cancer (except 
squamous cell carcinoma, basal cell carcinoma, or carcinoma in situ of the skin). 
3. Has a current diagnosis or history of hepatitis B (positive for surface hepatitis B 
antigen), hepatitis C, or HIV.  
4. Has had treatment with any other investigational drug within 30 days or within 5 half 
lives of the last dose (whichever is longer) prior to screening. 
5. Has abnormal pulmonary function tests (PFT) as defined below. Most adults with SCD 
will have compromised PFTs; therefore, subjects who have mild or moderate 
obstruction or restriction or diffusion defects will be allowed to participate in the 
study. However, subject with severe obstruction, restriction, or diffusion defects will 
be excluded, as follows:  
a. Moderate obstruction is defined per American Thoracic Society criteria as a 
forced expiratory volume in 1 second (FEV1) down to 60% of predicted, 
associated with a FEV1/forced vital capacity (FVC) ratio below the 95% 
confidence intervals. Moderate restriction is defined as a total lung capacity down 
to 60% of predicted. Moderate diffusion defect is defined as a diffusing capacity 
of carbon monoxide (DLCO)-corrected for hemoglobin down to 40% of 
predicted.  
b. Subjects will be ineligible for this study if their lung function falls below any of 
the following 3 criteria: i) FEV1<60% predicted with a FEV1/FVC ratio <95% 
confidence interval; ii) total lung capacity <60% of predicted; and iii) 
DLCO-corrected for hemoglobin <40%. 
6. Has evidence of uncontrolled bacterial, viral, or fungal infections (currently taking 
medication and progression of clinical symptoms) within 1 month prior to starting the 
conditioning regimen. Subjects with fever should await resolution of symptoms before 
starting the conditioning regimen. 

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7. Has a history of stroke or is at moderate to high risk of primary stroke (eg, receiving 
chronic transfusions or hydroxyurea for primary prevention of stroke; has severe 
cerebral vasculopathy defined as moderate stenosis in >2 arterial segments; and/or has 
severe stenosis/occlusion in ≤2 segments in the polygon of Willis or presence of 
Moyamoya-like disease). 
8. Has α-thalassemia (2 or more gene deletions or any α-globin structural variants) SCD.  
9. Has previous documented liver biopsy result performed before screening that shows 
cirrhosis, bridging hepatic fibrosis, or active hepatitis or subject has received chronic 
transfusions (>200 mL/kg body weight) and has previous documented evidence of 
iron overload (a serum ferritin level of >1000 ng/mL and a magnetic resonance 
imaging [MRI; T2* or FerriScan] estimated liver iron >15 mg/g dry weight) and 
previous documented evidence of liver fibrosis by noninvasive liver imaging.  
10. Has documented matched sibling donor, unless subject was fully informed about the 
benefits and risks of HSCT and has declined this option or this option is not feasible 
due to comorbidities or financial or logistical constraints. In order for subject to be 
considered eligible, documentation must be included as part of the informed consent 
process for subjects who decline this option.  
11. Has medical history of pulmonary hypertension documented as a tricuspid 
regurgitation jet velocity >3 m/s by transthoracic echocardiography and/or clinical 
signs and symptoms of pulmonary hypertension (mean pulmonary artery pressures 
>25 mm Hg).  
12. Has any condition, screening laboratory or diagnostic test result, or chronic physical or 
mental illness that, in the opinion of the investigator, makes participation ill advised. 
13. Has a known hypersensitivity to any study treatments (eg, melphalan, plerixafor). 
14. Is an employee or family member of the investigator or study site personnel. 
4.2 Withdrawal of Subjects From Study Treatment and/or the Study 
4.2.1 
Reasons for Withdrawal/Discontinuation 
Subjects may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the investigator or at the study site. Every effort should be made 

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to keep subjects in the study. The reasons for subjects not completing the study will be 
recorded (see below).  
Given the nature of the therapeutic intervention explored in this study and the intensity and 
duration of the preparations required before infusion of ARU-1801, subjects may be 
withdrawn from the study before receiving study treatment. Such subjects may be replaced 
(Section 4.2.3). In addition, since the therapy consists of a 1-time infusion, discontinuation of 
study treatment is not relevant to this study, except in the event that a subject does not 
tolerate the infusion of ARU-1801 and the procedure is interrupted before the intended 
volume has been administered.  
Before receiving the ARU-1801 infusion, a subject may be withdrawn from the study for any 
of the following reasons: 
• Subject is unable to tolerate HbS reduction to ≤30% via erythrocytapheresis or 
transfusions before HSC collection. 
• Baseline genetic evaluation of BM demonstrates an increased risk to development of 
hematologic malignancy. Identification of any of the following chromosomal 
abnormalities or genetic mutations must result in subject withdrawal and the subject 
should not undergo any further research procedures: 
o Cytogenetic chromosomal abnormalities, identified by karyotype evaluation, such 
as monosomy 7 or trisomy 8.  
o Chromosomal abnormalities associated with MDS, identified by FISH evaluation: 
RPN1, MECOM (3q21, 3q26.2) | 5q-, -5 (5p15, 5q31, 5q33) | 7q-, -7 (Cen 7, 
7q22, 7q31) | Trisomy 8 (Cen 8) MLL (11q23) | ETV6 (12p13) | 17p- (TP53 
17p13.1, NF1 17q11.2) | +19 (19p13.2, 19q13) | 20q-(20q12, 20qter). 
o Genetic mutations in the Neotype Myeloid Disorders Profile identified by Next 
Generation Sequencing (NGS) as part of the Neotype Myeloid Disorders Panel 
(ML/MPN/MDS/MDS-MPN). Currently these mutations include: ABL1, ASXL1, 
ATRX, BCOR, BCORL1, BRAF, CALR, CBL, CBLB, CBLC, CDKN2A, 
CEBPA, CSF3R, CUX1, DDX41, DNMT3A, ETNK1, ETV6, EZH2, FBXW7, 
FLT3, GATA1, GATA2, GNAS, GNB1, HRAS, IDH1, IDH2, IKZF1, JAK2 
including V617F and Exons 12+14, JAK3, KDM6A, KIT, KRAS, MLL, MPL, 
MYD88, NF1, NOTCH1, NPM1, NRAS, PDGFRA, PHF6, PML, PPM1D, 

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PTEN, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SH2B3, SMC1A, SMC3, 
SRSF2, STAG2, STAT3, STAT5B, TET2, TP53, U2AF1, WT1, ZRSR2. 
• Harvest of CD34+ cells is inadequate despite multiple harvest attempts. 
• Subject cannot tolerate further CD34+ harvest attempts in order to obtain adequate 
CD34+ cells. 
• Preparation of gene-modified cells is unsuccessful for any reason, including failure of 
transduction or tests for contamination, viability, and concentration.  
• Subject no longer meets the protocol inclusion or exclusion criteria. 
• Subject is noncompliant with the protocol. 
• Subject has a serious or intolerable AE that in the investigator’s opinion requires 
withdrawal from the study.  
• Subject has laboratory safety results that reveal clinically significant hematological or 
biochemical changes from the baseline values. 
• Subject has symptoms or an intercurrent illness not consistent with the protocol 
requirements or that justify withdrawal. 
• Subject becomes pregnant before receiving ARU-1801; if subject becomes pregnant 
after infusion of ARU-1801, she may remain in the study (see Section 6.7). 
• Sponsor terminates the study (see Section 11.3). 
All subjects who receive the ARU-1801 infusion will be encouraged to complete all 
follow-up visits. However, a subject may voluntarily withdraw from study participation at 
any time.  
After administration of the ARU-1801 infusion, a subject may be withdrawn from the study 
for the following reasons: 
• Subject is lost to follow-up. 
Upon occurrence of a serious or intolerable AE, whether before or after the ARU-1801 
infusion, the investigator will confer with the Sponsor. If a subject is withdrawn because of 
an AE, the event will be followed until it is resolved. Any subject may withdraw his or her 
consent at any time. At the time of consent withdrawal, the subject will be asked to provide 

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permission for collection of relevant source documentation from clinical records to ascertain 
the subject’s health status (Section 4.2.2). 
4.2.2 
Handling of Withdrawals 
Subjects are free to withdraw from the study at any time upon request. Subject participation 
in the study may be stopped at any time at the discretion of the investigator or at the request 
of the Sponsor. 
Subjects who no longer want to participate in the study should NOT be considered 
withdrawn from the study UNLESS consent is withdrawn. When possible, these subjects 
should return for protocol-scheduled visits as indicated in Appendix 1. If a subject fails to 
return for site visits for unknown reasons, the investigator or designee should make every 
effort to contact the subject. This contact should preferably be performed according to the 
schedules of events. If the subject cannot or is unwilling to attend any visit(s), the site staff 
should maintain regular telephone contact with the subject. Telephone contact should 
preferably be completed per the schedules of events (Appendix 1). At a minimum, in 
abbreviated visits, the following data should be collected at site visits or via telephone (per 
schedules of events): 
• Concomitant medications (including opioids) 
• AEs and SAEs 
• Survival status 
For subjects who withdraw consent, the reason(s) for withdrawal shall be recorded by the 
investigator on the relevant page of the electronic case report form (eCRF). Whenever 
possible, all subjects who withdraw from the study prematurely after receiving the 
ARU-1801 infusion will undergo safety procedures before withdrawal. In addition, every 
effort will be made to undertake protocol-specified, safety follow-up procedures, in particular 
for subjects who withdraw because of an AE or serious AE. For subjects who withdraw and 
are unwilling to return for a site visit, the investigator or designee may conduct a follow-up 
visit via telephone contact. Study sites should make every effort to re-establish contact with 
subjects who repeatedly fail to return for scheduled visits and who they are unable to contact, 
including searching public records (court, property, mortality). Subjects who fail to return for 

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final assessments after 2 documented telephone contact attempts and a registered letter will 
be considered lost to follow-up.  
Subjects who withdraw consent at any time will be asked at the time of withdrawal to 
provide permission for collection of relevant source documentation from clinical records to 
monitor any AEs. The permission request and response will be recorded in the appropriate 
eCRF. For subjects who withdraw before ARU-1801 infusion, any AE will be attributable to 
study procedures only and not to the gene product, which would not have been received. Any 
SAEs will be reported according to Section 6.3.1.5. 
4.2.3 
Replacements 
Any subject who withdraws from the study before or after receiving the ARU-1801 infusion 
may be replaced.  

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5 
Study Treatments 
5.1 
Method of Assigning Subjects to Treatment Groups 
This is an open-label study. No randomization or blinding will be performed. 
5.2 
Treatments Administered 
The investigational product, ARU-1801, consists of the CD34+ cells transduced with the 
-globin (sGbGM) LV vector. It may be given as a fresh infusion or cryopreserved for later 
administration. The product for fresh infusion is formulated in <10 mL/kg volume of 
Plasmalyte-A® supplemented with 1% human serum albumin and filled into a syringe. The 
cryopreserved product is formulated in a cryopreservation medium containing 10% dimethyl 
sulfoxide (DMSO) and filled into a bag. 
The investigational product, ARU-1801, will be administered via IV infusion over a period 
no longer than 15 minutes, followed by an IV infusion of 10 mL/kg bolus of saline over 
approximately 30 minutes. The goal is to infuse the subject with 4×106 CD34+ cells/kg body 
weight or higher. 
Detailed instruction for preparation and administration of autologous CD34+ cells transduced 
with the sGbGM LV vector are provided in the Pharmacy Manual. 
5.3 
Identity of Investigational Product 
The investigational product, ARU-1801, consists of the CD34+ cells transduced with the 
γ-globin (sGbGM) LV vector. 
Refer to the IB for further details related to the sGbGM LV vector. 
5.4 
Management of Clinical Supplies 
5.4.1 
Investigational Product Packaging and Storage 
The formulated subject ARU-1801 product for fresh infusion is placed in a 60-cc syringe 
contained in a sterile, reclosable, plastic overwrap and stored at 2°C to 8°C for up to 8 hours 
until the initial testing (final cell count, Gram stain, and endotoxin) is complete and it is 
released for infusion. The infusion of the released product must be complete within 8 hours, 

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although the Sponsor recommends that the cell product (ARU-1801) be infused as soon as 
possible. 
Alternatively, the CD34+ drug substance will be resuspended at a concentration of 1 to 
10106 cells/mL in CryoStor® CS10 cryopreservation media containing 10% DMSO and 
transferred to a 250-mL cryopreservation bag. ARU-1801 cryopreserved product will be 
stored at <-140°C in the vapor phase of liquid nitrogen. Upon thaw, the ARU-1801 DP 
should be administered by infusion from the bag immediately.  
5.4.2 
Test Article Accountability 
The investigator or designee is responsible for the following: 
• Logging receipt of each delivery of investigational product (ARU-1801) 
• Confirming the actual contents of delivery 
• Verifying receipt of the investigational product by signing the appropriate 
documentation provided by the Sponsor or designee 
• Indicating the status of each sterile tube or cryovial received 
The investigator will maintain accurate records of receipt of all test articles, including dates 
of receipt. In addition, accurate records will be kept regarding when and how much test 
article is dispensed and used for each subject in the study. Reasons for departure from the 
expected dispensing regimen must also be recorded. At the completion of the study, 
regulatory requirements regarding drug accountability will be followed. Guidance for 
investigational product accountability will be provided in the Pharmacy Manual. 
5.4.3 
Other Supplies 
The following drug supplies will be supplied by the site: 
• Melphalan (Evomela® [New Drug Application: 207155] or if not available a 
therapeutic equivalent melphalan will be used) 
• Plerixafor  
• Acetaminophen, diphenhydramine, hydrocortisone, and any other premedications 
given per institutional policy  

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Melphalan for injection is supplied as a dry powder. Detailed instructions for melphalan 
preparation and administration are provided in the Pharmacy Manual.  
Plerixafor, a hematopoietic stem cell mobilizer, will be used for peripheral blood 
mobilization. Drug preparation and administration should adhere to institutional standard 
practice and product prescribing information. 
As premedication before infusion of ARU-1801, subjects will receive oral or IV doses of 
acetaminophen (650 mg) and diphenhydramine (50 mg) and an IV dose of hydrocortisone 
(100 mg). The route of administration for acetaminophen and diphenhydramine is at the 
investigator’s discretion; hydrocortisone should be administered intravenously. 
5.5 Study Treatment Procedures and Administration 
Study treatment procedures are HSC collection (Section 5.5.1), CD34+ cells transduction 
with the γ-globin LV vector (Section 5.5.4), subject conditioning with melphalan 
(Section 5.5.3), and infusion of transduced CD34+ cells back to the subject (Section 5.5.5). 
5.5.1 
Hematopoietic Stem and Progenitor Cell Collection 
After completing the assessment for the Stem Cell Collection Clearance Visit (Table 13-1), 
HSCs will be collected from P-MPB (Section 5.5.1.1) (Section 5.5.1.2). The use of P-MPB is 
at the discretion of the investigator. The target for HSC collection is ≥8106 CD34+ cells/kg 
body weight (see Section 5.5.1.2). 
Because P-MPB procedures are not routinely performed in patients with SCD, it is difficult 
to estimate the amount of CD34+ cells that will be obtained from 1 sample collection. For 
this reason, serial sampling of peripheral blood CD34+ concentration will be assessed to 
understand the kinetics of CD34+ mobilization after plerixafor administration and guide the 
subsequent timing and duration of apheresis for each individual subject (Section 5.5.1.1). 
Overall, it is anticipated that multiple P-MPB procedures will be needed to achieve a 
minimum target CD34+ cell collection of ≥8×106 CD34+ cells/kg body weight. For subjects 
who provide separate consent, additional HSC collection will be performed to obtain HSCs 
for research purposes. 

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Target HbS and Hemoglobin Criteria 
Target HbS and hemoglobin values will be achieved using standard procedures, including 
serial simple transfusions done a few weeks apart, partial exchange transfusions (each a few 
weeks apart), or by using erythrocytapheresis; the methodology is at the discretion of the 
hematologist.  
After enrollment on study, subjects will begin the HbS reduction phase. The goal is to reduce 
HbS to ≤30% via erythrocytapheresis or transfusions for a period of 2 to 3 months. The 
frequency of required procedures and visits in order to achieve the target HbS at least 
2 months before HSC collection will be at the investigator’s discretion. The 2-month 
minimum requirement for HbS reduction may incorporate time required to receive 
erythrocytapheresis or transfusions just before screening as long as HbS ≤30% over time is 
documented in the subject’s medical records. Subjects may be treated with 
erythrocytapheresis or transfusions to maintain a HbS ≤30% for longer periods of time (eg, 
6 months) before HSC collection at the investigator’s discretion. 
Within 7 days prior to plerixafor administrations at the Stem Cell Collection Visit, the subject 
should have documented HbS ≤20% or have completed erythrocytapheresis to the goal HbS 
of ≤20%. Fluctuations in HbS outside of this range will be permitted as long as the subject 
meets the criteria at any 1 time point during the 7-day period. Minor deviations of these HbS 
target goals for a given subject may be made at the investigator’s discretion based upon 
consideration of safety and feasibility.  
5.5.1.1 
Plerixafor-Mobilized Peripheral Blood Collection  
Subjects will receive a 240 µg/kg subcutaneous injection of plerixafor and undergo apheresis 
at a time point informed by the CD34+ kinetic data (Section 5.5.1.1) and for a duration 
designed to maximize CD34+ cell yield and maintain subject safety. During the first 2 days 
of collection of the first cycle, blood samples will be collected to measure peripheral blood 
CD34+ cell counts before administration of plerixafor (baseline) and at approximately 1, 2, 4 
and 8 hours after plerixafor dosing to evaluate the stem cell mobilization kinetics of each 
subject. If additional collection cycles are needed, the kinetics may be omitted. The timing of 
apheresis initiation, duration, collection volume, interface parameters, and other apheresis 
parameters will also be recorded.  

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Based upon emerging data on CD34+ kinetics and cell yields in the study, apheresis 
parameters may be altered to maximize CD34+ cell yield and maintain subject safety. After 
consultation with the Sponsor, the collection time points for peripheral blood sampling for 
CD34+ cell measurements may be changed, the number of blood samples collected for 
peripheral blood CD34+ measurements may be reduced, and the time window for apheresis 
may be altered. 
If needed, a second dose of 240 µg/kg of plerixafor may be given the next day, followed by a 
second apheresis for stem cell collection. Additional P-MPB procedures (mobilization and 
apheresis) using the same dose of plerixafor and schedule may be performed until sufficient 
stem cells are collected. For those subjects who are consented and at least 12 x106 
CD34+ cells/kg body weight have been obtained from them and frozen for use in ARU-1801 
investigational product, additional HSC collection will be performed. These HSCs will be 
used for research purposes to support future manufacturing process improvements.  
Peripheral blood CD34+ cell count should be analyzed before and after (1, 2, 4 and 8 hours) 
each plerixafor administration (detailed above and in Section 5.5.1.1). Collection procedures 
using P-MPB may be performed on up to 5 consecutive days, if tolerable to subject or as 
directed by the investigator. If multiple cycles of plerixafor and apheresis are needed (ie, 
insufficient stem cells are collected after consecutive P-MPB procedures), at least 2 weeks 
should elapse between cycles. 
After apheresis, a blood sample will be collected for a complete blood count (CBC). The 
subject may be administered packed RBC (PRBC) or a platelet transfusion, as required, to 
maintain target levels of hemoglobin (>10.5 g/dL) and platelets (>100K; see Section 5.6.2). 
5.5.1.2 
HSC Collection Target 
Collected material will be evaluated for total nucleated cell count and CD34+ cell content. 
The overall goal of HSC collection is to collect ≥8×106 CD34+ cells/kg body weight before 
conditioning subject with melphalan.  
If the subject tolerates the HSC collection procedure well and <8×106 CD34+ cells/kg body 
weight are obtained from P-MPB apheresis, the cells will be cryopreserved and additional 
collections will be performed until the total target viable CD34+ cells (≥8×106 CD34+ 
cells/kg body weight) are obtained and cryopreserved.  

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If <8×106 CD34+ cells/kg body weight are obtained following P-MPB apheresis and no 
additional collections are performed due to the subject’s condition or preference, it will be 
deemed unfeasible to obtain sufficient CD34+ cells and the subject will not receive 
chemotherapy (Section 4.2). 
For those subjects who consented to the additional HSC collection, the HSC target will be 
≥12×106 CD34+ cells/kg body weight. If this target is obtained, excess collected HSCs will 
be used for research purposes. Any additional HSC collection will be done at the discretion 
of principal investigator and subject and will take into consideration how the subject tolerates 
the P-MPB procedure (mobilization and apheresis). 
5.5.2 
CD34+ Cell Isolation 
CD34+ cells will be isolated from apheresed material. The collected cells will be RBC-
depleted and enriched for CD34+ cells. The purified CD34+ cells will be resuspended in 
cryopreservative medium containing DMSO and cryopreserved until sufficient cells are 
collected. 
5.5.3 
Chemotherapy Conditioning With Melphalan 
Once sufficient stem cells are obtained, subjects will be prepared for administration of 
chemotherapy and administration of ARU-1801. Subjects will undergo a Chemotherapy 
Clearance Visit (Table 13-1), including evaluation of renal filtration by Cystatin C eGFR, 
nuclear medicine GFR, hematocrit, and height and weight. Detailed instructions for 
collection of the covariate data needed for the melphalan model-informed dose are provided 
below. Sites will be required to submit the accompanying de-identified source documentation 
to ePip once collected.  
• Gender, height, and weight: should be measured locally at the site during the 
Chemotherapy Clearance Visit and verified by two independent healthcare 
professionals. 
• Hematocrit: Should be measured after the last planned erythrocytapheresis or 
therapeutic blood transfusion that is done prior to chemotherapy, and no more than 
7 days before the planned administration of melphalan. Analysis at the central 
laboratory is preferred but may be performed locally if necessary. 

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• Cystatin C eGFR: Should be collected at the Chemotherapy Clearance Visit and 
analyzed at the central lab. May be analyzed at the site’s local lab if necessary. 
Nuclear medicine GFR will not be used to inform the model-informed dose of 
melphalan. 
Within no more than 7 days before planned administration of chemotherapy, the melphalan 
dose should be determined. The subject’s gender, height, weight, hematocrit, and cystatin C 
eGFR will be used to determine the predicted melphalan AUC.  
Subjects should also undergo HbS reduction to ensure the % HbS is less than 30% prior to 
chemotherapy. After clearance, subjects will then be admitted to the hospital in anticipation 
of chemotherapy administration and will remain in the hospital for close monitoring and 
supportive care until clinically fit for discharge after cell count recovery. Testing performed 
for clinical monitoring up to 30 days post-infusion should be recorded in the study database 
(CBC with reticulocyte and differential, clinical chemistry, and hemoglobin electrophoresis). 
At the investigator’s discretion, subjects who the site regards as reliable and highly compliant 
with the protocol and whose resource needs are met (eg, caregiver, transportation) may not 
require hospitalization for specific procedures and may instead return to the site at the 
frequency specified in the protocol to complete visits for collecting blood samples, 
determining cell counts, and completing other procedures. Investigators must instruct 
subjects and caregivers to immediately contact the site to report any AEs, including any signs 
or symptoms of infection (eg, fever). 
A RIC dose of melphalan will be given intravenously to all subjects at the Chemotherapy 
Visit. The exact dose of melphalan to be given to a subject will be based on predictive 
modeling using the formulas from Nath et al 2010, which are provided below. First, the 
predicted melphalan AUC for a conventional body-surface area-based dose of 140 mg/m2 is 
calculated (Equation 1). Subjects with a predicted melphalan AUC ≥8.0 μg.h/mL using this 
calculation will receive a dose of 140 mg/m2. Subjects with a predicted melphalan AUC 
<8.0 μg.h/mL will receive a model-informed dose of melphalan to achieve a target AUC of 
10.4 μg.h/mL. This dose is calculated using Equation 2. The model-informed dose of 
melphalan will be limited to a maximum of 200 mg/m2. A flow chart for determining the 
melphalan dose is provided in Section 13.6 Appendix 6. 

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Equation 1. 
Predicted AUCBSA.140 = 140 (mg/m2) x BSA (m2) / CLpred  
Equation 2. 
MELAUC10.4 Dose = 10.4 (mg*h/L) * CLpred 
Where 𝐶𝐿𝑝𝑟𝑒𝑑𝑖𝑐𝑡𝑒𝑑= 17 ∙(
𝐻𝐶𝑇
34 )
0.462
∙(
𝐹𝐹𝑀
53 )
0.75
+ 11.1 ∙
𝑒𝐺𝐹𝑅𝐶𝑦𝑠𝑡𝐶,𝑛𝑜𝑟𝑚𝑎𝑙𝑖𝑧𝑒𝑑
5.28
 [L/h] 
Equations for determination of eGFR, FFM, and ideal body weight are shown in Appendix 5 Section 13.5. 
Abbreviations: AUCBSA.140, area under the plasma concentration versus time curve for a body surface area-based 
dose of 140 mg/m2; BSA, body surface area (calculated using ideal body weight in subjects weighing 
>130% of ideal body weight); CLpred, predicted clearance; eGFRCystC,normalized, estimated glomerular 
filtration rate based on Cystatin C normalized to 70 kg; FFM, fat free mass; HCT, hematocrit; MELAUC10.4 
Dose, melphalan dose calculated for a target area under the plasma concentration versus time curve for a 
target of 10.4 μg.h/mL. 
 
Blood samples will be collected for measurement of melphalan concentration for 6 hours 
after the conditioning dose. The conditioning dose should be administered at least 36 hours 
before the infusion of ARU-1801 on Day 0. In subjects weighing >130% of ideal body 
weight, body surface area will be calculated using ideal body weight. Drug preparation and 
administration procedures, including use of antiemetics, should adhere to institutional 
standard practice, and product prescribing information. The investigator or designee should 
monitor subjects for melphalan-related side-effects and treat per standard practice. Known 
melphalan side effects and associated risks are summarized in Appendix 3. 
At least 36 hours after melphalan conditioning, the transduced CD34+ cells will be prepared 
for IV infusion.  
5.5.4 
Transduction of CD34+ Cells 
Manufacture of ARU-1801 will be performed in a Class 7 clean room environment according 
to defined standard operating procedures; all open manipulations are performed in a Class 5 
Biosafety Cabinet in accordance with FDA’s guidance for aseptic processing. Gene transfer is 
performed following good manufacturing practice requirements applicable for early phase 
clinical studies with formal quality assurance oversight. 
Purified CD34+ cells will be thawed, allowed to recover, pooled, and pre-stimulated in 
preparation for transduction. The pre-stimulated cells will be transduced ex vivo using the 
sGbGM- LV vector. Transduced cells will be infused following gene transfer either as a fresh 
product or a thawed cryopreserved product as detailed in Section 5.4.1. 

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5.5.4.1 
Safety and Efficacy Testing of Transduced Cells 
The final product will be released for infusion based on a portion of the full testing. This 
testing will include evaluating the CD34+ product for viable cell count, verifying that the 
product is negative for microbial contamination by Gram stain evaluation, and that viability 
is ≥70%. Endotoxin levels of the product will also be determined before the infusion, and the 
infused product must have <5 EU/kg body weight. The remaining tests will be performed 
after the infusion and are included on the final ARU-1801 product certificate of analysis. 
5.5.4.2 
Positive Microbial Culture Results 
A positive microbial report on a subject’s harvested or CD34-enriched cells will result in the 
following actions. 
• An antibiotic-sensitivity analysis will be performed. 
• The product may be infused if all conditional release criteria are met; the Gram stain 
is negative; if there is no impact to the safety, identity, strength, purity, and quality; 
and, if in the opinion of the investigator, the product is considered safe for infusion. If 
the product is infused the following precautions will be taken. 
• Physical examinations and evaluation for signs of infection daily for 3 days. 
• A CBC with differential daily for 3 days. 
• Blood and urine cultures daily for 3 days. 
• Appropriate broad-spectrum antibiotics will be administered intravenously, as 
determined by the investigator.  
An investigation as to the likely source of contamination will be conducted by the processing 
facility per institution’s standard operating procedures to determine if the positive culture 
occurred during the open manipulation. Reports of the investigation and associated corrective 
action will be reported to the Sponsor and the investigator for review and approval. 
5.5.5 
Infusion of ARU-1801  
At the end of transduction and at least 36 hours after the subject receives melphalan, 
transduced CD34+ cells will be prepared for IV infusion. 

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Subjects will be premedicated with acetaminophen (650 mg), diphenhydramine (50 mg), and 
hydrocortisone (100 mg) approximately 30 minutes prior to infusion of ARU-1801. Cells will 
be infused via IV infusion as detailed in Section 5.2. 
Subjects will be monitored closely for possible stem cell infusion-related toxicities, including 
fever within 24 hours and hypertension, as detailed in Section 5.6.3. Subjects will remain 
hospitalized after receiving the ARU-1801 until they are ready for discharge as per 
institutional protocols for transplant patients but not before the last melphalan PK sample has 
been collected (Section 6.6).  
Chronic transfusions will be continued for 3 months following transplant. Subjects will then 
be gradually weaned from transfusions with the goal of maintaining hemoglobin at ≥8 g/dL. 
The process for weaning transfusions is detailed in Section 5.7. 
5.6 Other Treatments: Supportive Care 
5.6.1 
Infectious Disease Prophylaxis 
Following receipt of melphalan, subjects will receive Pneumocystis prophylaxis per standard 
of care until adequate immune recovery is demonstrated. Antiviral and antifungal prophylaxis 
will be administered per standard of care when indicated. 
5.6.2 
Blood Product Support 
Because the administration of melphalan may produce cytopenias for 2 to 3 weeks, a CBC 
will be performed at a minimum twice weekly until absolute neutrophil count is >1×109/L 
and then weekly thereafter until the investigator considers the subject recovered. At 
investigator’s discretion, CBCs may be performed more frequently; all test results should be 
recorded. Note: granulocyte-colony stimulating factor (G-CSF) is contraindicated in patients 
with SCD (see Section 5.10.2). 
Platelet transfusions should be administered to maintain a platelet count >50,000/mm3. 
All red cell products should undergo extended RBC typing, specifically minor antigen 
matching for Kell, E and C blood groups for SCD identified and phenotypically matched, and 
transfusion of HbS negative units. Packed red cell transfusions should be given to maintain a 
hemoglobin at approximately 11 g/dL, and a HbS level ≤30% for the first 3 months after 
chemotherapy conditioning. 

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5.6.3 
Management of ARU-1801 Infusion-Related Toxicities  
After infusion of ARU-1801, the following guidelines should be followed for monitoring 
possible infusion-related toxicities: 
• Hypertension should be strictly controlled to prevent central nervous system toxicity. 
Blood pressure should be monitored closely and both systolic and diastolic 
hypertension should be treated promptly to maintain blood pressure at the subject’s 
pre-transplant baseline ± 20%. 
• Any subject who develops a fever to >38°C orally or axillary within 24 hours of 
infusion of ARU-1801 will undergo the following: 
• Immediate evaluation to identify the source of the fever 
• Collection of blood and urine for microbial culture 
• Collection of blood sample for CBC with differential to determine absolute 
neutrophil count 
• Intravenous administration of broad-spectrum antibiotics  
5.6.4 
Fertility Preservation 
Due to a potential risk of infertility/sterility in SCD subjects receiving melphalan 
conditioning, an option will be presented to each subject regarding a fertility consult and 
preservation. This research study will cover costs incurred up to $1000 per SCD subject. In 
the event that the subject’s insurance does not cover additional charges, the subject will be 
responsible for any fertility costs that exceed $1000. These costs will cover fertility consult, 
sperm preservation, and transportation, if needed. Additionally, regular reproductive testing 
will be performed (Section 6.3.2 and Appendix 1). 

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5.7 Transfusion Withdrawal 
In order to exert selective pressure on the gene-corrected CD34+ cells to proliferate, 
transfusion support after the gene transfer infusion will be slowly weaned. The projected plan 
for weaning transfusion support is outlined below. This plan will be implemented based on 
the practical capabilities of individual study sites and the health of the subjects: 
• Months 1 to 3 (inclusive) after transplant: In the initial months after gene therapy, 
subjects will receive simple erythrocyte transfusions approximately every 4 weeks to 
maintain target hemoglobin concentration of approximately 11 g/dL and HbS ≤30%. 
This will suppress endogenous erythropoiesis from occurring during this time while 
the gene-modified stem cells engraft.  
Months 4 to 5 after transplant:  After Month 3, the subject should begin to be 
weaned from transfusions to allow endogenous erythropoiesis, which is expected to 
stimulate erythropoiesis from gene-modified HSCs. At or after the Month 4 visit, the 
subject should be transfused if total Hb is <10 g/dL. The final transfusion should 
occur before the conclusion of Month 5. The investigator should use clinical 
judgment and may deviate from this weaning process if necessary to ensure the safe 
weaning of transfusions. As transfused blood washes out, subjects will return to their 
baseline hemoglobin (typically 7 to 9 g/dL) if gene transfer was ineffective. If gene 
transfer is effective, subjects may maintain their hemoglobin above baseline by 
increasing HbF. 
• HbF monitoring: HbF will be monitored at the time points indicated in the schedules 
of events (Appendix 1). 
5.8 Blinding 
This is an open-label study. 
5.9 Treatment Compliance 
The investigator will oversee compliance with HSC collection, chemotherapy conditioning, 
and infusion of ARU-1801. The investigator or designee will document the success and/or 
completeness of treatment administration and infusion of ARU-1801 and record information 
in the eCRF. 

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5.10 Prior and Concomitant Therapy  
Use of prior and concomitant medications will be recorded in the subject’s eCRF. The 
minimum requirement is that drug name and the dates of administration should be recorded. 
Medications reported will include all prescription drugs, over-the-counter medications, herbal 
products, vitamins, and minerals. Any changes in concomitant medications also will be 
recorded in the subject’s eCRF. The minimum information reported for concomitant 
procedures should be the name or description of the procedure and the date on which it was 
performed; the reason for the procedure should be included to the extent possible. 
5.10.1 
Prior Medications and Procedures 
Prior medications are those the subject was taking at the time the informed consent form 
(ICF) was signed. Prior procedures will be captured as part of medical history and will 
includes procedures performed up to 2 years before screening (Section 6.2). Restrictions on 
prior medications and procedures are as follows:  
• Disease-modifying therapies for the treatment of the subject’s SCD should be 
discontinued at the time that the subject initiates HbS reductive transfusions and must 
be discontinued at least 2 months before HSC collection. Example medications 
include hydroxyurea, L-glutamine, voxelotor and crizanlizumab.  
• Iron chelation therapy must be discontinued at least 48 hours before the start of 
melphalan conditioning and may not be resumed until 3 months after the ARU-1801 
infusion (see Section 5.10.3). 
5.10.2 
Concomitant Medications and Procedures 
Any concomitant medication or procedure deemed necessary for the welfare of the subject 
during the study may be given or performed at the investigator’s discretion. Restrictions on 
concomitant medications and procedures are as follows:  
• G-CSF is contraindicated in subjects with SCD. Increased leukocytosis from G-CSF 
has resulted in VOEs, ACS, and death (Fitzhugh et al 2009). 
• Elective surgeries in the first 12 months after the ARU-1801 infusion. 
Therapies and procedures that are permitted during study participation are as follows:  

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• Therapies for hemoglobinopathy, including exchange transfusions to prevent VOE, 
transfusions of blood or platelets to maintain appropriate cell counts, 
erythrocytapheresis, or any of these procedures to achieve target HbS and hemoglobin 
values before P-MPB. 
• Medications required to manage chronic pain and other complications from SCD at 
the investigator’s discretion.  
• Protocol-specified plerixafor for mobilization of peripheral blood before HSC 
harvest. 
• Protocol-specified premedication (acetaminophen, diphenhydramine, and 
hydrocortisone) before infusion of ARU-1801. 
• Medications for anesthesia during required study procedures, if needed.  
5.10.3 
Medications and Procedures After Treatment 
Restrictions and guidelines related to medications and procedures after treatment are as 
follows:  
• Iron chelation or a program of phlebotomy may be resumed 3 months after infusion 
of ARU-1801 at the discretion of the investigator. 
• Subjects will gradually wean use of transfusions starting 3 months after the infusion 
of ARU-1801 (Section 5.7). 

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6 
Study Assessments and Procedures 
Before performing any study procedures, all potential subjects will sign an ICF. Subjects will 
have the opportunity to have any questions answered before signing the ICF. The investigator 
must address all questions raised by the subject. The investigator or designee will also sign 
the ICF. 
The schedules of events are presented by visit in Table 13-1 (Screening and Study Treatment 
Visits), Table 13-2 (Post-infusion Visits: Day 7 to Year 2), and Table 13-3 (Long-term 
Follow-up Visits). 
6.1 Study Visits 
Screening: Screening assessments will be performed for all potential subjects to determine 
study eligibility. The screening assessments are summarized in Section 6.2 and indicated in 
Table 13-1. 
Enrollment: Following completion of all screening assessments, the investigator and 
Medical Monitor will independently verify eligibility. Upon final sign-off by the Medical 
Monitor, the subject will be ‘Enrolled.’ 
Baseline bone marrow aspirate (BMA): The baseline BM testing must be completed after 
enrollment and prior to initiation of additional research procedures. Specifically, the testing 
should be completed before a central line is placed (if applicable) or the subject is initiated on 
RBC transfusions. In addition, morphological assessment, immunophenotyping for 
leukemia/lymphoma, and NGS results must be complete and reviewed by the investigator 
before the first HbS Reduction Visit.  
• Subjects with cytogenetic abnormalities or genetic mutations associated with risk of 
hematologic malignancy will be withdrawn. See Section 4.2.1 for a full list of the 
chromosomal abnormalities or genetic mutations that would result in subject 
withdrawal. 
• Subject Counseling: The baseline BM genomic evaluation is being performed out of 
an abundance of caution and to protect subjects who may be at increased risk of 
developing myeloid malignancy after exposure to alkylating chemotherapy and 
autologous HSCT. Neither cytogenetics nor NGS evaluation are performed routinely 

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as a screening test in the absence of clinical evidence of a new hematologic disorder. 
The sensitivity and specificity of these tests in a population with no hematologic 
abnormalities is unknown. The positive predictive value of these tests to detect a 
genetic abnormality which will ultimately become clinically relevant is unknown. 
Although the precise negative predictive value is also unknown, at a wide range of 
sensitivity and specificity assumptions, and using a wide range of prevalence 
estimates, the negative predictive value of these tests is high. Subjects should be 
informed of any positive findings from these evaluations, and will be offered 
consultation with a genetic counselor to more completely understand the implications 
of their unique status. 
HbS Reductive Visit(s): Before HSC collection, subjects enrolled in this study will begin 
HbS reduction to ≤30% via erythrocytapheresis or transfusions over a period of 2 to 
3 months. Details for HbS reduction are provided in Section 5.5.1. The frequency of required 
procedures and visits in order to achieve HbS reduction ≤30% at least 2 months before HSC 
collection will be at the investigator’s discretion. Within 7 days before HSC collection, a 
subject’s HbS target is ≤20%. The assessments performed at this visit are indicated in 
Table 13-1. 
Stem Cell Collection Clearance Visit(s): This visit will occur within 7 days of HSC 
collection. This visit may be repeated, as required, if subjects require multiple cycles of 
P-MPB at Stem Cell Collection Visit (see Section 5.5.1.1 and Section 5.5.1.2). The 
assessments performed at this visit are indicated in Table 13-1. 
Stem Cell Collection Visit(s): Collection of HSCs will be from P-MPB, with details for each 
provided in Section 5.5.1.1 and Section 5.5.1.2, respectively. The use of P-MPB is at the 
investigator’s discretion. This visit may be repeated as necessary to achieve collection of 
targeted count of CD34+ cells (see Section 5.5.1.2). The assessments performed at this visit 
are indicated in Table 13-1. 
Chemotherapy Clearance Visit: Subjects will be cleared for administration of 
chemotherapy treatment with melphalan within 7 days before the Chemotherapy Visit. The 
assessments performed at this visit are indicated in Table 13-1. 
Note: The HbS Reductive Visit, Stem Cell Collection Clearance Visit, and Chemotherapy 
Clearance Visit can occur on the same day. If combined, the investigator will verify that the 

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subject has been cleared for HSC collection via P-MPB; and 3) cleared for administration of 
chemotherapy. Any procedures that are required for each respective visit may be completed 
only once when any of these visits are completed within the same 7-day time period. 
Chemotherapy Visit: Melphalan will be administered to subjects at least 36 hours before the 
infusion of ARU-1801. Samples for melphalan PK assessment are collected during this visit. 
Details regarding chemotherapy administration are provided in Section 5.5.3. The 
assessments performed at this visit are indicated in Table 13-1. 
Infusion Visit: Once the HSC transduction procedure has been completed (Section 5.5.4) and 
at least 36 hours after the subject has received melphalan (Section 5.5.3), subject will receive 
an infusion of ARU-1801 (see Section 5.5.5). 
Follow-up Visits: Subjects will have follow-up assessments at the time points indicated in 
Table 13-2 and Table 13-3. This will include assessments at Day 7, 14, 21, 30, 60, and 90 and 
at Months 4 through 12; Months 15, 18, 21; and Year 2. It is anticipated that a separate LTFU 
clinical study will be initiated. Once the LTFU study is approved at the site, all subjects who 
complete the Year 2 study visit in this study will be asked to consent and enroll in the LTFU 
study and will be followed for a total of 15 years after the ARU-1801 infusion. Long-term 
follow-up after Year 2 will continue in this Phase 1/2 study until subjects have transitioned 
into the LTFU study. 
6.2 Screening Assessments 
After the subject provides written informed consent, the subject will complete the following 
assessments at the screening visits, as indicated in Table 13-1, to confirm eligibility (the 
screening result will serve as baseline for each assessment): 
• Inclusion/exclusion criteria (Section 4.1) 
• Demographics and medical history, including reproductive health, VOE, opioid use, 
and other sickle events (Section 6.2.1) 
• Physical examination (complete; Section 6.3.3) 
• Vital sign measurements (Section 6.3.4) 
• Iron overload status (Section 6.3.6.2) 

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• Electrocardiogram (ECG; performed at screening only) and echocardiogram 
(Section 6.3.5) 
• Brain MRI and magnetic resonance angiography (MRA) (performed at screening 
only; can be omitted if performed within 6 months of consent; Section 6.3.5) 
• Concomitant medication review (Section 5.10) 
• Adverse event monitoring (Section 6.3.1) 
• Karnofsky performance status (Section 6.5.4) 
• Pulmonary function tests (oxygen saturation, spirometry, and diffusion) 
(Section 6.3.6.1) 
• Safety Laboratory Tests (Section 6.3.2): 
• Clinical chemistry 
• Urinalysis (macroscopic with reflex microscopic analysis) 
• Urine microalbumin 
• CBC with reticulocyte and differential (automated) 
• Serum ferritin  
• Reproductive testing 
• Globin gene mapping (and globin deletional analysis if not done previously) 
• Enzyme genetic analysis 
• Serum pregnancy test 
• Hepatitis and HIV testing 
• Cystatin C eGFR 
• Hemoglobin electrophoresis (Section 6.5.2.1) 
6.2.1 
Demographics and Baseline Medical History 
At the screening visits, subject demographics, and history of VOEs, opioid use, and other 
SCD events during the previous 2-year period before enrollment will be recorded. Each 
subject’s incidence of SCD-related events and opioid use will be monitored throughout the 
study.  

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The subject’s available medical records pertaining to SCD status (VOEs, organ function 
parameters, laboratory tests, medications, transfusions, etc) may be used to obtain history 
from the 2-year period before enrollment. Medical history will also include prior procedures 
performed up to 2 years before the screening visit. Additionally, significant surgeries and 
medical events that occurred longer than 2 years before screening should also be recorded. 
Subjects will be asked to provide a reproductive health history as part of the medical history 
recorded at screening. Baseline disease severity will also be determined from a retrospective 
review of the subject’s medical records for the last 2 years before the screening visit for 
subjects enrolled under previous versions of the protocol.  
6.3 Safety Assessments 
Safety will be assessed in this study through the assessment of AEs and SAEs, chronic 
conditions related to SCD, laboratory test results, physical examination findings, and vital 
sign measurements. Pulmonary function tests will be performed at screening. Safety testing 
will be performed on peripheral blood and BM samples.  
6.3.1 
Adverse Events 
6.3.1.1 
Definitions of Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to the investigational product (ARU-1801) or study 
medications/procedures. 
An AE is defined as any untoward medical occurrence in a subject enrolled into this study 
regardless of its causal relationship to investigational product. Subjects will be instructed to 
contact the investigator at any time after enrollment if any symptoms develop. Baseline 
conditions at study entry will be recorded on the medical history eCRF. If the baseline 
conditions worsen or increase in frequency, the investigator should reassess the event and 
record and report as an AE. 
A treatment-emergent AE is defined as any event that occurs after exposure to a study 
procedure, study medication, or the investigational product.  
If temporally associated with the use of an investigational product or a study 
medication/procedure, events meeting the definition of an AE include: 

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• An unexpected worsening, excluding minor fluctuations, in the nature, severity, 
frequency, or duration of a pre-existing condition. 
• A new condition detected or diagnosed after investigational product administration 
even though it may have been present before the start of the study. 
• Injury or accidents:  If a medical condition is known to have caused the injury or 
accident, the medical condition and the accident should be reported as 2 separate 
medical events (eg, for a fall secondary to dizziness, both “dizziness” and “fall” 
should be recorded separately). 
• An investigational abnormality (eg, laboratory parameter, vital sign, ECG) only if the 
abnormality is considered clinically significant by the investigator based on at least 1 
of the following criteria: 
• Induces clinical signs or symptoms 
• Requires active intervention 
• Requires interruption or discontinuation of the investigational product infusion 
• Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of study 
medications (eg, mobilization or conditioning regimens) or a concomitant medication. 
Events that do not meet the definition of an AE include: 
• Medical or surgical procedure (eg, endoscopy, appendectomy); the condition that 
leads to the procedure is an AE 
• Situations where an untoward medical occurrence did not occur (eg, planned 
hospitalization for an elective procedure or study-required procedure, with elective 
defined as known or planned at the time of signing of the informed consent; social 
and/or convenience admission to a hospital) 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen 

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6.3.1.2 
Serious Adverse Events 
An SAE is defined as any event that 
• Results in death  
• Is immediately life threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization  
Note: In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
Hospitalization for a study-required procedure or for elective treatment of a 
pre-existing condition that did not worsen from baseline is not considered an AE. 
• Results in persistent or significant disability/incapacity that subject had not previously 
experienced or aggravates a prior existing significant disability/incapacity  
• Results in a congenital anomaly/birth defect in the offspring of a female subject or 
female partner of a subject 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize the subject or may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include 
hematopoietic malignancy such as a leukemic transformation from the gene transfer, allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
6.3.1.3 
Eliciting and Documenting Adverse Events 
All AEs will be collected and reported from the time the subject signs the ICF until 2 years 
after the ARU-1801 infusion. After Year 2, it is anticipated that all subjects will be 

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transitioned from this study to the separate LTFU study and will be followed for a total of 
15 years after the ARU-1801 infusion. In the LTFU study and for subjects in this study who 
have not yet transitioned to the LTFU study, AE collection and reporting after the Year 2 
follow-up visit in this study will be limited to the following: 
• All SAEs 
• Nonserious AEs leading to study withdrawal or that are considered at least possibly 
related to investigational product or study medications/procedures  
• AEs of special interest (Section 6.3.1.7) 
• SCD VOEs (Section 6.5.3) 
At every study visit, subjects will be asked a standard nonleading question to elicit any 
medically related changes in their well-being. They will also be asked if they have been 
hospitalized, had any accidents, used any new medications, or changed concomitant 
medication regimens (both prescription and over-the-counter medications). 
In addition to subject observations, AEs identified from any study data (eg, laboratory values, 
physical examination findings) or identified from review of other documents that are relevant 
to subject safety will be documented on the AE page in the eCRF. 
6.3.1.4 
Reporting Adverse Events 
All AEs reported or observed during the study, as defined in Section 6.3.1.3, will be recorded 
on the AE page in the eCRF. Information to be collected includes the following: 
• Drug treatment 
• Dose 
• Event term 
• Time of onset 
• Investigator-specified assessment of severity and relationship to investigational 
product or study medications/procedures 
• Time of resolution of the event 

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• Seriousness 
• Any required treatment or evaluations 
• Outcome 
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, 
reactions to concurrent medications, or progression of disease states must also be reported. 
All AEs will be followed as described in Section 6.3.1.11. The Medical Dictionary for 
Regulatory Activities (MedDRA) will be used to code all AEs. 
Any pre-existing medical condition that is present at the time that the subject is screened but 
does not deteriorate should not be reported as an AE. However, if it deteriorates at any time 
during the study, it should be recorded as an AE. 
In general, an abnormal diagnostic or laboratory value should not be recorded as an AE 
unless it is associated with clinical signs or symptoms (ie, assessed as clinically significant), 
requires an intervention, results in an SAE, or results in study termination or 
interruption/discontinuation of study treatment. When recording an AE resulting from a 
diagnostic or laboratory abnormality, the medical condition or diagnosis rather than the 
abnormality itself should be recorded (eg, record “anemia” rather than “low hemoglobin”). 
For subjects enrolled under previous versions of the protocol (before Version 8.0), which did 
not stipulate recording all AEs during the first 2 years of follow-up after the ARU-1801 
infusion, the investigators or designee will query existing study source documents and 
medical records (if required) in a retrospective manner. Investigators or designee will record 
AE information in the study database for those AEs that were collected previously in source 
documents and/or medical records but not entered into the study database. 
6.3.1.5 
Reporting Serious Adverse Events 
Any AE that meets SAE criteria (Section 6.3.1.1) must be reported to PPD immediately (ie, 
within 24 hours) after the time site personnel first learn about the event regardless of the 
relationship (or lack of) of the SAE to study participation. The site should report SAEs via 
electronic data capture.  

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In the event that electronic data capture entry is not possible (eg, system failure or access 
problems), the site staff should complete the paper SAE report form and fax the form to PPD 
Pharmacovigilance within 24 hours of awareness. The following contact information should 
be used for SAE reporting with a paper SAE form: 
PPD Pharmacovigilance – North America 
24 Hour Safety Hotline: 
+1 800-201-8725 
Safety Hotline Fax: 
+1 888-488-9697 
6.3.1.6 
Sickle Cell-Related Events 
Chronic conditions related to SCD are those events that are known symptoms or associated 
conditions related to sickle cell anemia, stroke, or iron overload or an event related to 
standard clinical management, as all subjects enrolled in this study will receive all therapy 
and monitoring considered as standard of care for subjects with SCD. Acute and chronic 
conditions associated with SCD are listed in Table 6-1. Further, because all subjects in this 
study have a severe form of SCD, it is anticipated that certain AEs will occur that are related 
to the progression of the disease, which will be taken into account when determining whether 
or not an event is related to ARU-1801 or study procedures.  

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Table 6-1 
Acute and Chronic Conditions Associated With Sickle Cell Disease 
Albuminuria 
Elevated serum transaminases 
Pulmonary embolism 
Amenorrhea 
Fever 
Pulmonary hypertension 
Anemia 
Hematuria 
Pulmonary infiltrate (new) on 
chest x-ray consistent with acute 
chest syndrome 
Aplastic crisis 
Hemolysis 
Pyelonephritis 
Arthralgia 
Hepatic sequestration 
Renal insufficiency 
Avascular necrosis of 
hip/shoulder 
Hepatomegaly 
Renal papillary necrosis 
Bacteremia 
Hyperbilirubinemia 
(unconjugated) 
Reticulocytosis 
Bone infarction 
Hypersplenism 
Retinal hemorrhage 
Cardiac arrhythmia 
Hypertension 
Retinopathy 
Cardiomegaly 
Hypocalcemia 
Rhabdomyolysis 
Cholelithiasis 
Hyposthenuria 
Seizure 
Constipation 
Hypoxemia (O2 saturation 
<85 mm Hg) 
Septicemia 
Cranial nerve palsy 
Ileus 
Silent infarct 
Dactylitis 
Leukocytosis 
Skin ulcer 
Decreased lung function 
Meningitis 
Splenic sequestration 
Decreased renal function 
Nephropathy 
Splenomegaly 
Delayed growth/puberty 
Osteomyelitis 
Systemic Infection: bacterial, 
invasive catheter, viral 
Depression 
Pain: back, chest, joint, long bone, 
severe abdominal, sternal, or rib 
Transfusion 
Dizziness 
Pneumonia 
Vaso-occlusive pain 
Electrolyte Imbalance 
Priapism 
 
Elevated bilirubin 
Proteinuria 
 
 
6.3.1.7 
Adverse Events of Special Interest 
The following AEs are of special interest for evaluating the outcomes for subjects 
participating in this study: 
• Insertional mutagenesis related to administration of ARU-1801 
• Myelodysplastic syndrome and/or any hematological malignancy related to 
melphalan conditioning and/or vector insertion 

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6.3.1.8 
Suspected Unexpected Serious Adverse Reactions and 
Nonserious Adverse Events of Special Interest 
The Sponsor will promptly evaluate all suspected unexpected serious adverse reactions 
(SUSARs) and nonserious AEs of special interest against cumulative product experience to 
identify and expeditiously communicate possible new safety findings to investigators, 
institutional review boards (IRBs)/independent ethics committees (IECs)/research ethics 
boards (REBs), and applicable health authorities based on applicable legislation. The SUSAR 
events and AEs of special interest will also be reported expeditiously to the DSMB.  
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following: 
• ARU-1801 IB  
• Melphalan prescribing information 
• Plerixafor prescribing information 
• SCD-related events (Table 6-1)  
The Sponsor will compare the severity of each SUSAR and the cumulative event frequency 
reported for the study with the severity and frequency reported in the applicable reference 
document (eg, IB, melphalan prescribing information, plerixafor prescribing information). 
Reporting requirements will also be based on the investigator's assessment of causality and 
seriousness, with allowance for upgrading by the Sponsor as needed. 
AEs will be reported to the DSMB at the frequency defined in the DSMB charter. 
6.3.1.9 
Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the subject’s 
daily activities. The severity of all AEs should be graded according to the CTCAE v5.0. If the 
event is not found in the CTCAE v5.0, the event will be assessed using the grading provided 
in Table 6-2.  

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Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. Adverse events characterized 
as intermittent do not require documentation of onset and duration of each episode. 
Table 6-2 
Severity Grading for Events not Listed in the Common 
Terminology Criteria for Adverse Events Version 5.0 
Grade 
Severity 
Description 
1 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
2 
Moderate  
Minimal, local, or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADLa 
3 
Severe or medically 
significant but not 
immediately life 
threatening 
Hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADLb 
4 
Life-threatening 
consequences 
Urgent intervention indicated 
5 
Fatal 
Death related to adverse event 
Abbreviations: ADL, activities of daily living. 
a. 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
b. Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
6.3.1.10 
Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study drug is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. The Sponsor will make the final determination of causality. 

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The relationship or association of the investigational product or study 
medications/procedures in causing or contributing to the AE will be characterized using the 
following classification and criteria (Note. Study medication includes other study 
medications, such as mobilization and conditioning regimens): 
Unrelated: 
The event is unrelated to the investigational product or study 
medications/procedures. The event is consistent with and can be attributed to 
subject’s disease or another cause of the event is most plausible.  
Unlikely: 
The event or severity of event is doubtfully related to the investigational 
product or study medications/procedures. 
Possible: 
The event or severity of event is not usually associated by the clinical 
condition or standard of care for the condition, but there is no strong evidence 
to link the event to the investigational product or study 
medications/procedures. 
Probable: 
The event or severity of event is such that it can likely be correlated to the 
investigational product or study medications/procedures. 
Definite: 
There is a strong correlation between the event and the investigational 
product or study medications/procedures. 
 
6.3.1.11 
Follow-up of Subjects Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not clinically 
significant, or until the subject is considered to be stable.  
6.3.2 
Safety Laboratory Tests 
Samples for laboratory testing will be collected at the time points specified in the schedules 
of events (Appendix 1). Testing will be performed by the central laboratory, except when 
local laboratory results are required for safety monitoring and/or central laboratory results are 
not available. Processing, storage, and shipping procedures for all laboratory samples and 
central versus local laboratory testing are provided in the Laboratory Manual.  

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The following laboratory tests will be performed: 
• Clinical chemistry panel: alkaline phosphatase, ALT, AST, bicarbonate, bilirubin 
(total and indirect), blood urea nitrogen, calcium (total), carbon dioxide, chloride, 
creatinine, -glutamyltransferase, lactate dehydrogenase, magnesium, potassium, and 
sodium. 
• CBC with reticulocyte, differential (automated) and blood smear central and local 
testing (Section 5.6.3) 
• CD34+ cell count (performed locally; Section 5.5.1 and Section 5.5.2) 
• Urinalysis: Macroscopic analysis (with reflex microscopic analysis), albumin, and 
microalbumin 
• Reproductive testing (performed before fertility preservation [Section 5.6.4] for males 
and females; at a time point after fertility preservation for females; and at Month 12, 
Year 2, and Year 5 for males and females): 
• Female: luteinizing hormone, follicle-stimulating hormone, estradiol, and 
anti-Müllerian hormone. The date of the last menstrual period should be obtained 
at the time of hormonal testing to analyze results based on cyclical fluctuations. 
• Male: luteinizing hormone, follicle-stimulating hormone, testosterone, and 
inhibin B  
• Renal function: cystatin C eGFR 
• Infectious disease titer: cytomegalovirus antibody (immunoglobulin M and 
immunoglobulin G), HIV-1 and HIV-2, acute hepatitis panel, qualitative syphilis test, 
human T-lymphotropic virus (1 and 2), varicella zoster virus, and parvovirus  
• Pregnancy testing: Serum pregnancy test at screening; local urine pregnancy tests at 
all subsequent visits (Note: Test should be performed at the Chemotherapy Clearance 
Visit only if the last test was performed at study site >48 hours before visit.) 
• Additional screening tests: serum ferritin and HIV testing 

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Blood samples will be collected for the following genetic analyses (at screening only): 
• Globin gene mapping (and globin deletional analysis if not done previously) 
• Enzyme genetic analysis. Defects in the RBC enzyme, such as G6PD deficiency, are 
common in the SCD population and require a genetic test, as functional defects in 
patients with SCD cannot be determined by an enzyme assay alone. Subjects who are 
found to have a mutation for G6PD deficiency will be provided with guidance on 
concomitant medications that must be avoided. 
6.3.2.1 
Gene Transfer Safety Testing 
Safety testing for peripheral blood gene transfer will be performed as indicated in Table 13-1 
and Table 13-2. For subjects who have not yet transitioned to the LTFU study, analysis after 
Year 2 will also be performed as indicated in Table 13-3. Testing will include the following: 
• Replication competent LV assay: If all post-infusion assay results are negative in the 
first year, yearly follow-up samples may be discontinued. If any post-infusion results 
are positive, assay should be performed annually thereafter until Year 15 
• Vector insertion site analysis 
The safety tests on BM will be performed as indicated in Table 13-1 and Table 13-2. For 
subjects who have not yet transitioned to the LTFU study, if there is clinical or laboratory 
indication of a clonal dominance or oligoclonality, BM aspirates may be obtained as 
indicated in Table 13-3. Testing will include the following: 
• Standard morphology testing  
• Flow cytometry for leukemia panel 
• Genomic evaluation for myeloid malignancy (such as MDS or AML) via cytogenetic 
evaluation and NGS panel for myeloid malignancy 
• Vector insertion site analysis 
6.3.3 
Physical Examinations 
A complete or targeted physical examination will be conducted as indicated in the schedules 
of events (Appendix 1).  

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A complete physical examination will include height (screening visit only), weight, and 
evaluation of body systems, including but not limited to the following: skin; head, eyes, ears, 
nose, and throat; respiratory system; cardiovascular system; abdomen (liver, spleen); 
reproductive systems; and lymph nodes. The examinations performed at the HbS Reduction 
Visit(s) will only be required if >30 days have elapsed since last assessment. 
A targeted physical examination will include evaluation of the subject’s general appearance 
and other components as indicated by the subject’s medical history or symptoms. A targeted 
physical examination should be completed within 24 hours of the start of each stem cell 
collection cycle. 
6.3.4 
Vital Sign Measurements 
Vital signs will be measured as indicated in the schedules of events (Appendix 1) and include 
systolic and diastolic blood pressure, pulse rate, respiratory rate, and temperature). When 
scheduled at the same visit, vital sign measurements should be performed before collection of 
any blood or other samples. 
6.3.5 
Imaging 
Because plerixafor may cause splenic rupture, a baseline abdominal ultrasound for 
examination of the spleen will be performed before the first dose of plerixafor is at the P-
MPB Stem Cell Collection Visit.  
Echocardiograms will be performed at the time points indicated in the tables in Appendix 1. 
An ECG will be performed at screening and at other time points during the study as clinically 
indicated. 
Brain MRI and MRA will be performed at the screening visit only in order to assess risk of 
stroke (per exclusion #7 [Section 4.1.2]) and to establish the subject’s baseline status. If such 
imaging has been performed within 6 months before the date of informed consent, and the 
report and images are available within the medical record, there is no need to repeat the 
procedure at screening.  

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6.3.6 
Other Assessments 
6.3.6.1 
Pulmonary Function Tests 
Pulmonary function tests (oxygen saturation, spirometry, and diffusion) will be performed at 
screening to ensure subjects do not meet Exclusion Criterion 5 (Section 4.1.2). Subsequent 
PFTs will be performed at the time points indicated in Table 13-2 and Table 13-3. 
6.3.6.2 
Iron Overload Status 
Iron overload status will be evaluated at screening (Table 13-1) and as applicable per the 
investigator’s discretion. At screening, subjects will be evaluated for chronic transfusions 
>200 mL/kg and evidence of iron overload from FerriScan imaging performed as part of 
standard of care and hepatic fibrosis by noninvasive liver imaging obtained per the subject’s 
standard of care.  
6.3.6.3 
Nuclear Medicine GFR 
Nuclear medicine GFR should be completed within 30 days of administration of 
chemotherapy for conditioning. This will be used to evaluate the relationship between GFR, 
melphalan clearance and melphalan exposure. 
6.4 Safety Monitoring 
6.4.1 
Data Safety Monitoring Board 
The DSMB is an independent group of experts who are not affiliated with any study site and 
who will advise the Sponsor regarding the future of the study. The members of the DSMB 
serve in an individual capacity and provide their expertise and recommendations. The DSMB 
will be comprised of individuals with expertise in hematology, stem cell transplantation, and 
biostatistics. The DSMB will review the safety data from each subject before treating the 
next subject, although the DSMB may propose to alter this requirement as detailed in the 
DSMB charter. Details on the composition, meeting frequency, and other activities of the 
DSMB are outlined in the DSMB charter.   
The following are the primary responsibilities of the DSMB: 
• Periodically review and evaluate the accumulated study data for subject safety, study 
conduct, and progress. 

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• Make recommendations to the Sponsor concerning the continuation, modification, or 
termination of the study.  
The DSMB reviews will include but will not be limited to the following (see the DSMB 
charter for details): 
• SAEs, adverse events of special interest, and other specific AEs as described in 
DSMB charter  
• Toxicities of infused product 
• Toxicities related to gene transfer 
• Positive microbial culture results 
• Safety and feasibility criteria (Section 6.4.2) 
• Early stopping rules (Section 6.4.3) 
6.4.2 
Safety and Feasibility Criteria 
The primary toxicities for this study are those related to stem cell collection and 
chemotherapy and those related to the use of gene transfer.  
6.4.2.1 
Safety Criteria: Toxicity 
Safety criterion will be defined as follows: Toxicity events will be graded using CTCAE 
v5.0. The investigator or designee will be responsible for determining the attribution of 
events to study-related procedures. Study enrollment and procedures may be suspended 
pending DSMB review in the event of failing to meet the safety criterion as defined below 
and in Section 6.4.3. 
All irreversible/unresolvable Grade 3-4 toxicities that are probably or definitely attributable 
to the study procedure/s, and not the subject’s SCD, will be considered unsafe. 
The following will specifically constitute a failure to meet the safety criteria:  
• Grade 3 allergic reaction associated with infusion of the transduced cell product  
• Grade 4 infection following infusion of the transduced cell product uncontrolled for 
>14 days 

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• Grade 4 neutropenia lasting >1 month following melphalan  
• Grade 3 or 4 irreversible organ toxicity–neurologic, pulmonary, cardiac, GI, 
genitourinary, hepatic, or cutaneous–that is attributable to the study procedures 
• Death due to study procedures 
• Hematological malignancy due to vector insertion 
• Hematologic malignancy related to investigational product or study 
medications/procedures  
If a hematological cancer is reported in this study, the study will be temporarily suspended 
pending further analysis by the Sponsor and review by DSMB, to determine if the 
malignancy is attributable to the gene transfer procedure A detailed molecular analysis of the 
malignant clone will be performed in order to determine attribution to gene transfer. 
Insertional site analysis of the malignant clone and effect of the insertion on flanking cellular 
genes will be done to determine if the malignancy is caused by insertion of the vector.  
If a subject should develop a hematopoietic malignancy while on the study, the subject will 
be referred to an oncologist. The oncologist will be contacted by the study investigator to 
review the subject’s collected medical history and relay research-related information. 
Oncology records will be requested. Additional biological specimens may also be requested 
if needed to evaluate the causality of the malignancy. The study investigator will remain in 
contact with the subject’s oncologist throughout the treatment period.  
6.4.2.2 
Feasibility Criteria 
The feasibility criteria are defined as follows: 
• Adequate harvest and recovery of CD34+ cells  
• Transduced cell product meets release criteria  
• Successful engraftment of ex-vivo manipulated gene-modified cells determined in 
BM aspirates at 1-year post-infusion with ≥1% gene-marked cells. 
Failure to meet any one of the above 3 criteria will be considered as failure to meet the 
feasibility criteria. 

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6.4.3 
Early Study Stopping Rules 
The adult SCD population is a high-risk population where treatment-related mortality rates 
from HSCTs are nearly 25% following myeloablative conditioning for HSCT. A recent 
analysis of compiled HSCT data shows that even among children, adolescents do worse than 
younger children with a much lower overall and disease-free survival. Hence, an expected 
higher rate of toxicity and lack of feasibility is expected in the adult subject population in this 
study. 
In the initial cohort of 6 subjects, the target is to obtain ≥3 subjects (out of 6) who meet both 
the safety and feasibility criteria. Accrual will be suspended pending DSMB review as 
specified in Section 6.4.2 if 1 or more of the first 3 subjects do not meet the safety criteria or 
3 or more of 6 subjects do not meet either the safety or the feasibility criteria.  
The study will be stopped if 2 of the first 3 subjects fail to meet the safety criteria or at least 
4 subjects (of 6 subjects) fail to meet both the safety and feasibility criteria.  
Up to 2 of 6 subjects are allowed to fail to meet the safety criteria (with the exception noted 
previously where study is stopped if 2 of first 3 subjects fail to meet safety criteria) or up to 
3 of 6 subjects are allowed to fail to meet the feasibility criteria, since the safety and 
feasibility is expected to be low among adults due to the cumulative damage to organs and 
BM in subjects with severe SCD and the high risk from the chemotherapy conditioning 
regimen. Therefore, the target probability of the study drug being both safe and feasible is 
48% to ~64%. 
Table 6-3 presents the probability of early termination. The probability was calculated as: 
Prob (at or before 6 subjects) = Prob (safety criterion triggers the study to terminate early for 
the first 3 subjects) + Prob (safety criterion does not trigger the study to terminate early for 
the first 3 subjects, and the safety and feasibility criteria triggers the study to terminate for 
the first 6 subjects). 

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Table 6-3 
Probability of Early Termination in the First Stage of the Initial 
Cohort (6 Subjects) 
 
Probability (being safe) / Feasibility Rate 
Scenario A 
Scenario B 
Scenario C 
Scenario D 
0.8 / 20% 
0.8 / 80% 
0.6 / 20% 
0.6 / 80% 
Probability (both safe and feasible) 
0.16 
0.64 
0.12 
0.48 
At or before 3 subjects 
10.4% 
10.4% 
35.2% 
35.2% 
At or before 6 subjects 
33.2% 
12.2% 
64.6% 
41.3% 
 
Scenario B and D present cases close to the assumed target rate. When the probability of 
being both safe and feasible is 0.64 (64%), the study will be terminated at or before 
3 subjects with 10.4% probability, whereas at or before 6 subjects with 12.2% probability 
(Scenario B). Scenario D shows that at much higher rates when the intervention is only 
moderately safe, although the overall probability of being both safe and feasible is close to 
the target.   
In the cohort of 4 subjects, the target is to obtain ≥2 subjects who will meet both the safety 
and feasibility criteria. The study would suspend accrual pending DSMB review if the safety 
criteria are not met at any point.   
6.5 Feasibility and Efficacy Assessments 
The feasibility and efficacy endpoints in this study will be measured by analysis of BM and 
peripheral blood samples. 
6.5.1 
Feasibility Assessments 
Feasibility of gene transfer will be measured by peripheral blood and/or BM sample analysis 
as indicated in Table 13-1 and Table 13-2. For subjects who have not yet transitioned to the 
LTFU study, analysis after Year 2 will also be performed as indicated in Table 13-3. 
Feasibility assessments include the following: 
• Total number of CD34+ cells collected in peripheral blood and BM 
• Amount of transduced cells (CD34+ cells/kg body weight) from all collections 
combined 
• Percentage of gene-marked cells in BM aspirates 

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6.5.2 
Efficacy Assessments 
The efficacy of gene transfer will be measured by analysis of HbF in peripheral blood by 1) 
quantification of HbF and other variants; 2) vector copies in the WBC fraction; 3) the 
proportion of antisickling/sickling hemoglobin, (HbF+HbG16D+HbA2)/HbS; and 4) RBC 
testing. 
Efficacy will be measured from BM samples for CFU-c analysis for gene-marked CFU-c. 
After the first year of BM sample collection, if no vector marking in peripheral blood WBC 
is observed, BM aspirates will be discontinued.  
6.5.2.1 
Hemoglobin Electrophoresis 
Hemoglobin will be evaluated using peripheral blood as follows:  
• Hemoglobin electrophoresis analysis (CZE) for HbF and other variants: Performed 
before ARU-1801 infusion and as indicated in Table 13-1 and Table 13-2. For 
subjects who have not yet transitioned to the LTFU study, analysis after Year 2 will 
also be performed as indicated in Table 13-3.  
6.5.2.2 
Peripheral Blood Gene Transfer Testing  
Efficacy assessments of peripheral blood gene transfer will be performed as indicated in 
Table 13-1 and Table 13-2. For subjects who have not yet transitioned to the LTFU study, 
analysis after Year 2 will also be performed as indicated in Table 13-3. Testing will include 
the following: 
• Vector copy number (VCN) analysis on DNA by quantitative polymerase chain 
reaction (qPCR) on DNA from WBC fraction 
• VCN analysis (qPCR) on DNA from sorted cell subpopulations of erythroid, myeloid 
and B and T cells 
• F-RBC and F-retics by flow cytometry 
• RBC testing (P50 [partial pressure of oxygen in the blood at which hemoglobin is 
50% saturated] and ektacytometry with Oxygenscan); performed at institutions with 
the capability to run the tests, or samples will be shipped within the stability window 
to an institution or laboratory with the capability to perform the testing. 

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• Mononuclear cells and plasma for archiving 
6.5.2.3 
Bone Marrow Gene Transfer Testing 
Efficacy assessments of BM will be performed as indicated in Table 13-1 and Table 13-2. For 
subjects who have not yet transitioned to the LTFU study, if there is clinical or laboratory 
indication of a clonal dominance or oligoclonality, BM aspirates may be obtained as 
indicated in Table 13-3. Testing will include the following: 
• VCN analysis by qPCR on DNA isolated from BM mononuclear cells and sorted 
myeloid, T, B and precursor erythroid hematopoietic lineages 
• CFU-c assay for vector copies by qPCR on individual CFU-c 
6.5.3 
Incidence of SCD-Related Events and Parental Opioid Use 
Subjects should be queried throughout the study as indicated in the schedules of events 
(Appendix 1) for any new occurrences of SCD-related events and parental opioid use. The 
incidence of SCD-related events and parental opioid use should also be completed within 24 
hours of the start of each stem cell collection cycle.  
For subjects enrolled under previous versions of the protocol (before Version 8.0), which did 
not stipulate recording of all VOEs in the study, the investigators or designee will query 
existing study source documents and medical records in a retrospective manner. The 
investigator or designee will record VOE information in the study database for VOEs 
previously collected in source documents or medical records but not entered into the study 
database. 
Vaso-occlusive episodes include vaso-occlusive crises and other VOEs, including but not 
limited to ACS, stroke, priapism, dactylitis, and acute hepatic or splenic sequestration.  

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The following endpoint definitions are listed below to aid in the characterization of 
SCD-related events: 
• Vaso-occlusive crisis are acute episodes of pain, with no medically determined cause 
other than a VOE, that resulted in a medical facility visit (emergency department, 
clinic, or hospital) and treatment with narcotic agents or with nonsteroidal 
anti-inflammatory drugs. 
• Acute chest syndrome is an acute illness characterized by fever and/or respiratory 
symptoms, accompanied by a new pulmonary infiltrate on x-ray. 
• Splenic sequestration, as defined by an enlarged spleen, left upper quadrant pain, and 
an acute decrease in hemoglobin concentration of ≥2 g/dL. 
6.5.4 
Performance Status 
A modified Karnofsky Performance Status Scale will be administered at the time points 
indicated in the schedules of events (Appendix 1). The modified Karnofsky Scale is designed 
for recipients aged ≥10 years (Appendix 2). The scale is used to determine the score (10-100) 
that best represents the subject’s activity status at the requested time point. 
6.5.5 
Patient-Reported Outcomes: ASCQ-Me System 
As part of the secondary objectives of this study, changes from baseline in PROs will be 
assessed using the ASCQ-Me (Appendix 4). This PRO assessment should be administered in 
the subject’s local language at the time points indicated in the schedules of events 
(Appendix 1). The ASCQ-Me should be administered before any other tests, treatments, or 
receipt of any test result to avoid biasing the subject’s perspective. 
The ASCQ-Me is a PRO measurement system that assesses the physical, social, and 
emotional impact of SCD on adults. It includes questions enabling adults to describe their 
functioning and well-being according to 7 topics (emotional impact, pain episodes, pain 
impact, SCD medical history checklist, sleep impact, social functioning impact, and stiffness 
impact; Appendix 4). It is a copyrighted instrument and is relatively new, with development 
initiated in 2005. Substantial qualitative and quantitative evidence has been gathered that 
supports the validity of ASCQ-Me scores in discriminating levels of symptoms and outcomes 
important to individuals with SCD (Keller et al 2014). 

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Subjects should be given sufficient space and time to complete the ASCQ-Me, and all 
administered questionnaires should be reviewed for completeness. If missing responses are 
noted, subjects should be encouraged to complete and missing responses. Attempts should be 
made to collect responses to all questionnaires for all subjects; however, if a subject refuses 
to complete the questionnaire, this should be documented in the study source records. A 
subject’s refusal to complete study questionnaires will not be a protocol deviation.  
Completed questionnaires, including both response to the questions and any unsolicited 
comments written by the subject, must be reviewed and assessed by the investigator or 
designee for responses that may indicate potential AEs or SAEs. This review should be 
documented in the study source records. 
If an AE or SAE is confirmed, the investigator should record the event as instructed in 
Section 6.3.1.4 or Section 6.3.1.5, respectively. Investigators should not encourage the 
subjects to change responses reported in questionnaires. 
6.6 Pharmacokinetic Assessments 
Blood samples will be collected for analysis of melphalan PK for all subjects. 
The conditioning dose will be administered and associated PK blood sampling will occur at 
the Chemotherapy Visit (Section 5.5.3), approximately 7 days after the Chemotherapy 
Clearance Visit. 
Blood samples for quantification of melphalan concentration in plasma will be collected at 
pre-dose (within 60 minutes before the start of the melphalan infusion), immediately at the 
end of the melphalan infusion, and approximately 5 minutes, 15 minutes, 1 hour, 2 hours, 4 
hours, and 6 hours after the end of the infusion. The actual date and time of the start and stop 
of the melphalan infusion and the actual date and time of each melphalan PK sample 
collection will be recorded.  
Plasma melphalan concentrations will be determined using a validated analytical method 
under the direction of the Sponsor. Details of the PK sample collection, processing, storage, 
and shipping will be provided in the Laboratory Manual. 

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6.7 Pregnancy 
Female subjects should refrain from getting pregnant or planning to become pregnant for 
1 year after the ARU-1801 infusion. Male subjects should also refrain from a pregnancy with 
their prospective partner or planning to become pregnant for 1 year after the ARU-1801 
infusion, due to the teratogenic side effects of melphalan conditioning.  
Female subjects who become pregnant before the gene transfer procedure will be withdrawn 
from the study. They may be rescreened for potential inclusion once postpartum and no 
longer breastfeeding. Subjects who become pregnant after gene transfer may have selected 
study procedures deferred per investigator’s discretion (eg, BM procedures).  
All pregnancies, for both enrolled subjects and their prospective partners, from the time of 
informed consent until the end of the study will be reported on the appropriate pregnancy 
eCRF. For subjects who have not yet transitioned to the LTFU study, pregnancies will be 
reported on the appropriate pregnancy eCRF until the Year 15 follow-up visit. 
Pregnancy is not regarded as an AE unless there is a suspicion that an investigational product 
may have interfered with the effectiveness of a contraceptive medication. Any pregnancy that 
occurs within 2 years (≤2 years) of the ARU-1801 infusion must be reported using the same 
procedures as for reporting an SAE (Section 6.3.1.5). To ensure subject safety, each 
pregnancy must be reported to Aruvant or designee within 2 weeks of learning of its 
occurrence. The pregnancy must be followed up to determine outcome (including 
spontaneous miscarriage, elective termination, normal birth, or congenital abnormality) and 
status of mother and child, even if the subject was discontinued from the study. The child will 
be followed for 2 months after birth. Pregnancy complications and elective terminations for 
medical reasons must be reported as an AE or SAE. Spontaneous miscarriages must be 
reported as an SAE. 
6.8 Future Testing 
Baseline and follow-up samples (plasma, blood cells and serum) will be collected for 
potential future biomedical research or biomarker analyses related to gene therapy and/or 
SCD for those subjects who consent to participate in this component of the study. 
Participation is optional. Blood samples will be collected at the time points indicated in 

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Appendix 1.If subjects provide consent, any unused intermediates from the ARU-1801 
manufacturing process will also be utilized for research purposes. 
A small portion of the final transduced product may be retained for research purposes for 
those subjects who consent to participate in this component of the study. Participation is 
optional. 
The Sponsor will store the future testing samples in a secure storage space with adequate 
measures to protect confidentiality. The samples will be stored for no longer than the planned 
duration of the subject’s follow-up, including the intended LTFU study (approximately 
15 years). 

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7 
Statistical and Analytical Plan 
This is a clinical study that primarily concerns the safety and feasibility of the proposed 
treatment procedures in adult SCD subjects aged 18 to 45 years. The study uses a 2-stage 
design: in the first stage a cohort of 6 subjects will be accrued. Upon the establishment of the 
safety and feasibility of the procedures in this cohort, a cohort of up to 4 additional subjects 
will be enrolled in the second stage to further establish the safety, feasibility, and efficacy, for 
a total of 10 subjects treated in the study. 
The study endpoints are presented in Section 2.2. The primary endpoints of the study are the 
safety and feasibility of the proposed treatment procedures. Safety endpoints include the 
number of subjects that experience significant toxicity events, the incidences of significant 
toxicity events, and time to neutrophil and platelet recovery. Feasibility endpoints include the 
number of subjects that meet each feasibility criteria and the recovery rate of CD34+ cells for 
gene transfer. The secondary endpoints are for efficacy. Baseline for the secondary efficacy 
endpoint for disease severity is defined in Section 7.6.2. Baseline for other study variables 
will be defined in the statistical analysis plan (SAP), which will be finalized before the study 
database lock. 
7.1 Primary Safety and Feasibility Endpoints 
The primary safety endpoints are presented in Section 2.2.1. Of particular interest is whether 
a subject fails to meet any one of the safety criteria, as listed in Section 6.4.2.1. 
The primary feasibility endpoints are presented in Section 2.2.1. If a subject fails to meet any 
one of the feasibility endpoints, the subject will be considered as having failed the feasibility 
criteria. 
7.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints are presented in Section 2.2.2. The efficacy of gene 
transfer will be measured by the following: 
• Quantification of HbFG16D and other Hb subtypes, including HbF (endogenous), HbS, 
adult Hb (HbA), HbA2 and, if applicable, HbC and HbE  

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• Change in the proportion of antisickling/sickling hemoglobin 
([HbF+HbFG16D+HbA2]/HbS) in Months 6-24 post-transplantation compared with 
baseline 
• Flow cytometry for percentage of F-RBC and F-retics in peripheral blood 
• Determining vector copies in the WBC fraction 
• Determining gene transfer in BM based on the following: 
• Vector copies 
• CFU-c analysis for gene-marked CFU-c 
Change in disease severity from baseline will be measured by annualized VOEs 
pre-transplant versus post-transplant. Quality of life will be assessed using the ASCQ-Me.  
7.3 Exploratory Endpoints 
The exploratory endpoint for the PK of melphalan is presented in Section 2.2.3. Plasma PK 
parameters of melphalan will include AUC, Cmax, clearance, and volume of distribution. 
Change in VOEs requiring parenteral opioids will also be reported. 
7.4 Sample Size Calculations 
The primary objective of this proof-of-concept study is to demonstrate the safety and 
feasibility of the proposed treatment procedures in SCD subjects. A sample size of 
10 subjects is planned to obtain initial data on the safety and feasibility of γ-globin gene 
transfer in subjects with SCD, with enrollment in 2 stages, as described in Section 7.  
As specified in Section 6.4.3, early stopping rules are in place. Accrual of subjects into the 
study will be suspended pending DSMB review (see Section 6.4.2) if 1 or more of the first 
3 subjects do not meet the safety criteria or 3 or more of 6 subjects do not meet either the 
safety or the feasibility criteria. The study will be stopped if 2 of the first 3 subjects fail to 
meet the safety criteria or at least 4 subjects (of 6 subjects) fail to meet both the safety and 
feasibility criteria.  
According to the study stopping criteria and assuming the probability of being both safe and 
feasible to be 0.64 (64%), the study will terminate at or before 3 subjects with a probability 

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of 0.104, and at or before 6 subjects with a probability of 0.122. For details see Scenario B in 
Table 6-3. 
7.5 Analysis Sets 
The following analysis sets will be used in the statistical analyses. 
Safety analysis set: The safety analysis set will consist of all subjects who received the 
proposed treatment procedure. 
Full-analysis set (FAS): The FAS will consist of all subjects who received the proposed 
treatment procedure and had a least 1 post-infusion efficacy measurement.  
PK set (PKS): The PKS will consist of FAS subjects who receive melphalan and have at least 
1 measurable plasma concentration of melphalan. 
7.6 Statistical Analysis Methodology 
Statistical analysis will be performed using SAS software (SAS Institute, Inc, Cary, North 
Carolina) Version 9.3 or later. Continuous variables (absolute values and change from 
baseline values) will be summarized using the mean, standard deviation, median, minimum 
value, and maximum value. Categorical variables will be summarized using frequency counts 
and percentages. Shift tables from baseline to post-infusion visits may be provided. Data will 
be listed in data listings. In general, the change from baseline for continuous variables will be 
analyzed using the 1-sample paired t-test, and the categorical variables will be analyzed by 
chi-square or Fisher exact test on the shift table.  
Given the small sample size and single-arm design of the study, the focus of the statistical 
analysis will be on the provision of point estimates with 2-sided 95% confidence intervals. In 
addition, some exploratory informal testing analyses will be performed as outlined in 
Section 7.6.4, using a 2-sided significance level of 0.15 (15%) for informational purposes 
only. 
Details of the statistical analyses, methods, and data conventions will be described in the 
SAP, which will be finalized before the study database lock.  

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7.6.1 
Analysis of Primary Safety and Feasibility Endpoints 
Summary statistics of the number of subjects that failed the safety, feasibility, or both safety 
and feasibility criteria will be provided. For each of the safety and feasibility endpoints, 
summary statistics will be provided. The incidence of AEs and SAEs will also be provided. 
Moreover, the summary of the safety endpoints will be broken down into the following 
3 distinct parts: 
• Part 1 will include those events from study entry to the recovery from the stem cell 
collections.  
• Part 2 will include those events from immediately before administration (baseline) 
through 30 days after gene transfer infusion.  
• Part 3 will include capturing subject status at Day +30 post-infusion, defined as 
baseline through the remainder of the study.  
7.6.2 
Analysis of Secondary Efficacy Endpoints 
For each of the secondary gene transfer efficacy endpoints, summary statistics will be 
provided. 
Summary statistics will be presented for change from baseline in disease severity (eg, 
annualized VOE pre-transplant versus post-transplant). Baseline disease severity will be 
determined from a retrospective review of the subject’s medical records for the last 2 years 
before the screening visit. 
Summary statistics will be presented for ASCQ-Me scores at baseline and by post-baseline 
visits.  
7.6.3 
Analysis of Exploratory Pharmacokinetic Endpoint 
Plasma PK parameters for melphalan will be estimated from the plasma concentration versus 
time data for all evaluable subjects by noncompartmental methods using Phoenix® 
WinNonlin® (Certara LP, Princeton, New Jersey) Version 8.0 or higher.  
Individual plasma concentration of melphalan will be listed for each sampling time point and 
summarized using descriptive statistics (number of subjects, mean, standard deviation, 

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coefficient of variation, minimum, median, and maximum). Plasma PK parameters for 
melphalan including, but not limited to AUC from time zero (pre-dose) to time of last 
quantifiable concentration (AUC[0-t]), AUC from time zero (pre-dose) extrapolated to 
infinite time (AUC[0-∞]), Cmax, clearance, and volume of distribution will be listed 
individually for each subject and summarized using descriptive statistics (number of subjects, 
mean, standard deviation, coefficient of variation, geometric mean, geometric coefficient of 
variation, minimum, median, and maximum). Dose-normalized parameters also will be 
calculated. Individual and mean plasma concentration versus time profiles for melphalan will 
be plotted in both linear and semilogarithmic scales.  
The relationship between melphalan AUC and safety and efficacy endpoints will be explored 
using descriptive statistics. Correlation coefficients will be generated between PK versus 
pharmacodynamic parameters. 
Detailed PK analysis methods will be provided in the SAP. 
7.6.4 
Exploratory and Other Analyses 
Summary statistical analyses will be provided for demographics, medical history, physical 
examination, and risk factor variables at baseline. The Karnofsky Performance Status Scale 
will be summarized by visit. 
Summary statistics will be presented for change from baseline VOEs requiring parenteral 
opioids. Baseline parenteral opioid use will be determined from a retrospective review of the 
subject’s medical records for the last 2 years before the screening visit. 

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The following exploratory informal testing analyses will be performed, using a 2-sided 
significance level of 0.15 (15%) for informational purposes only: 
• Chi-Square test for a single proportion will be used to test the following feasibility 
and safety endpoints against a predefined threshold (which will be defined in the 
SAP): 
• Proportion of subjects with a total number of CD34+ cells recovered from all 
collections combined (mobilized peripheral blood and BM) of at least 8106/kg 
viable CD34+ cells 
• Proportion of subjects for which a minimum of 4106 CD34+ cells/kg body 
weight from all collections combined have been successfully transduced 
• Mortality rate 
• Paired t-test will be used to assess the following changes from baseline: 
• Change of adult HbS measurements from baseline 
• Change in the proportion of antisickling/sickling hemoglobin 
([HbF+HbFG16D+HbA2]/HbS) from baseline 
Detailed descriptions of these exploratory analyses will be documented in the SAP, which 
will be finalized before the study database lock. 
7.6.5 
Interim Analyses 
No formal interim analysis is planned. However, the primary objective of this unblinded, 
proof-of-concept study is to show the safety and feasibility of the proposed treatment 
procedure in SCD subjects. An independent group of experts, therefore, will advise the 
Sponsor regarding the future of the study by periodically reviewing and evaluating the 
accumulated study data for subject safety, study conduct, and progress, as specified in 
Section 6.4.1. 
Analyses may be performed for planning and regulatory purposes, such as in support of 
meetings or submission discussions, or to inform planning for future development. 

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8 
Data Quality Assurance 
This study will be conducted according to the International Council for Harmonisation (ICH) 
E6 risk and quality processes described in the applicable procedural documents. The quality 
management approach to be implemented in this study will be documented and will comply 
with the current ICH guidance on quality and risk management. 
8.1 Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. These source documents may include laboratory reports, radiology 
reports, etc. 
Investigative site personnel will enter subject data into Medidata Rave. The analysis data sets 
will be a combination of these data and data from other sources (eg, laboratory data). 
Clinical data management will be performed in accordance with applicable Aruvant 
standards and data cleaning procedures to ensure the integrity of the data, eg, removing errors 
and inconsistencies in the data. Adverse event terms will be coded using the MedDRA, an 
internal validated medical dictionary, and concomitant medications will be coded using the 
World Health Organization Drug Dictionary (WHODrug). 
All serious breaches must be reported to the Sponsor or designee, where a serious breach is 
defined as a breach likely to affect, to a significant degree, the safety and rights of a 
participant or the reliability and robustness of the data generated in the clinical study. The 
Sponsor or designee is responsible for notifying the IRB/IEC/REB and, if required, 
regulatory authorities. 
After database lock, each study site will receive a CDROM containing all of their site 
specific eCRF data as entered into Medidata Rave for the study, including full discrepancy 
and audit history. Additionally, a CDROM copy of all of the study site’s data from the study 
will be created and sent to the Sponsor for storage. PPD will maintain a duplicate CDROM 
copy for their records. In all cases, subject initials will not be collected or transmitted to the 
Sponsor. 

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9 
Ethics 
9.1 Institutional Review Board 
Federal regulations and the ICH guidelines require that approval be obtained from an 
IRB/IEC/REB before participation of human subjects in research studies. Before study onset, 
the protocol, informed consent, advertisements to be used for the recruitment of study 
subjects, and any other written information regarding this study to be provided to the subject 
must be approved by the IRB/IEC/REB. Documentation of all IRB/IEC/REB approvals and 
of the IRB/IEC/REB compliance with ICH harmonised tripartite guideline E6: Good Clinical 
Practice (GCP) will be maintained by the site and will be available for review by the Sponsor 
or its designee. 
All IRB/IEC/REB approvals should be signed by the IRB/IEC/REB chairman or designee 
and must identify the IRB/IEC/REB name and address, the clinical protocol by title or 
protocol number or both, and the date approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status of 
the study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC/REB. The 
investigator must promptly supply the Sponsor or its designee, the IRB/IEC/REB, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to subjects. 
9.2 Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, ICH GCP, the protocol, and all applicable regulations. 
9.3 Subject Information and Consent 
A written informed consent in compliance with US Title 21 Code of Federal Regulations 
(CFR) Part 50 shall be obtained from each subject before entering the study or performing 
any unusual or nonroutine procedure that involves risk to the subject. An informed consent 
template may be provided by the Sponsor to investigative sites. If any institution-specific 
modifications to study-related procedures are proposed or made by the site, the consent 
should be reviewed by the Sponsor or its designee or both before IRB/IEC/REB submission. 
Once reviewed, the consent will be submitted by the investigator to his or her IRB/IEC/REB 

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for review and approval before the start of the study. If the ICF is revised during the course 
of the study, all active participating subjects must sign the revised form. 
Subjects will be provided an IRB/IEC/REB-approved informed consent document to review. 
The study investigator or designee will review the content of this document with the subject.   
Subjects will be allowed sufficient time to ask questions and consider participation in the 
study. Subjects will be explicitly informed that choosing not to participate will in no way 
affect the quality of the medical care that they will receive. 
In addition, the consenting process will be witnessed by a person/advocate not directly 
involved in the study. The advocate should have knowledge of the informed consent process; 
however, the advocate does not need to be familiar with the study protocol. The advocate 
should document that sufficient time was allowed to review the consent, to ask questions, and 
to allow the subject to consider enrolling in the study. The advocate should document that the 
subject appears to understand what the study involves, understand the importance of coming 
to all study visits, and understand the potential risks. This will be documented by the 
advocate’s signature on the consent form. 
Prior to commencement of study procedures, the subject will be questioned again, in the 
presence of a witness, regarding his/her willingness to proceed. 
The investigator shall retain the signed original ICF(s) and give a copy of the signed original 
form to the subject. If subjects are seen at multiple sites, the responsibilities of the principal 
investigators with regard to consent should be followed as detailed in the Subject 
Management Plan (see Section 10).  

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10 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the 
IRB/IEC/REB but will not result in protocol amendments. 
In this study, the investigator will be the person responsible for the conduct of the study at a 
site. At sites where a team of individuals are involved in conducting the study, the 
investigator will be the responsible leader of the team and will be referred to as the principal 
investigator. Subinvestigators are any individual members of the clinical trial team 
designated and supervised by the investigator at a trial site to perform critical study-related 
procedures and/or to make important study-related decisions. Each principal investigator will 
maintain a list of appropriately qualified persons to whom the principal investigator has 
delegated significant study-related duties and ensure that all persons assisting with the study 
are adequately informed about the protocol, the investigational product, and their study-
related duties and functions. For subjects who are seen at multiple sites, principal investigator 
responsibilities are detailed in the Subject Management Plan, which will outline issues 
related to the informed consent process, safety monitoring activities (including AE 
reporting), and, if applicable, transfer of responsibilities. 
10.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the subject, except as necessary for monitoring and auditing by the Sponsor, its 
designee, the FDA, or the IRB/IEC/REB. 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the Sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 

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10.2 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the Sponsor to 
submit the complete and accurate certification or disclosure statements required under 
21 CFR 54. In addition, the investigator must provide to the Sponsor a commitment to 
promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study. 
Neither the Sponsor nor PPD is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither the Sponsor nor PPD is financially responsible for 
further treatment of the subject’s disease. 
10.3 Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6 8.2 and 
Title 21 of the CFR by providing the following essential documents, including but not limited 
to: 
• IRB/IEC/REB approval. 
• Original investigator-signed investigator agreement page of the protocol. 
• Form FDA 1572, fully executed, and all updates on a new fully executed Form 
FDA 1572 (or equivalent forms, as applicable, for non-US sites). 
• Curriculum vitae for the investigator and each subinvestigator listed on Form 
FDA 1572 (or equivalent forms, as applicable, for non-US sites). 
• Financial disclosure information to allow the Sponsor to submit complete and 
accurate certification or disclosure statements required under 21 CFR 54. In addition, 
the investigators must provide to the Sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and 
for 1 year after the completion of the study. 

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• IRB/IEC/REB-approved informed consent, samples of site advertisements for 
recruitment for this study, and any other written information regarding this study that 
is to be provided to the subject. 
• Laboratory certifications and normal ranges for any local laboratories used by the 
site, in accordance with 42 CFR 493. 
10.4 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of 
ICH E6. The investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations. Study information from this protocol will be 
posted on publicly available clinical trial registers before enrollment of subjects begins. 
10.5 Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6 and all applicable guidelines and regulations. 
10.6 Adverse Events and Study Report Requirements 
By participating in this study, the investigator agrees to submit reports of SAEs to the 
Sponsor and/or IRB/IEC/REB according to the time line and method outlined in the protocol. 
In addition, the investigator agrees to submit annual reports to the study site IRB/IEC/REB as 
appropriate. 
10.7 Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB/IEC/REB with a summary of 
the study’s outcome and the Sponsor and regulatory authority(ies) with any reports required. 
10.8 Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 

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requirements or by an agreement with the Sponsor. It is the responsibility of the Sponsor to 
inform the investigator/institution as to when these documents no longer need to be retained. 
10.9 Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the Sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and other related issues. The Sponsor has final approval authority over all 
such issues. 
Data are the property of the Sponsor and cannot be published without prior authorization 
from the Sponsor, but data and publication thereof will not be unduly withheld. 

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11 Study Management 
The administrative structure will include an DSMB. Details on the composition and the 
activities of the DSMB are outlined in the DSMB charter. 
11.1 Monitoring 
11.1.1 
External Data Monitoring Committee 
An external DSMB will regularly monitor safety in this study; details are provided in 
Section 6.4.1. 
11.1.2 
Monitoring of the Study 
The clinical monitor, as a representative of the Sponsor, has the obligation to follow the study 
closely. In doing so, the monitor will visit the investigator and study site at periodic intervals, 
in addition to maintaining necessary telephone and letter contact. The monitor will maintain 
current personal knowledge of the study through observation, review of study records and 
source documentation, and discussion of the conduct of the study with the investigator and 
personnel. 
All aspects of the study will be carefully monitored, by the Sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
11.1.3 
Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB/IEC/REB review, and regulatory inspections by providing direct access to all 
study records. In the event of an audit, the investigator agrees to allow the Sponsor, 
representatives of the Sponsor, or a regulatory agency access to all study records. 
The investigator should promptly notify the Sponsor and PPD of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the 
Sponsor. 

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11.2 Management of Protocol Amendments and Deviations 
11.2.1 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the subject, must be reviewed and approved by the Sponsor or its 
designee. Amendments to the protocol must be submitted in writing to the investigator’s 
IRB/IEC/REB for approval before subjects can be enrolled into an amended protocol. 
11.2.2 
Protocol Deviations 
The investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
subjects without prior IRB/IEC/REB approval. As soon as possible after such an occurrence, 
the implemented deviation or change, the reasons for it, and any proposed protocol 
amendments should be submitted to the IRB/IEC/REB for review and approval, to the 
Sponsor for agreement, and to the regulatory authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the Sponsor and the IRB/IEC/REB and agreed to by the 
investigator. A significant deviation occurs when there is nonadherence to the protocol by the 
subject or investigator that results in a significant, additional risk to the subject or has a 
significant impact on data quality or the scientific integrity of the study. Significant 
deviations can include nonadherence to inclusion or exclusion criteria, or nonadherence to 
FDA regulations or ICH GCP guidelines, and will lead to the subject being withdrawn from 
the study (Section 4.2). 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. Principal investigators will be notified in writing by the monitor of 
deviations. The IRB/IEC/REB should be notified of all protocol deviations in a timely 
manner. 
11.3 Study Termination 
Although Aruvant has every intention of completing the study, Aruvant reserves the right to 
discontinue the study at any time for clinical or administrative reasons. Predefined early 

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study stopping rules are detailed in Section 6.4.3. Should the Sponsor decide to terminate the 
study subjects who received ARU-1801 will be followed for safety for 15 years. 
The end of the study is defined as the date on which the last subject completes the last visit 
(includes follow-up visits). 
11.4 Final Report 
Whether the study is completed or prematurely terminated, the Sponsor will ensure that the 
clinical study reports are prepared and provided to the regulatory agency(ies) as required by 
the applicable regulatory requirement(s). The Sponsor will also ensure that the clinical study 
reports in marketing applications meet the standards of the ICH harmonised tripartite 
guideline E3: Structure and content of clinical study reports.  
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results. 
Upon completion of the clinical study report, the Sponsor will provide the investigator with 
the full summary of the study results. The investigator is encouraged to share the summary 
results with the study subjects, as appropriate. The study results will be posted on publicly 
available clinical trial registers. 

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Milone MC, O’Doherty U. Clinical use of lentiviral vectors. Leukemia. 2018;32(7):1529-41. 
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by self-inactivating lentiviral and gammaretroviral vectors. Mol Ther. 2009;17(11):1919-28. 
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Niihara Y, Miller ST, Kanter J, et al. A phase 3 trial of l-glutamine in sickle cell disease. N 
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13 Appendices 
13.1 Appendix 1: Schedules of Events (Screening and Study Treatment 
Visits, Post-infusion Visits, and Long-term Follow-up Visits) 
 

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Table 13-1 
Schedule of Events: Screening and Study Treatment Visits 
Assessment 
Screening 
Visit 
HbS 
Reductive 
Visita 
Stem Cell 
Collection 
Clearance 
Visitb 
(HbS ≤20%) 
Stem Cell 
Collection 
Visitc 
Chemo-
therapy 
Clearance 
Visit 
Chemo-
therapy Visitd 
Infusion Visit 
(Day 0) 
Visit Window 
NA 
Before stem 
cell 
collectiona 
≤7 days 
before stem 
cell collection 
≥2 weeks 
after CD34+ 
kinetics 
≤7 days 
before 
chemo-
therapy 
≥36 hours 
before 
infusion 
NA 
Screening and Other Clinical Assessments 
Informed consent  
X 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history, 
including 
reproductive health, 
VOE, opioid use, and 
other sickle eventse 
X 
 
 
 
 
 
 
Physical examination 
(complete)f 
X 
Xg 
X 
 
 
 
 
Physical examination 
(targeted)h 
 
 
 
Xi 
X 
X 
X 
Vital sign 
measurements 
X 
X 
X 
X 
X 
X 
X 
SCD-related events 
and parental opioid 
use  
 
X 
X 
Xi 
X 
X 
X 
Iron overload statusj 
X 
 
 
 
 
 
 

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Assessment 
Screening 
Visit 
HbS 
Reductive 
Visita 
Stem Cell 
Collection 
Clearance 
Visitb 
(HbS ≤20%) 
Stem Cell 
Collection 
Visitc 
Chemo-
therapy 
Clearance 
Visit 
Chemo-
therapy Visitd 
Infusion Visit 
(Day 0) 
Visit Window 
NA 
Before stem 
cell 
collectiona 
≤7 days 
before stem 
cell collection 
≥2 weeks 
after CD34+ 
kinetics 
≤7 days 
before 
chemo-
therapy 
≥36 hours 
before 
infusion 
NA 
Abdominal (spleen) 
ultrasound 
 
 
Xk 
 
 
 
 
Echocardiogram 
X 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
Brain MRI and MRAl 
X 
 
 
 
 
 
 
Review concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Karnofsky 
performance status 
X 
 
X 
 
X 
 
 
Patient-reported 
outcomes 
(ASCQ-Me) 
 
X 
 
 
X 
 
 
Pulmonary function 
tests (oxygen 
saturation, 
spirometry, and 
diffusion) 
X 
 
 
 
 
 
 
Nuclear medicine 
GFR 
 
 
 
 
Xy 
 
 
Clinical Laboratory Testing 

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Assessment 
Screening 
Visit 
HbS 
Reductive 
Visita 
Stem Cell 
Collection 
Clearance 
Visitb 
(HbS ≤20%) 
Stem Cell 
Collection 
Visitc 
Chemo-
therapy 
Clearance 
Visit 
Chemo-
therapy Visitd 
Infusion Visit 
(Day 0) 
Visit Window 
NA 
Before stem 
cell 
collectiona 
≤7 days 
before stem 
cell collection 
≥2 weeks 
after CD34+ 
kinetics 
≤7 days 
before 
chemo-
therapy 
≥36 hours 
before 
infusion 
NA 
Clinical chemistry 
X 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
X 
 
X 
 
 
Urine microalbumin 
X 
 
 
 
 
 
 
CBC with 
reticulocyte and 
differential 
(automated)m 
X 
X 
X 
X 
X 
Xm 
X 
Serum ferritin  
X 
 
 
 
 
 
 
Reproductive testingn 
X 
 
 
 
 
 
 
Globin gene mapping 
(and globin deletional 
analysis if not done 
previously) 
X 
 
 
 
 
 
 
Enzyme genetic 
analysis 
X 
 
 
 
 
 
 
Serum pregnancy test 
X 
 
 
 
 
 
 
Urine pregnancy test 
 
Xo 
Xo 
Xo 
Xo 
X 
 
Hepatitis and HIV 
testing 
X 
 
 
 
 
 
 
Cystatin C eGFR 
X 
 
X 
 
X 
 
 

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Assessment 
Screening 
Visit 
HbS 
Reductive 
Visita 
Stem Cell 
Collection 
Clearance 
Visitb 
(HbS ≤20%) 
Stem Cell 
Collection 
Visitc 
Chemo-
therapy 
Clearance 
Visit 
Chemo-
therapy Visitd 
Infusion Visit 
(Day 0) 
Visit Window 
NA 
Before stem 
cell 
collectiona 
≤7 days 
before stem 
cell collection 
≥2 weeks 
after CD34+ 
kinetics 
≤7 days 
before 
chemo-
therapy 
≥36 hours 
before 
infusion 
NA 
Infectious disease 
titer 
 
 
X 
 
 
 
 
Hemoglobin 
electrophoresis 
X 
 
X 
 
 
 
 
Quantitative HbS 
only 
 
X 
X 
Xp 
X 
 
 
Stem Cell Preparation and Collection 
Plerixafor 
administration 
(240 μg/kg) 
 
 
  
X 
 
 
 
HSC collection via P-
MPB  
 
 
 
X 
 
 
 
CD34+ cell countq 
 
 
Xq 
 
 
 
Gene Transfer Testing 
Blood: RCL assayr 
 
 
X 
 
 
 
 
Blood: mononuclear 
cells and plasma for 
archivings 
 
 
X 
 
 
 
 
Blood: F-RBC and 
F-retics by flow 
cytometryr 
 
 
X 
 
 
 
 

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Assessment 
Screening 
Visit 
HbS 
Reductive 
Visita 
Stem Cell 
Collection 
Clearance 
Visitb 
(HbS ≤20%) 
Stem Cell 
Collection 
Visitc 
Chemo-
therapy 
Clearance 
Visit 
Chemo-
therapy Visitd 
Infusion Visit 
(Day 0) 
Visit Window 
NA 
Before stem 
cell 
collectiona 
≤7 days 
before stem 
cell collection 
≥2 weeks 
after CD34+ 
kinetics 
≤7 days 
before 
chemo-
therapy 
≥36 hours 
before 
infusion 
NA 
RBC testings 
 
Xs 
 
 
 
 
 
Blood sample for 
future testing 
(optional)t 
 
X 
X 
 
 
 
 
Bone marrow: 
standard morphology 
assessmentu 
 
Xu 
 
  
 
 
 
Bone marrow: flow 
cytometry for 
leukemia panelu 
 
Xu 
 
 
 
 
 
Bone marrow: 
Genomic evaluation 
for myeloid 
malignancyu 
 
Xu 
 
 
 
 
 
Bone marrow sample 
for gene transfer 
testingu, v 
 
Xu 
 
  
 
 
 
Study Treatment Administration and Pharmacokinetic Assessments 
Melphalan Dose 
Modeling 
 
 
 
 
X 
 
 
Administration of 
melphalan 
 
 
 
 
 
X 
 

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Assessment 
Screening 
Visit 
HbS 
Reductive 
Visita 
Stem Cell 
Collection 
Clearance 
Visitb 
(HbS ≤20%) 
Stem Cell 
Collection 
Visitc 
Chemo-
therapy 
Clearance 
Visit 
Chemo-
therapy Visitd 
Infusion Visit 
(Day 0) 
Visit Window 
NA 
Before stem 
cell 
collectiona 
≤7 days 
before stem 
cell collection 
≥2 weeks 
after CD34+ 
kinetics 
≤7 days 
before 
chemo-
therapy 
≥36 hours 
before 
infusion 
NA 
Melphalan PK sample 
collectionw 
 
 
 
 
 
X 
 
ARU-1801 infusionx 
 
 
 
 
 
 
X 
Abbreviations: ASCQ-Me, adult sickle cell quality-of-life measurement; CBC, complete blood count; CFU-c, colony-forming unit cells; eGFR, 
estimated glomerular filtration rate; F-RBC, fetal hemoglobin content in red blood cells; F-retics, fetal hemoglobin content in reticulocytes; HbF, 
fetal hemoglobin; HbS, sickle hemoglobin; HIV, human immunodeficiency virus; HSC, hematopoietic stem cell; MRA, magnetic resonance 
angiography; MRI, magnetic resonance imaging; NA, not applicable; P50, partial pressure of oxygen in the blood at which hemoglobin is 50% 
saturated; PK, pharmacokinetic; P-MPB, plerixafor-mobilized peripheral blood; qPCR, quantitative polymerase chain reaction; RBC, red blood 
cell; RCL, replication competent lentivirus; SCD, sickle cell disease; VOE, vaso-occlusive episode. 
a. 
Subjects enrolled in this study will begin HbS reduction to ≤30% via erythrocytapheresis or transfusions over a period of 2 to 3 months. Multiple 
visits may be needed and will be permitted in order to achieve the target HbS at least 2 months before HSC collection; frequency of visits is at the 
investigator’s discretion (Section 5.5.1). 
b. Within 7 days prior to stem cell collection, the subject should have documented HbS <20% or have completed erythrocytapheresis to the goal 
HbS of ≤20%. The Stem Cell Collection Clearance Visit may be repeated, as required, if subjects require multiple cycles for stem cell collection. 
c. 
Subjects may undergo multiple procedures over multiple visits, if required, in order to obtain sufficient CD34+ cell content (Section 5.5.1.1). 
d. Subjects should be hospitalized before the infusion of the melphalan dose for conditioning and will remain hospitalized until the investigator 
determines they are fit for discharge but not before the last melphalan PK sample has been collected (Section 6.6). At the investigator’s discretion 
and based on the subject’s compliance, subjects may complete clinical monitoring assessments as an outpatient (Section 5.5.3). Testing performed 
for clinical monitoring up to 30 days post-infusion should be recorded in the study database (CBC with reticulocyte and differential, clinical 
chemistry, and hemoglobin electrophoresis). 
e. 
Available medical records pertaining to SCD status (VOEs, organ function parameters, laboratory tests, medications, transfusions, etc) may be 
used to obtain history from the 2-year period before enrollment. Medical history will also include prior procedures performed up to 2 years before 
the screening visit and significant surgeries and medical events that occurred >2 years before screening. Reproductive health history will also be 

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recorded. For subjects enrolled under previous versions of the protocol, baseline disease severity will also be determined from a retrospective 
review of medical records for the last 2 years before the screening visit. 
f. 
A complete physical examination will include height (screening visit only), weight, and evaluation of body systems, including but not limited to 
the following: skin; head, eyes, ears, nose, and throat; respiratory system; cardiovascular system; abdomen (liver, spleen); reproductive systems; 
and lymph nodes. 
g. Physical examination required only if >30 days have elapsed since last assessment. 
h. A targeted physical examination will include evaluation of the subject’s general appearance and other components as indicated by the subject’s 
medical history or symptoms. 
i. 
Physical examination (targeted) and incidence of SCD-related events and parental opioid use should be completed within 24 hours of the CD34+ 
kinetics assessment and the start of each stem cell collection cycle. 
j. 
At screening, subjects will be evaluated for chronic transfusions >200 mL/kg, evidence of iron overload from FerriScan imaging performed as 
part of standard of care, and hepatic fibrosis by noninvasive liver imaging obtained per the subject’s standard of care. 
k. An abdominal ultrasound for examination of the spleen will be performed once, within 7 days before the first plerixafor dose.  
l. 
Brain MRI and MRA will be performed at screening only, to assess risk of stroke (per exclusion #7) and to establish the subject’s baseline status. 
If such imaging has been performed within 6 months before the date of informed consent, and the report and images are available within the 
medical record, there is no need to repeat the procedure at screening.  
m. After chemotherapy (melphalan) administration, CBC monitoring performed at local laboratory is required at a minimum of twice weekly until 
absolute neutrophil count >1×109/L and weekly thereafter until the investigator considers the subject recovered (Section 5.6.2).  
n. Reproductive laboratory tests for female and male subjects are listed in Section 6.3.2. Testing will be performed before fertility preservation 
(Section 5.6.4) for males and females; at a time point after fertility preservation for females; and at Month 12, Year 2, and Year 5 for males and 
females. The date of the last menstrual period should be obtained from females at the time of testing. 
o. Perform urine pregnancy test only if last test performed at study site was >48 hours before visit. 
p. Quantitative HbS should be performed within 24 hours of the CD34+ kinetics assessment and Stem Cell Collection. The HbS level only needs to 
be performed within 24 hours of the first HSC collection per cycle (Section 5.5.1). 
q. CD34+ cell count will be analyzed locally before administration of plerixafor (baseline) and at approximately 1, 2, 4 and 8 hours after plerixafor 
dosing to evaluate the stem cell mobilization kinetics of each subject. After consultation with the Sponsor, the collection time points may be 
changed and the number of blood samples collected for peripheral blood CD34+ measurements may be reduced. 
r. 
A baseline blood sample should be collected at the first Stem Cell Collection Clearance Visit, and sample collection does not need to be repeated. 
s. 
Testing (P50 and ektacytometry with Oxyscan) will be performed at institutions with the capability to run the tests, or samples will be shipped 
within the stability window to an institution or laboratory with the capability to perform the testing. The testing is performed at the HbS Reductive 
Visit before the first blood transfusion, then at the Month 6, Month 12 (Year 1), and Year 2 post-infusion visits. Efforts should be made to perform 
baseline testing before initiation of transfusions. 

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t. 
Baseline and follow-up blood samples (1 tube each for blood cells, plasma and serum) will be collected for potential future biomedical research or 
biomarker analyses for subjects who consent to participate in this component of the study (Section 6.8). Participation is optional. 
u. The baseline bone marrow testing must be completed after enrollment and prior to initiation of additional research procedures. Specifically, the 
testing should be completed before a central line is placed or the subject is initiated on RBC transfusions. Results from the baseline bone marrow 
evaluation must be complete and reviewed by the investigator before the initiation of the first HbS Reduction visit. 
v. 
Bone marrow samples for gene transfer testing will be performed before ARU-1801 infusion and every 6 months through Year 2 (Months 6, 12, 
18, and 24), and at Year 3 (Month 36) and comprises the following (see Section 6.5.2.3): qPCR and DNA for vector copies and hematopoietic 
lineages, CFU-c assay for vector copies by qPCR on individual CFU-c and vector insertion site analysis. 
w. Blood samples for quantification of melphalan concentration in plasma will be collected at pre-dose (within 60 minutes before start of melphalan 
infusion), immediately at the end of the melphalan intravenous infusion, and approximately 5 minutes, 15 minutes, 1 hour, 2 hours, 4 hours, and 
6 hours after the end of infusion (Section 6.6).  
x. Before ARU-1801 infusion, subjects will be premedicated with acetaminophen, diphenhydramine, and hydrocortisone (Section 5.5.5). 
y.  May be performed up to 30 days before the chemotherapy infusion.

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Table 13-2 
Schedule of Events: Post-infusion Visits (Day 7 Through Year 2) 
Assessments  
D7, 14, 
and 21 
D30 
D60 
D90 
M4 
and 5 
M6 
M7 
M8 
and 9 
M10 
M11 
M12 
M15 
M18 
M21 
Y2 
Visit Window 
(days) 
±2 
±5 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±14 
SCD-related events 
and parental opioid 
use 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination 
(complete)a 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination 
(targeted)b 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital sign 
measurements 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Echocardiogram 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Karnofsky 
performance status 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient-reported 
outcomes 
(ASCQ-Me) 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 

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Assessments  
D7, 14, 
and 21 
D30 
D60 
D90 
M4 
and 5 
M6 
M7 
M8 
and 9 
M10 
M11 
M12 
M15 
M18 
M21 
Y2 
Visit Window 
(days) 
±2 
±5 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±14 
Pulmonary function 
tests (oxygen 
saturation, 
spirometry, and 
diffusion) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Clinical Laboratory Testing 
Clinical chemistry 
Xe 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Urine 
microalbumin 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Urine pregnancy 
test 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with 
reticulocyte and 
differential 
(automated)   
Xe 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reproductive 
testingf 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Cystatin C eGFR 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Hemoglobin 
electrophoresis 
 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Gene Transfer Testing 

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Assessments  
D7, 14, 
and 21 
D30 
D60 
D90 
M4 
and 5 
M6 
M7 
M8 
and 9 
M10 
M11 
M12 
M15 
M18 
M21 
Y2 
Visit Window 
(days) 
±2 
±5 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±14 
Blood: bulk vector 
DNA qPCR 
 
X 
X 
X 
X 
X 
 
Xg 
 
 
X 
 
X 
X 
X 
Blood: sorted cell 
subpopulations and 
vector DNA qPCR 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
Blood: RCL assayh 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
Blood: vector 
insertion site 
analysis 
 
 
 
X 
 
X 
 
Xg 
 
 
X 
 
X 
 
X 
Blood: F-RBC and 
F-retics by flow 
cytometry 
 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
Blood sample for 
future testing 
(optional)i 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
RBC testingj 
 
 
 
 
 
Xj 
 
 
 
 
X 
 
 
 
X 
Bone marrow: 
standard 
morphology 
assessment  
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
Bone marrow: flow 
cytometry for 
leukemia panel 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 

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Assessments  
D7, 14, 
and 21 
D30 
D60 
D90 
M4 
and 5 
M6 
M7 
M8 
and 9 
M10 
M11 
M12 
M15 
M18 
M21 
Y2 
Visit Window 
(days) 
±2 
±5 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±14 
Bone marrow: 
Genomic evaluation 
for myeloid 
malignancy 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
Bone marrow 
samples for gene 
transfer testingk 
 
 
 
 
 
X 
 
 
 
 
X 
 
Xl 
 
Xl 
Abbreviations: AE, adverse event; ASCQ-Me, adult sickle cell quality-of-life measurement; CBC, complete blood count; CFU-c, colony-forming unit 
cells; D, day; eGFR, estimated glomerular filtration rate; F-RBC, fetal hemoglobin content in red blood cells; F-retics, fetal hemoglobin content in 
reticulocytes; M, month; P50, partial pressure of oxygen in the blood at which hemoglobin is 50% saturated; qPCR, quantitative polymerase chain 
reaction; RCL, replication competent lentivirus; SAE, serious adverse event; SCD, sickle cell disease; VOE, vaso-occlusive episodes; Y, year. 
a. 
A complete physical examination will include height (screening visit only), weight, and evaluation of body systems, including but not limited to 
the following: skin; head, eyes, ears, nose, and throat; respiratory system; cardiovascular system; abdomen (liver, spleen); reproductive systems; 
and lymph nodes. 
b. A targeted physical examination will include evaluation of the subject’s general appearance and other components as indicated by the subject’s 
medical history or symptoms. 
c. 
Adverse events will be assessed from the time the subject signs the informed consent form until 2 years after the ARU-1801 infusion. After the 
Year 2 follow-up visit in this study, AE collection and reporting will be limited to all SAEs, nonserious AEs leading to study withdrawal or that 
are considered at least possibly related to the investigation product or study medications/procedures, AEs of special interest, and SCD VOEs 
(Section 6.3.1.3). 
d. Collect at Month 6 only. 
e. 
Testing performed for clinical monitoring up to 30 days post-infusion should be recorded in the study database (CBC with reticulocyte and 
differential, clinical chemistry, and hemoglobin electrophoresis).  
f. 
Reproductive laboratory tests for female and male subjects are listed in Section 6.3.2. Testing will be performed before fertility preservation 
(Section 5.6.4) for males and females; at a time point after fertility preservation for females; and at Month 12, Year 2, and Year 5 for males and 
females. The date of last menstrual period should be obtained from females at the time of testing. 

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g. Collect at Month 9 only. 
h. If all post-infusion RCL assay results are negative in the first year, yearly follow-up samples may be discontinued. If any post-infusion results are 
positive, assay should be performed annually thereafter until Year 15. 
i. 
Baseline and follow-up blood samples (1 tube each of blood cells, plasma and serum) will be collected for potential future biomedical research or 
biomarker analyses for subjects who consent to participate in this component of the study (Section 6.8). Participation is optional. 
j.  Testing (P50 and ektacytometry with Oxyscan) will be performed at institutions with the capability to run the tests, or samples will be shipped 
within the stability window to an institution or laboratory with the capability to perform the testing. The testing is performed at the Month 6, 
Month 12 (Year 1), and Year 2 post-infusion visits. 
k. Bone marrow samples for gene transfer testing will be performed before ARU-1801 infusion, every 6 months through Year 2 (Months 6, 12, 18, 
and 24), and at Year 3 (Month 36) and comprises the following (see Section 6.5.2.3): qPCR and DNA for vector copies and hematopoietic 
lineages, CFU-c assay for vector copies by qPCR on individual CFU-c, and vector insertion site analysis. 
l. 
If there is no vector marking in peripheral blood WBC at 2 previous time points, bone marrow aspirates will be discontinued. 

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Table 13-3 
Schedule of Events: Long-term Follow-up Visits (Month 30 Through Year 15) 
Assessment 
M30 
Year 3  
M42 
Year 4 
M54 
Year 5 
Year 6, 
7, 8, 
and 9 
Year 10 
Year 11 
and 12 
Year 13 
and 14 
Year 15 
Visit Window (days) 
±14 
±30 
±14 
±30 
±14 
±30 
±30 
±30 
±30 
±30 
±30 
SCD-related events and 
parental opioiduse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
(complete)a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurements 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Karnofsky performance 
status 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Patient-reported 
outcomes (ASCQ-Me) 
 
X 
 
X 
 
X 
 
 
 
 
 
Clinical Laboratory Testing 
Clinical Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Urine microalbumin  
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Urine pregnancy test 
X 
X 
 
 
 
 
 
 
 
 
 
CBC with reticulocyte 
and differential  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reproductive testingc 
 
 
 
 
 
X 
 
 
 
 
 
Cystatin C eGFR  
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Hemoglobin 
electrophoresis 
X 
Xd 
X 
Xd 
X 
Xd 
X 
X 
X 
X 
X 

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Assessment 
M30 
Year 3  
M42 
Year 4 
M54 
Year 5 
Year 6, 
7, 8, 
and 9 
Year 10 
Year 11 
and 12 
Year 13 
and 14 
Year 15 
Visit Window (days) 
±14 
±30 
±14 
±30 
±14 
±30 
±30 
±30 
±30 
±30 
±30 
Gene Transfer Testing 
Blood: bulk vector DNA 
qPCR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood: sorted cell 
subpopulations and vector 
DNA qPCR 
 
X 
 
X 
 
X 
 
 
 
 
 
Blood: RCL assayd 
 
(X) 
 
(X) 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Blood: vector insertion 
site analysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood: F-RBC and 
F-retics by flow 
cytometry 
 
X 
 
 
 
 
 
 
 
 
 
Bone marrow: standard 
morphology assessment  
 
X 
 
 
 
 
 
 
 
 
 
Bone marrow: flow 
cytometry for leukemia 
panel 
 
X 
 
 
 
 
 
 
 
 
 
Bone marrow: Genomic 
evaluation for myeloid 
malignancy 
 
X 
 
 
 
 
 
 
 
 
 
Bone marrow sample for 
gene transfer testinge, f, g 
 
X 
 
 
 
 
 
 
 
 
 
Abbreviations: AE, adverse event; ASCQ-Me, adult sickle cell quality-of-life measurement; CBC, complete blood count; CFU, colony-forming unit 
cells; eGFR, estimated glomerular filtration rate; F-RBC, fetal hemoglobin content in red blood cells; F-retics, fetal hemoglobin content in 
reticulocytes; LTFU, long-term follow-up; M, month; qPCR, quantitative polymerase chain reaction; RCL, replication competent lentivirus; SAE, 
serious adverse event; SCD, sickle cell disease; VOE, vaso-occlusive episode; WBC, white blood cell. 

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Note: It is anticipated that a separate LTFU clinical study will be initiated. Once the LTFU study is approved at the site, all subjects who complete the 
Year 2 study visit in this study will be asked to consent and enroll into the LTFU study and will be followed for a total of 15 years after the 
ARU-1801 infusion. Subjects who have not yet transitioned to the LTFU study should follow the assessments detailed in this table. 
a. 
A complete physical examination will include height (screening visit only), weight, and evaluation of body systems, including but not limited to 
the following: skin; head, eyes, ears, nose, and throat; respiratory system; cardiovascular system; abdomen (liver, spleen); reproductive systems; 
and lymph nodes. 
b. After the Year 2 follow-up visit in this study, AE collection and reporting will be limited to all SAEs, nonserious AEs leading to study withdrawal 
or that are considered at least possibly related to the investigation product or study medications/procedures, AEs of special interest, and SCD 
VOEs (Section 6.3.1.3). 
c. 
Reproductive laboratory tests for female and male subjects are listed in Section 6.3.2. Testing will be performed before fertility preservation 
(Section 5.6.4) for males and females, at a time point after fertility preservation for females, and at Month 12, Year 2, and Year 5 for males and 
females. The date of last menstrual period should be obtained from females at the time of testing. 
d. If any post-infusion results are positive during the first year, the assay should be performed annually thereafter until Year 15. 
e. 
Bone marrow samples for gene transfer testing will be performed before ARU-1801 infusion, every 6 months through Year 2 (Months 6, 12, 18, 
and 24), and at Year 3 (Month 36) and comprises the following (see Section 6.5.2.3): qPCR and DNA for vector copies and hematopoietic 
lineages, CFU-c assay for vector copies by qPCR on individual CFU-c, burst-forming unit-erythroid (pooled) for RNA, and vector insertion site 
analysis. 
f. 
If there is no vector marking in peripheral blood WBC at 2 previous time points, bone marrow aspirates will be discontinued. 
g. For LTFU from Year 4 through Year 15, bone marrow will be collected for gene transfer testing only if warranted. 

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13.2 Appendix 2: Karnofsky Scores  
Table 13-4 
Karnofsky Scores (Age 10 and Older) 
Performance Status 
Karnofsky Score 
Asymptomatic and fully active 
100% 
Symptomatic; fully ambulatory; restricted in physically strenuous activity 
80%-90% 
Symptomatic; ambulatory; capable of self-care; more than 50% of waking 
hours are spent out of bed 
60%-70% 
Symptomatic; limited self-care; spends more than 50% of time in bed, but not 
bedridden 
40%-50% 
Completely disabled; no self-care; bedridden 
20%-30% 
 

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13.3 Appendix 3: Side Effects Related to Melphalan Chemotherapy 
Table 13-5 
Risks and Side Effects Related to Melphalan 
 
Common 
Occurs for 21 to 100 
of every 100 persons 
Occasional 
Occurs for 5 to 20 of 
every 100 persons 
Rare 
Occurs for <5 of every 
100 persons 
Immediate: 
Within 1 to 2 days of 
receiving drug 
Anorexia 
Nausea 
Vomiting 
Hyponatremia 
 
Anaphylaxis 
Hypotension 
Diaphoresis 
Pruritus 
Atrial fibrillation 
SIADH 
Seizures 
Prompt:  
Within 2-3 weeks 
Myelosuppression 
Mucositis 
Diarrhea 
Alopecia 
 
Abnormal liver 
function tests 
Jaundice 
Hepatitis 
Delayed:  
Any time later during 
therapy, excluding the 
above conditions 
 
Amenorrhea 
Testicular suppression 
Bone marrow failure 
Hemolytic anemia 
Pulmonary fibrosis 
Interstitial 
pneumonitis 
Rash 
Late:  
Any time after 
completion of 
treatment 
 
Sterility 
Primary ovarian 
failure 
Secondary 
malignancy 
Abbreviations: SIADH, syndrome of inappropriate antidiuretic hormone secretion. 
 

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13.4 Appendix 4: Adult Sickle Cell Quality-of-Life Measurement 
(ASCQ-Me) 

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13.5 Appendix 5: Formulas and Methods for Melphalan Dosing 
Body surface area (BSA) in m2 by Dubois formula (Dubois, 1916) 
• Where 𝑊𝑇 is total body weight in kg, 𝐻𝑇 is height in cm, and 
 
𝐵𝑆𝐴= 𝑊𝑇0.425 ∗𝐻𝑇0.725 ∗0.007184
(1) 
 
Ideal body weight (IBW) in kg by Devine formula (Devine, 1974) 
• Where 𝐻𝑇 is height in inches 
 
𝐼𝐵𝑊 (𝑚𝑎𝑙𝑒) = 50 + 2.3(𝐻𝑇−60) 
(2) 
𝐼𝐵𝑊 (𝑓𝑒𝑚𝑎𝑙𝑒) = 45.5 + 2.3(𝐻𝑇−60) 
 
Fat free mass (FFM) in kg from Janmahasatian et al, 2005 
• Where 𝑊𝑇 is total body weight in kg, 𝐻𝑇 is height in m 
 
𝐹𝐹𝑀 (𝑚𝑎𝑙𝑒) = 
9270 ∙𝑊𝑇
(6680 + 216 ∙𝑊𝑇
𝐻𝑇2)
(3) 
 
𝐹𝐹𝑀 (𝑓𝑒𝑚𝑎𝑙𝑒) = 
9270 ∙𝑊𝑇
(8780 + 244 ∙𝑊𝑇
𝐻𝑇2)
 
 
Cystatin C eGFR (eGFRCysC,input) provided in units of mL/min/1.73m2 by Aruvant. 
Converted to units of L/h for use in Nath model (eGFRCysC) as follows: 
 
𝑒𝐺𝐹𝑅𝐶𝑦𝑠𝑡𝐶=  𝑒𝐺𝐹𝑅𝐶𝑦𝑠𝑡𝐶,𝑖𝑛𝑝𝑢𝑡∙
𝐵𝑆𝐴
1.73𝑚2 ∙
1𝐿
1000𝑚𝐿∙60 𝑚𝑖𝑛
1ℎ
 
(4) 
 
Cystatin C eGFR normalized by weight in kg (eGFRCysC,normalized; in L/h): 
𝑒𝐺𝐹𝑅𝐶𝑦𝑠𝑡𝐶,𝑛𝑜𝑟𝑚𝑎𝑙𝑖𝑧𝑒𝑑= 𝑒𝐺𝐹𝑅𝐶𝑦𝑠𝑡𝐶∙70𝑘𝑔
𝑊𝑇 
(5) 
 
Predicted melphalan clearance (CLpredicted) in units of L/h, calculated using subject 
covariates: 
 
• Where hematocrit (𝐻𝐶𝑇 ) is provided in %, 𝐹𝐹𝑀 in kg, 𝑒𝐺𝐹𝑅𝐶𝑦𝑠𝑡𝐶,𝑛𝑜𝑟𝑚𝑎𝑙𝑖𝑧𝑒𝑑 in L/h 
• Modifications from the paper: 

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o In the paper, the normalization for FFM is 50 kg. The Sponsor implemented 
the Nath model based on a NONMEM file provided by Nath, where 53 kg is 
used as the normalization. 
o In the paper, normalization for eGFR is given as 88 mL/min. Since CL is used 
in units of L/h, the Sponsor converted 88 mL/min to 5.28 L/h here. 
 
𝐶𝐿𝑝𝑟𝑒𝑑𝑖𝑐𝑡𝑒𝑑= 17 ∙(𝐻𝐶𝑇
34 )
0.462
∙(𝐹𝐹𝑀
53 )
0.75
+ 11.1 ∙𝑒𝐺𝐹𝑅𝐶𝑦𝑠𝑡𝐶,𝑛𝑜𝑟𝑚𝑎𝑙𝑖𝑧𝑒𝑑
5.28
 
(6) 
 
 
Model-informed Individualized Dose Determination: 
 
Predicted melphalan AUC (AUCpredicted) in subjects after conventional 140 mg/m2 dose, units 
of ug.h/mL: 
 
𝐴𝑈𝐶𝑝𝑟𝑒𝑑𝑖𝑐𝑡𝑒𝑑= 140 ∙𝐵𝑆𝐴𝑐𝑎𝑝𝑝𝑒𝑑
𝐶𝐿𝑝𝑟𝑒𝑑𝑖𝑐𝑡𝑒𝑑
 
(7) 
 
Where 𝐵𝑆𝐴𝑐𝑎𝑝𝑝𝑒𝑑 is BSA calculated with ideal body weight replacing total body weight in 
Equation 1 if the patient’s total body weight (WT) is greater than 1.3 times their ideal body 
weight (IBW), and using total body weight when WT ≤ 1.3 x IBW. 
 
Subjects with a AUCpredicted ≥ 8.0 μg.h/mL, as determined using Equation 7 will receive a dose 
of 140 mg/m2, normalized to 𝐵𝑆𝐴𝑐𝑎𝑝𝑝𝑒𝑑.  
 
If the subject’s AUCpredicted is < 8.0 μg.h/mL, the subject will receive a model-informed dose 
calculated to achieve a target AUC of 10.4 μg.h/mL, limited to a maximum of 200 mg/m2, 
i.e. the lesser of Equations 8 and 9:.  
 
𝑀𝑒𝑙𝑝ℎ𝑎𝑙𝑎𝑛 𝐷𝑜𝑠𝑒𝐴𝑈𝐶10.4 = 10.4 ∙𝐶𝐿𝑝𝑟𝑒𝑑𝑖𝑐𝑡𝑒𝑑
(8) 
𝑀𝑒𝑙𝑝ℎ𝑎𝑙𝑎𝑛 𝐷𝑜𝑠𝑒200𝑚𝑔/𝑚2 = 200 ∙𝐵𝑆𝐴𝑐𝑎𝑝𝑝𝑒𝑑
(9) 

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13.6 Appendix 6: Flow Chart for Melphalan Dosing 
 
(4) Individualized Melphalan Dose
𝐸𝑞𝑢𝑎𝑡𝑖𝑜𝑛𝑠8 & 9 𝑖𝑛𝐴𝑝𝑝𝑒𝑛𝑑𝑖𝑥13.5
(3) Compare dose predicted to 
achieve target AUC to ceiling dose
𝐸𝑞𝑢𝑎𝑡𝑖𝑜𝑛𝑠3 −7 𝑖𝑛𝐴𝑝𝑝𝑒𝑛𝑑𝑖𝑥13.5
(2) Evaluate Individual Predicted 
AUC for 140mg/m2
𝐸𝑞𝑢𝑎𝑡𝑖𝑜𝑛𝑠1 −2 𝑖𝑛𝐴𝑝𝑝𝑒𝑛𝑑𝑖𝑥13.5
(1) BSA calculation adjusted to use 
ideal body weight for heavy patients 
Step 1
Determine BSA comparing WT and ideal 
body weight (IBW)
For WT ≤130% of IBW, use WT in 
BSA calculation
Step 2
Calculate Predicted AUC for 
a dose of 140 mg/m2
Predicted AUC < 8.0 
µg∙h/mL
Step 3
Calculate Dose (in mg) to Target 
AUC of 10.4 µg∙h/mL (DoseAUC10.4)
DoseAUC10.4 < 200 
mg/m2 x BSA
Calculated 
DoseAUC10.4
DoseAUC10.4 ≥ 200 
mg/m2x BSA
200 mg/m2
Predicted AUC ≥8.0 
µg∙h/mL
140 mg/m2
For WT > 130% of IBW weight, use 
IBW in BSA calculation