A Phase 1/2 Study Evaluating Gene Therapy by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With the LentiGlobin BB305 Lentiviral Vector in Subjects With Severe Sickle Cell Disease
Phase: PHASE1
Conditions: Sickle Cell Disease
Sponsor: Genetix Biotherapeutics Inc.



Protocol HGB-206 Version 13.0 
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SUMMARY OF CHANGES 
Version and date of the previous version: Version 12.0 (01 June 2022) 
Version and date of the new version: Version 13.0 (17 January 2023) 
Substantial changes, defined as changes that are likely to have a significant impact on the safety 
or physical or mental integrity of the clinical study participants, or the scientific value of the 
study, compared to Protocol HGB-206 Version 12.0 are described in the table below. These 
changes include adding ISA assessments on bone marrow at Month 12 and Month 24 (Early 
Termination Visits Assessments); updating the definition of oligoclonality within the ISA 
algorithm; and providing a detailed explanation for assessments used for risk and clinical work-
up for hematologic malignancy. 
Substantial and non-substantial are described below. In addition, several minor changes were 
also made to reorganize content for clarity, correct typographical errors, and align the use of 
terminology and formatting with current standards.
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DESCRIPTION OF EACH SUBSTANTIAL CHANGE 
Note: in the following table, added text is in bold italics and deleted text is in strikethrough. 
Section of current document 
Changes in New Document 
(Version 13.0 as compared to Version 12.0) 
Rationale 
Section(s) concerned: 
Section 6.1 Schedule of Events, Table 4 
 
Procedures 
D360 
D720 
M12 
(±30) 
M24 
(±30) 
Central lab: 
Bone marrow 
for NGS14, 
storage19, and 
exploratory PD 
X 
X 
 
Section(s) concerned: 
Section 6.1 Schedule of Events, Table 4 
 
Procedures 
D360 
D720 
M12 
(±30) 
M24 
(±30) 
Central lab: 
Bone marrow 
for NGS14, ISA, 
storage19, and 
exploratory PD 
X 
X 
 
Added integration 
site analysis 
(ISA) assessment 
on bone marrow 
(BM) at M12 and 
M24 (Early 
Termination Visit 
Assessments) to 
enable 
exploratory 
comparison of 
ISA results on 
BM and 
peripheral blood 
(PB). 
 
Section(s) concerned: 
Section 6.2.28.1 Assessment of Oligoclonality by 
Integration Site Analysis 
 
[…] 
 
ISA monitoring may be repeated more frequently if there 
is an indication of oligoclonality. As shown in Figure 4  if 
an IS is detected at ≥ 10% relative frequency (RelFreq), 
ISA will be repeated within 3 months of receipt of this 
result. If the ≥ 10% RelFreq result is confirmed, the IS will 
be considered as of interest, and a report of persistent 
oligoclonality will be submitted to the relevant Health 
Authorities within 30 days. This repeated observation will 
Section(s) concerned: 
Section 6.2.28.1 Assessment of Oligoclonality by Integration 
Site Analysis 
 
[…] 
 
ISA monitoring may be repeated more frequently if there is an 
indication of oligoclonality. As shown in Figure 4  if an IS is 
detected at ≥ 10% relative frequency (RelFreq) for 1 IS, or 
≥ 5% RelFreq for ≥ 2 IS, ISA will be repeated within 3 months 
of receipt of this result. If the ≥ 10% RelFreq result is 
confirmed, the IS will be considered as of interest, and a report 
of persistent oligoclonality will be submitted to the relevant 
Health Authorities within 30 days. This repeated observation 
Out of an 
abundance of 
caution, and to 
help inform 
future 
understanding of 
clonal 
frequencies and 
the impact of 
clonal dynamics 
on potential risk 
for malignancy, 
the ISA algorithm 
was updated to 
redefine 
oligoclonality to 
include ≥ 5% 
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Rationale 
a ISA is assessed per the schedule of events; CBC with differential 
and VCN are to be carried out whenever ISA is performed (Table 
4). 
b If ISA is assessed concurrently from PB and BM, the assessment 
with higher RelFreq values should be used. 
c Samples obtained one month or more apart can be considered 
consecutive measurements. 
d Persistent oligoclonality will be reported to the relevant Health 
Authorities within 30 days. 
e At a minimum, enhanced monitoring includes CBC with 
differential every 3 months and ISA every 6 months.Additional 
monitoring for malignancy may be instituted by the treating 
physician/Principal Investigator (see Section 6.2.29). 
[…] 
 
Section(s) concerned: 
Section 6.2.28.2 Clinical Work-up for Potential Malignancy 
 
In the event of any suspicion of hematological malignancy (i.e., 
myelodysplasia, leukemia, or lymphoma), the Medical Monitor 
will be notified and a work-up will be performed by the 
Investigator per appropriate standard of care. A suspicion of 
malignancy could arise in the setting of otherwise unexplained 
cytopenia(s), and consideration of insertional oncogenesis could 
arise if cytopenia(s) occurs in conjunction with a rising RelFreq 
of an IS in a gene of known biological relevance to 
carcinogenesis (i.e., oncogene or tumor suppressor gene), 
accompanied by a rapid increase in PB VCN. 
The clinical work-up may include the following: 
• 
Physical exam 
• 
CBC with differential 
• 
Lymphocyte subsets 
Section(s) concerned: 
Section 6.2.28.229 Assessments for Risk of Hematologic 
Malignancy and Clinical Work-up for Potential Malignancy 
 
In the event of any suspicion of hematological malignancy (i.e., 
myelodysplasia, leukemia, or lymphoma), the Medical Monitor will 
be notified and a work-up will be performed by the Investigator per 
appropriate standard of care. A suspicion of malignancy could arise 
in the setting of otherwise unexplained cytopenia(s), and 
consideration of insertional oncogenesis could arise if cytopenia(s) 
occurs in conjunction with a rising RelFreq of an IS in a gene of 
known biological relevance to carcinogenesis (i.e., oncogene or 
tumor suppressor gene), accompanied by a rapid increase in PB VCN. 
The clinical work up may include the following: 
• 
Physical exam 
• 
CBC with differential 
• 
Lymphocyte subsets 
Per FDA 
recommendation, 
a detailed 
explanation is 
included for how 
primary 
assessments are 
intended to 
inform the 
potential decision 
for clinical work-
up for potential 
hematologic 
malignancy. 
Additionally, 
specific 
recommendations 
are providing 
around the use of 
reflexive 
assessments 
during clinical 
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Section of current document 
Changes in New Document 
(Version 13.0 as compared to Version 12.0) 
Rationale 
• 
Imaging studies 
• 
Bone marrow analysis 
• 
Cytogenetic and molecular analyses which can 
include fluorescence in situ hybridization (FISH), 
SNP microarray, karyotyping, or whole-genome 
sequencing 
 
[…] 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Imaging studies 
• 
Bone marrow analysis 
• 
Cytogenetic and molecular analyses which can include 
fluorescence in situ hybridization (FISH), SNP 
microarray, karyotyping, or whole-genome sequencing 
 
Routine assessments carried out per the SOE (Table 4 ) for risk of 
potential hematologic malignancy are presented in Figure 5 . 
Clinical presentation and CBC with differential are considered 
standard assessments, whereas BM biopsy, ISA, NGS, and 
karyotyping are considered supportive assessments in the context of 
gene therapy. In the event of suspicion of hematologic malignancy 
(i.e., myelodysplasia, leukemia, or lymphoma), discussion with the 
Medical Monitor is required and should include an evaluation of 
local versus central testing. Clinical work-up is to be performed by 
the Investigator per appropriate standard of care and in alignment 
with WHO and NCCN guidelines (Arber et al. 2016; Greenberg et 
al. 2022). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
work-up for 
potential 
hematologic 
malignancy. 
Notably, if BM 
biopsy is 
performed as part 
of clinical work-
up, ISA on BM 
should be 
included. 
 
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Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
For clinical work-up after identification of persistent 
oligoclonality and confirmed presence of abnormal CBC, 
bone marrow analysis is recommended if not previously 
performed as part of the clinical work-up. 
 
 
 
 
 
 
 
Figure 5: Assessments for Risk of Hematologic Malignancy 
per Schedule of Events and Clinical Work-up 
 
 
Abbrev.: AML, acute myeloid leukemia; BM, bone marrow; CBC, 
complete blood count; FISH, fluorescence in situ hybridization; IS, 
insertion site; ISA, integration site analysis; MDS, myelodysplastic 
syndrome; NCCN, National 
Comprehensive Cancer Network; NGS, next generation 
sequencing; RNA-seq, RNA sequencing; SNP, single nucleotide 
polymorphism; VCN, vector copy number; WHO, World Health 
Organization 
a Routine monitoring include assessments per SOE (Table 4) and 
ongoing patient education on risk of malignancy. 
b Turnaround times for ISA results can vary in duration, typically 
taking approximately 10 weeks from sample collection to data 
delivery. ISA may be done on PB or BM per the SOE (Table 4). 
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Section of current document 
Changes in New Document 
(Version 13.0 as compared to Version 12.0) 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c In addition to NGS and karyotype, other genetic testing results 
that are suggestive of potential risk for malignancy may be taken 
into account. 
d If a subject has persistent oligoclonality (see Section 6.2.29) and 
other cause for clinical work-up, additional assessments such as 
BM biopsy, RNA-seq, lineage-specific ISA (to be performed on BM 
only if as available), or IS-specific VCN can be considered; (Arber 
et al. 2016; Greenberg et al. 2022). 
e ISA should be done on BM if taken as part of clinical work-up 
.f In the context of clinical work-up for hematologic malignancy, 
FISH assessments should be local, according to guidelines, as local 
laboratories are certified in this context. Central FISH may be 
performed retrospectively on stored samples if results from local 
work-up are unclear. 
 
Under specific circumstances, after discussion with the Medical 
Monitor, BM biopsy, RNA-seq/RT-PCR, lineage-specific ISA, and 
IS-specific VCN may be considered appropriate assessments during 
clinical work-up, specifically if there is persistent oligoclonality as 
identified with ISA AND at least one of the following: 
• 
Medical History, physical exam, or evaluation findings 
suggestive of developing malignancy OR 
• 
Unexplained hematologic changes consistent with 
malignancy OR  
• 
Clinically significant findings suggestive for malignancy 
on BM pathology OR 
• 
Concerning cytogenetic or molecular findings on 
karyotype, NGS, or other genetic testing results that are 
suggestive of potential risk for malignancy 
Note at any time, regardless of clonality measurements, any 
additional clinical work-up may be performed at the Investigator’s 
discretion if there is suspicion of malignancy. In the event of 
unclear diagnosis, additional supportive assessments (e.g., whole 
genome sequencing or whole exome sequencing) can be considered 
in individual, specific cases. 
 
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Section of current document 
Changes in New Document 
(Version 13.0 as compared to Version 12.0) 
Rationale 
In addition, clinical work-up to rule out infectious cause or 
autoimmune disease may be considered. If the clinical work-up 
indicates no evidence of myelodysplasia, leukemia, or 
lymphoma, the subject will continue to be monitored as per the 
protocol-defined SOE, or more frequently at discretion of the 
treating physician/Principal Investigator. If the clinical work-up 
indicates a diagnosis of myelodysplasia, leukemia, or lymphoma, 
the Sponsor will convene an urgent safety review meeting. 
Further analyses will be determined by the Sponsor, in 
consultation with the DMC. All efforts should be made to 
confirm the source of malignancy. It should be noted that it may 
not be possible to distinguish the source of malignancy (e.g., 
arising from underlying pathophysiology of the disease, 
transplant-related medications or procedures, or from expansion 
of gene-modified cells due to insertional oncogenesis). 
 
For clinical work-up after identification of persistent 
oligoclonality and confirmed presence of abnormal CBC, bone 
marrow analysis is recommended if not previously performed as 
part of the clinical work-up. 
In addition, clinical work up to rule out infectious cause or 
autoimmune disease may be considered. If the clinical work-up 
indicates no evidence of myelodysplasia, leukemia, or lymphoma, the 
subject will continue to be monitored as per the protocol-defined 
SOE, or more frequently at discretion of the treating 
physician/Principal Investigator. If the clinical work-up indicates a 
diagnosis of myelodysplasia, leukemia, or lymphoma, the Sponsor 
will convene an urgent safety review meeting. Further analyses will 
be determined by the Sponsor, in consultation with the DMC. All 
efforts should be made to confirm the source of malignancy. It should 
be noted that it may not be possible to distinguish the source of 
malignancy (e.g., arising from underlying pathophysiology of the 
disease, transplant-related medications or procedures, or from 
expansion of gene-modified cells due to insertional oncogenesis). 
 
For clinical work up after identification of persistent oligoclonality 
and confirmed presence of abnormal CBC, bone marrow analysis is 
recommended if not previously performed as part of the clinical 
work up. 
 
 
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DESCRIPTION OF EACH NON-SUBSTANTIAL CHANGE 
• 
Added clarifying footnotes to the schedule of events (Table 4) to specify that CBC with 
differential and VCN are to be carried out whenever ISA is performed. 
• 
Section 6.2.28.1, Assessment of Oligoclonality by Integration Site Analysis, was 
redesignated as Section 6.2.28. Section 6.2.28.2, Clinical Work-up for Potential 
Malignancy, was redesignated as Section 6.2.29 and renamed for clarity to align to new 
content (Assessments for Risk of Hematologic Malignancy and Clinical Work-up). 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Protocol Title: 
A Phase 1/2 Study Evaluating Gene Therapy by Transplantation of 
Autologous CD34+ Stem Cells Transduced Ex Vivo with the LentiGlobin 
BB305 Lentiviral Vector in Subjects with Severe Sickle Cell Disease 
Protocol Number: 
HGB-206 
Objectives: 
Primary objective 
Evaluate the efficacy of treatment with bb1111 (lovotibeglogene autotemcel, 
also known as LentiGlobin BB305 Drug Product for Sickle Cell Disease) in 
subjects with severe sickle cell disease (SCD). 
Secondary objective 
Evaluate the safety of treatment with bb1111 in subjects with severe SCD. 
Study Design: 
This is a non-randomized, open label, multi-site, single dose, Phase 1/2 
study in approximately 50 adults and adolescents with severe SCD. The 
study will evaluate hematopoietic stem cell (HSC) transplantation (HSCT) 
using bb1111 (lovotibeglogene autotemcel, also known as LentiGlobin 
BB305 Drug Product for SCD), an autologous CD34+ cell-enriched 
population from patients with sickle cell disease that contains hematopoietic 
stem cells transduced with BB305 lentiviral vector encoding the 
βA-T87Q-globin gene, suspended in cryopreservation solution.  
Treatment is divided into 4 stages, as follows. 
Stage 1- Screening and eligibility assessment 
Subjects will be screened and undergo clinical, imaging, and laboratory 
assessments for eligibility determination.  
Stage 2 - Stem cell harvest, drug product manufacture and disposition 
If subjects are taking hydroxyurea (HU), it must be discontinued at least 
30 days prior to stem cell harvest. It may be restarted between completion of 
the stem cell harvest(s) and admission to the hospital for myeloablation but 
should be stopped again at least 2 days before initiating myeloablation.  
For at least 60 days prior to stem cell harvest and continuing through until 
the start of conditioning, subjects will undergo a transfusion regimen 
(exchange or simple, as available or needed) to reach a target hemoglobin 
(Hb) of 10 g/dL prior to mobilization (and 8 to 10 g/dL prior to 
conditioning; not to exceed 12 g/dL prior to either mobilization or 
conditioning) and a pre-transfusion target hemoglobin S (HbS) proportion in 
the blood of < 30% to reduce the risk of SCD-related complications. The last 
exchange transfusion must occur within 4 days of start of mobilization, and 
the HbS proportion in the blood must be < 20% after the last exchange 
transfusion. If a subject experiences an SCD-related crisis within 1 month of 
the start of mobilization, the transfusion regimen will be adjusted, and 
mobilization will be postponed until the subject is crisis-free for a period of 
1 month. In case of iron overload, subjects should be adequately chelated; 
however, iron chelation must be discontinued at least 7 days prior to stem 
cell harvest. It may be restarted between completion of the stem cell 
harvest(s) and admission to the hospital for myeloablation but should be 
stopped again at least 7 days before initiating myeloablation. 
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Subjects who are not documented to have met these parameters or who have 
experienced any significant new sickle-related complications within 1 month 
of the start of mobilization will require additional approval from the Medical 
Monitor before undergoing mobilization/apheresis. 
Subjects will undergo stem cell harvest via mobilization with plerixafor 
(0.24 mg/kg) and subsequent apheresis to collect HSCs for both drug 
product manufacture and cryopreservation of back-up cells for rescue. 
Apheresis should begin approximately 4-6 hours after plerixafor 
administration. If more than 1 apheresis day is required, platelet counts must 
be confirmed to be ≥ 75 × 109/L within 24 hours of subsequent apheresis 
sessions, prior to administration of plerixafor on that day. If platelet counts 
do not meet these criteria, mobilization and apheresis should be deferred 
until platelet counts recover to ≥ 75 × 109/L. At least 1.5 × 106 CD34+ 
cells/kg will be cryopreserved for rescue. Following transduction of isolated 
CD34+ HSCs with BB305 lentiviral vector, the bb1111 cell dose will be 
≥ 3.0 × 106 CD34+ cells/kg for each subject.  
Subjects for whom adequate HSCs are collected to achieve the minimum 
cell dose but not for rescue, and who do not tolerate plerixafor or do not 
effectively mobilize with plerixafor may be offered the option of bone 
marrow harvest for collection of back-up cells only, provided that bb1111 
manufactured from mobilized cells has met criteria for dispositioning for 
clinical use. 1.0 × 108 total nucleated cells (TNC)/kg derived from bone 
marrow will be collected for rescue.  
Subjects were divided into 3 groups, depending on how stem cells were 
harvested, and their use for either rescue (back-up cells) or drug product 
manufacture, as shown in the following schematic: 
 
In Groups A and B1 (no further enrollment), both drug product and back-up 
cells were derived from bone marrow.  
In Group B2 (no further enrollment), plerixafor mobilization and apheresis 
were used for collection of back-up cells and exploratory manufacturing 
development, and it was planned for subjects in Group B2 to then undergo 
bone marrow harvest for drug product manufacture.  
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Subjects in Group B2 who tolerated and successfully mobilized with 
plerixafor for back-up cells, and who had not yet had drug product 
manufactured with bone marrow harvest, were given the option to delay 
collection of cells for drug product manufacture until Group C opened, and 
they could undergo drug product manufacture from cells obtained by a 
subsequent cycle of plerixafor mobilization.  
Group C was opened upon (1) confirmation of the safety and tolerability of 
plerixafor mobilization in Group B2, and (2) regulatory authority approval 
of the drug product manufacturing process with plerixafor-mobilized HSCs.  
In Group C, it is planned that all subjects will undergo mobilization with 
plerixafor and subsequent apheresis to collect HSCs both for drug product 
manufacture and for cryopreservation of back-up cells for rescue. Subjects 
who do not tolerate plerixafor or do not effectively mobilize with plerixafor 
may be offered the option of bone marrow harvest for collection of back-up 
cells only, provided that drug product manufactured from mobilized cells 
has met criteria for dispositioning for clinical use. 
As of Version 8.0 of this protocol, Group C will include adolescent subjects 
≥ 12 and < 18 years of age in addition to subjects ≥ 18 and ≤ 50 years of age. 
It should also be noted that while all Group A subjects and some Group B 
subjects received drug product manufactured using “Process 1”, all current 
and future Group C subjects will receive drug product manufactured using 
an optimized process termed “Process 2”. Treatment with drug product 
manufactured using Process 2 (versus Process 1) has resulted in increased 
drug product vector copy number (VCN), peripheral blood VCN, and 
hemoglobin A containing βA-T87Q-globin (HbAT87Q) levels across multiple 
bluebird bio-sponsored clinical studies. 
bb1111 must be release tested and dispositioned for clinical use and stored at 
the study site before the subject can begin myeloablative conditioning with 
busulfan. 
Stage 3 –Myeloablative conditioning and infusion of bb1111 
The subject’s suitability for transplant will be reconfirmed with clinical 
laboratory tests (complete blood count [CBC], serum chemistry, liver 
function tests, and pregnancy test), physical examination, performance 
status, cytogenetics, and other tests based on institutional requirements. The 
results of these tests will be reviewed, and availability of the drug product on 
site and the availability of back-up cells will be confirmed before the site can 
proceed with conditioning.  
As described above, a transfusion regimen (exchange or simple, as available 
and needed) will be continued until the start of conditioning to reach a target 
Hb (prior to conditioning) of 8 to 10 g/dL (not to exceed 12 g/dL) and a 
pre-transfusion target HbS proportion in the blood of < 30% to reduce the 
risk of SCD-related complications; last exchange transfusion must occur 
within 1 week of start of the conditioning regimen. In the event of 
pulmonary complications (e.g., acute chest syndrome (ACS), pneumonia) 
between Screening and the start of conditioning, a pulmonary function test 
(PFT) must be performed. After resolution of pulmonary complications, and 
prior to conditioning, PFT results must meet the following requirements: 
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o Baseline oxygen saturation ≥ 90% without supplemental oxygen 
(excluding periods of SCD crisis, severe anemia or infection).  
o Baseline carbon monoxide diffusing capacity (DLCO) 
≥ 50% (corrected for Hb) in the absence of infection. If DLCO 
cannot be assessed due to age or cognition-related restrictions, 
there must be a normal respiratory exam, chest radiograph without 
pulmonary infiltrates, and oxygen saturation by pulse oximetry 
≥ 90% on room air.  
Busulfan (Busulfex® preferred, if available) will be administered 
intravenously (IV) at a starting dose of 3.2 mg/kg/day or 0.8 mg/kg every 
6 hours (q6h) for 4 consecutive days (for subjects weighing < 35 kg, a q6h 
dose of 0.8 mg/kg is preferred; for subjects weighing ≥ 35 kg, either once 
daily (qd) or q6h dosing can be used, at the discretion of the Investigator). 
The dose of busulfan will be adjusted based upon busulfan pharmacokinetics 
(PK) in order to maintain appropriate levels for myeloablation (area under 
the curve [AUC] goal of 1250 [range 1100 to 1350] µM*min for a q6h 
dosing regimen, or 5000 [range 4400 to 5400] µM*min for a qd dosing 
regimen). The dosage should be calculated on the basis of the lower of the 
ideal versus actual body weight. The dose may be adjusted appropriately 
based upon actual plasma busulfan levels observed. Clinical sites must be 
able to measure first and third day busulfan PK. Based on busulfan PK 
results for day 1 and day 3 of busulfan dosing, busulfan dose adjustments 
should be made for subsequent dosing. If feasible, daily busulfan PK 
measurement is recommended. 
Anti-seizure prophylaxis must begin at least 12 hours before initiating 
busulfan and must continue for at least 24 hours after completion of the 
4 days of busulfan administration. All drugs other than phenytoin are 
allowed for anti-seizure prophylaxis. 
After completion of the 4-day course of busulfan, there must be a minimum 
of 48 hours before bb1111. Busulfan levels will be measured 48 and 
72 hours after final dose of busulfan for retrospective confirmation of 
adequate wash-out. 
On Day 1, bb1111 will be administered after thawing via IV infusion. 
Stage 4 – Follow-up for approximately 24 months after drug product 
infusion 
Subjects will be followed in the hospital for adverse events (AEs), and 
laboratory parameters will be followed to monitor engraftment. The subject 
may be discharged after neutrophil engraftment occurs (≥ 0.5 × 109 absolute 
neutrophil count (ANC)/L for 3 consecutive measurements on different days 
after the initial post-infusion nadir) and the subject is considered medically 
stable per institutional guidelines. 
From drug product infusion through hospital discharge after neutrophil 
engraftment, subjects are to be medically managed with the goal of 
maintaining the following hematologic targets: 
• 
Hb 8 to 10 g/dL (not to exceed 12 g/dL), HbS < 30% and  
• 
platelet count ≥ 50 × 109/L  
After discharge, management of transfusions for subjects with SCD will 
follow the institutional standard of care at the clinical site to achieve total Hb 
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and HbS proportions appropriate for each subject's clinical status. To 
achieve this, the transfusion program may be progressively reduced as the 
contribution of Hb containing βA-T87Q-globin rises. Continued transfusion 
needs > 6 months post-treatment or any alternative plans should be discussed 
with the Medical Monitor.  
Subjects will be followed in this protocol through the Month 24 Visit. 
Thereafter, subjects are expected to enroll in a separate long-term follow-up 
protocol that will assess safety and efficacy beyond Month 24 for a total of 
15 years after drug product infusion. 
Number of Subjects 
Planned: 
A total of approximately 50 subjects will be treated with bb1111 in 
Study HGB-206. 
Seven subjects have already been treated in Group A, and 2 subjects have 
been treated in Group B. A total of approximately 41 subjects in Group C 
(including subjects consented under Versions 7.0, 8.0, and 9.0 of this 
protocol) will be treated with bb1111, approximately 35 of which must meet 
the severe vaso-occlusive event (VOE) criteria as set forth in Inclusion 
Criterion #3.1.  
Subjects who withdraw prior to drug product infusion may be replaced. 
Inclusion Criteria: 
Subjects must: 
1. Be ≥ 12 and ≤ 50 years of age at time of consent.  
2. Have a diagnosis of SCD, with either βS/βS or βS/β0 or βS/β+ genotype.  
3. Previous Inclusion Criterion #3 is no longer applicable and has been 
replaced with Criterion #3.1. 
3.1. In the setting of appropriate supportive care measures (e.g., pain 
management plan) have experienced at least 4 severe VOEs in the 
24 months prior to informed consent as defined below. 
For the purposes of this study, a severe VOE is defined as an event 
with no medically determined cause other than a vaso-occlusion, 
requiring a ≥ 24-hour hospital or emergency room (ER) observation 
unit visit or at least 2 visits to a day unit or ER over 72 hours with 
both visits requiring intravenous treatment. Exception: priapism 
does not require hospital admission but does require a medical 
facility visit; 4 priapism episodes that require a visit to a medical 
facility (without inpatient admission) are sufficient to meet criterion.  
Severe VOEs include: 
a. an episode of acute pain with no medically determined cause 
other than a VOE  
b. Acute chest syndrome (ACS), defined by an acute event with 
pneumonia-like symptoms (e.g., chest pain, fever [> 38.5°C], 
tachypnea, wheezing or cough, or findings upon lung 
auscultation) and the presence of a new pulmonary infiltrate 
consistent with ACS and requiring oxygen treatment and/or 
blood transfusion.  
c. Acute hepatic sequestration, defined by a sudden increase in 
liver size associated with pain in the right upper quadrant, 
abnormal results of liver-function test not due to biliary tract 
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disease, and reduction in Hb concentration by at least 2 g/dL 
below the baseline value 
d. Acute splenic sequestration, defined as sudden enlargement of 
the spleen and reduction in Hb concentration by at least 2 g/dL 
below the baseline value. 
e. Acute priapism: defined as a sustained, unwanted painful 
erection lasting more than 2 hours and requiring care at a 
medical facility (with or without hospitalization) 
4. Previous Inclusion Criterion #4 is no longer applicable as of Protocol 
Amendment 8.0. 
5. Have a Karnofsky performance status of ≥ 60 (≥ 16 years of age) or a 
Lansky performance status of ≥ 60 (< 16 years of age).  
6. Previous Inclusion Criterion #6 is no longer applicable as of Protocol 
Amendment 8.0. 
7. Have either experienced HU failure at any point in the past (defined 
as > 1 VOE or ≥ 1 ACS after HU has been prescribed for at least 
6 months) or must have intolerance to HU (intolerance is defined as 
the patient being unable to continue to take HU per PI judgment). 
8. Be treated and followed for at least the past 24 months prior to 
Informed Consent in medical center(s) that maintained detailed 
records on sickle cell disease history, including incidence of VOEs 
and severe VOEs, aplastic crises, infectious complications, 
SCD-related chronic complications, SCD-related surgery, 
neurovascular evaluation (including MRI/A and TCD), pRBC 
transfusions (including indications, volume and units of pRBCs, 
associated pre-transfusion HbS and total Hb values and post-
transfusion adverse events [including allo-immunization]), 
SCD-specific treatment history (e.g., HU, L-glutamine, iron overload, 
and chelation history), and use of pain medication. 
Exclusion Criteria: 
Subjects are excluded if they meet any of the following criteria: 
1. Positive for presence of human immunodeficiency virus type 1 or 2 
(HIV-1 or HIV-2), hepatitis B, hepatitis C, human T-lymphotrophic 
virus-1 (HTLV-1) or -2 (HTLV-2), active syphilis. Note that 
subjects who have been vaccinated against hepatitis B [hepatitis B 
surface antibody-positive] who are negative for other markers of 
prior hepatitis B infection [e.g., negative for hepatitis B core 
antibody] are eligible. Subjects with past exposure to HBV [HBc Ab 
positive and/or HBe Ab positive] are also eligible for the study 
provided they are negative for HBV DNA. Subjects who are positive 
for anti-hepatitis C antibody are eligible as long as they have an 
undetectable hepatitis C viral load. Where clinically and/or 
regionally indicated, other tests may be performed, in which case 
relevant positive results suggesting active infection would exclude 
the subject from participating, depending on regional guidelines: for 
example, malaria, tuberculosis, active toxoplasmosis, Trypanosoma 
cruzi, or West Nile Virus. 
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2. Clinically significant, active bacterial, viral, fungal, or parasitic 
infection, as determined by the Investigator, e.g., active relapsing 
malaria. 
3. Inadequate bone marrow function, as defined by an absolute 
neutrophil count of < 1 × 109/L (< 0.5 × 109/L for subjects on 
hydroxyurea treatment) or a platelet count < 100 × 109/L 
4. Previous Exclusion Criterion #4 is no longer applicable as of 
Protocol Amendment 8.0. 
4.1 Severe cerebral vasculopathy, defined by any history of: overt 
ischemic or hemorrhagic stroke, abnormal transcranial Doppler 
(> 200 cm/sec) requiring chronic transfusion, occlusion or stenosis 
in the circle of Willis, or presence of Moyamoya disease. Subjects 
with radiologic evidence of silent infarction in the absence of any of 
the above criteria would still be eligible.  
5. Previous Exclusion Criterion #5 is no longer applicable as of 
Protocol Amendment 8.0. 
6. Previous Exclusion Criterion #6 is no longer applicable as of 
Protocol Amendment 8.0. 
7. Previous Exclusion Criterion #7 is no longer applicable as of 
Protocol Amendment 8.0. 
8. Baseline oxygen saturation < 90% without supplemental oxygen 
(excluding periods of SCD crisis, severe anemia or infection). 
9. Baseline carbon monoxide diffusing capacity (DLCO) < 50% 
(corrected for Hb) in the absence of infection. If DLco cannot be 
assessed due to age or cognition-related restrictions, there must be a 
normal respiratory exam, chest radiograph without pulmonary 
infiltrates, and oxygen saturation by pulse oximetry ≥ 90% on room 
air.  
10. Baseline left ventricular ejection fraction (LVEF) < 45% measured 
by cardiac echography. 
11. Clinically significant pulmonary hypertension at baseline, as defined 
by the requirement for ongoing pharmacologic treatment or the 
consistent or intermittent use of supplemental home oxygen. 
12. Baseline estimated glomerular filtration rate (eGFR) 
< 70 mL/min/1.73 m2, as determined using the Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) equation (see 
http://www.kidney.org/professionals/kdoqi/gfr_calculator.cfm). 
13. Advanced liver disease, defined as: 
a. Persistent aspartate transaminase, alanine transaminase, or 
direct bilirubin value > 3× the upper limit of normal (ULN), 
or 
b. Baseline prothrombin time or partial thromboplastin time 
> 1.5× ULN, suspected of arising from liver disease, or 
c. Magnetic Resonance Imaging (MRI) of the liver 
demonstrating clear evidence of cirrhosis, or 
d. MRI findings suggestive of active hepatitis, significant 
fibrosis, inconclusive evidence of cirrhosis, or liver iron 
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concentration ≥ 15 mg/g require follow-up liver biopsy in 
subjects ≥ 18 years of age. In subjects < 18 years of age, 
these MRI findings are exclusionary, unless in the opinion 
of the Investigator, a liver biopsy could provide additional 
data to confirm eligibility and would be safe to perform. If a 
liver biopsy is performed based on MRI findings, any 
evidence of cirrhosis, bridging fibrosis, or significant active 
hepatitis will be exclusionary.  
14. For subjects who have history of iron overload or serum ferritin 
levels > 1000 ng/mL, a cardiac MRI is required. Cardiac 
T2* < 10 ms results in exclusion. 
15. Contraindication to anesthesia. 
16. Any contraindications to the use of plerixafor during the 
mobilization of hematopoietic stem cells and any contraindications 
to the use of busulfan and any other medicinal products required 
during the myeloablative conditioning, including hypersensitivity to 
the active substances or to any of the excipients. 
17. Any prior or current malignancy or immunodeficiency disorder, 
except previously treated, non-life threatening, cured tumors such as 
squamous cell carcinoma of the skin.  
18. Prior receipt of an allogeneic transplant.  
19. Immediate family member with a known or suspected Familial 
Cancer Syndrome (including but not limited to hereditary breast and 
ovarian cancer syndrome, hereditary non-polyposis colorectal cancer 
syndrome, and familial adenomatous polyposis). 
20. Diagnosis of significant psychiatric disorder of the subject that, in 
the Investigator’s judgment, could seriously impede the ability to 
participate in the study. 
21. Pregnancy, or breastfeeding in a postpartum female, or absence of 
adequate contraception for fertile subjects. Females of childbearing 
potential must agree to use a medically acceptable method of birth 
control such as oral contraceptive, intrauterine device, barrier and 
spermicide, or contraceptive implant/injection from time of consent 
through at least 6 months after drug product infusion. Male subjects 
must agree to use effective contraception (including condoms) from 
Conditioning through at least 6 months after drug product infusion.   
22. Participation in another clinical study with an investigational drug 
within 30 days of Screening. 
23. Previous Exclusion Criterion #23 is no longer applicable as of 
Protocol Amendment 8.0. 
24. Prior receipt of gene therapy. 
25. Previous Exclusion Criterion #25 is no longer applicable as of 
Protocol Amendment 9.0.  
26. An assessment by the Investigator that the subject or 
parents/caregivers (as required) will not be able to comply with the 
study procedures outlined in the study protocol. 
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27. Patients needing therapeutic anticoagulation treatment during the 
period of conditioning through platelet engraftment (patients on 
prophylactic doses of anticoagulants not excluded per this criteria). 
28. Unable to receive RBC transfusion.   
29. Any other condition that would render the subject ineligible for 
HSCT, as determined by the attending transplant physician. 
30. Applicable to subjects < 18 years of age only: Availability of a 
willing, matched HLA-identical sibling hematopoietic cell donor. 
Concomitant 
Medications/Therapies: 
Subjects will be permitted to take their usual medications during the study, 
with the following exceptions: erythropoietin, which should be discontinued 
60 days prior to stem cell collection; HU, which should be discontinued 
30 days prior to HSC mobilizations and collections; and iron chelation 
therapy, which should be discontinued at least 7 days prior to conditioning. 
Hydroxyurea may be restarted between completion of the stem cell 
harvest(s) and admission to the hospital for myeloablation but should be 
stopped again at least 2 days before initiating myeloablation. In case of iron 
overload, subjects should be adequately chelated; however, iron chelation 
must be discontinued at least 7 days prior to stem cell harvest. Phlebotomy 
or iron chelation therapy may be restarted no sooner than 3 months after 
transplant. Subjects should not use medications with anti-retroviral activity 
(such as those used for HIV prophylaxis) from within 1 month of initiating 
mobilization until after completion of stem cell collection for drug product 
manufacture. Blood products will be filtered and irradiated, as needed. 
Management of post-transplant transfusions for subjects with SCD will 
follow the institutional standard of care at the clinical site to achieve total Hb 
and HbS proportions appropriate for each subject's clinical status. To 
achieve this, the transfusion program may be progressively reduced as the 
contribution of hemoglobin containing βA-T87Q-globin rises. Continued 
transfusion needs > 6 months post-treatment or any alternative plans should 
be discussed with the Medical Monitor. Following HSC transplant, 
medications other than blood transfusions to treat sickle cell disease or 
anemia (e.g., HU, erythropoietin, L-glutamine, crizanlizumab, voxelotor) are 
not permitted without prior discussion with and explicit approval of the 
Sponsor’s Medical Monitor. 
Duration of Subject 
Participation: 
Time between Screening and drug product infusion will be variable and is 
estimated generally to be between 3 to 5 months (e.g., up to 3 months 
between Screening and Mobilization, followed by approximately 2 months 
before drug product infusion). Thereafter the subject is planned to remain on 
study for approximately 24 months. Eligible subjects are expected to enroll 
in a separate long-term follow-up study until approximately 15 years 
post-drug product infusion. 
Test Product, Dose and 
Mode of 
Administration: 
bb1111 is an autologous CD34+ cell-enriched population from patients with 
sickle cell disease that contains hematopoietic stem cells transduced with 
BB305 lentiviral vector encoding the βA-T87Q-globin gene, suspended in 
cryopreservation solution. All subjects are to receive 
≥ 3.0 × 106 CD34+ cells/kg of bb1111 on Day 1 via intravenous infusion. 
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Efficacy Endpoints: 
Primary Efficacy Endpoint: 
VOE-CR, defined as complete resolution of VOEs, between 6 months and 
18 months after drug product infusion 
Key Secondary Efficacy Endpoints:  
• 
sVOE-CR, defined as complete resolution of severe VOEs, between 
6 months and 18 months after drug product infusion  
• 
Globin Response, defined as meeting the following criteria for a 
continuous period of at least 6 months after drug product 
infusion: 
a. Weighted average HbAT87Q percentage of non-transfused total Hb1 
≥ 30%  
AND  
b. Weighted average non-transfused total Hb1 increase of ≥ 3 g/dL 
compared to baseline total Hb2 OR weighted average non-transfused 
total Hb1 ≥ 10 g/dL 
Additional Secondary Efficacy Endpoints: 
Clinical and Disease Evaluation Endpoints: 
• 
Change in the annualized number of VOEs in the 24 months after 
drug product infusion compared to the 24 months prior to Informed 
Consent 
• 
Change in the annualized number of severe VOEs in the 24 months 
after drug product infusion compared to the 24 months prior to 
Informed Consent 
• 
VOE-CR24, defined as complete resolution of VOEs, between 
6 months and 24 months after drug product infusion 
• 
sVOE-CR24, defined as complete resolution of severe VOEs 
between 6 months and 24 months after drug product infusion 
• 
sVOE-75, defined as at least a 75% reduction in annualized severe 
VOEs in the 24 months after drug product infusion compared to the 
24 months prior to Informed Consent 
Characterization of Globin Response: 
• 
Proportion of subjects who meet the definition of Globin Response at 
Month 24 
• 
Duration of Globin Response 
Hematologic Endpoints: 
• 
Weighted average for the following at Month 6, 12, 18, and 24: 
- non-transfused total Hb1 
- HbS percentage of non-transfused total Hb1  
- HbS percentage of non-transfused total Hb1 ≤ 70%, ≤ 60%, ≤ 50% 
- HbAT87Q percentage of non-transfused total Hb1 
- non-HbS3 percentage of non-transfused total Hb1 
• 
Assessment of the following over time: 
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- non-transfused total Hb1  
- HbS percentage of non-transfused total Hb1 
- HbAT87Q percentage of non-transfused total Hb1 
- non-HbS3 percentage of non-transfused total Hb1 
• 
Change from baseline in hemolysis markers, including absolute 
reticulocyte count, % reticulocytes/erythrocytes, total bilirubin, 
haptoglobin, and lactate dehydrogenase 
• 
Change from baseline in markers of iron stores including ferritin, 
liver iron content, and if assessed at baseline, cardiac iron content 
• 
Change from baseline in annualized frequency and volume of packed 
red blood cell (pRBC) transfusions between 6 months and 24 months 
after drug product infusion  
• 
Change from baseline in markers of stress erythropoiesis, including 
erythropoietin and serum transferrin receptor 
SCD Burden and Chronic Complications Assessments:  
• 
Change from baseline in renal function as measured by eGFR  
• 
Change from baseline in cardiac-pulmonary function via 
echocardiogram (tricuspid regurgitant jet velocity [TRJV], LVEF) 
and pulmonary function tests 
• 
Change from baseline in meters walked during 6-minute walk test  
Hospitalizations and Quality of Life: 
• 
Change from baseline in annualized VOE-related hospital admissions 
and days  
• 
Change from baseline in patient-reported quality of life, as measured 
by Patient Reported Outcomes Measurement Information 
System (PROMIS) 
Exploratory Efficacy Endpoints: 
• 
Change from baseline in cerebral vasculature and prior brain 
parenchymal injury evaluation at Month 12 and Month 24 (as 
measured by cerebral magnetic resonance angiography 
[MRA]/magnetic resonance imaging [MRI] in all subjects, and 
transcranial Doppler [TCD] for subjects ≤ 16 years old at Informed 
Consent) 
• 
Change from baseline in bone mineral density (BMD) evaluation 
using dual x-ray absorptiometry (DXA) at Month 24 
• 
Change from baseline in brain natriuretic peptide 
• 
Change from baseline in Patient reported Outcome (PRO) measures 
including:  
- Overall health: EuroQol-5D (EQ-5D-3L or EQ-5D-Y) 
- Work productivity, as measured by the Work Productivity and 
Activity Impairment Questionnaire-General Health (WPAI-GH or 
Caregiver WPAI-GH) 
- Cognitive function as measured by PROMIS Short Form 6a  
• 
Evaluation of chronic pain using AAPT 
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•
Change from baseline in pain medication use
•
Exploratory assays to assess change from baseline in sickle cell
characteristics and bone marrow pathophysiology
Pharmacodynamic 
Endpoints: 
•
Vector copy number (VCN) in peripheral blood over time
•
Expression of βA-T87Q-globin, βS-globin, and other β-like-globins in
peripheral blood over time
Additional methods may be used to evaluate pharmacodynamics. 
Safety Endpoints: 
Safety will be evaluated by the following: 
•
Safety and tolerability of plerixafor for mobilization
•
Success and kinetics of HSC engraftment
•
Transplant-related mortality through 100 days post-drug product
infusion and through 365 days post-drug product infusion
•
Detection of vector-derived replication competent lentivirus (RCL) in
any subject
•
The number of subjects with insertional oncogenesis
(myelodysplasia, leukemia, lymphoma, etc.)
•
The number of subjects with persistent oligoclonality
•
Frequency and severity of AEs/SAEs
•
Laboratory parameters over time, including the following
immunology tests: Screening for irregular antibodies, lymphocyte
subpopulation evaluation (CD3, CD4, CD8, CD19, CD16/CD56)
•
Incidence of acute and/or chronic graft-versus-host disease (GVHD)
•
Other safety labs over time: chemistries, LFTs (AST, ALT, ALP,
GGT, bilirubin [total and direct]), hematology, coagulation
parameters
•
Hormonal testing over time: estradiol (females only); total
testosterone (males only) TSH, free T3, free T4, cortisol, ACTH,
FSH, LH (all subjects)
•
Change from baseline in methemoglobin concentration at Month 12
and Month 24
•
Number of subjects with presence of a chromosomal abnormality or
genetic mutation associated with hematologic malignancies over time
Statistical Methods: 
Sample Size Estimation 
The sample sizes for Group A and B were not determined by formal 
statistical methods. Approximately 41 subjects will be enrolled in Group C, 
approximately 35 of whom must meet the severe VOE criteria as set forth in 
Inclusion Criterion #3.1. 
Assuming 80% of subjects in Group C who have at least 4 VOEs in the 
24 months prior to Informed Consent will meet the primary efficacy 
endpoint VOE-CR, 35 subjects will provide more than 99% power to reject 
the null hypothesis of 40% at 1-sided alpha of 0.025, using the Exact Test 
per EAST® (Version 6). The success criterion is 60% (21 out of 35) of 
subjects meeting the primary efficacy endpoint, if exactly 35 subjects with at 
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least 4 VOEs in the 24 months prior to Informed Consent are enrolled and 
received drug product in Group C.  
Power calculations were also performed for the key secondary efficacy 
endpoints of sVOE-CR and Globin Response. Assuming 85% of subjects in 
Group C with at least 4 VOEs in the 24 months prior to Informed Consent 
will meet sVOE-CR, 35 subjects will provide more than 99% power to reject 
the null hypothesis of 50% at 1-sided alpha of 0.025, using the Exact Test 
per EAST® (Version 6); the success criterion is 69% (24 out of 35) of 
subjects meeting sVOE-CR, if exactly 35 subjects with at least 4 VOEs in 
the 24 months prior to Informed Consent are enrolled and receive drug 
product in Group C. Assuming 70% of subjects will meet Globin Response, 
41 subjects will provide approximately 96% power to reject the null 
hypothesis of 40% at 1-sided alpha of 0.025, using the Exact Test per 
EAST® (Version 6); the success criterion is 59% (24 out of 41) of subjects 
meeting Globin Response, if exactly 41 subjects are enrolled and received 
drug product in Group C. 
Populations for analysis 
The following subject populations will be evaluated and used for 
presentation and analysis of the data: 
• 
Intent-to-Treat (ITT) Population: All subjects who initiate any study 
procedures, beginning with stem cell collection procedures 
(mobilization/apheresis or bone marrow harvest).  
• 
Transplant Population (TP): All subjects who receive drug product.  
• 
Transplant Population for VOE (TPVOE): Subset of TP subjects 
with at least 4 VOEs in the 24 months prior to Informed Consent.  
• 
Successful Engraftment Population (SEP): A subset of TP subjects 
who, following busulfan myeloablation and drug product infusion, 
successfully engraft with drug product, defined as 3 consecutive 
absolute neutrophil count (ANC) ≥ 0.5 × 109/L laboratory values 
obtained on different days after the initial post-infusion nadir by 
Day 43. 
The ITT is the primary population for the analysis of safety, the TPVOE is 
the primary population for VOE-related endpoints including the primary 
efficacy endpoint of VOE-CR and the key secondary endpoint of sVOE-CR, 
the TP is the primary population for the key secondary efficacy endpoint of 
Globin response, and the other secondary efficacy endpoints and 
pharmacodynamic endpoints. The SEP will be used to provide supportive 
data for subjects who engraft. 
Analysis of the primary efficacy endpoint in Group C 
The primary endpoint of VOE-CR will be tested against the null hypothesis 
of 40% using a 1-sided exact binomial test. The number and percentage of 
subjects reaching the primary endpoint will be presented. The associated 
2-sided exact 95% confidence interval will be provided. The primary 
endpoint will be analyzed in the TPVOE population in Group C subjects. 
Analysis of the key secondary efficacy endpoints in Group C 
The key secondary endpoint of sVOE-CR will be tested against the null 
hypothesis of 50% using a 1-sided exact binomial test. The number and 
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percentage of subjects reaching the endpoint will be presented. The 
associated 2-sided exact 95% confidence interval will be provided. The 
endpoint will be analyzed in the TPVOE population in Group C subjects. 
The key secondary endpoint of Globin Response will be tested against the 
null hypothesis of 40% using a 1-sided exact binomial test. The number and 
percentage of subjects reaching the endpoint will be presented. The 
associated 2-sided exact 95% confidence interval will be provided. The 
endpoint will be analyzed in the TP in Group C subjects. 
The planned statistical methodology details will be presented in the 
Statistical Analysis Plan (SAP).  
1 Non-transfused total Hb is the total g/dL of HbS + HbF + HbA2 + HbAT87Q. For subjects with a β+ 
allele, HbA will also be included in the calculation of “non-transfused total Hb” only for samples taken 
≥ 60 days after last pRBC transfusion.  
2 Baseline total Hb is defined as follows:  
The average of the 2 most recent Hb assessments made at or prior to the Screening evaluation, which 
meet the following criteria:  
(i) Assessments must be separated by at least 1 month from each other.  
(ii) Assessments must have been drawn no earlier than 24 months prior to Informed Consent and 
may include the Hb result from Screening.  
(iii) The subject will not have received a pRBC transfusion within 3 months prior to each Hb 
assessment. 
For subjects who are on chronic, recurrent transfusions, and do not have 2 Hb assessments which meet 
criteria (i), (ii), and (iii), the following criteria can be used: 2 Hb values which meet criteria (i) and (iii) 
that are found within 24 months prior to the start of a regular transfusion program. 
3 Non-HbS is the total g/dL of HbF + HbA2 + HbAT87Q. For subjects with a β+ allele, HbA will also be 
included in the calculation of “non-HbS” only for samples taken ≥ 60 days after last pRBC transfusion. 
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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
6MWD 
the distance that a patient can quickly walk on a flat, hard 
surface in a period of 6 minutes 
6MWT 
six-minute walk test 
ACS 
acute chest syndrome 
AE 
adverse event 
allo-HSCT 
allogeneic hematopoietic stem cell transplantation 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMD 
bone mineral density 
BNP 
brain natriuretic peptide 
CBC 
complete blood count 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CMV 
cytomegalovirus 
CRE 
conditioning-related events  
CRF 
case report form 
CRP 
C-reactive protein 
DLCO 
carbon monoxide diffusing capacity 
DLT 
dose limiting toxicities 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DXA 
dual x-ray absorptiometry 
EBV 
Epstein-Barr virus  
EC 
Ethics Committee 
EFS 
event-free survival 
EU 
European Union 
eGFR 
estimated glomerular filtration rate 
FDA 
Food and Drug Administration 
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Abbreviation 
Definition 
FEV1 
forced expiratory volume in 1 second 
FISH 
fluorescence in situ hybridization 
FSH 
follicle stimulating hormone 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony stimulating factor 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transferase 
GVHD 
graft-versus-host-disease 
Hb 
hemoglobin 
HbA 
hemoglobin A, that contains β-globin 
HbA2 
hemoglobin A2, that contains -globin 
HbAT87Q 
HbA, that contains βA-T87Q-globin 
HBcAb 
hepatitis B core antibody 
HbF 
hemoglobin F, that contains γ-globin 
HbS 
hemoglobin S, that contains βS-globin 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HIV-1 
human immunodeficiency virus type 1 
HIV-2 
human immunodeficiency virus type 2 
HLA 
human leukocyte antigen 
HPC-A 
hematopoietic progenitor cells obtained by apheresis 
HPLC 
high-performance liquid chromatography 
HSC 
hematopoietic stem cell 
HSCT 
hematopoietic stem cell transplantation 
HSV 
herpes simplex virus 
HTLV-1 
human T lymphotrophic virus 1 
HTLV-2 
human T lymphotrophic virus 2 
HU 
hydroxyurea 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
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Abbreviation 
Definition 
IEC 
Independent Ethics Committee 
INN 
international nonproprietary name 
IRB 
Institutional Review Board 
IS 
insertion site 
ISA 
integration site analysis 
ITT 
intent-to-treat 
IV 
intravenous 
LCR 
locus control region 
LDH 
lactate dehydrogenase 
LH 
luteinizing hormone 
LVEF 
left ventricular ejection fraction 
LVV 
lentiviral vector 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRA 
magnetic resonance angiography 
MRI 
magnetic resonance imaging 
MSD 
matched-sibling donor 
NGS 
next generation sequencing 
OS 
overall survival 
PBLs 
peripheral blood leukocytes 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PFTs 
pulmonary function tests 
PI 
Principal Investigator 
PK 
pharmacokinetics 
pRBC(s) 
packed red blood cell(s) 
PRO 
Patient-reported Outcome 
PROMIS 
Patient-reported Outcomes Measurement Information System 
PT 
prothrombin time 
PTH 
parathyroid hormone 
q6h 
every 6 hours 
qd 
once daily 
qPCR 
quantitative polymerase chain reaction 
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Abbreviation 
Definition 
RBC 
red blood cell 
RCL 
replication-competent lentivirus 
RNA 
ribonucleic acid 
RV 
respiratory volume 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCD 
sickle cell disease 
SEP 
successful engraftment population 
SOE 
Schedule of Events 
SOM 
Study Operations Manual 
SUSAR 
suspected unexpected serious adverse reaction 
T3 
3,5,3’triiodothyronine 
T4 
thyroxine 
TCD 
transcranial Doppler 
TNC 
total nucleated cells 
TP 
transplant population 
TPVOE 
transplant population for VOE 
TRJV 
tricuspid regurgitant jet velocity 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
VCN 
vector copy number 
VOC 
vaso-occlusive crisis 
VOE 
vaso-occlusive event 
VZV 
varicella zoster virus 
WBC 
white blood cell (count) 
WPAI-GH 
Work Productivity and Activity Impairment Questionnaire – 
General Health 
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TABLE OF CONTENTS 
SUMMARY OF CHANGES ...........................................................................................................2 
DESCRIPTION OF EACH SUBSTANTIAL CHANGE................................................................3 
DESCRIPTION OF EACH NON-SUBSTANTIAL CHANGE....................................................10 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................11 
LIST OF ABBREVIATIONS ........................................................................................................25 
TABLE OF CONTENTS ...............................................................................................................29 
LIST OF TABLES .........................................................................................................................34 
LIST OF FIGURES .......................................................................................................................34 
1. 
INTRODUCTION ......................................................................................................35 
1.1. 
Sickle Cell Disease .....................................................................................................35 
1.2. 
bb1111 ........................................................................................................................38 
1.3. 
Rationale .....................................................................................................................39 
1.3.1. 
Rationale for the Study ...............................................................................................39 
1.3.2. 
Rationale for Selection of Primary and Key Secondary Efficacy Endpoints .............41 
1.3.3. 
Rationale for the β-globin Gene Used ........................................................................41 
1.3.4. 
Rationale for Plerixafor Mobilization .........................................................................42 
1.3.5. 
Rationale for the Dose Selected ..................................................................................43 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................44 
2.1. 
Study Objectives .........................................................................................................44 
2.2. 
Study Endpoints ..........................................................................................................44 
2.2.1. 
Efficacy Endpoints ......................................................................................................44 
2.2.1.1. 
Primary Efficacy Endpoint .........................................................................................44 
2.2.1.2. 
Key Secondary Efficacy Endpoints ............................................................................44 
2.2.1.3. 
Additional Secondary Efficacy Endpoints ..................................................................44 
2.2.1.4. 
Exploratory Efficacy Endpoints .................................................................................46 
2.2.2. 
Pharmacodynamic Endpoints .....................................................................................46 
2.2.3. 
Safety Endpoints .........................................................................................................47 
3. 
INVESTIGATIONAL PLAN .....................................................................................48 
3.1. 
Overall Design and Plan of the Study .........................................................................48 
3.2. 
Data Monitoring Committee .......................................................................................52 
3.3. 
Event Adjudication Committee ..................................................................................52 
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3.4. 
Engraftment Failure ....................................................................................................53 
3.5. 
Treatment Discontinuation and Enrollment Suspension Criteria ...............................53 
3.5.1. 
Stopping Rules for Plerixafor .....................................................................................53 
3.5.2. 
Stopping Rules for Busulfan .......................................................................................53 
3.5.3. 
Stopping Rules for bb1111 .........................................................................................53 
3.5.4. 
Enrollment Suspension Criteria ..................................................................................53 
4. 
STUDY POPULATION .............................................................................................55 
4.1. 
Number of Subjects ....................................................................................................55 
4.2. 
Inclusion Criteria ........................................................................................................55 
4.3. 
Exclusion Criteria .......................................................................................................56 
4.4. 
Subject Screening and Registration ............................................................................58 
4.5. 
Subject Withdrawal from the Study ...........................................................................58 
4.6. 
Screen Failures ............................................................................................................59 
5. 
STUDY TREATMENTS............................................................................................61 
5.1. 
Description of bb1111 ................................................................................................61 
5.2. 
Summary of Treatments to be Performed or Administered ........................................61 
5.2.1. 
Transfusion Regimen Prior to Drug Product Infusion ................................................61 
5.2.2. 
Stem Cell Harvest: Bone Marrow ...............................................................................61 
5.2.3. 
Mobilization and Apheresis Procedure .......................................................................62 
5.2.4. 
Transduction Process, Storage of Drug Product, Packaging and Labeling, 
and Traceability ..........................................................................................................66 
5.2.5. 
Conditioning ...............................................................................................................67 
5.2.5.1. 
Busulfan Dosing .........................................................................................................67 
5.2.5.2. 
Pharmacokinetics for Busulfan Dose Adjustments ....................................................68 
5.2.6. 
Drug Product Infusion Procedures, Dose, and Administration ..................................68 
5.3. 
Method of Assigning Subjects to Treatment ..............................................................69 
5.4. 
Blinding, Packaging and Labeling ..............................................................................70 
5.4.1. 
Blinding and Breaking the Blind ................................................................................70 
5.4.2. 
Packaging and Labeling ..............................................................................................70 
5.5. 
Duration of Subject Participation ...............................................................................70 
5.6. 
Assessment of Treatment Compliance .......................................................................71 
5.7. 
Product Accountability ...............................................................................................71 
5.8. 
Prior and Concomitant Medication .............................................................................71 
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5.8.1. 
Prior Medication .........................................................................................................71 
5.8.2. 
Concomitant Medications and Therapies ...................................................................71 
5.8.3. 
Infection Surveillance and Prophylaxis ......................................................................74 
6. 
STUDY ASSESSMENTS ..........................................................................................76 
6.1. 
Schedule of Events .....................................................................................................76 
6.2. 
Study Measures ...........................................................................................................89 
6.2.1. 
Demographics and Medical History ...........................................................................89 
6.2.2. 
SCD-specific History and Outcome Measures ...........................................................89 
6.2.3. 
Physical Examination and Performance Status ..........................................................89 
6.2.4. 
Vital Signs ..................................................................................................................90 
6.2.5. 
Vaso-occlusive Events (VOEs) ..................................................................................90 
6.2.6. 
Pain Assessment .........................................................................................................91 
6.2.7. 
Clinical Laboratory Tests ...........................................................................................91 
6.2.7.1. 
Clinical Work-up for Unexpected Blood Test Results ...............................................92 
6.2.8. 
Additional Laboratory Tests .......................................................................................92 
6.2.9. 
Hormonal Testing .......................................................................................................93 
6.2.10. 
Sperm / Testicular Tissue or Oocyte Banking ............................................................93 
6.2.11. 
Reconfirmation of Suitability for Transplant .............................................................93 
6.2.12. 
Immunological studies ................................................................................................94 
6.2.13. 
Brain Natriuretic Peptide ............................................................................................94 
6.2.14. 
Busulfan concentrations ..............................................................................................94 
6.2.15. 
Hemoglobin Analysis .................................................................................................94 
6.2.16. 
Testing for SCD Genotype, Vector Copy Number, Replication Competent 
Lentivirus, and Integration Site Analysis ...................................................................95 
6.2.17. 
Bone Marrow Aspiration ............................................................................................95 
6.2.18. 
Conventional Cytogenetics (Karyotyping) and NGS Mutational Testing ..................95 
6.2.19. 
Bone Marrow for Exploratory PD ..............................................................................96 
6.2.20. 
Blood for Exploratory PD ...........................................................................................96 
6.2.21. 
Blood and Bone Marrow for Storage ..........................................................................96 
6.2.22. 
Samples for Potential Biomarker Analyses ................................................................96 
6.2.23. 
Imaging Studies ..........................................................................................................97 
6.2.24. 
Liver Biopsy ...............................................................................................................98 
6.2.25. 
Pulmonary Function Tests ..........................................................................................98 
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6.2.26. 
Patient-reported Outcome Measures ...........................................................................98 
6.2.27. 
Six-Minute Walk Test .................................................................................................99 
6.2.28. 
Assessment of Oligoclonality by Integration Site Analysis .......................................99 
6.2.29. 
Assessments for Risk of Hematologic Malignancy and Clinical Work-up ..............101 
6.2.30. 
Adverse Events .........................................................................................................102 
6.2.30.1. 
Assessments During Study .......................................................................................102 
6.2.30.2. 
Adverse Events Definitions ......................................................................................103 
6.2.30.3. 
Adverse Event Assessment of Severity and Relationship ........................................105 
6.2.30.4. 
Procedures for AE and SAE Collection and Reporting ............................................105 
6.2.30.5. 
Immediate Reporting of SAEs ..................................................................................106 
6.2.30.6. 
Safety Reporting to Regulatory Authorities, Ethics Committees, and 
Investigators ..............................................................................................................106 
6.2.31. 
Pregnancy and Contraception ...................................................................................106 
6.2.32. 
Unscheduled Visits ...................................................................................................108 
6.2.33. 
Long-term Follow-up Protocol .................................................................................108 
7. 
STATISTICAL PROCEDURES ..............................................................................109 
7.1. 
Sample Size Estimation ............................................................................................109 
7.2. 
Populations for Analysis ...........................................................................................109 
7.3. 
Planned Analyses ......................................................................................................110 
7.3.1. 
Interim Analyses .......................................................................................................110 
7.3.2. 
Final Analysis ...........................................................................................................110 
7.3.3. 
Additional Data Review ...........................................................................................110 
7.3.4. 
Impact of the COVID-19 Pandemic .........................................................................110 
7.4. 
Statistical Methods ....................................................................................................110 
7.4.1. 
General Methods .......................................................................................................110 
7.4.2. 
Disposition of Subjects .............................................................................................111 
7.4.3. 
Demographic and Baseline Characteristics ..............................................................111 
7.4.4. 
Efficacy Analysis ......................................................................................................111 
7.4.4.1. 
Analysis of Primary Efficacy Endpoint ....................................................................112 
7.4.4.2. 
Analysis of Key Secondary Efficacy Endpoints .......................................................112 
7.4.4.3. 
Analyses of Other Secondary Efficacy Endpoints ....................................................113 
7.4.4.4. 
Analyses of Exploratory Efficacy Endpoints ...........................................................115 
7.4.4.5. 
Correlation Analyses between Efficacy Endpoints ..................................................115 
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7.4.5. 
Safety Analyses ........................................................................................................115 
7.4.6. 
Pharmacodynamic Analyses .....................................................................................115 
8. 
ADMINISTRATIVE REQUIREMENTS ................................................................116 
8.1. 
Good Clinical Practice ..............................................................................................116 
8.2. 
Ethical Considerations ..............................................................................................116 
8.3. 
Subject Information and Informed Consent .............................................................116 
8.4. 
Subject Confidentiality .............................................................................................116 
8.5. 
Protocol Compliance ................................................................................................117 
8.6. 
Direct Access to Source Data ...................................................................................117 
8.7. 
Case Report Form Completion .................................................................................117 
8.8. 
Record Retention ......................................................................................................118 
8.9. 
Liability and Insurance .............................................................................................118 
8.10. 
Publication and Presentation of Study Findings and Use of Information ................118 
9. 
REFERENCES .........................................................................................................119 
10. 
APPENDICES ..........................................................................................................127 
10.1. 
Performance Status Assessments ..............................................................................127 
10.1.1. 
Karnofsky Performance Status Scale ........................................................................127 
10.1.2. 
Lansky Performance Status Scale .............................................................................127 
10.2. 
Health-Related Quality of Life, Cognitive Function, and Work Productivity 
Assessments ..............................................................................................................128 
 
 
 
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LIST OF TABLES 
Table 1: 
Dose of bb1111 or Back-up Cells for Severe SCD in Study HGB-206 .....................43 
Table 2: 
Schedule of Events: Screening and Stem Cell Harvest ..............................................76 
Table 3: 
Schedule of Events: Conditioning and Drug Product Infusion ..................................81 
Table 4: 
Schedule of Events: Follow-up ...................................................................................84 
Table 5: 
Patient-reported Outcome Measures ...........................................................................99 
 
LIST OF FIGURES 
Figure 1: 
Schematic for Study Design .......................................................................................49 
Figure 2: 
Mobilization and Apheresis Plan for Back-up Cell Collection (Group B2) ...............64 
Figure 3: 
Mobilization and Apheresis Plan (Group C) ..............................................................65 
Figure 4: 
Algorithm for Frequency of ISA Monitoring ...........................................................100 
Figure 5: 
Assessments for Risk of Hematologic Malignancy per Schedule of Events 
and Clinical Work-up ...............................................................................................101 
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1. 
INTRODUCTION 
1.1. 
Sickle Cell Disease 
Sickle cell disease (SCD) is a rare hereditary blood disorder caused by a point mutation within 
codon 6 of the β-globin gene that results in the production of an abnormal βE6V-globin 
(βS-globin) (INGRAM 1957). The most frequent and severe SCD phenotype, also known as 
sickle cell anemia, results when 2 copies of the βS-globin gene (βS) are present (homozygous 
βS genotype, βS/βS). Compound heterozygosity with certain other mutations in the β-globin gene 
(e.g., βS/βC (SC genotype) or βS/β0 genotypes, where a β0 mutation does not produce a -globin 
[Sβ-thalassemia genotype]), can produce an SCD spectrum that may be as phenotypically severe 
as that typically associated with βS/βS SCD. 
Worldwide, neonatal screening indicates that the number of newborns with SCD is 
approximately 400,000 annually, with 312,000 being of the βS/βS genotype, mostly in 
sub‑Saharan Africa and India (Piel et al. 2013). The US Centers for Disease Control and 
Prevention estimates SCD to affect 90,000 to 100,000 persons in the US (Centers for Disease 
Control and Prevention, http://www.cdc.gov/ncbddd/sicklecell/data.html). While SCD is 
relatively rare in the US and Europe, it represents a significant public health burden, given the 
intensive management needed to improve survival and care for affected patients. From 1989 to 
1993, an average of 75,000 hospitalizations due to SCD occurred in the US (Centers for Disease 
Control and Prevention). 
Sickle cell disease is associated with significant morbidity and mortality, particularly in 
developing countries where it is most prevalent. Mortality in Africa is high, with the most 
vulnerable period being under 5 years of age (Makani et al. 2011), mainly due to bacterial 
infections associated with the early loss of splenic function resulting from splenic damage 
from sickle cells. In the US and Europe, neonatal diagnosis, early penicillin prophylaxis, 
extended vaccinations, and comprehensive care have improved health outcomes and survival 
during childhood (Quinn et al. 2010; Colombatti et al. 2016). 
βS-globin causes hemoglobin S (HbS) to form rigid polymers upon deoxygenation or other stress, 
e.g., dehydration, fever, etc. In turn, the intracellular formation of HbS polymers results 
in deformation of the red blood cell (RBC) into the characteristic sickle shape that decreases 
its flexibility and is responsible for chronic hemolytic anemia and acute microvascular 
vaso-occlusions or infarctions, resulting in acute life-threatening conditions, chronic multiple 
organ damage and premature death (Madigan and Malik 2006). Moreover, systemic endothelial 
dysfunction develops related to a decrease in nitric oxide bioavailability due to hemolysis, 
reactive oxygen species production, and intravascular inflammation (Morris et al. 2000, 2005; 
Aslan et al. 2001; Reiter et al. 2002; Gladwin et al. 2003; Reiter and Gladwin 2003; Dubert et al. 
2017).The individual baseline rate of hemolysis is stable over time (Taylor et al. 2008). While a 
single point mutation leading to the production of HbS is the primary source of clinical 
complications in SCD, the presentation of the disease is heterogeneous. Severely affected 
patients may experience diverse complications such as severe anemia, repeated acute painful 
vaso-occlusive events (VOEs) due to small-vessel obstruction (vaso-occlusive crises [VOCs]; 
sickle cell crises), acute chest syndrome (ACS; acute event with pneumonia-like symptoms), 
cerebral vasculopathy, and chronic organ damage that may involve the bones, kidneys, heart, 
liver, and lungs or result in severe infectious complications related to functional hyposplenism. 
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The need for intensive therapies, including transfusions, and frequent hospitalizations greatly 
impairs activities of daily living and quality of life. Most patients experience painful, chronic 
symptoms due to recurrent underlying crises and potentially chronic complications such as bone 
and joint damage and ulcers. The burden of the disease increases with age and is associated with 
early mortality. 
Cerebro-vascular accidents are a common cause of neurological injury. The chance of 
having a cerebro-vascular accident by 20 years of age was estimated at 11% for βS/βS SCD 
patients (Ohene-Frempong et al. 1998). Although early transcranial Doppler (TCD) 
screening and intensification therapy allowed the reduction of stroke risk by age 18 to 1.9% 
in a recent study, the cumulative cerebral risk (including stroke, abnormal TCD, stenosis, and 
silent strokes) remains high at approximately 50% by age 14 (Bernaudin et al. 2011). Both 
silent cerebral infarcts and overt stroke are associated with lower cognitive functioning 
(Armstrong et al. 1996). Although stroke is the major cause of morbidity in patients with SCD, 
ACS is the major cause of mortality in these patients. In the cooperative study of SCD (CSSCD), 
patients older than 20 years of age with an episode of ACS had lower survival compared to SCD 
patients without an episode of ACS (Castro et al. 1994).   
Two overlapping subphenotypes of SCD have been proposed (Kato et al. 2007): the 
“hyperviscosity” subphenotype with higher hemoglobin (Hb) levels and a higher prevalence of 
vaso-occlusive pain crises, ACS, and osteonecrosis, and the “hyperhemolysis-endothelial 
dysfunction” subphenotype, in which patients have a pattern of low Hb levels and higher levels 
of hemolysis markers, such as reticulocyte count, serum lactate dehydrogenase (LDH), and 
bilirubin, as well as a higher prevalence of pulmonary hypertension, stroke, leg ulcers and 
priapism.  
Management of SCD entails a number of approaches, including prevention and treatment of 
infection, pain management and transfusion therapy. Specific treatment for SCD is limited to 
chronic blood transfusions, Endari (L-glutamine), Droxia or Siklos (hydroxyurea; referred to as 
HU), Adakveo (crizanlizumab-tmca), Oxbryta (voxelotor), and allogeneic hematopoietic stem 
cell (HSC) transplantation (HSCT), which to date has been the only curative treatment. 
Chronic blood transfusion therapy to maintain HbS below 30% significantly reduces the 
risk of recurrent stroke and decreases the incidence of associated co-morbidities but leads to 
allo‑immunization or delayed hemolysis transfusion reactions in approximately 30% of 
transfused SCD patients compared to 2 to 5% of all transfusion recipients. Thus, continued 
transfusions are problematic and may lead to life-threatening complications (Friedman et al. 
1996; Meunier et al. 2008; Campbell-Lee and Kittles 2014). Iron overload is often a major issue 
in SCD patients on chronic transfusion therapy, with ensuing long-term liver complications and 
the need for iron chelation therapy (de Montalembert et al. 2017). In addition, chronic active 
hepatitis and resultant hepatic failure is a significant complication of transfusion therapy. As 
many as 11% to 20% of patients with SCD on chronic transfusion regimens are infected with 
hepatitis C virus (HCV) (DeVault et al. 1994; Arlet et al. 2016). 
L-glutamine oral powder (Endari) is approved in the US (Endari PI, 2017) for use in reducing the 
acute complications of SCD in adults and pediatric patients ≥ 5 years of age. In May 2019, the 
Committee of Medicinal Products for Human Use (CHMP) in the European Union (EU) issued a 
negative opinion for Xyndari (brand name in EU) stating that the data in the marketing 
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authorization application did not show that the drug was effective at reducing the number of 
SCD crises or hospital visits. 
Hydroxyurea (HU) has been helpful in a subset of patients only, with response rates of 
approximately 40% to 50% (Ma et al. 2007). Patients who respond show a decrease in the rate of 
pain and ACS events (Charache et al. 1995; Steinberg et al. 1997), and beneficial findings in 
other organs have also been reported (Hankins et al. 2008). Hydroxyurea is a well-tolerated 
medication with few significant short-term toxicities; e.g., transient and reversible myelotoxicity, 
occasional gastrointestinal discomfort, nail or skin hyperpigmentation, and skin ulceration. 
However, HU is a chemotherapeutic drug; and given its primary mechanism of action and in 
vitro reports as a clastogen, mutagen, teratogen and carcinogen, the long-term safety profile of 
HU treatment in SCD remains an ongoing concern (McGann and Ware 2011). Although most 
studies to date have confirmed the beneficial role of HU in preventing VOEs and ACS in all age 
groups, the inferiority of HU in patients with stroke and chronic transfusions has been 
established (Ware and Helms 2012). Importantly, HU is a palliative, but not a curative, treatment 
modality, and studies assessing the utilization of HU in patients with SCD have identified patient 
compliance as a barrier to its use and efficacy (Brandow and Panepinto 2010). While there is 
some non-randomized evidence that patients treated with HU may live longer than those not 
treated with HU, patients treated with HU still experience SCD complications and, unfortunately, 
still die of their disease (Bakanay et al. 2005; Voskaridou et al. 2010).  
Adakveo (crizanlizumab) is a humanized IgG2 kappa monoclonal antibody against P-selectin 
that blocks interactions between endothelial cells, platelets, red blood cells, and leukocytes. It is 
indicated to reduce the frequency of VOCs in adults and pediatric patients aged 16 years and 
older with SCD (Adakveo PI, 2019). Adakveo does not impact that pathophysiological basis of 
the disease but is designed to reduce a specific symptom of the disease, namely pain due to 
vaso-occlusive disease. Efficacy was evaluated in the pivotal study and Adakveo demonstrated a 
lower median annual rate of VOC compared to placebo (1.63 versus 2.98); however, VOC often 
persisted despite treatment. Thus, it could not be considered a potentially curative therapy and 
symptoms often persist despite treatment.  
Oxbryta (voxelotor) is a hemoglobin S polymerization inhibitor indicated for the treatment of 
SCD in adults and pediatric patients 12 years of age and older. In clinical trials, Oxbryta 
treatment led to an increase in total hemoglobin of approximately 1 g/dL (Oxbryta PI, 2019). 
However, subjects who were receiving chronic packed red blood cell (pRBC) transfusions were 
excluded from these studies. Importantly, treatment with Oxbryta did not demonstrate any 
difference in annualized vaso-occlusive events nor did it show any improvement in 
patient-reported outcomes. Thus, severely affected patients who can experience acute, painful 
and quantifiable VOEs may not benefit from this treatment given no notable reductions in 
VOC/ACS events were observed in Oxbryta clinical trials. 
Allogeneic hematopoietic stem cell transplantation is currently the only available curative 
treatment for patients with SCD, and is indicated for pediatric patients with an HLA-matched 
sibling donor who have severe clinical symptoms such as clinically overt stroke, frequent VOEs, 
and ACS while on HU (Fitzhugh et al. 2014), where organ damage has been documented and 
reduced lifespan is expected. Unfortunately, only approximately 14% of patients have a suitable, 
sibling, human leukocyte antigen (HLA)-matched donor, and identifying a matched donor is a 
major barrier to allogeneic HSCT (Vermylen 2003). Furthermore, allogeneic HSCT is associated 
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with 5 to 20% mortality, in large part due to complications from graft-versus-host-disease 
(GVHD) (Lucarelli et al. 1993; Locatelli et al. 2003; Vermylen 2003). 
Allogeneic hematopoietic stem cell transplantation involves a conditioning regimen to eradicate 
existing HSCs to allow for successful engraftment of subsequently infused allo-HSCs. 
Specific inclusion and exclusion criteria to maximize success rates and minimize risks of the 
procedure are now well established (Bernaudin et al. 2007; Walters et al. 2010). Allogeneic 
hematopoietic stem cell transplantation outcomes are generally better when performed earlier in 
life (Kamani et al. 2011). In a recent study of 1000 patients with SCD who received allo-HSCT 
from an HLA-matched sibling donor, 5-year probabilities of overall survival (OS) and event-free 
survival (EFS) were 92.9% and 91.4%, respectively. The 5-year OS was 95% and 81% for 
patients younger than 16 years and those aged 16 years or older respectively; the corresponding 
EFS was 93% and 81% (Gluckman et al. 2017).  
The use of intra-familial, partially matched donors or matched, unrelated donors presents a safety 
risk to patients, and is infrequently employed for SCD. Additional donor sources and 
modifications to allo-HSCT are being investigated but are currently limited to experienced 
centers and clinical trials (Bolaños-Meade et al. 2012; Hsieh et al. 2014; Shenoy et al. 2016; 
Allen et al. 2017). In the context of SCD, an international expert panel has recommended that 
allo-HSCT should only be offered using a myeloablative conditioning regimen and only to 
young symptomatic patients with available matched-sibling donors (MSDs) (Angelucci et al. 
2014). The absence of suitable donors, the significant risks of transplantation, and the 
requirement for post-transplant immunosuppression indicate unmet medical needs, even with 
allogeneic HSCT, for SCD patients. 
1.2. 
bb1111 
bb1111 (lovotibeglogene autotemcel, also known as LentiGlobin BB305 Drug Product for SCD) 
is an autologous CD34+ cell-enriched population from patients with sickle cell disease that 
contains HSCs transduced with BB305 lentiviral vector encoding the βA-T87Q-globin gene. 
Expression of βA‑T87Q‑globin is driven by the erythroid lineage-specific globin locus control 
region (LCR). βA-T87Q-globin is a single amino acid variant of β-globin that conserves the 
protein’s function while allowing for quantification relative to other globin species. Additionally, 
βA-T87Q-globin has anti-sickling properties because the amino acid change from threonine to 
glutamine at position 87 sterically inhibits the polymerization of Hb chains.   
After undergoing myeloablation, subjects receive bb1111 via intravenous (IV) infusion, leading 
to peripheral reconstitution with corrected erythrocytes. As bb1111 consists of genetically 
modified autologous cells, there is no risk of GVHD.  
Extensive nonclinical studies have demonstrated that transfer of the human βA-T87Q-globin gene 
under the control of the β-globin promoter and enhancer elements of the -globin locus control 
region (LCR) into HSCs by means of LVVs reliably results in long-term correction of SCD in 
relevant mouse models (Pawliuk et al. 2001). Similarly, effective ex vivo βA-T87Q-globin gene 
transfer into human CD34+ HSCs was observed (Imren et al. 2004) (see the Investigator’s 
Brochure).  
As described in the protocol synopsis, Study HGB-206 includes 3 cohorts (Groups A, B, and C). 
In Group A, drug product was manufactured using stem cells collected via bone marrow harvest 
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and using a manufacturing process termed Process 1, a process which has since been 
discontinued. In Group B, bone marrow harvest was also used to collect stem cells for drug 
product manufacture; however, a new drug manufacturing process termed Process 2 (currently in 
use) was implemented. Of the 2 subjects in Group B, 1 subject received drug product 
manufactured entirely via Process 2, and the other subject (Subject 1313) received a drug 
product lot manufactured via Process 1 and a drug product lot manufactured via Process 2. In 
Group C, drug product was manufactured from stem cells collected via plerixafor mobilization 
followed by apheresis, and all Group C subjects have received drug product manufactured using 
Process 2. All subjects enrolled into Group C are planned to receive drug product manufactured 
via Process 2 using stem cells collected by plerixafor mobilization followed by apheresis. 
Through the improvements introduced into Study HGB-206 with Process 2, we have shown that 
production of hemoglobin A containing βA-T87Q-globin (HbAT87Q) is dependent on VCN, such 
that increased VCN leads to sustained HbAT87Q expression and HbS decrease. With the 
introduction of Process 2, subjects have achieved robust anti-sickling Hb levels in the absence of 
exogenous hemoglobin A (HbA) from pRBC transfusions and experienced reductions in 
VOC/ACS events post-treatment. These data suggest that HbAT87Q production may improve the 
clinical status of patients with SCD. 
The safety profile post bb1111 gene therapy is generally consistent with that of autologous stem 
cell transplant, myeloablative single-agent busulfan conditioning, and underlying SCD. See the 
Investigator’s Brochure for details and safety/efficacy updates. 
1.3. 
Rationale 
1.3.1. 
Rationale for the Study 
Severe SCD is a devastating monogenic disease with a clear unmet need. While SCD varies 
substantially from patient to patient, at a population level there are broad trends in presentation 
of the disease by age. Infants with SCD, who have hemoglobin F (HbF) levels that are 
preventative of HbS polymerization, are largely asymptomatic. When HbF production decreases, 
and HbS production increases, the disease can present with a number of hallmark acute 
symptoms including dactylitis, anemia, mild jaundice or an enlarged spleen. Acute attacks from 
splenic sequestration can occur as early as 3 months of age but, more typically, before 2 years of 
age (Serjeant 2013). The most frequent clinical complications in pediatric SCD are pain, 
infection, acute splenic sequestration, ACS, and stroke (Kanter and Kruse-Jarres 2013). Pediatric 
SCD patients are also at a substantially elevated risk for overt and silent strokes that can 
negatively impact cognition. One recent study demonstrated that approximately 50% of patients 
have some form of cerebral vasculopathy by age 14 (Bernaudin et al. 2011). In recent decades, 
interventions such as neonatal diagnosis, penicillin prophylaxis, extended vaccination, and 
comprehensive care have significantly reduced childhood mortality for people with SCD 
in developed countries (Lanzkron et al. 2013). However, the accumulated burden of 
SCD‑associated morbidity increases as patients enter adulthood, resulting in progressive organ 
damage (Buchanan et al. 2010), more frequent emergency department visits and hospitalizations 
(Brousseau et al. 2010), reduced quality of life (Dampier et al. 2011), and ultimately 
shortened survival. Approximately 50% of people with SCD do not survive to the fifth decade 
of life, and nearly half of those who do will have some form of irreversible organ damage 
(Powars et al. 2005). The most common causes of death among adult SCD patients include ACS, 
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VOE complications, multiorgan or renal failure, stroke, and heart failure (Platt et al. 1994; 
Kanter and Kruse-Jarres 2013). Although stroke is the major cause of morbidity in adult patients 
with SCD, ACS is the major cause of mortality in these patients. 
In the US and Europe, the life expectancy of adults with SCD is estimated to be 20 to 30 years 
lower than that for unaffected individuals, with a median age at death for patients with SCD 
of approximately 39 years of age (Hassell 2010) to 45 years of age, and not exceeding the 
5th decade of life since the 1990s (Platt et al. 1994; Hassell 2010; Lanzkron et al. 2013; Ngo et al. 
2014; Payne et al. 2017). Between 1979 and 2005, pediatric mortality has decreased by 3% per 
year, while adult mortality has increased by 1% per year (Lanzkron et al. 2013). Several studies 
have reported that the risk of death is particularly high during the transition time from pediatric 
to adult care, potentially due to a lack of adult health care for these patients, or to the fact that 
these patients didn’t survive before HU and transfusion therapy (Quinn et al. 2010; Hamideh and 
Alvarez 2013).  
Allo-HSCT from an MSD is the only potentially curative treatment available. However, 
unfortunately, only approximately 14% of patients have a suitable, sibling, human leukocyte 
antigen (HLA)-matched donor, and identifying a matched donor is a major barrier to allo‑HSCT 
(Vermylen 2003). Furthermore, allo-HSCT is associated with 5% to 20% mortality, in large part 
due to complications from graft-versus-host disease (GVHD) (Lucarelli et al. 1993; Platt et al. 
1994; Locatelli et al. 2003; Vermylen 2003). Engraftment failure and rejection are also 
significant risks of such therapy. The use of intra-familial, partially matched donors or matched, 
unrelated donors is infrequently employed as it is not an option for most patients with SCD given 
the higher risk associated with these transplants. The absence of suitable donors, the significant 
risks of transplantation, and the requirement for post-transplant immunosuppression therapy 
indicate an unmet medical need, even with allo-HSCT, for patients with SCD.  
In order to provide a potentially curative treatment to a larger number of patients with SCD, the 
Sponsor is developing bb1111, an autologous CD34+ cell-enriched population from patients 
with SCD that contains HSCs transduced with BB305 LVV encoding the βA-T87Q-globin gene.  
Treatment of the subject’s own HSCs with BB305 LVV through transduction should eliminate 
the risk of GVHD. Furthermore, clinical benefit should be obtainable without all HSCs being 
transduced. A number of clinical studies have demonstrated that after allo-HSCT (using 
myeloablative or non-myeloablative conditioning regimens), stable mixed chimerism is 
sufficient to reverse SCD-related symptoms (Walters et al. 2001; Andreani et al. 2011; Hsieh et 
al. 2014; King et al. 2015; Saraf et al. 2016). It has been recently demonstrated that a minimum 
of 20% donor myeloid chimerism is required to reverse the SCD phenotype in subjects 
undergoing nonmyeloablative HSCT from HLA-matched sibling or haploidentical donors 
(Fitzhugh et al. 2017). These findings suggest that low levels of donor engraftment can result in 
significant donor-derived erythrocyte levels and functional improvement of hemoglobinopathies 
(Andreani et al. 2011). This can be explained by the large differences between donor and 
recipient RBC survival times, and the progressive advantage of the selection of donor cells 
during erythroid differentiation, contrary to what is usually observed in cases of mixed 
chimerism after allograft for a malignant hematologic disease (Wu et al. 2005). 
This Phase 1/2 study will assess the efficacy and safety of transplantation with bb1111 in adults 
and adolescents with severe SCD. Efficacy endpoints that evaluate complete resolution of severe 
VOEs, production of HbAT87Q, and changes in total Hb levels, along with secondary endpoints 
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assessing HbS percentage of total Hb, reduction in frequency of VOEs, hemolysis, and other 
biochemistry and physiological parameters, will allow for an evaluation of whether 
transplantation with bb1111 will provide clinical benefit. In combination with the safety 
endpoints, these data should allow for a determination of benefit: risk of this treatment modality 
in patients with severe SCD and be the basis for subsequent larger efficacy studies. 
1.3.2. 
Rationale for Selection of Primary and Key Secondary Efficacy Endpoints 
The primary endpoint of VOE-CR (see Section 2.2.1.1) assesses for complete resolution of 
VOEs between 6 months and 18 months after drug product infusion.  
VOEs are associated with declining quality of life, increased risk of acute and chronic 
morbidities, cumulative disease progression and an increased risk of sudden death (Ballas et al. 
2012; Novelli and Gladwin 2016; Kato et al. 2018; Payne et al. 2020). These traumatic events 
happen frequently, with estimates that vaso-occlusive crises result in 90% of SCD-related 
hospital admissions (Jang et al. 2021), and 88% of patients report contending with VOE pain at 
home (Thompson and Eriator 2014). VOEs are also frequently underreported, with only 10% of 
patients seeking treatment for pain events and many opting to delay medical treatment (Smith et 
al. 2008; Linton et al. 2020). Complete resolution of VOEs therefore represents a clinically 
meaningful outcome of drug product treatment. 
The key secondary endpoint of sVOE-CR (see Section 2.2.1.2) assesses for complete resolution 
of severe VOEs between 6 months and 18 months after drug product infusion. These events are 
VOEs that require significant medical intervention and treatment (see Section 6.2.5). Severely 
affected patients can experience VOEs that require intravenous (IV) opioids and hospitalization, 
and resolution of these sVOEs also represents a clinically meaningful outcome of drug product 
treatment.  
The key secondary endpoint of Globin Response (see Section 2.2.1.2) is a composite endpoint 
for evaluation of production of HbAT87Q and total (non-transfused) Hb. Assessment of Hb 
production was chosen for the following reasons: chronic anemia induces hypoxia, which is a 
crucial factor in the onset of sickle cell-related events; a correlation is expected between 
resolution of anemia and correction of other manifestations of SCD. In addition, by measuring 
the increase in total Hb, we can also assess subjects with hemolysis (these subjects may not 
experience frequent VOEs, and therefore a reduction in these events cannot be measured). 
Production of HbAT87Q is being evaluated because the βA-T87Q-globin gene encodes a β-globin 
variant that has been shown to exhibit anti-sickling properties while otherwise maintaining the 
same functionality as wild-type β-globin. 
1.3.3. 
Rationale for the β-globin Gene Used 
The β-globin transgene used in this study encodes the wild-type human β-globin with a single 
modification at amino acid position 87 [βA87 Thr:Gln (βA-T87Q)]. This βA-T87Q-globin has an 
advantage over normal β-globin for gene therapy of SCD, as βA-T87Q-globin has been shown in 
vitro and in vivo to have anti-sickling properties similar to those of human γ-globin (fetal Hb) 
and thus should be more active in preventing sickling in subjects with SCD than the wild-type 
β-globin, which does not actively inhibit sickling (Pawliuk et al. 2001). In addition, the in vivo 
protein level expressed by this variant can be quantified by high-performance liquid 
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chromatography (HPLC) and distinguished from that of wild-type β-globin from transfused 
RBCs (Cavazzana-Calvo et al. 2010). 
1.3.4. 
Rationale for Plerixafor Mobilization 
Transduction of CD34+ cells after their mobilization and apheresis using a combination of 
granulocyte colony stimulating factor (G-CSF) and plerixafor has led to successful 
engraftment of transduced cells with high levels of therapeutic transgene in subjects with 
β-thalassemia (Thompson et al. 2018). Although G-CSF is generally well-tolerated for stem cell 
mobilization, severe complications, including multi-organ failure, ACS and vaso-occlusive 
episodes have been reported with its use in patients with SCD, presumed due to the 
hyperleukocytosis caused by G-CSF (Fitzhugh et al. 2009). Plerixafor, which reversibly 
inhibits the CXCR4–SDF1 interaction within the bone marrow microenvironment resulting in 
rapid mobilization, has been proposed as an alternative to G-CSF due to its different mode of 
action and its emerging safety profile (Yannaki et al. 2012, 2013). Single-agent use of plerixafor 
has been shown to be safe and effective for the rapid mobilization of CD34+ cells in both 
healthy subjects (Liles et al. 2003) and patients with multiple myeloma and non-Hodgkin’s 
lymphoma (Devine et al. 2004). More recently, in thalassemic patients, mobilization with 
plerixafor alone resulted in CD34+ cell yields similar to those obtained using G-CSF 
mobilization (Yannaki et al. 2012). Plerixafor mobilization in these subjects produced only mild 
adverse events (AEs), e.g., nausea, diarrhea and injection site erythema. Most relevant to the 
SCD population, who are often functionally asplenic, single-agent plerixafor did not cause the 
same dose-limiting leukocytosis observed in splenectomized thalassemic patients receiving 
G-CSF. 
A recent Phase 1/2 study has shown that plerixafor can be safely used to mobilize HSCs in sickle 
cell patients; a single injection of plerixafor resulted in rapid mobilization of large numbers of 
CD34+ cells that engrafted very efficiently in immunodeficient mice, and no AEs were observed 
(Lagresle-Peyrou et al. 2018). The interim results of another clinical trial of plerixafor 
mobilization in SCD were also recently published (Boulad et al. 2018).This study is a Phase 1 
dose escalation study to support the safety and efficacy of single-agent plerixafor use in 
15 subjects with severe SCD. Relatively high numbers of CD34+ cells were mobilized after 
plerixafor administration at dose levels ranging from 0.08 mg/kg to 0.24 mg/kg. Although 
increases in white cell counts and absolute neutrophil counts were observed, the levels seen were 
assessed as acceptable for the safety of subjects with SCD. There was a low rate of serious 
adverse events (SAEs); 2 subjects developed vaso-occlusive crises at plerixafor doses of 
0.08 mg/kg and 0.24 mg/kg, respectively. 
These data suggested that the risk of plerixafor provoking severe SCD complications should be 
substantially less than that of G-CSF. In addition, a recent multicenter Phase 1/2 study has 
provided evidence that plerixafor mobilization/apheresis is safer than bone marrow harvest as a 
method for collection of stem cells from patients with SCD (Tisdale et al. 2020). 
As of 17 May 2017, 3 subjects in Study HGB-206 had undergone mobilization with plerixafor 
followed by subsequent apheresis, without dose-limiting toxicity. All 3 subjects received a single 
dose of 0.24 mg/kg of plerixafor, followed approximately 4 to 6 hours later by apheresis, during 
which between 5.6 ×106 and 15.3 ×106 CD34+ cells/kg were collected. After cells were removed 
for rescue, the remaining CD34+ cells were sent to bluebird bio for exploratory manufacturing 
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development. The CD34+ cells procured from plerixafor-mobilized apheresis were of sufficient 
quantity and quality for the manufacture of bb1111 based on process recovery and drug product 
characterization data. Based on these data, and after adjudication by the DMC, the decision was 
made to move forward with plerixafor mobilization and apheresis for the collection of CD34+ 
cells for drug product manufacture for all enrolled subjects. 
Safety evaluation of subjects in Study HGB-206 has demonstrated the general safety and 
tolerability of plerixafor at a dose of 0.24 mg/kg, and none of the life-threatening 
sequelae associated with G-CSF administration in this population has been observed. 
Based upon these data, dose-limiting toxicities (DLTs) are no longer collected, and the safety of 
plerixafor is now monitored in a standard manner. 
1.3.5. 
Rationale for the Dose Selected 
The bb1111 cell dose will be ≥ 3.0 × 106 CD34+ cells/kg, with drug product manufactured using 
cells collected by apheresis after plerixafor mobilization for each subject. 
The dose of CD34+ cells to be administered is based on accepted safe practice to achieve rapid 
and robust hematopoietic reconstitution with long-term engraftment after autologous 
transplantation. Although the theoretical objective is to provide as many CD34+ cells as possible 
with doses up to 15 × 106 cells/kg (Jillella and Ustun 2004), this dose is rarely achievable. A 
minimum dose of CD34+ cells to be administered is not clearly defined in the literature, as doses 
of 1.0 × 106 CD34+ cells/kg or lower result in engraftment, but with delays in neutrophil and 
platelet recovery (Miyamoto et al. 2004). There is a consensus that the minimum CD34+ dose 
associated with favorable engraftment kinetics is approximately 1.5 × 106 to 3.0 × 106 cells/kg 
(Bender et al. 1992; Perez-Simon et al. 1998; Miyamoto et al. 2004; Jillella and Ustun 2004). 
Table 1 summarizes the minimum dose of bb1111 and back-up cells to be given.  
 
Table 1: 
Dose of bb1111 or Back-up Cells for Severe SCD in Study HGB-206 
Usage 
Dose 
Drug Product (cells obtained by apheresis) 
≥ 3.0 × 106 CD34+ cells/kga 
Back-up Cells (cells obtained by bone marrow harvest) 
≥ 1.0 × 108 TNC/kg 
Back-up Cells (cells obtained by apheresis) 
≥ 1.5 × 106 CD34+ cells/kg 
 
Abbrev.: TNC, total nucleated cells 
a Note that this dose represents the cell count after transduction. If more than 1 transduction is performed, the total 
dose of the drug products together must meet this criterion 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
The primary study objective is to: 
• Evaluate the efficacy of treatment with bb1111 in subjects with severe SCD. 
The secondary study objective is to: 
• Evaluate the safety of treatment with bb1111 in subjects with severe SCD. 
2.2. 
Study Endpoints 
2.2.1. 
Efficacy Endpoints 
2.2.1.1. 
Primary Efficacy Endpoint  
VOE-CR, defined as complete resolution of VOEs, between 6 months and 18 months after drug 
product infusion 
2.2.1.2. 
Key Secondary Efficacy Endpoints  
• sVOE-CR, defined as complete resolution of severe VOEs, between 6 months and 18 
months after drug product infusion  
• Globin Response, defined as meeting the following criteria for a continuous period of 
at least 6 months after drug product infusion: 
a. Weighted average HbAT87Q percentage of non-transfused total Hb1 ≥ 30%  
AND  
b. Weighted average non-transfused total Hb1 increase of ≥ 3 g/dL compared to 
baseline total Hb2 OR weighted average non-transfused total Hb1 ≥ 10 g/dL 
1 Non-transfused total Hb is the total g/dL of HbS + HbF + HbA2 + HbAT87Q. For subjects with a β+ allele, HbA will 
also be included in the calculation of “non-transfused total Hb” only for samples taken ≥ 60 days after last pRBC 
transfusion.  
2 Baseline total Hb is defined as follows:  
The average of the 2 most recent Hb assessments made at or prior to the Screening evaluation, which meet the 
following criteria:  
(i) Assessments must be separated by at least 1 month from each other.  
(ii) Assessments must have been drawn no earlier than 24 months prior to Informed Consent and may include the Hb 
result from Screening.  
(iii) The subject will not have received a pRBC transfusion within 3 months prior to each Hb assessment. 
For subjects who are on chronic, recurrent transfusions, and do not have 2 Hb assessments which meet criteria (i), 
(ii), and (iii), the following criteria can be used: 2 Hb values which meet criteria (i) and (iii) that are found within 24 
months prior to the start of a regular transfusion program. 
2.2.1.3. 
Additional Secondary Efficacy Endpoints 
Clinical and Disease Evaluation Endpoints: 
• Change in the annualized number of VOEs in the 24 months after drug product 
infusion compared to the 24 months prior to Informed Consent  
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• Change in the annualized number of severe VOEs in the 24 months after drug product 
infusion compared to the 24 months prior to Informed Consent 
• VOE-CR24, defined as complete resolution of VOEs between 6 months and 
24 months after drug product infusion 
• sVOE-CR24, defined as complete resolution of severe VOEs between 6 months and 
24 months after drug product infusion 
• sVOE-75, defined as at least a 75% reduction in annualized severe VOEs in the 
24 months after drug product infusion compared to the 24 months prior to Informed 
Consent  
Characterization of Globin Response: 
• Proportion of subjects who meet the definition of Globin Response at Month 24 
• Duration of Globin Response 
Hematologic Endpoints: 
• Weighted average for the following at Month 6, 12, 18, and 24: 
− non-transfused total Hb1 
− 
HbS percentage of non-transfused total Hb1  
− HbS percentage of non-transfused total Hb1 ≤ 70%, ≤ 60%, ≤ 50% 
− HbAT87Q percentage of non-transfused total Hb1 
− non-HbS3 percentage of non-transfused total Hb1 
• Assessment of the following over time: 
− non-transfused total Hb1  
− HbS percentage of non-transfused total Hb1 
− HbAT87Q percentage of non-transfused total Hb1 
− non-HbS3 percentage of non-transfused total Hb1 
1 Non-transfused total Hb is the total g/dL of HbS + HbF + HbA2 + HbAT87Q. For subjects with a β+ allele, HbA will 
also be included in the calculation of “non-transfused total Hb” only for samples taken ≥ 60 days after last pRBC 
transfusion. 
3Non-HbS is the total g/dL of HbF + HbA2 + HbAT87Q. For subjects with a β+ allele, HbA will also be included in the 
calculation of “non-HbS” only for samples taken ≥ 60 days after last pRBC transfusion. 
• Change from baseline in hemolysis markers, including absolute reticulocyte count, 
% reticulocytes/erythrocytes, total bilirubin, haptoglobin, and lactate dehydrogenase 
• Change from baseline in markers of iron stores including ferritin, liver iron content, 
and if assessed at baseline, cardiac iron content 
• Change from baseline in annualized frequency and volume of packed red blood cell 
(pRBC) transfusions between 6 months and 24 months after drug product infusion  
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• Change from baseline in markers of stress erythropoiesis, including erythropoietin 
and serum transferrin receptor 
SCD Burden and Chronic Complications Assessments:  
• Change from baseline in renal function as measured by eGFR  
• Change from baseline in cardiac-pulmonary function via echocardiogram (tricuspid 
regurgitant jet velocity [TRJV], LVEF) and pulmonary function tests 
• Change from baseline in meters walked during 6-minute walk test  
Hospitalizations and Quality of Life: 
• Change from baseline in annualized VOE-related hospital admissions and days  
• Change from baseline in patient-reported quality of life, as measured by Patient 
Reported Outcomes Measurement Information System (PROMIS) 
2.2.1.4. 
Exploratory Efficacy Endpoints 
• Change from baseline in cerebral vasculature and prior brain parenchymal injury 
evaluation at Month 12 and Month 24 (as measured by cerebral magnetic resonance 
angiography [MRA]/magnetic resonance imaging [MRI] in all subjects, and 
transcranial Doppler [TCD] for subjects ≤ 16 years old at Informed Consent) 
• Change from baseline in bone mineral density (BMD) evaluation using dual x-ray 
absorptiometry (DXA) at Month 24 
• Change from baseline in brain natriuretic peptide 
• Change from baseline in Patient reported Outcome (PRO) measures including:  
− Overall health: EuroQol-5D (EQ-5D-3L or EQ-5D-Y) 
− Work productivity, as measured by the Work Productivity and Activity 
Impairment Questionnaire-General Health (WPAI-GH or Caregiver WPAI-GH) 
− Cognitive function as measured by PROMIS Short Form 6a  
• Evaluation of chronic pain using AAPT 
• Change from baseline in pain medication use 
• Exploratory assays to assess change from baseline in sickle cell characteristics and 
bone marrow pathophysiology 
2.2.2. 
Pharmacodynamic Endpoints 
• Vector copy number (VCN) in peripheral blood over time 
• Expression of βA-T87Q-globin, βS-globin, and other β-like globins in peripheral blood 
over time  
Additional methods may be used to evaluate pharmacodynamics. 
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2.2.3. 
Safety Endpoints  
Safety will be evaluated by the following: 
• Safety and tolerability of plerixafor for mobilization 
• Success and kinetics of HSC engraftment 
• Transplant-related mortality through 100 days post-drug product infusion and through 
365 days post-drug product infusion 
• Detection of vector-derived replication competent lentivirus (RCL) in any subject 
• The number of subjects with insertional oncogenesis (myelodysplasia, leukemia, 
lymphoma, etc.) 
• The number of subjects with persistent oligoclonality 
• Frequency and severity of AEs/SAEs 
• Laboratory parameters over time, including the following immunology tests: 
Screening for irregular antibodies, lymphocyte subpopulation evaluation (CD3, CD4, 
CD8, CD19, CD16/CD56) 
• Incidence of acute and/or chronic graft-versus-host disease (GVHD) 
• Other safety labs over time: chemistries, LFTs (AST, ALT, ALP, GGT, bilirubin 
[total and direct]), hematology, coagulation parameters 
• Hormonal testing over time: estradiol (females only); total testosterone (males only) 
TSH, free T3, free T4, cortisol, ACTH, FSH, LH (all subjects) 
• Change from baseline in methemoglobin concentration at Month 12 and Month 24 
• Number of subjects with presence of a chromosomal abnormality or genetic mutation 
associated with hematologic malignancies over time 
 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Design and Plan of the Study 
This is a non-randomized, open label, multi-site, single dose, Phase 1/2 study in approximately 
50 adults and adolescents with severe SCD. The study will evaluate HSCT using bb1111, an 
autologous CD34+ cell-enriched population from patients with SCD that contains HSCs 
transduced with BB305 LVV encoding the βA-T87Q-globin gene. 
Treatment is divided into 4 stages as follows. 
Stage 1 – Screening and eligibility-assessment 
Subjects will be screened and undergo clinical, imaging, and laboratory assessments for 
eligibility determination.  
Stage 2 – Stem cell harvest, drug product manufacture and disposition 
If subjects are taking HU, it must be discontinued at least 30 days prior to stem cell harvest. 
It may be restarted between completion of the stem cell harvest(s) and admission to the hospital 
for myeloablation but should be stopped again at least 2 days before initiating myeloablation.  
For at least 60 days prior to stem cell harvest and continuing through until the start of 
conditioning, subjects will undergo a transfusion regimen (exchange or simple, as 
available or needed) to reach a target Hb of 10 g/dL prior to mobilization (and 8 to 10 g/dL 
prior to conditioning; not to exceed 12 g/dL prior to either mobilization or conditioning) 
and a pre‑transfusion target HbS proportion in the blood of < 30% to reduce the risk of 
SCD-related complications. The last exchange transfusion must occur within 4 days of start 
of mobilization, and the HbS proportion in the blood must be < 20% after the last exchange 
transfusion. If a subject experiences an SCD-related crisis within 1 month of the start of 
mobilization, the transfusion regimen will be adjusted, and mobilization will be postponed until 
the subject is crisis-free for a period of 1 month. In case of iron overload, subjects should be 
adequately chelated; however, iron chelation must be discontinued at least 7 days prior to stem 
cell harvest. It may be restarted between completion of the stem cell harvest(s) and admission to 
the hospital for myeloablation but should be stopped again at least 7 days before initiating 
myeloablation. 
Subjects who are not documented to have met these parameters or who have experienced any 
significant new SCD-related complications within 1 month of the start of mobilization will 
require additional approval from the Medical Monitor before undergoing mobilization/apheresis. 
Subjects will undergo stem cell harvest via mobilization with plerixafor (0.24 mg/kg) and 
subsequent apheresis to collect HSCs for both drug product manufacture and cryopreservation of 
back-up cells for rescue. Apheresis should begin approximately 4‑6 hours after plerixafor 
mobilization. If more than 1 apheresis day is required, platelet counts must be confirmed to be 
≥ 75 × 109/L within 24 hours of subsequent apheresis sessions, prior to administration of 
plerixafor on that day. If platelet counts do not meet these criteria, mobilization and apheresis 
should be deferred until platelet counts recover to ≥ 75 × 109/L. At least 1.5 × 106 CD34+ 
cells/kg will be cryopreserved for rescue. Following transduction of isolated CD34+ HSCs with 
BB305 lentiviral vector, the bb1111 cell dose will be ≥ 3.0 × 106 CD34+ cells/kg for each 
subject.   
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Subjects for whom adequate HSCs are collected to achieve the minimum cell dose but not for 
rescue, and who do not tolerate plerixafor or do not effectively mobilize with plerixafor may be 
offered the option of bone marrow harvest for collection of back-up cells only, provided that 
drug product manufactured from mobilized cells has met criteria for dispositioning for clinical 
use. 1.0 × 108 total nucleated cells (TNC)/kg derived from bone marrow will be collected for 
rescue. 
Subjects were divided into 3 groups, depending on how stem cells were harvested, and their 
use for either rescue or drug product manufacture, as shown in the schematic below 
(see Figure 1). 
In Group A, both drug product and back-up cells were derived from bone marrow. Treatment 
was staggered between the first and second subject in Group A: the second subject began 
myeloablative conditioning only after the first subject engrafted (defined as 3 consecutive ANC 
laboratory values ≥ 0.5 × 109/L obtained on different days) and the DMC reviewed the initial 
safety data from the first subject.  
In Group B1, both drug product and back-up cells were derived from bone marrow.  
Figure 1: 
Schematic for Study Design 
 
In Group B2, plerixafor mobilization and apheresis were used for collection of back-up cells and 
exploratory manufacturing development, and it was planned for subjects in Group B2 to then 
undergo bone marrow harvest for drug product manufacture. At least 3 subjects in Group B2 
were required for evaluation of DLT at each dose of plerixafor. Plerixafor dosing of initial 
subjects in Group B2 was staggered. Data Monitoring Committee members reviewed the AE 
profile during plerixafor treatment in mobilization cycle 1 for the first subject treated in Group 
B2 and planned to adjudicate on any issues of potential safety significance that could affect 
determination of DLT before dosing of the second subject with plerixafor. A similar procedure 
was followed after dosing of the second subject in order to permit dosing of the third subject. 
The DMC reviewed aggregate safety data in Group B2 after 3 subjects had been dosed and 
confirmed that there are no safety concerns precluding dosing of subjects in Group C with 
plerixafor.  
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Group C was opened upon (1) confirmation of the safety and tolerability of plerixafor 
mobilization in Group B2, and (2) regulatory authority approval of the drug product 
manufacturing process with plerixafor-mobilized HSCs. In Group C, it is planned that all 
subjects will undergo mobilization with plerixafor and subsequent apheresis to collect HSCs both 
for drug product manufacture and for cryopreservation of back-up cells for rescue.  
The first 2 subjects in Group C received drug product infusion in a staggered fashion: neutrophil 
engraftment must occur in the first subject treated in Group C before initiating busulfan 
conditioning for the second subject. 
Subjects who were consented under a prior version of the protocol (and who may or may not 
have back-up cells collected and/or inadequate drug product manufactured under a prior version 
of the protocol), may be allowed to be reconsented under the current version of the protocol. 
Depending on the disposition of previously collected/manufactured cells, subjects may be 
excluded from the overall non-safety analyses of the Group in which they participated. 
Subjects in Group B2 who tolerated and effectively mobilized with plerixafor were given the 
option to postpone drug product manufacture until Group C opened, to allow drug product 
manufacture using plerixafor mobilized cells. In Group C, subjects for whom adequate HSCs are 
collected to achieve the minimum cell dose but not for rescue, and who do not tolerate plerixafor 
or do not effectively mobilize with plerixafor may be offered the option of bone marrow harvest 
for collection of back-up cells only, provided that drug product manufactured from mobilized 
cells has met criteria for dispositioning for clinical use.  
As of Version 8.0 of this protocol, Group C will include adolescent subjects ≥ 12 and < 18 years 
of age in addition to subjects ≥ 18 and ≤ 50 years of age. It should also be noted that while all 
Group A subjects and some Group B subjects received drug product manufactured using 
“Process 1”, all current and future Group C subjects will receive drug product manufactured 
using an optimized process termed “Process 2”. Treatment with drug product manufactured 
using Process 2 (versus Process 1) has resulted in increased drug product VCN, peripheral blood 
VCN, and HbAT87Q levels across multiple bluebird bio-sponsored clinical studies. 
The drug product must be release tested and dispositioned for clinical use and stored at the study 
site before the subject can begin myeloablative conditioning with busulfan. 
Stage 3 –Myeloablative conditioning and infusion of bb1111 
The subject’s suitability for transplant will be reconfirmed with clinical laboratory tests 
(complete blood count [CBC], serum chemistry, liver function tests, and pregnancy test), 
physical examination, performance status, cytogenetics, and other tests based on institutional 
requirements. The results of these tests will be reviewed, and availability of the drug product on 
site and the availability of back-up cells will be confirmed before the site can proceed with 
conditioning. 
As described above, a transfusion regimen (exchange or simple, as available and needed) will be 
continued until the start of conditioning to reach a target Hb (prior to conditioning) of 
8 to 10 g/dL (not to exceed 12 g/dL) and a pre-transfusion target HbS proportion in the blood of 
< 30% to reduce the risk of SCD-related complications; last exchange transfusion must occur 
within 1 week of start of the conditioning regimen. In the event of pulmonary complications 
(e.g., ACS, pneumonia) between Screening and the start of conditioning, a PFT must be 
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performed. After resolution of pulmonary complications, and prior to conditioning, PFT results 
must meet the following requirements: 
• Baseline oxygen saturation ≥ 90% without supplemental oxygen (excluding periods 
of SCD crisis, severe anemia or infection).  
• Baseline carbon monoxide diffusing capacity (DLCO) ≥ 50% (corrected for Hb) in the 
absence of infection. If DLCO cannot be assessed due to age or cognition-related 
restrictions, there must be a normal respiratory exam, chest radiograph without 
pulmonary infiltrates, and oxygen saturation by pulse oximetry ≥ 90% on room air.  
Busulfan (Busulfex® preferred, if available) will be administered intravenously (IV) at a 
starting dose of 3.2 mg/kg/day or 0.8 mg/kg every 6 hours (q6h) for 4 consecutive days; 
for subjects weighing < 35 kg, a q6h dose of 0.8 mg/kg is preferred; for subjects weighing 
≥ 35 kg, either once daily (qd) or q6h dosing can be used, at the discretion of the Investigator. 
The dose of busulfan will be adjusted based upon busulfan pharmacokinetics (PK) in order to 
maintain appropriate levels for myeloablation (area under the curve [AUC] goal of 
1250 [range 1100 to1350] µM*min for a q6h dosing regimen, or 5000 [range 4400 to 
5400] µM*min for a qd dosing regimen). The dosage should be calculated on the basis of the 
lower of the ideal versus actual body weight. The dose may be adjusted appropriately based upon 
actual plasma busulfan levels observed. Clinical sites must be able to measure first and third day 
busulfan PK. Based on busulfan PK results for day 1 and day 3 of busulfan dosing, busulfan dose 
adjustments should be made for subsequent dosing. If feasible, daily busulfan PK measurement 
is recommended. 
Anti-seizure prophylaxis must begin at least 12 hours before initiating busulfan and must 
continue for at least 24 hours after completion of the 4 days of busulfan administration. All drugs 
other than phenytoin are allowed for anti-seizure prophylaxis. 
After completion of the 4-day course of busulfan, there must be a minimum of 48 hours before 
drug product infusion. Busulfan levels will be measured 48 and 72 hours after final dose of 
busulfan for retrospective confirmation of adequate wash-out. 
On Day 1, bb1111 will be administered after thawing via IV infusion. 
Stage 4 – Follow-up, for approximately 24 months after drug product infusion 
Subjects will be followed in the hospital for AEs, and laboratory parameters will be followed to 
monitor engraftment. The subject may be discharged after neutrophil engraftment occurs 
(≥ 0.5 × 109 ANC/L for 3 consecutive measurements on different days after the initial post-
infusion nadir) and the subject is considered medically stable per institutional guidelines. 
From drug product infusion through hospital discharge after neutrophil engraftment, subjects are 
to be medically managed with the goal of maintaining the following hematologic targets: 
• Hb 8 to 10 g/dL (not to exceed 12 g/dL), HbS < 30% and  
• platelet count ≥ 50 × 109/L.  
After discharge, management of transfusions for subjects with SCD will follow the institutional 
standard of care at the clinical site to achieve total Hb and HbS proportions appropriate for each 
subject's clinical status. To achieve this, the transfusion program may be progressively reduced 
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as the contribution of Hb containing βA-T87Q-globin rises. Continued transfusion needs 
> 6 months post-treatment or any alternative plans should be discussed with the Medical 
Monitor.  
Subjects will be followed in this protocol through the Month 24 Visit. Thereafter, subjects are 
expected to enroll in a separate, non-interventional, long-term follow-up protocol that will assess 
safety and efficacy beyond Month 24 for a total of 15 years after drug product infusion. The end 
of Study HGB-206 will be defined as the last visit for the last subject. 
3.2. 
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) comprised of members with appropriate 
scientific and medical expertise to monitor the safety of subjects participating in the study will be 
convened before the study is opened. The DMC will make recommendations regarding study 
conduct (including stopping enrollment), but the ultimate decision is with the Sponsor. The 
composition, responsibilities, and meeting frequencies of the DMC will be described in the DMC 
charter.  
Prior to myeloablative conditioning and subsequent infusion of drug product of the second 
subject in Group A, the DMC reviewed the safety data from the first subject treated after that 
subject had engrafted. The second subject was not enrolled into Group A until the DMC had 
determined that there were no safety concerns with the first subject. Thereafter, subject 
enrollment proceeded in parallel and the DMC reviewed safety data during their regular 
meetings.  
During safety evaluation of plerixafor in Group B2, dosing of initial subjects was staggered. The 
DMC reviewed the AE profile during plerixafor treatment in mobilization cycle 1 for initial 
subjects, and evaluated on any issues of potential safety significance that could have affected 
determination of DLT and plerixafor dose before subsequent subjects were dosed with plerixafor 
(see also Section 5.2.3).  
The first 2 subjects in Group C were infused with drug product in a staggered fashion: neutrophil 
engraftment was required to occur in the first subject treated in Group C before busulfan 
conditioning was initiated for the second subject.  
3.3. 
Event Adjudication Committee  
An independent Event Adjudication Committee comprised of members with appropriate 
scientific and medical expertise to review subject source documents will be convened during 
Group C. The Event Adjudication Committee will be responsible for adjudication of all 
investigator reported VOEs, irrespective of the severity, duration, or need for medical facility 
visit. The committee will review events that occurred prior to enrollment (retrospectively) as 
well as during the study for Groups A, B, and C. The committee may also be responsible for the 
adjudication of any subject deaths that occur after drug product infusion. 
A charter describing the composition and conduct of this committee will be issued by the 
Sponsor and agreed to by all members prior to conducting any reviews. 
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3.4. 
Engraftment Failure 
Neutrophil engraftment failure is defined as failure to achieve 3 consecutive ANC laboratory 
values ≥ 0.5 × 109 cells/L obtained on different days after the initial post-infusion nadir by 
Day 43, or receiving back-up cells at any time during the neutropenic phase, and is reported as 
an SAE (see Section 6.2.30.2). 
3.5. 
Treatment Discontinuation and Enrollment Suspension Criteria 
3.5.1. 
Stopping Rules for Plerixafor 
Once mobilization with plerixafor has begun, there are no protocol-defined stopping rules for 
plerixafor. Mobilization with plerixafor followed by apheresis was introduced under Protocol 
HGB-206 Amendment 7.0. A plerixafor dose of 0.24 mg/kg was identified as having an 
acceptable safety profile by the DMC, and dose-limiting toxicities (DLTs) were no longer being 
assessed as of Protocol HGB-206, Amendment 8.0. 
3.5.2. 
Stopping Rules for Busulfan 
The drug product must be release tested and dispositioned for clinical use and stored at the study 
site, and a sufficient number of back-up cells must have been collected and stored at the study 
site before the subject can begin myeloablative conditioning with busulfan. 
Once myeloablation with busulfan has begun, there are no protocol-defined stopping rules for 
busulfan. In the anticipated very rare event of consent withdrawal during conditioning or the 
development of a new medical condition that, in the Investigator’s opinion, puts the subject at 
risk with continued busulfan treatment, the Medical Monitor should be contacted immediately. In 
such situations in which busulfan conditioning has not been completed per protocol, the drug 
product should not be given, and it is likely that rescue with back-up cells will be required. 
3.5.3. 
Stopping Rules for bb1111 
bb1111 is given as a single IV infusion; once the infusion has been given, there are no 
protocol‑defined stopping rules for treatment of individual subjects.  
Drug product infusion for an individual subject will not be initiated if: 
• the drug product fails to meet criteria for dispositioning for clinical use. The 
Investigator, in consultation with the subject, may decide to proceed with an 
additional stem cell collection, with the approval of the Medical Monitor. 
3.5.4. 
Enrollment Suspension Criteria 
Enrollment in this study and other study procedures may be temporarily suspended at any time 
for safety reasons.  
Following any of the events listed below occurring in a subject treated with bb1111 in a bluebird 
bio-sponsored clinical study, the Sponsor will convene an urgent safety review meeting to 
determine if enrollment (and other study procedures) in this study should be temporarily 
suspended, inform the DMC chair of the event, and convene an ad hoc DMC meeting as 
appropriate: 
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• Death 
• Report of a hematologic malignancy (e.g., leukemia, lymphoma, myelodysplastic 
syndrome, or other hematologic malignancies) 
• Detection of vector-derived RCL in any subject (confirmed on co-culture assay) 
• Failure to achieve hematopoietic reconstitution with transduced cells requiring use of 
back-up cells  
Subjects who have already been treated with drug product will continue in the study. 
The Sponsor will inform the regulatory authorities, Investigators, and each site’s Institutional 
Review Board (IRB)/ Independent Ethics Committee (IEC) and other appropriate institutional 
regulatory authorities if a decision to temporarily suspend enrollment is made.  
 
 
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4. 
STUDY POPULATION 
4.1. 
Number of Subjects 
A total of approximately 50 subjects will be treated with bb1111 in Study HGB-206. 
Seven subjects have already been treated in Group A, and 2 subjects have been treated in 
Group B. A total of approximately 41 subjects in Group C (including subjects consented under 
Versions 7.0, 8.0, and 9.0 of this protocol) will be treated with bb1111, approximately 35 of 
which must meet the severe VOE criteria as set forth in Inclusion Criterion #3.1.  
Subjects who withdraw prior to drug product infusion may be replaced. 
4.2. 
Inclusion Criteria 
Subjects must: 
1. Be ≥ 12 and ≤ 50 years of age at time of consent. 
2. Have a diagnosis of SCD, with either βS/βS or βS/β0 or βS/β+ genotype. 
3. Previous Inclusion Criterion #3 is no longer applicable and has been replaced with 
Criterion #3.1. 
3.1. In the setting of appropriate supportive care measures (e.g., pain management plan) have 
experienced at least 4 severe VOEs in the 24 months prior to informed consent as 
defined below. 
For the purposes of this study, a severe VOE is defined as an event with no medically 
determined cause other than a vaso-occlusion, requiring a ≥ 24-hour hospital or 
emergency room (ER) observation unit visit or at least 2 visits to a day unit or ER over 
72 hours with both visits requiring intravenous treatment. Exception: priapism does not 
require hospital admission but does require a medical facility visit; 4 priapism episodes 
that require a visit to a medical facility (without inpatient admission) are sufficient to 
meet criterion.  Severe VOEs include: 
a. an episode of acute pain with no medically determined cause other than a VOE  
b. Acute chest syndrome (ACS), defined by an acute event with pneumonia-like 
symptoms (e.g., chest pain, fever [> 38.5°C], tachypnea, wheezing or cough, or 
findings upon lung auscultation) and the presence of a new pulmonary infiltrate 
consistent with ACS and requiring oxygen treatment and/or blood transfusion.  
c. Acute hepatic sequestration, defined by a sudden increase in liver size associated with 
pain in the right upper quadrant, abnormal results of liver-function test not due to 
biliary tract disease, and reduction in Hb concentration by at least 2 g/dL below the 
baseline value 
d. Acute splenic sequestration, defined as sudden enlargement of the spleen and 
reduction in Hb concentration by at least 2 g/dL below the baseline value. 
e. Acute priapism: defined as a sustained, unwanted painful erection lasting more than 
2 hours and requiring care at a medical facility (with or without hospitalization) 
4. Previous Inclusion Criterion #4 is no longer applicable as of Protocol Amendment 8.0. 
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5. Have a Karnofsky performance status of ≥ 60 (≥ 16 years of age) or a Lansky 
performance status of ≥ 60 (< 16 years of age).  
6. Previous Inclusion Criterion #6 is no longer applicable as of Protocol Amendment 8.0. 
7. Have either experienced HU failure at any point in the past (defined as > 1 VOE or 
≥ 1 ACS after HU has been prescribed for at least 6 months) or must have intolerance to 
HU (intolerance is defined as the patient being unable to continue to take HU per PI 
judgment). 
8. Be treated and followed for at least the past 24 months prior to Informed Consent in 
medical center(s) that maintained detailed records on sickle cell disease history, 
including incidence of VOEs and severe VOEs, aplastic crises, infectious complications, 
SCD-related chronic complications, SCD-related surgery, neurovascular evaluation 
(including MRI/A and TCD), pRBC transfusions (including indications, volume and units 
of pRBCs, associated pre-transfusion HbS and total Hb values and post-transfusion AEs 
[including allo-immunization]), SCD-specific treatment history (e.g., HU, L-glutamine, 
iron overload, and chelation history), and use of pain medication. 
4.3. 
Exclusion Criteria 
Subjects are excluded if they meet any of the following criteria: 
1. Positive for presence of human immunodeficiency virus type 1 or 2 (HIV1 or HIV2), 
hepatitis B, hepatitis C, human T-lymphotrophic virus1 (HTLV1) or -2 (HTLV-2), active 
syphilis. Note that subjects who have been vaccinated against hepatitis B [hepatitis B 
surface antibody-positive] who are negative for other markers of prior hepatitis B 
infection [e.g., negative for hepatitis B core antibody] are eligible. Subjects with past 
exposure to HBV [HBc Ab positive and/or HBe Ab positive] are also eligible for the 
study provided they are negative for HBV DNA. Subjects who are positive for anti-
hepatitis C antibody are eligible as long as they have an undetectable hepatitis C viral 
load. Where clinically and/or regionally indicated, other tests may be performed, in 
which case relevant positive results suggesting active infection would exclude the subject 
from participating, depending on regional guidelines: for example, malaria, tuberculosis, 
active toxoplasmosis, Trypanosoma cruzi, or West Nile Virus. 
2. Clinically significant, active bacterial, viral, fungal, or parasitic infection, as determined 
by the Investigator, e.g., active relapsing malaria. 
3. Inadequate bone marrow function, as defined by an ANC of < 1 × 109/L (< 0.5 × 109/L 
for subjects on HU treatment) or a platelet count < 100 × 109/L 
4. Previous Exclusion Criterion #4 is no longer applicable as of Protocol Amendment 8.0. 
4.1 Severe cerebral vasculopathy, defined by any history of: overt ischemic or hemorrhagic 
stroke, abnormal TCD (> 200 cm/sec) requiring chronic transfusion, occlusion or stenosis 
in the circle of Willis, or presence of Moyamoya disease. Subjects with radiologic 
evidence of silent infarction in the absence of any of the above criteria would still be 
eligible.  
5. Previous Exclusion Criterion #5 is no longer applicable as of Protocol Amendment 8.0. 
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6. Previous Exclusion Criterion #6 is no longer applicable as of Protocol Amendment 8.0. 
7. Previous Exclusion Criterion #7 is no longer applicable as of Protocol Amendment 8.0. 
8. Baseline oxygen saturation < 90% without supplemental oxygen (excluding periods of 
SCD crisis, severe anemia or infection). 
9. Baseline carbon monoxide diffusing capacity (DLCO) < 50% (corrected for Hb) in the 
absence of infection. If DLco cannot be assessed due to age or cognition-related 
restrictions, there must be a normal respiratory exam, chest radiograph without 
pulmonary infiltrates, and oxygen saturation by pulse oximetry ≥ 90% on room air.  
10. Baseline left ventricular ejection fraction (LVEF) < 45% measured by cardiac 
echography. 
11. Clinically significant pulmonary hypertension at baseline, as defined by the requirement 
for ongoing pharmacologic treatment or the consistent or intermittent use of supplemental 
home oxygen. 
12. Baseline estimated glomerular filtration rate (eGFR) < 70 mL/min/1.73 m2, as determined 
using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (see 
http://www.kidney.org/professionals/kdoqi/gfr_calculator.cfm). 
13. Advanced liver disease, defined as: 
a. Persistent aspartate transaminase, alanine transaminase, or direct bilirubin value 
> 3 × the upper limit of normal (ULN), or 
b. Baseline prothrombin time or partial thromboplastin time > 1.5 × ULN, suspected of 
arising from liver disease, or 
c. Magnetic Resonance Imaging (MRI) of the liver demonstrating clear evidence of 
cirrhosis, or 
d. MRI findings suggestive of active hepatitis, significant fibrosis, inconclusive 
evidence of cirrhosis, or liver iron concentration ≥ 15 mg/g require follow-up liver 
biopsy in subjects ≥ 18 years of age. In subjects < 18 years of age, these MRI findings 
are exclusionary, unless in the opinion of the Investigator, a liver biopsy could 
provide additional data to confirm eligibility and would be safe to perform. If a liver 
biopsy is performed based on MRI findings, any evidence of cirrhosis, bridging 
fibrosis, or significant active hepatitis will be exclusionary.  
14. For subjects who have history of iron overload or serum ferritin levels > 1000 ng/mL, a 
cardiac MRI is required. Cardiac T2* < 10 ms results in exclusion. 
15. Contraindication to anesthesia. 
16. Any contraindications to the use of plerixafor during the mobilization of HSCs and any 
contraindications to the use of busulfan and any other medicinal products required during 
the myeloablative conditioning, including hypersensitivity to the active substances or to 
any of the excipients. 
17. Any prior or current malignancy or immunodeficiency disorder, except previously 
treated, non-life threatening, cured tumors such as squamous cell carcinoma of the skin.  
18. Prior receipt of an allogeneic transplant.  
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19. Immediate family member with a known or suspected Familial Cancer Syndrome 
(including but not limited to hereditary breast and ovarian cancer syndrome, hereditary 
non-polyposis colorectal cancer syndrome, and familial adenomatous polyposis). 
20. Diagnosis of significant psychiatric disorder of the subject that, in the Investigator’s 
judgment, could seriously impede the ability to participate in the study. 
21. Pregnancy, or breastfeeding in a postpartum female, or absence of adequate contraception 
for fertile subjects. Females of childbearing potential must agree to use a medically 
acceptable method of birth control such as oral contraceptive, intrauterine device, barrier 
and spermicide, or contraceptive implant/injection from time of consent through at least 
6 months after drug product infusion. Male subjects must agree to use effective 
contraception (including condoms) from Conditioning through at least 6 months after 
drug product infusion.   
22. Participation in another clinical study with an investigational drug within 30 days of 
Screening. 
23. Previous Exclusion Criterion #23 is no longer applicable as of Protocol Amendment 8.0. 
24. Prior receipt of gene therapy. 
25. Previous Exclusion Criterion #25 is no longer applicable as of Protocol Amendment 9.0.  
26. An assessment by the Investigator that the subject or parents/caregivers (as required) will 
not be able to comply with the study procedures outlined in the study protocol. 
27. Patients needing therapeutic anticoagulation treatment during the period of conditioning 
through platelet engraftment (patients on prophylactic doses of anticoagulants not 
excluded per this criteria). 
28. Unable to receive RBC transfusion.   
29. Any other condition that would render the subject ineligible for HSCT, as determined by 
the attending transplant physician. 
30. Applicable to subjects < 18 years of age only: Availability of a willing, matched 
HLA‑identical sibling hematopoietic cell donor. 
4.4. 
Subject Screening and Registration 
Subjects willing to participate in the study will provide written informed consent according to 
Good Clinical Practice (GCP). Written informed consent must be obtained before the conduct of 
any Screening tests. 
Upon signing the informed consent, the subject will be registered and assigned a unique subject 
number. Once a subject number has been assigned, it cannot be reused. If the subject is 
re-enrolled after discontinuation, he/she will be assigned a new unique subject number. 
4.5. 
Subject Withdrawal from the Study 
Subjects have the right to withdraw from the study at any time for any reason. After giving 
informed consent and assent (as applicable), subjects may withdraw or be withdrawn from study 
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related procedures and treatments (e.g., apheresis, busulfan conditioning) under the following 
conditions: 
• withdrawal of consent or assent 
• the subject is unable to comply with protocol-defined visits or other requirements of 
the protocol 
• pregnancy prior to conditioning 
• adequate cells are not collected during harvests, or failure of transduced cells to be 
dispositioned for clinical use 
• any medical condition which, in the opinion of the Investigators, would put the 
subject at risk for continuing treatment or follow-up studies 
Although subjects have the right to withdraw from the study at any time, withdrawal after the 
start of conditioning and before administration of the drug product is strongly discouraged, as 
this would be considered deleterious to the subject. In such cases, it is likely that rescue will be 
required using the subject’s stored unmanipulated HSCs (rather than transduced cells). 
For subjects who withdraw consent or assent (if relevant), no further data will be collected on 
the subject; if they have received drug product, they are expected to enroll in the long-term 
follow-up study.  
For subjects who withdraw for reasons other than withdrawal of consent, any SAEs open at the 
time of discontinuation should be followed up until resolution or are determined to be a stable or 
chronic condition. See also Section 6.2.30.1 for AEs monitoring of subjects who withdraw from 
the study. 
• If withdrawal is before drug product infusion, subjects should remain on study for at 
least 30 days after any invasive study procedure (e.g., mobilization, liver biopsy) 
before withdrawal. In the rare case a subject undergoes myeloablation and receives 
back-up cells instead of bb1111, subject should remain on the study for at least 3 
months post myeloablation. 
• If subject withdraws after drug product has been manufactured but before infusion, 
the drug product may be shipped to bluebird bio for additional process development 
and characterization studies. 
• If withdrawal is after drug product infusion, subjects will be asked to complete the 
same assessments as specified in the Schedule of Events (SOE) for Month 24 
(Early Termination Visit assessments) and are expected to enroll in the long-term 
follow-up study. 
Subjects withdrawn from the study prior to drug product infusion may be replaced. 
4.6. 
Screen Failures 
Subjects are Screen Failures if: 
• They sign the main informed consent form, but cannot finish assessments for 
Screening or are ineligible based on those assessments 
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Data collected on Screen Failure subjects will only include: 
• Demography 
• Eligibility criteria for which subject was ineligible or did not finish assessment 
• Note: Serious adverse events (SAEs) must still be immediately reported for Screen 
Failure subjects from consent until the time they are determined to be a Screen 
Failure 
Upon consultation with the Medical Monitor, screen-failed subjects may be allowed to re-screen 
to be assessed for eligibility to enter the study.  
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5. 
STUDY TREATMENTS 
5.1. 
Description of bb1111 
BB305 Lentiviral Vector: BB305 LVV is a replication defective, self-inactivating, HIV-1 based 
LVV, pseudotyped with the vesicular stomatitis virus G envelope protein, carrying the human 
β-globin gene with a single modification in the coding region at codon 87 (βA87 Thr:Gln 
[βA-T87Q]). 
bb1111: bb1111 is defined as an autologous CD34+ cell-enriched population from patients with 
sickle cell disease that contains HSCs transduced with BB305 LVV encoding the βA-T87Q-globin 
gene, suspended in cryopreservation solution. 
5.2. 
Summary of Treatments to be Performed or Administered 
5.2.1. 
Transfusion Regimen Prior to Drug Product Infusion 
For at least 60 days prior to stem cell harvest and continuing through until the start of 
conditioning, subjects will undergo a transfusion regimen (exchange or simple, as available or 
needed) to reach a target Hb of 10 g/dL prior to mobilization (and 8 to 10 g/dL prior to 
conditioning; not to exceed 12 g/dL prior to either mobilization or conditioning) and a 
pre-transfusion target HbS proportion in the blood of < 30% to reduce the risk of SCD-related 
complications. The last exchange transfusion must occur within 4 days of start of mobilization, 
and the HbS proportion in the blood must be < 20% after the last exchange transfusion.  
If a subject experiences an SCD-related crisis within 1 month of the start of mobilization, the 
transfusion regimen will be adjusted, and mobilization will be postponed until the subject is 
crisis-free for a period of 1 month. In case of iron overload, subjects should be adequately 
chelated; however, iron chelation must be discontinued at least 7 days prior to stem cell harvest. 
It may be restarted between completion of the stem cell harvest(s) and admission to the hospital 
for myeloablation but should be stopped again at least 7 days before initiating myeloablation. 
Subjects who are not documented to have met these parameters or who have experienced any 
significant new sickle-related complications within 1 month of the start of mobilization will 
require additional approval from the Medical Monitor before undergoing mobilization/apheresis.  
While simple transfusions may be utilized for the majority of the transfusion period, it is strongly 
recommended that approximately 24 to 48 hours prior to receiving plerixafor for mobilization, an 
exchange transfusion (rather than simple transfusion) be performed in an attempt to ensure that 
the HbS proportion in the blood is < 20%.  
5.2.2. 
Stem Cell Harvest: Bone Marrow 
See flow diagram for study design in Section 3.1. 
Subjects in Groups A and B1 underwent bone marrow harvest for both manufacture of drug 
product and back-up cells.  
Subjects in Group B2 underwent mobilization with plerixafor and apheresis for collection of 
back-up cells and exploratory manufacturing development. 
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Subjects in Group C will undergo mobilization with plerixafor and apheresis for both 
manufacture of drug product and back-up cells. Group C subjects for whom adequate HSCs are 
collected to achieve the minimum cell dose but not for rescue, and who are not able to tolerate 
further plerixafor or did not mobilize well with plerixafor may be offered the option of bone 
marrow harvest for collection of back-up cells only, provided that drug product manufactured 
from mobilized cells has met criteria for dispositioning for clinical use. More than 1 bone 
marrow harvest is allowed if needed to obtain the minimum cell number required for potential 
rescue, provided that each bone marrow harvest is separated by at least 4 weeks. 
Bone marrow harvest should be performed under general anesthesia and using sterile 
precautions, as per local procedures at the clinical site. Subjects should be monitored for safety 
as per local procedures for a bone marrow harvest, which must include vital signs and physical 
exam prior to the procedure and then again prior to discharge. Sickle red cells collected during 
the harvest procedure are prone to clumping when placed in the hypoxic environment of the bag; 
therefore, efficient collection, anti-coagulation, and frequent mixing of the collected bone 
marrow is strongly advised. The bone marrow aspirated should not exceed 20 mL/kg with the 
aim of obtaining a TNC count of ≥ 1 × 108/kg per subject.  
Note: as of Protocol Amendment 8.0, bone marrow harvest can no longer be used to collect stem 
cells for drug product manufacture. Under Protocol Amendment 7.0, each subject in Group B, 
for whom bone marrow manufacture was planned underwent a minimum of 2 bone marrow 
harvests, separated by at least 4 weeks. More than 2 bone marrow harvests were allowed if 
needed to obtain additional cells for manufacture and potential rescue (to meet the cell dose 
minimum), provided that each bone marrow harvest was separated by at least 4 weeks. When 
more than 1 bone marrow harvest was used to produce bb1111, then separate drug products were 
manufactured, release tested and dispositioned from each harvest, but infused on the same day to 
meet criterion for a single dose. 
5.2.3. 
Mobilization and Apheresis Procedure 
See flow diagram for study design in Section 3.1. 
Subjects in Group B2 underwent mobilization with plerixafor and apheresis for collection of 
back-up cells prior to undergoing bone marrow harvest for drug product manufacture (with bone 
marrow harvest for drug product manufacture occurring at least 14 days after the last apheresis 
session). Subjects in Group B2 who tolerated plerixafor mobilization and underwent successful 
apheresis with adequate collection of back-up cells were given the option to defer bone marrow 
harvest for drug product manufacture and instead wait for Group C to open and undergo drug 
product manufacture using plerixafor-mobilized and apheresed cells. 
Subjects in Group C undergo mobilization and apheresis both for collection of back-up cells 
and manufacture of drug product. Administration of aspirin (80 to 325 mg) is recommended 
(between 12 hours and 30 minutes prior to initiation of apheresis). Subjects undergoing 
mobilization/apheresis should remain in the supine position to minimize symptoms 
(including hypotension) from plerixafor dosing through the end of apheresis each day. Placement 
of a central venous catheter prior to mobilization is highly recommended to ensure adequate flow 
rate during apheresis. Platelet count should be confirmed to be ≥ 100 × 109/L within 12 hours 
before the first day of apheresis session in the Cycle. Following plerixafor administration, 
subjects will be monitored for AEs, e.g., hypotension, syncope, hypoxia, per institutional 
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practice. Throughout apheresis, subjects will have frequent measures of heart rate, blood 
pressure, and pulse oximetry, e.g., every 20 minutes for adults, and every 10 minutes for 
pediatric subjects. If additional apheresis days are required, platelet counts must be confirmed to 
be ≥ 75 × 109/L within 24 hours of subsequent apheresis sessions, prior to administration of 
plerixafor on that day. If platelet counts do not meet these criteria, mobilization and apheresis 
should be deferred until platelet counts recover to ≥ 75 × 109/L. A separate manual on apheresis 
requirements and recommended parameters will be provided.  During the entire time frame 
leading up to, during and after mobilization and apheresis, close attention should be paid to 
anticipation and management of pain and anxiety, repletion of electrolyte imbalances, and 
adequate hydration. 
Group B2 (no further enrollment): 
If fewer than 1.5 × 106 CD34+ cells/kg are obtained during the initial apheresis session, and the 
subject has tolerated this session, then the subject must wait for a period of at least 14 days to 
initiate the next apheresis procedure (Mobilization Cycle 2, Apheresis Day 1; see Figure 2).  
During mobilization/apheresis, subjects will be monitored for evidence of plerixafor-associated 
toxicity.  
Plerixafor dosing of initial subjects in Group B2 (enrolled under Protocol Version 6.0) was 
staggered. Data Monitoring Committee members reviewed the AE profile during plerixafor 
treatment in mobilization Cycle 1 for the first subject treated in Group B2 and planned to 
adjudicate on any issues of potential safety significance that could affect determination of 
DLT before dosing of the second subject with plerixafor. A similar procedure was followed after 
dosing of the second subject in order to permit dosing of the third subject. The DMC reviewed 
aggregate safety data in Group B2 after 3 subjects had been dosed and confirmed that there are 
no safety concerns precluding dosing of subjects in Group C with plerixafor. See also 
Section 3.2. 
Subjects unable to tolerate plerixafor mobilization may be offered bone marrow harvests for 
collection of back-up cells and for drug product manufacture. Subjects who do tolerate plerixafor 
mobilization will be given the option of waiting for Group C to open for drug product 
manufacture.  
Figure 2 below depicts the mobilization and apheresis plan for collection of back-up cells from 
subjects in Group B2. If plerixafor is tolerated, and ≥ 1.5 × 106 CD34+ cells/kg are collected 
during Mobilization Cycle 1, then 1.5 × 106 CD34+cells /kg will be stored for rescue, and any 
remaining cells will be sent to the Sponsor for exploratory manufacturing development 
(minimum of 0.5 × 106 CD34+ cells/kg required in shipment).  
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Figure 2: 
Mobilization and Apheresis Plan for Back-up Cell Collection (Group B2) 
 
 
If < 1.5 × 106 CD34+ cells/kg are collected during the first mobilization cycle, all of these cells 
will be sent to the Sponsor for exploratory process development work, and a second mobilization 
cycle may be performed (14 days after the completion of Mobilization Cycle 1), if the subject 
tolerated the first cycle of mobilization. 
After successful mobilization and apheresis of back-up cells, subjects may undergo bone marrow 
harvests for drug product manufacture at least 14 days after the last apheresis session. See 
Section 5.2.2 for details surrounding bone marrow harvest. All cells collected from bone marrow 
will be sent to the transduction facility and utilized for drug product manufacture. 
If < 1.5 × 106 CD34+ cells/kg are recovered in the second cycle of mobilization, as well as in the 
first, then the subject will be considered an apheresis failure, all recovered cells will be sent to 
the Sponsor (minimum of 0.5 × 106 CD34+ cells/kg required in shipment), and the subject will 
proceed to bone marrow harvest at least 14 days after completion of the last 
mobilization/apheresis cycle, for both back-up cell isolation and drug product manufacture.  
If ≤ 1 of 3 subjects receiving plerixafor in Group B2 has a DLT during Cycle 1 of mobilization, 
then Group C may begin dosing with plerixafor. 
If > 1 of 3 subjects receiving plerixafor in Group B2 has a DLT during Cycle 1, then a dose of 
plerixafor ≥ 0.16 and < 0.24 mg/kg may be investigated for mobilization in up to an additional 
3 to 6 subjects. Treatment scheme will be as described above. 
Group C: 
Once the safety and tolerability of plerixafor had been confirmed in Group B2 and regulatory 
authorities approved the drug product manufacturing process with plerixafor-mobilized HSCs, 
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subjects began dosing with plerixafor in Group C. The first 2 subjects in Group C received drug 
product infusion in a staggered fashion: neutrophil engraftment was required to occur in the first 
subject treated in Group C before busulfan conditioning could be initiated for the second subject. 
For subjects in Group C, plerixafor dose is 0.24 mg/kg. Apheresis should begin approximately 
4 to 6 hours after plerixafor administration. If more than 1 apheresis day is required, platelet 
counts must be confirmed to be ≥ 75 × 109/L within 24 hours of subsequent apheresis sessions, 
prior to administration of plerixafor on that day. If platelet counts do not meet these criteria, 
mobilization and apheresis should be deferred until platelet counts recover to ≥ 75 × 109/L. For 
subjects undergoing more than 1 mobilization cycle, each cycle must be separated by at least 
14 days. Subjects will receive daily plerixafor prior to each apheresis collection. A 3rd day of 
mobilization and apheresis (to be used for collection of back-up cells only) may be permitted 
only after prior discussion with the Medical Monitor and if the subject tolerated prior plerixafor 
and apheresis. If a sufficient number of cells are collected after the first mobilization cycle, no 
further mobilization/apheresis is required. 
For Group C subjects, collection of cells for drug product manufacture will be prioritized over 
collection of cells for rescue. Subjects for whom back-up cells have already been collected 
(e.g., participation in Group B2) underwent a separate mobilization/apheresis cycle or bone 
marrow harvest during which all cells collected were submitted for drug product manufacture.  
The schematic below (Figure 3) outlines the plans for plerixafor mobilization and apheresis in 
Mobilization Cycles 1 and 2 and beyond for subjects in Group C. 
 
Figure 3: 
Mobilization and Apheresis Plan (Group C) 
 
 
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If plerixafor is tolerated, and ≥ 16.5 × 106 CD34+ cells/kg are collected after the first apheresis 
procedure of mobilization cycle 1, then 1.5 × 106 cells/kg will be saved for rescue and the 
remainder of cells will be sent to the transduction facility for drug product manufacture (as per 
the Study Operations Manual). If the site is unable to split the collection, then send all cells for 
drug product manufacture, and collect back-up cells during Apheresis Day 2 of mobilization 
cycle 1. CD34+ cells for rescue should be stored indefinitely at the clinical site or per local 
procedures.  
If the Apheresis Procedure Day 1 collection of mobilization cycle 1 is < 16.5 × 106 CD34+ 
cells/kg, this collection should be held overnight, at a controlled storage facility at the clinical 
site (should be shipped immediately to the transduction facility if storage is not possible; 
minimum of 1.0 × 106 CD34+ cells/kg required in shipment), and the subject should return for 
Apheresis Procedure Day 2. If the combined yield from Days 1 + 2 of mobilization cycle 1 is 
≥ 16.5 × 106 CD34+ cells/kg, then 1.5 × 106 cells/kg will be saved for rescue, and the remainder 
of cells will be sent to the transduction facility for drug product manufacture. If the combined 
yield from Days 1 + 2 is 2.5 to 16.5 × 106 CD34+ cells/kg, then all cells will be shipped for drug 
product manufacturing, and cells for rescue may be collected during a third day of apheresis in 
the mobilization cycle, or alternatively, during an additional mobilization cycle that occurs at 
least 14 days after the last apheresis day of the prior mobilization cycle, at the discretion of the 
Investigator and Medical Monitor. If the Day 1 + 2 combined yield is 
< 2.5 × 106 CD34+ cells/kg, then up to 1.5 × 106 CD34+ cells/kg will be saved for rescue, with 
remaining cells shipped for process development, and a second mobilization cycle will be 
required for collection of cells for drug product manufacturing. If fewer than 
1.5 × 106 CD34+ cells/kg were collected during mobilization cycle 1, all cells will be sent to 
bluebird bio, and collection of cells for both drug product manufacturing and rescue will occur in 
mobilization cycle 2. 
If after drug product manufacture is complete at the central manufacturing facility, a total of 
< 3.0 × 106 CD34+cells/kg are obtained in the final drug product, or if drug product fails to meet 
specifications for any reason, subjects may undergo repeat apheresis and manufacture of new 
drug product, which should occur no sooner than 14 days after completion of the most recent 
mobilization/apheresis cycle.  
Group C subjects for whom adequate HSCs are collected to achieve the minimum cell dose but 
not for rescue, and who are not able to tolerate further plerixafor or did not mobilize well with 
plerixafor may be offered the option of bone marrow harvest for collection of back-up cells only, 
provided that drug product manufactured from mobilized cells has met criteria for dispositioning 
for clinical use. More than 1 bone marrow harvest is allowed if needed to obtain the minimum 
cell number required for potential rescue, provided that each bone marrow harvest is separated 
by at least 4 weeks. 
5.2.4. 
Transduction Process, Storage of Drug Product, Packaging and Labeling, and 
Traceability 
All cell manipulation procedures will be performed in transduction facilities in accordance with 
Current Good Manufacturing Practices following process-specific procedures.  
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The subject’s CD34+ cells transduced with BB305 LVV are stored and frozen in 
cryopreservative solution (containing 5% dimethyl sulfoxide) in the vapor phase of liquid 
nitrogen at the transduction facility until release testing and dispositioning. 
In some circumstances, drug product that does not meet the established specification may be 
administered. This requires justification of medical need as assessed by the Investigator and the 
Sponsor's Responsible Medical Officer. The subject must be informed and, if applicable, a 
notification to the appropriate IRBs/ECs and regulatory agency(ies) must occur prior to the start 
of myeloablative conditioning. 
The drug product will be labeled by the transduction facility according to Good Manufacturing 
Practices, and detailed records will be maintained to allow for accurate traceability of the drug 
product, to ensure that the drug product is administered to the original donor. 
Refer to Section 5.7 (Product Accountability) and the Study Operations Manual (SOM) for 
details regarding traceability. 
Note that samples routinely collected as part of the process of manufacturing the drug product 
may be used to study the manufacturing process. In particular, these samples may be used to 
understand how the process may be improved or made more robust. Additionally, these samples 
may be analyzed if clinically indicated. 
If more than 1 stem cell harvest is necessary to produce the minimum cell dose of bb1111, they 
will be manufactured, release tested, and dispositioned independently as separate drug products, 
but infused on the same day to meet criterion for a single dose. 
5.2.5. 
Conditioning 
5.2.5.1. 
Busulfan Dosing 
Myeloablative conditioning of the subject will be performed using busulfan. Conditioning will 
only begin after the following criteria are met: 
• all drug product lots to be used for the subject have been release tested, dispositioned 
for clinical use, and stored at the clinical site 
• a sufficient number of back-up cells has been collected and stored at the clinical site  
• the subject has undergone interim assessments for updated medical history, AE, 
concomitant medications, physical examination, vital signs, and laboratory tests, all 
as per the SOE, and continues to meet the eligibility criteria based on these results 
• subjects have undergone a transfusion regimen (Hb > 10 g/dL and HbS < 30%) and 
are off HU for at least 2 days and iron chelation for at least 7 days prior to the start of 
conditioning 
• results of conventional cytogenetics (karyotyping) and cytogenetics by FISH from the 
bone marrow have been received and reviewed by the Investigator and the Medical 
Monitor; in the presence of a chromosomal abnormality or genetic mutation that does 
not render the subject ineligible for HSCT per the Investigator's judgment, approval 
of the Medical Monitor is required before the subject can proceed with conditioning 
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(see Section 6.2.11) and subject must sign appropriate informed consent before 
proceeding with conditioning and treatment with bb1111. 
Busulfan will be administered at a starting dose of 3.2 mg/kg/day for 4 consecutive days via 
IV infusion on Days -6 through -3. The preferred schedule is busulfan via a central venous line 
(CVL) as a 3-hour infusion once daily for 4 consecutive days for a total of 4 doses. Divided 
dosing is permitted. In this case, busulfan should be administered as a 2-hour infusion every 
6 hours for 16 consecutive doses. For subjects weighing < 35 kg, a q6h dose of 0.8 mg/kg is 
preferred; for subjects weighing ≥ 35 kg, either once daily (qd) or q6h dosing can be used, at the 
discretion of the Investigator. Please note that the timing of busulfan PK sample collection is 
based on whether a 2-hour or 3-hour infusion is used. 
Clinical sites that use a test dose of busulfan before myeloablation to pre-determine the busulfan 
pharmacokinetics and predict an optimal dose may do so in this protocol. The recommended test 
dose of busulfan is 0.8 mg/kg, administered approximately 3 to 10 days before planned initiation 
of conditioning. Note that clinical sites must be able to measure first and third day busulfan PK, 
as described below. 
5.2.5.2. 
Pharmacokinetics for Busulfan Dose Adjustments 
The dose of busulfan will be adjusted based upon busulfan PK in order to maintain appropriate 
levels for myeloablation (AUC goal of 1250 [range 1100 to 1350] µM*min for a q6h dosing 
regimen, or 5000 [range 4400 to 5400] µM*min for a qd dosing regimen). The dosage should be 
calculated on the basis of the lower of the ideal versus actual body weight. The dose may be 
adjusted appropriately based upon actual plasma busulfan levels observed. Clinical sites must be 
able to measure first and third day busulfan PK. Based on busulfan PK results for day 1 and day 
3 of busulfan dosing, busulfan dose adjustments should be made for subsequent dosing. If 
feasible, daily busulfan PK measurement is recommended. It is recommended that the busulfan 
clearance rate is also calculated. 
Instructions for once daily dosing: Samples for busulfan concentration should be collected at the 
end of the 3-hour infusion, 195 minutes after start of infusion, and 4, 5, 6, and 8 hours after the 
start of the infusion. Samples should not be drawn from the lumen used to infuse busulfan.  
Instructions for q6h dosing: Samples for busulfan concentration should be collected at the end of 
the 2-hour infusion, 135 minutes after start of infusion, 150 minutes after start of infusion, and 
3, 4, 5, and 6 hours after the start of the infusion. Samples should not be drawn from the lumen 
used to infuse busulfan.  
After completion of the 4-day course of busulfan, there must be a minimum of 48 hours before 
drug product infusion to achieve optimal engraftment. Busulfan levels will be measured 48 and 
72 hours after final dose of busulfan for retrospective confirmation of adequate wash-out. 
5.2.6. 
Drug Product Infusion Procedures, Dose, and Administration 
Pre-hydration and pre-medication of the subject are not required and should follow local 
procedures for bone marrow infusion at the clinical site.  
Prior to administration, bb1111 is thawed at the clinical site (typically in a 37°C water bath), and 
the infusion of the drug product should be completed immediately after thawing and within a 
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maximum of 4 hours of its thawing. All procedures involving bb1111 must be performed using 
aseptic techniques by trained personnel. 
bb1111 will be administered on Day 1 via IV infusion at the clinical site. The dose to be 
administered is ≥ 3.0 × 106 CD34+ cells/kg (for mobilized apheresed cells). Subjects who 
undergo more than 1 stem cell collection procedure (and subsequent transduction of those cells) 
will have more than 1 drug product lot, which should be administered in sequence, with one 
administered immediately after the other. Disposition of back-up cells collected and/or partial 
drug product manufactured under a prior version of the protocol will be made after discussion 
between the Investigator and Medical Monitor.  
Vital signs are to be monitored concurrently during drug product infusion no less frequently than 
at the start, once during, and upon completion of the infusion. Infusion reactions, including 
anaphylaxis, will be managed according to the medical judgment of the physician overseeing the 
infusion. 
5.3. 
Method of Assigning Subjects to Treatment 
Seven subjects who consented and received drug product under version 5.0 (or earlier) of the 
protocol were retrospectively assigned to Group A, in which both drug product and back-up cells 
were derived from bone marrow.  
In addition to the above 7 subjects, 1 subject who had consented under version 5.0 of the 
protocol, but had not yet been treated with drug product, was reconsented under protocol version 
6.0 and participated in Group B1. 
Subjects initially consented under version 6.0 of this protocol were part of Group B or C. In 
Group B1, both drug product and back-up cells were derived from bone marrow. In Group B2, 
plerixafor mobilization and apheresis were used for collection of back-up cells and exploratory 
manufacturing development prior to undergoing bone marrow harvest for drug product 
manufacture. At least 3 subjects were required to enroll in Group B, and at least 3 subjects in 
Group B2 were required for evaluation of DLT at each dose of plerixafor. 
Group C was opened upon (1) confirmation of the safety and tolerability of plerixafor 
mobilization in Group B2, and (2) regulatory authority approval of the drug product 
manufacturing process with plerixafor-mobilized HSCs. In Group C, both drug product and 
back-up cells are derived from HSCs collected by plerixafor-mobilized apheresis.  
Subjects in Group B2 who tolerated and successfully mobilized with plerixafor for back-up cells, 
and who had not yet had drug product manufactured with bone marrow harvest, were given the 
option to delay collection of cells for drug product manufacture until Group C opened, and they 
could undergo drug product manufacture from cells obtained by a subsequent cycle of plerixafor 
mobilization. 
Subjects in Group C will undergo mobilization with plerixafor and apheresis for both 
manufacture of drug product and back-up cells. Group C subjects for whom adequate HSCs 
are collected to achieve the minimum cell dose but not for rescue, and who are not able to 
tolerate further plerixafor or did not mobilize well with plerixafor may be offered the option 
of bone marrow harvest for collection of back-up cells only, provided that drug product 
manufactured from mobilized cells has met criteria for dispositioning for clinical use.  
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5.4. 
Blinding, Packaging and Labeling 
5.4.1. 
Blinding and Breaking the Blind 
This is an unblinded, open-label study. 
5.4.2. 
Packaging and Labeling 
bb1111 consists of an autologous CD34+ cell-enriched population from patients with SCD that 
contains HSCs transduced with BB305 LVV encoding the βA-T87Q-globin gene, suspended in 
cryopreservation solution in the final infusion bag. 
The drug product will be labeled by the transduction facility according to Good Manufacturing 
Practices. Refer to Section 5.7 for additional details regarding product accountability. 
5.5. 
Duration of Subject Participation 
Time between Screening and drug product infusion will be variable and is estimated generally to 
be between 3 to 5 months (e.g., up to 3 months between Screening and Mobilization, followed by 
approximately 2 months before drug product infusion). Thereafter the subject is planned to 
remain on study for approximately 24 months. Eligible subjects are then expected to enroll in a 
separate long-term follow-up study until approximately 15 years post-drug product infusion. For 
subjects enrolled in Group B2 who opted to defer manufacture of drug product until Group C 
opened, the time between Screening and drug product infusion was extended as long as the 
subject continued to meet eligibility criteria.   
If the subject is unable to undergo mobilization for drug product manufacture within 
approximately 3 months of the initiation of Screening, some assessments may need to be 
repeated to confirm continuing eligibility or to provide a reliable baseline prior to study 
procedures. In particular, physical exam, vital signs, performance status, HRQoL, 
echocardiogram, complete blood count, chemistry, urinalysis, and liver function tests, and for 
women of child-bearing potential, tests for pregnancy, must be performed within 3 months of 
proceeding to evaluation for mobilization. For subjects with exposure risks for HIV, HBV and 
HCV, these tests should also be repeated. Some of these assessments may be performed 
immediately prior to mobilization, as specified in the SOE. Where clinically and/or regionally 
indicated, other tests for infectious pathogens may be performed, as required by regional 
regulations or at physician discretion. Other blood tests, including those for immune subsets, 
hormonal or dyserythropoiesis testing only need to be repeated if more than 6 months have 
transpired, unless there is clinical concern due to an initial screening test (e.g., borderline thyroid 
function). Cerebral MRA/MRI and echocardiogram performed within 3 months of ICF and PFT 
results performed within 6 months of ICF may be used, unless there is clinical indication for 
repeat testing, or initial testing was borderline. The need for liver biopsy should be guided by 
MRI findings, as described in the protocol, unless a biopsy performed within 1 year of 
mobilization exhibited no evidence of fibrosis or hepatitis. Sickle cell disease genotyping, 
baseline VCN, baseline RCL and baseline βA-T87Q-globin, once performed, do not have to be 
repeated. 
Subjects who enroll in the trial but discontinue prior to myeloablation should be followed for at 
least 1 month after completion of harvesting, or until resolution of any study procedure-related 
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AEs, whichever is later. In the rare case a subject undergoes myeloablation but does not undergo 
drug product infusion, follow up should continue on trial for at least 3 months, or until resolution 
of any study-procedure related AEs, whichever is later. 
5.6. 
Assessment of Treatment Compliance 
Eligible subjects will receive bb1111 on a single day as inpatients and thus will be monitored by 
hospital personnel. 
5.7. 
Product Accountability 
Drug product accountability and traceability is ultimately the responsibility of the Investigator 
and Sponsor. However, this responsibility may be delegated to suitably qualified personnel listed 
on Food and Drug Administration (FDA) Form 1572 who have had appropriate study-specific 
training and whose names have been appropriately listed on the Delegation of Responsibility 
Log for this task. 
Detailed records will be maintained to allow for accurate accountability of the drug product as 
per applicable Sponsor and clinical site procedures. These records will include details of storage 
of the drug product, transfer of the drug product from the transduction facility, administration to 
subjects, and disposal of remaining materials.  
In the event that drug product cannot be administered due to triggering of stopping rules or other 
reasons, drug product will be kept cryopreserved in the vapor phase of liquid nitrogen until 
further instruction by the Sponsor.  
All material containing bb1111 will be treated and disposed of as hazardous waste in accordance 
with governing regulations and clinical site procedures 
5.8. 
Prior and Concomitant Medication 
5.8.1. 
Prior Medication 
All medications taken within 30 days prior to the Screening Visit are to be recorded in the Prior 
and Concomitant Medication case report form (CRF). Note additional requirements for 
collection of HU and pRBC transfusion history as detailed in Section 6.2.1 and Section 6.2.2. 
5.8.2. 
Concomitant Medications and Therapies 
All concomitant medications and therapies (i.e., those that are taken by the subject after signing 
the informed consent form [ICF]) should be documented. 
Instructions and/or restrictions regarding specific concomitant medications and therapies are 
listed below. Concomitant medications and therapies not explicitly listed below may be used at 
the discretion of the treating physician and as per local standard of care.  
• Granulocyte colony stimulating factor (G-CSF): G-CSF should not be used prior to 
Day 43 without explicit approval from the bluebird bio Medical Monitor.  
• Venous access: Subjects will have appropriate long-term central venous access 
placed, per institutional standard practice, prior to beginning the preparative regimen. 
For subjects planned to undergo apheresis, placement of central venous access prior 
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to the first dose of plerixafor is strongly advised. For access, a double lumen tunneled 
catheter is recommended. 
• Hydroxyurea: Hydroxyurea must be discontinued at least 30 days prior to stem cell 
harvest. It may be restarted between completion of the stem cell harvest(s) and 
admission to the hospital for myeloablation but should be stopped again at least 
2 days before initiating myeloablation. Following HSC transplant, HU is not 
permitted without prior discussion with and explicit approval of the Sponsor’s 
Medical Monitor. 
• Erythropoietin: Erythropoietin is excluded and must be discontinued 60 days prior to 
stem cell harvest, as it may prevent engraftment of the transduced cells. Following 
HSC transplant, erythropoietin is not permitted without prior discussion with and 
explicit approval of the Sponsor’s Medical Monitor. 
• L-glutamine, crizanlizumab, and voxelotor: Following HSC transplant, medications 
other than blood transfusions to treat sickle cell disease or anemia (e.g., HU, 
erythropoietin, L-glutamine, crizanlizumab, voxelotor) are not permitted without 
prior discussion with and explicit approval of the Sponsor’s Medical Monitor. 
• Iron chelation therapy: Iron chelation therapy must be discontinued at least 7 days 
prior to stem cell harvest and conditioning. Phlebotomy or iron chelation therapy 
using deferasirox or deferoxamine may be restarted at the discretion of the treating 
physicians no sooner than after discharge from the hospital post-transplant. 
Deferiprone use is not permitted without prior discussion with and explicit approval 
of the Sponsor’s Medical Monitor. Deferiprone may be used no sooner than 3 months 
after transplant due to the potential risk of myelosuppression (as per prescribing 
information for Deferiprone).  
• Seizure prophylaxis: Starting at least 12 hours prior to the first dose of busulfan for 
conditioning, subjects will be treated with anticonvulsants for seizure prophylaxis. 
The choice of anticonvulsant is at the discretion of the treating physician, but 
phenytoin is not allowed. Seizure prophylaxis can be discontinued 24 hours after the 
last dose of busulfan. 
• Subjects should not use medications with anti-retroviral activity (such as those used 
for HIV prophylaxis) from within 1 month of initiating mobilization until after 
completion of stem cell collection for drug product manufacture. 
• pRBC Transfusions: A transfusion regimen will be implemented for at least 60 days 
before stem cell harvest, and will continue through until busulfan conditioning 
(exchange or simple, as available or needed) to reach a target Hb of 10 g/dL prior to 
mobilization (and 8 to 10 g/dL prior to conditioning; not to exceed 12 g/dL prior to 
either mobilization or conditioning) and a pre-transfusion target HbS proportion in 
the blood of < 30% to reduce the risk of SCD-related complications. The last 
exchange transfusion must occur within 4 days of start of mobilization (or within 
1 week of start of conditioning regimen), and the HbS proportion in the blood must be 
< 20% after the last exchange transfusion prior to mobilization, and < 30% after the 
last exchange transfusion prior to conditioning. Hemoglobin S should be quantified 
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prior to and (if possible) within 48 hours of transfusion. Subjects are recommended to 
continue transfusions during the pancytopenia phase to maintain Hb ≥ 8 g/dL. For 
subjects who were on a chronic transfusion regimen prior to study entry, once 
engrafted and discharged post-transplant, it is recommended that the frequency of 
routine pRBC transfusions be adjusted to maintain Hb ≥ 8 g/dL. Simple transfusions 
are recommended during this phase of follow-up and the period between transfusions 
will gradually be increased while maintaining safe HbS levels. Continued transfusion 
needs > 6 months post-treatment or any alternative plans should be discussed with the 
Medical Monitor. Following HSC transplant, medications other than blood 
transfusions to treat sickle cell disease or anemia (e.g., HU, erythropoietin, 
L-glutamine, crizanlizumab, voxelotor) are not permitted without prior discussion 
with and explicit approval of the Sponsor’s Medical Monitor. 
• Platelet transfusion parameters: during the hospitalization for transplantation, 
platelets should be transfused to maintain a platelet count of > 50,000/µL until 
platelet engraftment. After hospital discharge, subjects should get platelet count 
monitored approximately weekly and at least 8 days after the most recent platelet 
transfusion until platelet engraftment. Platelet engraftment is defined as 3 consecutive 
platelet count laboratory values ≥ 50 × 109/L obtained on different days while no 
platelet transfusions administered for 7 days immediately preceding and during the 
evaluation period. The day of platelet engraftment is the first day of the 3 consecutive 
platelet measurements. 
• Blood pressure in patients with SCD is often lower than “normal" for age. Subjects 
should be closely monitored and antihypertensive medications started at the earliest 
sign of hypertension to maintain blood pressure (both systolic and diastolic) within 
20% of the baseline.  
• Other concomitant therapies during conditioning may include hyperdiuresis, 
prophylactic or therapeutic administration of anti-emetics, and veno-occlusive disease 
prophylaxis, e.g., ursodeoxycholic acid. 
• See also next Section 5.8.3 for infection prophylaxis. 
For the purposes of this study, vaccines (e.g., COVID-19 vaccines) are considered concomitant 
medications. Although interactions between a vaccine and bb1111 are not expected, the protocol 
includes use of immunomodulatory (plerixafor) and immunosuppressive medication (busulfan). 
Local guidelines should be followed regarding a minimum time period between any medication 
to be provided as part of treatment with bb1111 and any vaccine; it is recommended that 
vaccines are not administered to subjects within 1 month of initiating mobilization for stem cell 
collection, within 1 week after receiving mobilization agents, within 1 month of initiating 
myeloablative conditioning, or within 6 months after drug product infusion. Revaccination post-
drug product infusion should be considered per Investigator's discretion due to potential loss of 
immunity after myeloablative conditioning and may be administered following local guidelines. 
The prescribing information of the vaccine administered should be referred to for the latest 
indication, contraindications and safety information as well as the latest general clinical 
recommendations on vaccine administration in the country or region. 
All vaccinations during the study period should be documented in the CRF. 
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5.8.3. 
Infection Surveillance and Prophylaxis 
Opportunistic infection surveillance and prophylaxis are recommended for subjects treated with 
bb1111 (see suggested approach below). Alternative approaches that follow institutional 
practices may be employed after discussion with the Medical Monitor.  
• In subjects with past exposure to HBV, regular monitoring of HBV DNA by PCR and 
pre-emptive lamivudine is advised for any increase in HBV DNA titer (HBV 
reactivation). Subjects should not use medications with anti-retroviral activity from 
within 1 month of initiating mobilization until after completion of stem cell collection 
for drug product manufacture. 
• Herpes simplex virus (HSV) prophylaxis: Acyclovir prophylaxis is recommended for 
at least 3 months after drug product infusion for patients who are sero-positive for 
HSV or varicella zoster virus (VZV). Where systemic VZV is a concern, acyclovir 
may be continued until either T cell recovery or anti-VZV response can be 
documented. 
• Pneumocystis pneumonia prophylaxis: Trimethoprim-sulphamethoxazole or an 
equivalent drug is recommended for at least 3 months after drug product infusion.  
• Penicillin prophylaxis is allowed for asplenic or hyposplenic subjects per institutional 
guidelines. 
• Fungal prophylaxis: Anti-fungal prophylaxis is recommended with agents such as 
Fluconazole for at least 3 months after drug product infusion.  
• Cytomegalovirus (CMV) surveillance: CMV should be tested per institutional 
practices.  Antiviral therapy for CMV reactivation should be commenced pre-
emptively if CMV testing reveals a high or rising viral load. If CMV reactivation 
occurs at or before engraftment, Foscarnet may be considered to prevent marrow 
suppression. 
• Adenovirus surveillance: Testing for adenovirus infection is recommended in the 
event of symptoms suspicious for infection such as diarrhea, hepatic dysfunction, 
respiratory symptoms, etc. If diagnosed with an active systemic infection, therapy 
should be instituted with cidofovir or other active agents. 
• Epstein-Barr virus (EBV) surveillance: EBV monitoring by PCR is recommended per 
institutional practices. In the event of persistent EBV viremia or signs/symptoms 
consistent with EBV-related PTLD (adenopathy, fever, etc.) therapy such as 
Rituximab is recommended. 
• BK virus, JC virus, and HHV-6 virus surveillance: Any patient diagnosed with 
progressive multi-focal leukoencephalopathy based on cerebral MRI will be 
monitored for BK, JC and HHV-6 viruses by blood PCR based methods. All patients 
with non-engraftment should be screened for HHV-6 infection. 
• Maintain Intravenous Immune Globulin (IgG) levels at > 400 mg/dL or as per 
institutional standards. 
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• Follow institutional post-transplantation guidelines for re-immunization of subjects 
[see (Dykewicz et al. 2000)]. 
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6. 
STUDY ASSESSMENTS 
6.1. 
Schedule of Events 
The study has 4 distinct stages, as follows. 
• Stage 1: 
Screening and Eligibility Assessments 
• Stage 2: 
Stem Cell Harvest and Drug Product Manufacture and Disposition 
• Stage 3: 
Myeloablative Conditioning and Infusion of bb1111 
• Stage 4: 
Follow-up through Month 24 
The Schedule of Events (SOE) to be performed is outlined in Table 2 for Stages 1 and 2, Table 3 
for Stage 3, and Table 4 for Stage 4.  
Detailed descriptions of the efficacy, pharmacodynamics, and safety procedures to be conducted 
during this study are provided in the following subsections. Additional details, including 
administrative information, will be provided in the Study Operations Manual. 
Evaluations and procedures identified in the SOE may be performed at unscheduled visits, as 
clinically indicated, at the Investigator’s discretion in consultation with the Sponsor. 
If a subject is not able to visit the study site due to force of nature (e.g., COVID-19 pandemic), 
then a telehealth visit should be considered to ensure appropriate oversight and safety 
monitoring. In addition to this, if the subject is able to visit a local doctor and/or laboratory, then 
pre-defined assessments may be performed at a local laboratory or doctor’s office, per 
Investigator discretion. 
Table 2: 
Schedule of Events: Screening and Stem Cell Harvest 
Procedure 
Screening 
(up to 
90 days 
before 
harvest 
Stem Cell Harvest 
Up to 7 
days 
before 
harvest 
Day(s) of 
apheresis (or 
bone marrow 
harvest)  
Signing of informed consent form (ICF)1 
X 
 
 
Demographics 
X 
 
 
Medical History, including all VOEs2 
X 
 
 
Physical examination3 
X 
X 
X 
Chronic pain assessment4 
X 
 
 
Performance status5 
X 
X 
 
Tanner staging (for subjects < 18 years of age) 
X 
 
 
Vital signs6 
X 
X 
X6 
Cardiovascular monitoring and oximetry 
 
 
X7 
Local lab: Blood for clinical laboratory tests: 
 
 
 
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Table 2: 
Schedule of Events: Screening and Stem Cell Harvest 
Procedure 
Screening 
(up to 
90 days 
before 
harvest 
Stem Cell Harvest 
Up to 7 
days 
before 
harvest 
Day(s) of 
apheresis (or 
bone marrow 
harvest)  
 
Hematology8 
X 
X 
X9 
 
Serum Chemistry10 
X 
X 
X 
 
Coagulation Analysis11 
X 
X 
 
 
Iron Metabolism Studies12 
X 
X 
 
 
Haptoglobin 
X 
X 
 
Local lab: Blood for hormonal testing13 
X 
 
 
Local lab: Urinalysis14 
X 
 
 
Local lab: Blood for serology 
X15 
X 
 
Local lab: Blood for immunological studies 
X16 
 
 
Screening for irregular antibodies 
X 
 
 
Local lab: Blood for serum β-human chorionic gonadotropin for 
women of child-bearing potential (serum pregnancy test) 
X 
X 
 
Local lab: Blood for brain natriuretic peptide (BNP) 
X 
 
 
Local lab: Blood for CD34+ cell count 
X 
 
X17 
Central lab: Blood for SCD genotyping 
X 
 
 
Central lab: Blood for RCL, VCN, and globin analysis 
X18 
 
 
Central lab: Blood for potential biomarker analysis (optional) 
X 
 
 
Specialty lab: Blood for methemoglobin assay 
X 
 
 
bluebird bio lab: Blood for 
PD 
X 
 
 
bluebird bio lab: HPC-A sample for 
 PD 
 
 
X19 
bluebird bio lab: Bone marrow for 
 PD 
X20 
 
 
Sperm / testicular tissue or oocyte banking, if requested 
X21 
 
 
Liver MRI (and liver biopsy, depending on MRI results), and cardiac 
MRI, if required22 
X 
 
 
Imaging studies: cerebral magnetic resonance angiography 
(MRA)/magnetic resonance imaging (MRI; TCD if ≤ 16 years of 
age), and echocardiogram (including LVEF and TRJV) 
X23 
 
 
Imaging studies: Bone mineral density evaluation 
X24 
 
 
Pulmonary function tests  
X25 
 
 
6-minute walk test 
X 
 
 
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Table 2: 
Schedule of Events: Screening and Stem Cell Harvest 
Procedure 
Screening 
(up to 
90 days 
before 
harvest 
Stem Cell Harvest 
Up to 7 
days 
before 
harvest 
Day(s) of 
apheresis (or 
bone marrow 
harvest)  
Transfusion regimen 
X26 
X26  
 
 
Local lab: Blood for electrophoresis to assess globin fractions 
(i.e., %HbS, %HbA) 
X27 
 
X27, 28 
X28  
Plerixafor dosing and apheresis (Group C) 
 
 
X29 
Bone marrow harvest (for collection of back-up cells, as applicable) 
 
 
X 
Quality of life tests: EQ-5D-3L/Proxy Version 1, EQ-5D-Y /Proxy 
Version 1, PROMIS-57 Version 2.1, PROMIS Pediatric 
Profile/Parent Proxy Profile 49 Version 2.0 
X30 
 
 
Work Productivity Assessment (WPAI)/Caregiver WPAI-GH 
X30 
 
 
Cognitive Function Assessments: PROMIS Short Form 6a 
X30  
 
 
Vaso-occlusive event collection 
Continuous from ICF signing 
Adverse event collection 
Continuous from ICF signing 
Prior and concomitant medications 
Continuous from ICF signing 
 
1 If a subject is < 18 years of age at signing of informed consent/assent and turns 18 while on study, the subject 
should re-consent to the adult ICF at the next scheduled study visit. 
2 See Section 6.2.1 and Section 6.2.2. 
3 Any leg (skin) ulceration noted upon physical exam or as part of medical history must include severity 
classification. 
4 Chronic pain will be assessed using the AAPT Diagnostic Criteria for Chronic Pain Associated with SCD (see 
Section 6.2.6). 
5 Karnofsky performance status (≥ 16 years of age) or a Lansky performance status (< 16 years of age). 
6 Vital signs include systolic/diastolic blood pressure, pulse, temperature, oxygen saturation, weight, and height 
(height only required at Screening). 
7 Following plerixafor administration, subjects will be monitored for AEs, e.g., hypotension, syncope, hypoxia, per 
institutional practice. Throughout apheresis, subjects will have frequent measures of heart rate, blood pressure, and 
pulse oximetry, e.g., every 20 minutes for adults, and every 10 minutes for pediatric subjects. Subjects should 
remain supine from plerixafor dosing through the end of apheresis each day. 
8 Hematology will include CBC with differential, nucleated erythrocytes, platelets, and reticulocytes. 
9 CBC with differential to be performed immediately before stem cell harvest, and immediately before and 2 hours 
after each dose of plerixafor. Complete blood count should be performed 24 hours post-plerixafor dose after the 
last day of apheresis. Complete blood count is also needed at the following 2 time points: 1) Within 1 hour prior to 
the start of apheresis (or if site is unable to do this, sample can be obtained upon initiation of apheresis). Complete 
blood count should be run STAT (the differential does not have to be STAT). 2) Immediately post-apheresis. If 
more than 1 apheresis day is required, platelet counts must be confirmed to be ≥ 75 × 109/L within 24 hours of 
subsequent apheresis sessions, prior to administration of plerixafor on that day. If platelet counts do not meet these 
criteria, mobilization and apheresis should be deferred until platelet counts recover to ≥ 75 × 109/L. 
10 Chemistry will include sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, calcium, 
magnesium, phosphate, albumin, total protein, uric acid, LDH, liver enzymes (GGT, ALP, ALT, AST, direct and 
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total bilirubin), glucose and CRP at Screening, Pre-mobilization, and Stem cell harvest. Erythropoietin to be 
performed at Screening only. 
11 Coagulation analysis will include PT/aPTT, D-Dimers. 
12 Iron studies include the following: serum iron, serum ferritin, serum transferrin, iron saturation (transferrin 
saturation), and serum transferrin receptor. 
13 Hormonal testing will include: Estradiol, (females only); total Testosterone (males only); TSH, free T3, free T4, 
AM cortisol, ACTH, 25 OH Vitamin D, PTH, FSH, LH (all subjects). 
14 Urinalysis includes color, appearance, specific gravity, pH, microalbumin, protein, creatinine, glucose, ketones, 
occult blood. 
15 Including HIV-1, HIV-2, HBcAb, HBsAb, HBsAg, HCV antibody, VZV, HTLV-1, HTLV-2, syphilis (RPR), 
toxoplasmosis, Trypanosoma cruzi, and West Nile Virus. Where clinically and/or regionally indicated, other tests 
for infectious pathogens may be performed, as required by regional regulations or at physician discretion. 
16 T cells (CD3), T cell subsets (CD4, CD8), B cells (CD19), natural killer cells (CD16/CD56), and antibody titers 
against tetanus, pneumococcus, and measles/mumps/rubella.  
17 CD34+ count required immediately prior to morning plerixafor dose, 2 hours post-plerixafor, as apheresis is being 
initiated, immediately after apheresis (and 24 hours post-plerixafor dose if no further apheresis procedures are 
planned in that mobilization cycle). 
18 Analysis of RCL, VCN, and globin chains does not need to be repeated if greater than 90 days between lab 
collection and mobilization/apheresis cycle 
19 Four mL HPC-A product must be collected from the first day of apheresis of all mobilization cycles where cells 
will be sent for drug product manufacturing. 
20 Bone marrow aspiration procedure will not be performed if not clinically appropriate per local standard of care 
(e.g., bone marrow aspirate would require general anesthesia which would be considered an unacceptable risk to 
the subject) or not considered by the Investigator to be in the best interest of the subject to perform. 
21 This can be done at any time before the start of conditioning once enough cells have been harvested for drug 
product manufacture. If surgery is required, this must be done a minimum of 2 weeks prior to initiation of 
conditioning. Subjects must be transfused within 4 days prior to surgery. 
22 Liver biopsy within 1 year and liver and cardiac MRIs within 3 months prior to consent may be used. If liver MRI 
findings suggest active hepatitis, significant fibrosis, inconclusive evidence of cirrhosis, or liver iron concentration 
≥ 15 mg/g, subjects ≥ 18 years of age require a follow-up liver biopsy (in subjects < 18 years of age, these MRI 
findings are exclusionary, unless in the opinion of the Investigator, a liver biopsy could provide additional data to 
confirm eligibility and would be safe to perform). Subjects unable to undergo otherwise required liver MRI 
(e.g., have metal implants) can instead have a liver biopsy performed to rule out advanced liver disease. For 
subjects who have a medical history of iron overload or serum ferritin > 1000 ng/mL, a cardiac MRI is required at 
Screening and at Month 24 Visit. 
23 Cerebral MRA/MRI and echocardiogram results performed within 3 months of ICF may be used unless there is 
clinical indication for repeat testing. Cerebral MRA/MRI alternative procedure: For subjects unable to undergo 
cerebral MRA/MRI, a CT scan can be performed instead.  
24 If BMD evaluation was performed within 1 year of Informed Consent, these results may be used for Screening and 
do not need to be repeated. 
25 Including % predicted FVC, % predicted FEV1; % predicted RV; and % predicted DLCO (corrected for Hb). 
Adapt to pediatric use per institutional practices. If performed within 6 months prior to ICF, those results may be 
used and do not need to be repeated. In the event of pulmonary complications (e.g., ACS, pneumonia) between 
Screening and the start of conditioning, an unscheduled PFT must be performed. 
26 Transfusion regimen should be initiated at least 60 days prior to stem cell harvest. Last exchange transfusion must 
occur within 4 days of start of mobilization, and the HbS proportion in the blood must be < 20% after the last 
exchange transfusion. 
27 Hb electrophoresis will be performed within 48 hours prior and 48 hours post pRBC transfusions during the 
transfusion regimen. 
28 Hb electrophoresis will be performed within 48 hours of mobilization/bone marrow harvest (and after final 
transfusion before mobilization/bone marrow harvest). 
29 Apheresis should begin approximately 4 to 6 hours after plerixafor administration 
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30 Baseline assessment should occur as close to Day -90 as possible, and where possible, must occur before start of 
pRBC transfusions. Subjects should complete PRO questionnaires at the beginning of the Visit (prior to 
undergoing any other procedures during the Visit.
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Table 3: 
Schedule of Events: Conditioning and Drug Product Infusion 
 
Preconditioning 
Up to 7 days 
before busulfan 
Conditioning 
Day -6 to -3 
inclusive  
Infusion 
Day 1 
Day 2 until 
hospitalization 
discharge 
Physical examinationa 
X 
X 
Xb 
Xb 
Performance statusc 
X 
 
 
 
Vital Signsd 
X 
X 
Xe 
Xf 
Local lab: Blood for clinical laboratory tests 
 
 
 
 
 
Hematologyg 
X 
X 
X 
Xh 
 
Serum Chemistryi 
X 
X 
X 
X 
 
Coagulation Analysisj 
X 
 
 
 
 
Iron Metabolism Studiesk 
X 
 
 
 
 
Haptoglobin 
X 
 
 
 
Local lab: Blood for serology 
Xl 
 
 
 
Local lab: Blood for serum β-human chorionic 
gonadotropin for women of child-bearing 
potential (serum pregnancy test) 
X 
 
 
 
Local lab: Blood for electrophoresis to assess 
globin fractions (i.e., %HbS, %HbA, %HbF) 
Xm 
 
 
Xn 
Bone marrow aspirationo: 
 
 
 
 
Bone marrow smearp 
Xq 
 
 
 
Local lab: Bone marrow for conventional 
cytogenetics (karyotyping) 
Xq 
 
 
 
Central lab: Bone marrow for storager 
Xq 
 
 
 
Central lab: Blood for next generation 
sequencing (NGS) mutational testings 
Xq 
 
 
 
Central lab: Blood for storager 
Xq 
 
 
 
Sperm / testicular tissue or oocyte banking, if 
requested 
X 
 
 
 
Reconfirmation of suitability for transplant 
Xt 
 
 
 
Anti-seizure prophylaxis 
Xu 
Xu 
 
 
Busulfan chemotherapy (daily or q6h regimen, 
for 4 days) 
 
X 
 
 
Local lab: Blood for busulfan 
pharmacokineticsv 
X 
X 
 
 
Infusion of bb1111 
 
 
X 
 
Transfusion regimen 
Xw 
 
 
 
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Table 3: 
Schedule of Events: Conditioning and Drug Product Infusion 
 
Preconditioning 
Up to 7 days 
before busulfan 
Conditioning 
Day -6 to -3 
inclusive  
Infusion 
Day 1 
Day 2 until 
hospitalization 
discharge 
Vaso-occlusive event collection 
Continuous from ICF signing 
Adverse event collection 
Continuous from ICF signing 
Concomitant medication collectionx 
Continuous from ICF signing 
 
a Any leg (skin) ulceration noted upon physical exam or as part of medical history must include severity 
classification. 
b To be performed on Day 1 before drug product infusion. A physical examination should be performed at least 
twice a week until discharge. 
c Karnofsky performance status (≥ 16 years of age) or a Lansky performance status (< 16 years of age). 
d Vital signs include systolic/diastolic blood pressure, pulse, temperature, oxygen saturation, weight (weight only 
required at preconditioning and conditioning), and height (height only required at preconditioning). 
e To be measured on Day 1 no less frequently than at the start, once during, and upon completion of the infusion. 
f Vital signs to be collected at least once a week during hospitalization post-infusion. 
g Hematology will include CBC with differential, nucleated erythrocytes, platelets and reticulocytes. Reticulocytes 
are not needed from D2 to neutrophil engraftment. 
h CBC daily during hospitalization. For pediatric subjects, daily measurements can be every other day due to blood 
volume concerns. After hospital discharge, subjects should get platelet count monitored approximately weekly and 
at least 8 days after the most recent platelet transfusion until platelet engraftment. 
i During hospitalization, chemistry will include sodium, potassium, chloride, bicarbonate, blood urea nitrogen, 
creatinine, calcium, magnesium, phosphate, albumin, total protein, liver enzymes (GGT, ALP, ALT, AST, direct 
and total bilirubin), and glucose daily, and CRP, uric acid, and LDH weekly. For pediatric subjects, daily 
measurements can be every other day due to blood volume concerns. 
j Coagulation analysis includes PT/aPTT, D-Dimers. 
k Iron studies include the following: serum iron, serum ferritin, serum transferrin, iron saturation (transferrin 
saturation), and serum transferrin receptor. 
l For subjects with exposure risks for HIV, HBV and HCV, these assessments should also be repeated during the 
preconditioning visit. 
m Hb electrophoresis will be performed within 48 hours prior and 48 hours post pRBC transfusions during the 
transfusion regimen. 
n Weekly from Day 2 until hospital discharge. 
o See Section 6.2.17. 
p Bone marrow smear should be read locally; additional bone marrow slides are to be archived for potential central 
analyses. 
q Collection of bone marrow aspirate and blood for conventional cytogenetics (karyotyping), NGS, and storage may 
be performed any time prior to conditioning and is not required to be within the 7 days prior to busulfan. 
r See Section 6.2.21. 
s In exceptional situations NGS mutational testing may be performed by a local lab upon agreement with the 
Medical Monitor.  
t Review CBC, serum chemistry (chemistry will include sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen, creatinine, calcium, phosphate, albumin, total protein, uric acid, LDH, liver enzymes [GGT, ALP, ALT, 
AST, direct and total bilirubin], glucose and CRP), physical examination, cytogenetics, and performance status; 
verification that the drug product has been dispositioned for clinical use, is available on site and that back-up cells 
are available. If PFTs have not been performed within 3 months of initiation of conditioning, then these tests must 
be repeated prior to conditioning. While not mandatory, cardiac Doppler echocardiology (including left ventricular 
ejection fraction) and cerebral MRI should be repeated prior to conditioning if clinically indicated. 
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u Anti-seizure prophylaxis to start at least 12 hours before initiating busulfan and to continue at least 24 hours after 
completion of 4-day busulfan course. 
v Blood for busulfan PK collected at Preconditioning time point only if a busulfan test dose was administered. 
Clinical sites must be able to measure first and third day busulfan PK. Based on busulfan PK results for day 1 and 
day 3 of busulfan dosing, busulfan dose adjustments should be made for subsequent dosing. If feasible, daily 
busulfan PK measurement is recommended. In addition, busulfan levels will be measured 48 and 72 hours after 
final dose of busulfan for retrospective confirmation of adequate wash-out. 
w Transfusion regimen should be initiated at least 60 days prior to stem cell harvest and continue through to start of 
conditioning. Last exchange transfusion must occur within 1 week of start of conditioning. 
x Hydroxyurea must be discontinued at least 30 days before stem cell harvest and at least 2 days before initiating 
busulfan. Iron chelation must be discontinued at least 7 days prior to stem cell harvest and 7 days before initiating 
busulfan. 
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Table 4: 
Schedule of Events: Follow-up 
Procedures 
Follow-Up: Day (D), Month (M) (Visit Window, days) 
D30 
D60 
D90 
D135 
D180 
D270 
D360 
D450 
D540 
D630 
D720 
M1 
(±7) 
M2 
(±7) 
M3 
(±7) 
M4.5 
(±14) 
M6 
(±14) 
M9 
(±14) 
M12 
(±30) 
M15 
(±30) 
M18 
(±30) 
M21 
(±30) 
M24 
(±30) 
Physical Examination1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chronic pain assessment2 
 
 
 
 
X 
 
X 
 
X 
 
X 
Performance Status3 
 
 
 
 
X 
 
X 
 
X 
 
X 
Tanner staging (for subjects < 18 
years of age) 
 
 
 
 
X 
 
X 
 
X 
 
X 
Vital signs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local lab: Blood for clinical 
laboratory tests5 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Chemistry7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation Analysis8 
 
 
 
 
 
 
X 
 
 
 
X 
 
Iron Metabolism Studies9 
 
 
X 
 
 
X 
X 
 
X 
 
X 
 
Haptoglobin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local lab: Hormonal testing10 
 
 
 
 
 
 
X 
 
 
 
X 
Local lab: Urinalysis11 
 
 
 
 
 
 
X 
 
 
 
X 
Local lab: Blood for immunological 
studies12 
 
 
X 
 
X 
X 
X 
 
 
 
X 
Screening for new irregular 
antibodies13 
 
X 
X 
 
 
 
 
 
 
 
 
Local lab: Blood for BNP and 
Erythropoietin 
 
 
 
 
 
 
X 
 
 
 
X 
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Table 4: 
Schedule of Events: Follow-up 
Procedures 
Follow-Up: Day (D), Month (M) (Visit Window, days) 
D30 
D60 
D90 
D135 
D180 
D270 
D360 
D450 
D540 
D630 
D720 
M1 
(±7) 
M2 
(±7) 
M3 
(±7) 
M4.5 
(±14) 
M6 
(±14) 
M9 
(±14) 
M12 
(±30) 
M15 
(±30) 
M18 
(±30) 
M21 
(±30) 
M24 
(±30) 
Central lab: Blood for globin and 
VCN14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Central lab: Blood for RCL 
detection 
 
 
X 
 
X 
 
X 
 
 
 
X15 
Central lab: Blood for ISA16 
 
 
 
 
X 
 
X 
 
X 
 
X 
Central lab: Blood for NGS 
mutational testing17 
 
 
 
 
 
 
X 
 
 
 
X 
Central lab: Blood for storage18 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Central lab: Blood for potential 
biomarker analysis (optional) 
 
 
 
 
 
 
X 
 
 
 
X 
Specialty lab: Blood for 
methemoglobin assay 
 
 
 
 
 
 
X 
 
 
 
X 
bluebird bio lab: Blood for 
 PD 
 
 
X 
 
X 
 
X 
 
X 
 
X 
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Table 4: 
Schedule of Events: Follow-up 
Procedures 
Follow-Up: Day (D), Month (M) (Visit Window, days) 
D30 
D60 
D90 
D135 
D180 
D270 
D360 
D450 
D540 
D630 
D720 
M1 
(±7) 
M2 
(±7) 
M3 
(±7) 
M4.5 
(±14) 
M6 
(±14) 
M9 
(±14) 
M12 
(±30) 
M15 
(±30) 
M18 
(±30) 
M21 
(±30) 
M24 
(±30) 
Bone marrow aspiration19: 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow smear20 
 
 
 
 
 
 
X 
 
 
 
X 
Local lab: Bone marrow for 
conventional cytogenetics 
(karyotyping)21: 
 
 
 
 
 
 
X 
 
 
 
X 
Central lab: Bone marrow for 
NGS17, ISA16, storage22, and 
 PD 
 
 
 
 
 
 
X 
 
 
 
X 
Imaging studies: 
 
 
 
 
 
 
 
 
 
 
 
Cerebral MRA/MRI23, and, if 
≤ 16 years of age, TCD 
 
 
 
 
 
 
X 
 
 
 
X 
Echocardiogram (including 
LVEF and TRJV) 
 
 
 
 
 
 
 
 
 
 
X 
 
Cardiac MRI24 
 
 
 
 
 
 
 
 
 
 
X 
 
Liver MRI 
 
 
 
 
 
 
 
 
 
 
X 
 Bone mineral density evaluation 
 
 
 
 
 
 
 
 
 
 
X 
Pulmonary function test25 
 
 
 
 
 
 
X 
 
 
 
X 
6-minute walk test 
 
 
 
 
 
 
X 
 
 
 
X 
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Table 4: 
Schedule of Events: Follow-up 
Procedures 
Follow-Up: Day (D), Month (M) (Visit Window, days) 
D30 
D60 
D90 
D135 
D180 
D270 
D360 
D450 
D540 
D630 
D720 
M1 
(±7) 
M2 
(±7) 
M3 
(±7) 
M4.5 
(±14) 
M6 
(±14) 
M9 
(±14) 
M12 
(±30) 
M15 
(±30) 
M18 
(±30) 
M21 
(±30) 
M24 
(±30) 
Quality of life tests:26 
EQ-5D-3L/Proxy Version 1, EQ-
5D-Y /Proxy Version 1, PROMIS-
57 Version 2.1, PROMIS Pediatric 
Profile//Parent Proxy Profile 49 
Version 2.0 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Work Productivity Assessment 
(WPAI)/Caregiver WPAI-GH26 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Cognitive Function Assessments: 
PROMIS Short Form 6a26 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Vaso-occlusive event collection 
Continuous from ICF signing27 
Adverse event collection 
Continuous from ICF signing 
Concomitant medication collection 
Continuous from ICF signing 
 
1 Any leg (skin) ulceration noted upon physical exam or as part of medical history must include severity classification. 
2 Chronic pain will be assessed using the AAPT Diagnostic Criteria for Chronic Pain Associated with SCD (see Section 6.2.6). 
3 Karnofsky performance status (≥ 16 years of age) or a Lansky performance status (< 16 years of age). 
4 Vital signs include systolic/diastolic blood pressure, pulse, temperature, oxygen saturation, weight, and height. 
5 CBC with differential should be carried out whenever ISA is performed. 
6 Hematology will include CBC with differential, nucleated erythrocytes, platelets and reticulocytes. Subjects should get platelet count monitored approximately 
weekly and at least 8 days after the most recent platelet transfusion until platelet engraftment. 
7 Chemistry will include sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, calcium, magnesium, phosphate, albumin, total protein, uric 
acid, LDH, liver enzymes (GGT, ALP, ALT, AST, direct and total bilirubin), glucose and CRP at every visit. 
8 Coagulation analysis includes PT/aPTT, D-Dimers. 
9 Iron studies include the following: serum iron, serum ferritin, serum transferrin, iron saturation (transferrin saturation), and serum transferrin receptor. Iron 
studies should be performed prior to restarting iron chelation, if needed. 
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10 Hormonal testing will include: Estradiol, (females only); total Testosterone (males only); TSH, free T3, free T4, AM cortisol, ACTH, 25 OH Vitamin D, PTH, 
FSH, LH (all subjects). 
11 Urinalysis includes color, appearance, specific gravity, pH, microalbumin, protein, creatinine, glucose, ketones, occult blood. 
12 T cells (CD3), T cell subsets (CD4, CD8), B cells (CD19), natural killer cells (CD16/CD56), and antibody titers against tetanus, pneumococcus, and 
measles/mumps/rubella.  
13 For subjects who receive final pRBC transfusion after the Month 3 Visit, screening for new irregular antibodies must be performed at the scheduled visit 
occurring immediately after last pRBC transfusion. 
14 VCN is to be carried out whenever ISA is performed. 
15 If RCL screening tests are negative up to and including the Month 12 Visit, RCL screening will cease, and the Month 24 co-culture RCL sample only will be 
collected and archived. 
16 CBC with differential and VCN are to be carried out whenever ISA is performed. 
17 In exceptional situations NGS mutational testing may be performed by a local lab upon agreement with the Medical Monitor. 
18 See Section 6.2.21. 
19 Post drug product infusion, bone marrow aspirate is to be taken per SOE unless discussed with the Medical Monitor for exceptions, such as if not clinically 
appropriate per local standard of care (e.g., bone marrow aspirate would require general anesthesia which would be considered an unacceptable risk to the 
subject) or not considered by the Investigator to be in the best interest of the subject to perform.  
20 Bone marrow smear should be read locally; additional bone marrow slides are to be archived for potential central analyses. 
21 Conventional cytogenetics should be performed locally 
22 See Section 6.2.21. 
23 Cerebral MRA/MRI alternative procedure: For subjects unable to undergo cerebral MRA/MRI, a CT scan can be performed instead. 
24 For subjects who have a medical history of iron overload or serum ferritin > 1000 ng/mL, a cardiac MRI is required at Screening and at Month 24 Visit. 
25 Including % predicted FVC, % predicted FEV1; % predicted RV; and % predicted DLCO (corrected for Hb). Adapt to pediatric use per institutional practices. 
26 Subjects should complete PRO questionnaires at the beginning of the Visit (prior to undergoing any other procedures during the Visit). 
27 If the Month 18 Visit does not include 18 calendar months, a telephone contact assessment for VOEs is to take place after 18 calendar months (post-drug 
product infusion) have elapsed. 
. 
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6.2. 
Study Measures 
6.2.1. 
Demographics and Medical History 
Subject demographic data such as gender, age, race, and ethnicity, will be obtained at Screening, 
as per the SOE.  
Medical history is to include all prior and current medical history, e.g., history of infectious 
events (including aplastic crises), iron overload, thromboembolism events, surgical procedures, 
medications (including pain medications). 
6.2.2. 
SCD-specific History and Outcome Measures 
Sickle cell disease-specific medical history will be obtained at Screening as per the SOE, 
including the following: 
1. Any history of severe cerebral vasculopathy event, stroke, or TCD acceleration and any 
associated visits to medical facilities and/or hospitals prior to Informed Consent.  
History of any other acute or chronic SCD-related complications and any associated visits 
to medical facilities and/or hospitals in the 24 months prior to Informed Consent. Sickle 
cell disease-related complications may include, but are not limited to, any of the 
following: 
− VOEs/severe VOEs, pulmonary hypertension (TRJV), cardiomyopathy, 
osteonecrosis, gall bladder lithiasis, leg (skin) ulceration, sickle cell nephropathy, 
silent cerebral infarct, transient ischemic attack  
2. Baseline Hb, as defined in Section 7.4.1  
3. History of HU use, including any history of HU intolerance or failure.  
4. History of L-glutamine use  
5. History of pRBC transfusions (including date, indications, mL/kg and units of pRBCs, 
associated pre-transfusion HbS and total Hb values and post-transfusion AEs [including 
allo-immunization]) within the 24 months prior to Informed Consent will be obtained at 
Screening, as per the SOE. Iron chelator use within the 24 months prior to Informed 
Consent 
6. In addition, for subjects who are receiving regular transfusions at the time of study entry: 
− other indication for chronic transfusions  
− if available, the history of VOEs/severe VOEs for the 2 years prior to the date at 
which regular transfusions started should be documented. 
6.2.3. 
Physical Examination and Performance Status   
A complete physical examination is to be conducted as per the SOE for the identification of 
medical history or AEs and reported on the appropriate CRF.   
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Screening PE and performance status should be performed within 90 days prior to mobilization. 
If > 90 days has elapsed, PE and performance status should be re-assessed during the screening 
period. 
Any leg (skin) ulceration noted upon physical exam or as part of medical history must include 
severity classification. 
Karnofsky and Lansky performance status (see Appendix 10.1) is to be assessed as per the SOE. 
Additionally, Tanner staging (subjects < 18 years of age) should be performed at Screening and 
every 6 months after infusion during puberty. 
6.2.4. 
Vital Signs 
Vital signs are to be measured per the SOE and include systolic/diastolic blood pressure, pulse, 
temperature, oxygen saturation, weight, height, and pain evaluation. Screening vital signs should 
be performed within 90 days prior to mobilization. If > 90 days has elapsed, vital signs should be 
re-assessed during the screening period. 
6.2.5. 
Vaso-occlusive Events (VOEs) 
All VOEs 24 months prior to ICF and following ICF for the duration of the study will be 
recorded. VOE categories include acute pain with no medically determined cause other than 
VOE (e.g., VOC), acute chest syndrome (ACS), acute hepatic sequestration, acute splenic 
sequestration, and acute priapism. All VOEs that, in the opinion of the Investigator, represent at 
least one of these events (regardless of duration, severity, treatment, or need for medical facility 
visit) must be recorded. A VOE can be home-managed only, and does not require a visit to a 
medical facility or hospitalization to be reported. It is recognized that retrospective collection of 
VOE information may be challenging; however, complete collection and reporting of VOEs 
should be done to the best of the clinical site’s ability.  
Subject eligibility is determined by the Investigator based on that subject having at least 4 
protocol-defined severe VOEs (i.e., protocol sVOEs) in the 24 months prior to ICF as set forth in 
Section 4.2.  
For the purposes of this study, a protocol-defined VOE (i.e., protocol VOE) is any of the 
following events (with or without hospitalization):  
a. an episode of acute pain with no medically determined cause other than a VOE 
(e.g., VOC) lasting more than 2 hours and requiring care at a medical facility  
b. ACS, defined by an acute event with pneumonia-like symptoms (e.g., chest pain, 
fever [> 38.5°C], tachypnea, wheezing or cough, or findings upon lung auscultation), 
and the presence of a new pulmonary infiltrate consistent with ACS, and requiring 
oxygen treatment and/or blood transfusion  
c. acute hepatic sequestration, defined by a sudden increase in liver size associated with 
pain in the right upper quadrant, abnormal results of liver-function test not due to 
biliary tract disease, and reduction in Hb concentration by at least 2 g/dL below the 
baseline value  
d. acute splenic sequestration, defined as sudden enlargement of the spleen and 
reduction in Hb concentration by at least 2 g/dL below the baseline value  
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e. an event of acute priapism: defined as a sustained, unwanted painful erection lasting 
more than 2 hours and requiring care at a medical facility  
A protocol sVOE is defined for the purposes of this study as a protocol VOE requiring ≥ 24-hour 
hospital or emergency room (ER) observation unit visit, or at least 2 visits to a day unit or ER 
over 72 hours with both visits requiring intravenous treatment, with the exception of priapism 
(all protocol VOEs of priapism are also protocol sVOEs).  
All reported VOEs will also be adjudicated by an independent event adjudication committee for 
purposes of endpoint analysis (see Section 3.3). 
6.2.6. 
Pain Assessment 
Acute pain will be assessed as part of the patient-reported outcome assessment by PROMIS (see 
Section 6.2.26). 
Chronic pain will be assessed per the SOE and includes evaluation of the following 
AAPT Diagnostic Criteria for Chronic Pain Associated with SCD [adapted from (Dampier et al. 
2017)]: 
1. Reports of ongoing pain present on most days over the past 6 months either in a single 
location or in multiple locations 
2. Must display at least 1 sign: 
− Palpation of the region of reported pain elicits focal pain or tenderness 
− Movement of the region of reported pain elicits focal pain 
− Decreased range of motion or weakness in the region of reported pain 
− Evidence of skin ulcer in the region of reported pain 
− Evidence of hepatobiliary or splenic imaging abnormalities (e.g., splenic infarct, 
chronic pancreatitis) consistent with the region of reported pain 
− Evidence of imaging abnormalities consistent with bone infarction or avascular 
necrosis in the region of reported pain 
3. There is no other diagnosis that better explains the signs and symptoms  
6.2.7. 
Clinical Laboratory Tests 
Blood samples for clinical laboratory tests, including hematology, serum chemistry, liver 
function tests, renal function tests, coagulation studies, and iron studies, are to be collected per 
the SOE. These tests are to be performed by the local laboratory and reviewed by the 
Investigator or qualified designee (e.g., physician’s assistant, nurse practitioner). 
Screening clinical labs should be performed within 90 days prior to mobilization. If > 90 days 
has elapsed, clinical labs should be re-assessed during the screening period.  
The following clinical laboratory parameters are to be determined:  
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Hematology 
Serum chemistry 
Liver function tests 
Coagulation 
complete blood count 
[CBC] with 
differential, 
reticulocyte count, 
nucleated erythrocytes, 
platelets, 
haptoglobin 
sodium 
potassium 
chloride 
bicarbonate  
creatinine 
albumin 
glucose 
CRP 
blood urea nitrogen  
calcium 
uric acid 
phosphate 
total protein 
magnesium 
lactate dehydrogenase 
erythropoietin 
estimated glomerular 
filtration rate (as determined 
using the Chronic Kidney 
Disease Epidemiology 
Collaboration (CKD-EPI) 
equation) 
aspartate aminotransferase  
alanine aminotransferase 
alkaline phosphatase 
total and direct bilirubin 
gamma-glutamyl 
transferase 
prothrombin time 
[PT]/activated partial  
thromboplastin time 
[aPTT] 
D-Dimers 
Iron studies 
serum iron  
serum ferritin 
serum transferrin 
serum transferrin 
receptor 
iron saturation 
(transferrin saturation)  
Urine for urinalysis (sent to local lab) is to be collected per the SOE, and urinalysis includes 
color, appearance, specific gravity, pH, microalbumin, protein, creatinine, glucose, ketones, 
occult blood. 
Additional clinical laboratory tests may be performed at the Investigator’s discretion. 
6.2.7.1. 
Clinical Work-up for Unexpected Blood Test Results 
If the results from blood tests are not as expected, additional testing may need to be performed to 
allow for further investigation and may include: 
• Physical exam 
• Blood tests 
• Imaging tests 
• Bone marrow biopsy and/or aspiration (may also be archived for additional analysis 
in the future; see Section 6.2.21) 
6.2.8. 
Additional Laboratory Tests 
Blood samples will be collected for additional eligibility-determining laboratory tests, according 
to the SOEs. 
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• Serology  
Screening serology will be evaluated using standard methods. The serology panel for 
eligibility includes HIV-1 and HIV-2; hepatitis B core antibody (HBcAb); hepatitis B 
surface antibody (HBsAb); hepatitis B surface antigen (HBsAg); hepatitis C virus 
(HCV) antibody; varicella zoster virus (VZV) IgG; HTLV-1 and HTLV-2, syphilis 
(RPR), toxoplasmosis, Trypanosoma cruzi, and West Nile Virus. Any other serology 
required by institutional guidelines before stem cell harvest and transplantation of 
drug product (including, for example, testing for CMV, EBV, and HSV) are 
permitted.  
For subjects with exposure risks for HIV, HBV and HCV, these assessments should 
also be repeated during the preconditioning visit. Where clinically and/or regionally 
indicated, other tests for infectious pathogens may be performed, as required by 
regional regulations or at physician discretion. 
• Serum β-human chorionic gonadotropin pregnancy test 
Only required for females of child-bearing potential.  
6.2.9. 
Hormonal Testing 
Hormonal testing is to be performed as per the SOE and includes: estradiol, (females only); total 
testosterone (males only); TSH, free T3, free T4, AM cortisol, ACTH, 25 OH Vitamin D, PTH, 
FSH, LH (all subjects). 
Hormonal testing should be performed within 90 days prior to mobilization. If > 90 days has 
elapsed, PE and performance status should be re-assessed during the screening period. 
6.2.10. 
Sperm / Testicular Tissue or Oocyte Banking 
Sperm or testicular tissue banking for males or oocyte aspiration following ovarian stimulation 
and cryopreservation for females will be done at the discretion of the subject. If a subject elects 
to undergo these procedures, the procedures must occur during the period between mobilization 
and conditioning and can be done at any time before the start of conditioning once enough cells 
have been harvested for drug product manufacture. If surgery is required, this must be done a 
minimum of 2 weeks prior to initiation of conditioning. Subjects must be transfused within 
4 days prior to surgery. 
6.2.11. 
Reconfirmation of Suitability for Transplant 
At Pre-conditioning, review CBC, serum chemistry (chemistry will include sodium, potassium, 
chloride, bicarbonate, blood urea nitrogen, creatinine, calcium, magnesium, phosphate, albumin, 
total protein, uric acid, LDH, liver enzymes (GGT, ALP, ALT, AST, direct and total bilirubin), 
glucose and CRP), physical examination, cytogenetics, and performance status; verification that 
the drug product has been dispositioned for clinical use, is available on site and that back-up 
cells are available. If PFTs have not been performed within 3 months of initiation of 
conditioning, then these tests must be repeated prior to conditioning. While not mandatory, 
cardiac Doppler echocardiology (including LVEF) and cerebral MRI should be repeated prior to 
conditioning if clinically indicated. 
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Bone marrow aspirate will be collected prior to conditioning for assessment of chromosomal 
abnormalities or genetic mutations, particularly those associated with myelodysplastic syndrome 
(MDS) or acute myeloid leukemia (AML), by conventional cytogenetics (karyotyping). These 
results will be used to assess individual benefit-risk for a subject’s suitability to proceed with 
HSCT. If a chromosomal abnormality that may put the subject at an increased risk of MDS/AML 
per the Investigator’s judgment is identified in the bone marrow prior to conditioning, the subject 
will be withdrawn from the study and not proceed with conditioning or treatment with bb1111. If 
other chromosomal abnormalities are identified in the bone marrow prior to conditioning that do 
not render the subject ineligible for HSCT per the Investigator’s judgment, approval of the 
Medical Monitor is required before the subject can proceed with conditioning, and the subject 
can proceed with conditioning and treatment with bb1111 after providing appropriate informed 
consent.  
6.2.12. 
Immunological studies 
Immunological testing includes measuring levels of T cells (CD3), T cell subsets (CD4, CD8), 
B cells (CD19), and natural killer cells (CD16/CD56), irregular antibodies, and antibody titers 
against tetanus, pneumococcus, and measles/mumps/rubella. 
Screening for irregular antibodies is required for all subjects at Screening. Screening for new 
irregular antibodies is required at Month 2 and Month 3 and may also occur at physician’s 
discretion. For subjects who receive their final pRBC transfusion after the Month 3 Visit, 
screening for new irregular antibodies must be performed at the scheduled visit occurring 
immediately after last pRBC transfusion. 
6.2.13. 
Brain Natriuretic Peptide  
Blood samples are to be collected per the SOE for BNP. This assay should be performed at the 
local laboratory. 
6.2.14. 
Busulfan concentrations  
Blood for measuring busulfan PK and making appropriate adjustments of the busulfan dose 
should be drawn for local testing as per Section 5.2.5.2. 
6.2.15. 
Hemoglobin Analysis 
Blood samples are to be collected per the SOE for assessment at a central laboratory of globin 
chain levels by HPLC, including βA-T87Q-globin. Blood sample collection details are included in 
the Laboratory Manual for this study.  
Blood samples will also be collected per the SOE to assay for methemoglobin concentration 
(specialty lab). 
Additionally, blood samples will be analyzed by electrophoresis in local laboratories to monitor 
the percentages of HbS and HbA during the transfusion regimen through hospital discharge post-
infusion (HbF results should be collected if available). 
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6.2.16. 
Testing for SCD Genotype, Vector Copy Number, Replication Competent 
Lentivirus, and Integration Site Analysis 
Blood samples will be collected according to the SOE for assessments of the following: 
• SCD genotype 
• VCN 
• RCL 
• Integration site analysis (ISA) 
Blood sample collection details are included in the Laboratory Manual for this study.  
Note that ISA may be discontinued if a subject's VCN is less than 0.01 copies per cell.  
Results from these analyses may be accessed by viewing the appropriate electronic case report 
forms within the electronic data capture system. 
6.2.17. 
Bone Marrow Aspiration 
Bone marrow aspirate is to be taken per SOE. After drug product infusion, a bone marrow 
aspirate is to be taken unless discussed with the Medical Monitor for exceptions, such as if not 
clinically appropriate per local standard of care (e.g., bone marrow aspirate would require 
general anesthesia which would be considered an unacceptable risk to the subject) or not 
considered by the Investigator to be in the best interest of the subject to perform. A bone marrow 
smear is to be collected at the time of each bone marrow aspiration; site monitoring to include: 
cell count and differential, cellularity, M:E ratio, peripheral smear, iron stores, and morphologic 
report at a minimum (refer to SOM for additional detail). The bone marrow aspiration will be 
performed in accordance with institutional practices. Bone marrow smears should be read 
locally; additional bone marrow slides are to be archived for potential central analyses. Bone 
marrow aspirate collection details are included in the Laboratory Manual.  
Bone marrow samples will be used for cytogenetics and mutational testing (Section 6.2.18), and 
storage (including slides; see Section 6.2.21), and may also be used for 
PD 
(Section 6.2.19). 
6.2.18. 
Conventional Cytogenetics (Karyotyping) and NGS Mutational Testing 
Bone marrow aspirate (see Section 6.2.17) and blood will be collected according to the SOE for 
assessment of chromosomal abnormalities or genetic mutations, particularly those associated 
with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), by conventional 
cytogenetics (karyotyping) and NGS mutational testing.  
If available, bone marrow and blood samples collected per SOE may be used for retrospective 
genetic testing. 
Results from conventional cytogenetics (karyotyping) from the bone marrow prior to 
conditioning will be used to assess suitability for transplant (see  Section 6.2.11 ). 
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6.2.19. 
Bone Marrow for Exploratory PD 
Bone marrow samples (see Section 6.2.17) will be shipped to the Sponsor and used to evaluate 
biomarkers of the pathology of SCD in bone marrow (e.g., morphology, cellularity, cell count of 
bone marrow, CD34+ count). These samples may also be analyzed if clinically indicated. 
6.2.20. 
Blood for Exploratory PD 
Blood samples will be collected according to the SOE and sample collection details are included 
in the Laboratory Manual.  
These samples will be shipped to the Sponsor and used to evaluate potential PD biomarkers after 
drug product infusion using exploratory techniques. Exploratory assays may include but not 
limited to single-colony VCN, single-cell analysis of percent lentiviral vector positive (%LVV+) 
cells, ex vivo sickling, and single-cell western for βA-T87Q-globin. 
These samples may also be analyzed if clinically indicated. 
6.2.21. 
Blood and Bone Marrow for Storage 
Bone marrow aspirates (see Section 6.2.17) and blood will be collected according to the SOE, 
and these samples will be shipped to a central laboratory for storage and may be analyzed if 
clinically indicated or may be used for exploratory PD. Leftover samples from protocol 
procedures (e.g., drug product manufacture, blood draw for ISA) may also be stored and 
analyzed if clinically indicated or used for exploratory PD. 
Samples may be stored until the samples are exhausted or until the repository is discontinued. 
The Sponsor will be the custodian of the samples in the repository any unused samples will be 
destroyed at the Sponsor’s discretion. The Sponsor may share these stored samples for future 
research with collaborators, such as research laboratories, academic or non-profit institutions, 
and scientific advisors. 
6.2.22. 
Samples for Potential Biomarker Analyses 
Optional blood samples will be collected per the SOE for future research. These samples may be 
used for biomarker analyses of proteins, DNA, RNA and other molecules to study SCD and/or 
gene therapy. Such samples may be stored until the samples are exhausted or until the repository 
is discontinued. The Sponsor will be the custodian of the samples in the repository and any 
unused samples will be destroyed at the Sponsor’s discretion.   
Collection and storage of the samples described above will be subject to discretionary approval 
from each center’s IRB/IEC and the subject’s specific written consent. Samples will be labeled 
with a unique identification number that includes no subject identifying information.  
As samples allow, leftover samples from protocol procedures (described in Section 6.2.21) may 
also be used for potential future analyses as described above. The Sponsor may share these 
stored samples for future research with collaborators, such as research laboratories, academic or 
non-profit institutions, and scientific advisors. 
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6.2.23. 
Imaging Studies 
Liver MRI 
Subjects with advanced liver disease (as described in the eligibility criteria) are excluded from 
participation in this study. 
At Screening and at Month 24 Visit, a liver MRI is required for all subjects. For subjects who 
have a medical history of iron overload or serum ferritin > 1000 ng/mL, a cardiac MRI is 
required at Screening and at Month 24 Visit. 
If a liver MRI was performed within 3 months prior to signing the informed consent, these 
results may be used as part of the eligibility assessment and the MRI does not need to be 
repeated.  
Subjects unable to undergo otherwise required liver MRI (e.g., have metal implants) can instead 
have a liver biopsy performed to rule out advanced liver disease. 
Cardiac MRI 
For subjects who have a medical history of iron overload or screening serum ferritin 
> 1000 ng/mL, a cardiac MRI is required at Screening to evaluate for baseline cardiac disease 
due to iron overload. Patients with a Cardiac T2* < 10 ms are excluded from participation in this 
study. 
If a cardiac MRI was performed within 3 months prior to signing the informed consent, these 
results may be used as part of the eligibility assessment and the screening MRI does not need to 
be repeated.  
Subjects who have a cardiac MRI at screening will have a second cardiac MRI at Month 24 to 
evaluate cardiac iron stores. 
Cerebral MRI/MRA 
Cerebral vasculature and prior brain parenchymal injury evaluation (as measured by cerebral 
MRA/MRI will be performed per the SOE. Cerebral MRA/MRI results performed within 
3 months of ICF may be used, unless there is clinical indication for repeat testing.  
For subjects unable to undergo cerebral MRI (e.g., have metal implant), a CT scan can be 
performed instead.  
Transcranial doppler ultrasound (TCD) 
Subjects ≤ 16 years old (at time of ICF signing) will undergo a TCD per the SOE.  
Cardiac echocardiogram 
Cardiac Doppler echocardiography, including the assessment of LVEF and TRJV, will be 
performed per the SOE. Echocardiogram results performed within 3 months of ICF may be used, 
unless there is clinical indication for repeat testing. 
Bone mineral density 
Bone mineral density (BMD) evaluation will be performed per SOE unless not allowed by 
institutional standard of care. All attempts will be made to use the same DXA machine for all 
assessments of a given subject throughout the duration of the trial.  
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Bone mineral density will be performed per the SOE using dual x-ray absorptiometry (DXA) at 
3 reference sites: the lumbar spine and the right femoral neck, or whole body less head for 
pediatric subjects. In subjects with a history of hip surgery, the contralateral hip is assessed. If 
BMD evaluation was performed within 1 year of Informed Consent, these results may be used 
for Screening and do not need to be repeated. 
6.2.24. 
Liver Biopsy 
Liver biopsy may be performed in subjects with liver MRI findings suggestive of active 
hepatitis, significant fibrosis, inconclusive evidence of cirrhosis, or liver iron concentration 
≥ 15 mg/g to evaluate for presence of advanced liver disease and study eligibility.   
Liver biopsy samples should be reviewed for liver pathology (e.g., portal fibrosis, cirrhosis, 
hepatitis) and measured for hepatic iron content. Any evidence of cirrhosis, bridging fibrosis, or 
significant active hepatitis will be exclusionary. If a liver biopsy was performed within the year 
prior to signing the informed consent, these results may be used as part of the eligibility 
assessment and the biopsy does not need to be repeated.  
6.2.25. 
Pulmonary Function Tests 
Pulmonary function testing will be performed per the SOE. Pulmonary function tests include: 
% predicted forced vital capacity (FVC); % predicted forced expiratory volume in 1 second 
(FEV1); % predicted respiratory volume (RV); and % predicted DLCO (corrected for Hb). If 
performed within 6 months prior to ICF, those results may be used and do not need to be 
repeated. In the event of pulmonary complications (e.g. ACS, pneumonia) between the Screening 
PFT and the start of conditioning, an unscheduled PFT must be performed. After resolution of 
pulmonary complications, and prior to conditioning, PFT results must meet the following 
requirements: 
• Baseline oxygen saturation ≥ 90% without supplemental oxygen (excluding periods 
of SCD crisis, severe anemia or infection).  
• Baseline carbon monoxide diffusing capacity (DLCO) ≥ 50% (corrected for Hb) in the 
absence of infection.  
• If DLCO cannot be assessed due to age or cognition-related restrictions, then 
respiratory exam, chest radiograph and oxygen saturation should be performed.   
6.2.26. 
Patient-reported Outcome Measures  
The following assessments (see Table 5 and Appendix 10.2) are to be performed at Screening, 
Month 3, Month 6, and every 6 months thereafter up to Month 24: 
• Quality of life, as measured by performance on PROMIS 
− For patients ≥ 18 years old, performance on PROMIS-57 Version 2.1 
− For patients < 18 years old, performance on PROMIS Pediatric Profile 
(age 12 to 17 years) or PROMIS Parent Proxy Profile 49 (age 12 to 17 years) 
Version 2.0, as applicable 
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• Work productivity, as measured by the Work Productivity and Activity 
Impairment Questionnaire-General Health (WPAI-GH; age ≥ 15 years)/Caregiver 
WPAI-GH 
• Cognitive function as measured by PROMIS Short Form 6a (age ≥ 18 years) 
• Overall health status as measured by EuroQol-5D (EQ-5D-3L, age ≥ 16 years or 
EQ‑5D-Y, age 12 to 15 years). The EQ-5D-3L Proxy Version 1 or EQ-5D-Y Proxy 
Version 1 to be used instead only if subject unable to use the EQ-5D 
Table 5: 
Patient-reported Outcome Measures 
Age1 ≥ 18 
years 
Agea < 18 years 
18+ 
17 
16 
15 
12 - 14 
PROMIS-572b 
PROMIS 
Pediatric Profile 
49 or  
PROMIS Parent 
Proxy Profile 49 
PROMIS 
Pediatric Profile 
49 or  
PROMIS Parent 
Proxy Profile 49 
PROMIS Pediatric 
Profile 49 or  
PROMIS Parent 
Proxy Profile 49 
PROMIS Pediatric 
Profile 49 or  
PROMIS Parent Proxy 
Profile 49 
PROMIS Short 
Form 6ac 
N/A 
N/A 
N/A 
N/A 
WPAI-GHd 
WPAI-GH or 
WPAI-Caregiver 
form 
WPAI-GH or 
WPAI-Caregiver 
form 
WPAI-GH or 
WPAI-Caregiver 
form 
WPAI-Caregiver form 
EQ-5D-3L5e 
EQ-5D-3L 
EQ-5D-3L 
EQ-5D-Y 
EQ-5D-Y 
 
Abbrev.: EQ-5D, EuroQol-5D; N/A, not applicable; PROMIS, Patient Reported Outcomes Measurement 
Information System; WPAI, Work Productivity and Activity Impairment Questionnaire. 
 
a For all assessments, age at time of assessment determines which form should be used. PRO form may change from 
baseline depending on subject age 
b PROMIS-57 Version 2.1 or PROMIS Pediatric Profile/Parent Proxy Profile 49 Version 2.0. The numeric rating 
scale that assesses pain is part of the pain assessment tool 
c PROMIS SF 6a is a measure of cognitive function 
d Either the WPAI or WPAI-Caregiver form should be used depending which has the greatest impact on the family. 
Whoever completes the WPAI at baseline should be the person who completes it for the remainder of the trial 
e EQ-5D-3L/EQ-5D-Y: Proxy form to be used instead only if subject unable to use the EQ-5D-3L or EQ-5D-Y 
6.2.27. 
Six-Minute Walk Test  
The six-minute walk test (6MWT) is to be performed per the SOE, and will be conducted by 
following the American Thoracic Society Guidelines for the Six-Minute Walk Test (2002). This 
test measures the distance that a patient can quickly walk on a flat, hard surface in a period of 
6 minutes (6MWD). The 6MWT is a measure of moderate effort tolerance. Change in 6MWD 
equal to or greater than 50 m is used in pulmonary disease clinical trials. 
6.2.28. 
Assessment of Oligoclonality by Integration Site Analysis 
Integration site analysis (ISA) will be performed to determine the insertion site (IS) profile of 
subjects over time, as indicated in the SOE. Figure 4 shows the algorithm that determines the 
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frequency of monitoring by ISA to assess oligoclonality, in accordance with FDA Guidance 
(FDA 2020). While oligoclonality itself, or even monoclonality, will not a priori result in a 
malignancy, changes in IS relative frequency may be associated with an increase in the risk of a 
malignancy. Therefore ISA monitoring is performed every 6 months for the first 5 years after 
drug product administration, and annually thereafter. This is coupled with monitoring for 
hematological abnormalities via complete blood count (CBC) with differential every 6 months 
through 15 years after drug product administration (see Section 6.2.33 for information on long-
term follow-up).  
ISA monitoring may be repeated more frequently if there is an indication of oligoclonality. As 
shown in Figure 4, if an IS is detected at ≥ 10% relative frequency (RelFreq) for 1 IS, or ≥ 5% 
RelFreq for ≥ 2 IS each, ISA will be repeated within 3 months of receipt of this result. If the 
result is confirmed, a report of persistent oligoclonality will be submitted to the relevant Health 
Authorities within 30 days. This repeated observation will also trigger enhanced monitoring for 
hematological abnormalities, increasing the frequency of CBC with differential to every 3 
months along with ISA and VCN every 6 months until the criteria for oligoclonality is no longer 
met. 
Based on clinical and ISA findings, additional monitoring for malignancy may be instituted by 
the treating physician/Principal Investigator or Sponsor. See the following section for 
recommended clinical work-up for malignancy. 
Figure 4: 
Algorithm for Frequency of ISA Monitoring  
 
Abbrev.: IS, insertion site(s); ISA, integration site analysis; RelFreq, relative frequency 
a ISA is assessed per the schedule of events; CBC with differential and VCN are to be carried out whenever ISA is 
performed (Table 4). 
b If ISA is assessed concurrently from PB and BM, the assessment with higher RelFreq values should be used. 
c Samples obtained one month or more apart can be considered consecutive measurements. 
d Persistent oligoclonality will be reported to the relevant Health Authorities within 30 days. 
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e At a minimum, enhanced monitoring includes CBC with differential every 3 months and ISA and VCN every 
6 months. Additional monitoring for malignancy may be instituted by the treating physician/Principal Investigator 
(see Section 6.2.29). 
6.2.29. 
Assessments for Risk of Hematologic Malignancy and Clinical Work-up 
Routine assessments carried out per the SOE (Table 4) for risk of potential hematologic 
malignancy are presented in Figure 5. Clinical presentation and CBC with differential are 
considered standard assessments, whereas BM biopsy, ISA, NGS, and karyotyping are 
considered supportive assessments in the context of gene therapy. In the event of suspicion of 
hematologic malignancy (i.e., myelodysplasia, leukemia, or lymphoma), discussion with the 
Medical Monitor is required and should include an evaluation of local versus central testing. 
Clinical work-up is to be performed by the Investigator per appropriate standard of care and in 
alignment with WHO and NCCN guidelines (Arber et al. 2016; Greenberg et al. 2022). 
Figure 5: 
Assessments for Risk of Hematologic Malignancy per Schedule of Events and 
Clinical Work-up 
 
Abbrev.: AML, acute myeloid leukemia; BM, bone marrow; CBC, complete blood count; FISH, fluorescence in situ 
hybridization; IS, insertion site; ISA, integration site analysis; MDS, myelodysplastic syndrome; NCCN, National 
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Comprehensive Cancer Network; NGS, next generation sequencing; RNA-seq, RNA sequencing; SNP, single 
nucleotide polymorphism; VCN, vector copy number; WHO, World Health Organization 
a Routine monitoring include assessments per SOE (Table 4) and ongoing patient education on risk of  malignancy. 
b Turnaround times for ISA results can vary in duration, typically taking approximately 10 weeks from sample 
collection to data delivery. ISA may be done on PB or BM per the SOE (Table 4). 
c In addition to NGS and karyotype, other genetic testing results that are suggestive of potential risk for malignancy 
may be taken into account. 
d If a subject has persistent oligoclonality (see  Section 6.2.29 ) and other cause for clinical work-up, additional 
assessments such as BM biopsy, RNA-seq, lineage-specific ISA (to be performed on BM only if as available), or 
IS-specific VCN can be considered; (Arber et al. 2016; Greenberg et al. 2022). 
e ISA should be done on BM if taken as part of clinical work-up. 
f In the context of clinical work-up for hematologic malignancy, FISH assessments should be local, according to 
guidelines, as local laboratories are certified in this context. Central FISH may be performed retrospectively on 
stored samples if results from local work-up are unclear. 
 
Under specific circumstances, after discussion with the Medical Monitor, BM biopsy, 
RNA-seq/RT-PCR, lineage-specific ISA, and IS-specific VCN may be considered appropriate 
assessments during clinical work-up, specifically if there is persistent oligoclonality as identified 
with ISA AND at least one of the following: 
• 
Medical History, physical exam, or evaluation findings suggestive of developing 
malignancy OR 
• 
Unexplained hematologic changes consistent with malignancy OR  
• 
Clinically significant findings suggestive for malignancy on BM pathology OR 
• 
Concerning cytogenetic or molecular findings on karyotype, NGS, or other genetic 
testing results that are suggestive of potential risk for malignancy 
Note at any time, regardless of clonality measurements, any additional clinical work-up may be 
performed at the Investigator’s discretion if there is suspicion of malignancy. In the event of 
unclear diagnosis, additional supportive assessments (e.g., whole genome sequencing or whole 
exome sequencing) can be considered in individual, specific cases. 
If the clinical work-up indicates no evidence of myelodysplasia, leukemia, or lymphoma, the 
subject will continue to be monitored as per the protocol-defined SOE, or more frequently at 
discretion of the treating physician/Principal Investigator. If the clinical work-up indicates a 
diagnosis of myelodysplasia, leukemia, or lymphoma, the Sponsor will convene an urgent safety 
review meeting. Further analyses will be determined by the Sponsor, in consultation with the 
DMC. All efforts should be made to confirm the source of malignancy. It should be noted that it 
may not be possible to distinguish the source of malignancy (e.g., arising from underlying 
pathophysiology of the disease, transplant-related medications or procedures, or from expansion 
of gene-modified cells due to insertional oncogenesis). 
6.2.30. 
Adverse Events  
6.2.30.1. Assessments During Study 
Monitoring of AEs will be conducted from the signing of informed consent. Adverse events, as 
defined in Section 6.2.30.2 will be documented from the time informed consent is signed through 
the following time points for Groups A and B: 
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• ≥ Grade 1 AEs: through 30 days after drug product infusion. 
• ≥ Grade 2 AEs: through 12 months after drug product infusion. 
• All serious adverse events (SAEs), ≥ Grade 3 AEs, and drug product-related AEs: 
through 24 months after drug product infusion. 
For Group C, AEs for all subjects (excluding screen failures) will be recorded in the CRFs 
starting from the time informed consent is signed through the Month 24 Visit. All SAEs 
(including screen failures) will be reported from the signing of informed consent/assent on the 
SAE report form. Group C subjects enrolled under Version 7.0 of Protocol HGB-206 will have 
AEs retrospectively documented to be in accordance with Version 8.0 and Version 9.0 of 
Protocol HGB-206. 
All AEs should be monitored until they are resolved or are clearly determined to be due to a 
subject’s stable or chronic condition or inter-current illness(es). See also Section 4.5 for AE 
monitoring of subjects who withdraw from the study. 
For subjects who withdraw for reasons other than withdrawal of consent, any SAEs open at the 
time of discontinuation should be followed up until resolution or are determined to be a stable or 
chronic condition. If withdrawal is before drug product infusion, subjects should remain on study 
for at least 30 days after any invasive study procedure (e.g., mobilization, liver biopsy) before 
withdrawal and ongoing AEs should be monitored for the 30-day duration. In the rare case a 
subject undergoes myeloablation and receives back-up cells instead of bb1111, subject should 
remain on the study for at least 3 months post-myeloablation and AEs should be followed for the 
3-month duration. 
If withdrawal is after drug product infusion, subjects will be asked to complete the same 
assessments as specified in the SOE for Month 24 (Early Termination Visit assessments) and are 
expected to enroll in the long-term follow-up study. 
Note that at the completion of Study HGB-206, subjects are expected to enroll into a long-term 
follow-up study, that will monitor the safety of subjects (including drug product-related AEs) 
through a total of 15 years after drug product infusion. If there is a gap of time between the final 
visit in Study HGB-206 (e.g., Month 24 study visit) and participation in the long-term follow-up 
study (i.e., signature on long-term follow-up ICF), all SAEs that start during that gap should be 
reported on the Study HGB-206 SAE report form and submitted according to Section 6.2.30.5. 
6.2.30.2. Adverse Events Definitions 
Adverse Events 
An AE is any untoward medical occurrence associated with the use of a drug in subjects, 
whether or not considered drug related. An AE may include a change in physical signs, 
symptoms, and/or a clinically significant laboratory change occurring in any phase of a clinical 
study. This definition includes intercurrent illnesses or injuries, and exacerbation of pre-existing 
conditions. A pre-existing condition is a clinical condition (including a condition being treated) 
that is diagnosed before the subject signs the ICF and is documented as part of the subject’s 
medical history. 
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For the purposes of this study, neutrophil engraftment failure is defined as an SAE and is to be 
reported as such. For this protocol, neutrophil engraftment failure is defined as failure to achieve 
an ANC laboratory value of ≥ 0.5 × 109 cells/L for 3 consecutive measurements on different days 
by Day 43 or receiving back-up cells at any time during the neutropenic phase. 
Unexpected Adverse Events 
An AE is considered unexpected with the drug product if it is not consistent in nature or severity 
with the reference safety information contained in the current Investigator’s Brochure.  
Conditioning-related Adverse Events 
Busulfan IV is a cytotoxic drug that causes profound myelosuppression. Accordingly, subjects 
will experience intended hematologic events (e.g., neutropenia, thrombocytopenia, anemia) and 
expected non-hematologic events (e.g., mucositis, nausea, vomiting, alopecia, pyrexia) as a result 
of receiving busulfan IV. For the purposes of this protocol, these events, which are familiar to 
transplant physicians and are described in the busulfan prescribing information, are considered 
conditioning-related events (CREs).  
The intended profound myelosuppression (manifested by neutropenia, thrombocytopenia, and/or 
anemia) and expected events that occur after the initiation of busulfan IV conditioning are 
considered to be the direct consequence of busulfan conditioning and are to be reported as AEs 
but should be attributed to conditioning agent on the AE eCRF, as applicable. 
Serious Adverse Events  
An SAE is any AE that: 
• Results in death. 
• Is immediately life-threatening; i.e., the subject was at immediate risk of death at the 
time of the event. It does not include an AE that, had it occurred in a more severe 
form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization. 
Hospitalization admissions occurring during the study period that are for procedures 
planned prior to study entry do not meet these criteria, unless there is a complication 
resulting from a procedure that prolongs hospitalization. 
• Results in persistent or significant disability/incapacity; or a substantial disruption of 
a subject’s ability to conduct normal life functions. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event. An important medical event is an AE that may not 
result in death, be life threatening, or require hospitalization but may be considered 
serious when, based upon appropriate medical judgment, it may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
For the purposes of this study, any new malignancy or new diagnosis of a neurologic, 
rheumatologic, or hematologic disorder that, in the Investigator’s opinion, is clinically significant 
and requires medical intervention will be considered medically important and therefore serious. 
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6.2.30.3. Adverse Event Assessment of Severity and Relationship 
For all AEs, the Investigator must determine both the severity of the event and the relationship of 
the event to treatment with drug product. 
Severity will be assessed by the Investigator, including for AEs that are a result of a laboratory 
abnormality: 
• Grade 1: Mild, asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL).  
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self‑care ADL. 
• Grade 4: Life-threatening consequences; urgent intervention indicated. 
• Grade 5: Death related to AE. 
If the Grade changes within a day, the maximum Grade should be recorded.  
Relationship: The Investigator is required to provide an assessment of the relationship of drug 
product to all AEs. The following is a guideline for determining the relationship of drug product 
to an AE: 
• Not Related: Exposure to the study treatment did not occur, or the occurrence of the 
AE is not reasonably related in time, or the AE is considered not related to the study 
treatment. 
• Unlikely Related:  The study treatment and the AE were not closely related in time, 
and/or the AE could be explained more consistently by causes other than exposure to 
the study treatment product. 
• Possibly Related:  The study treatment and the AE were reasonably related in time, 
and the AE could be explained equally well by causes other than exposure to the 
study treatment product. 
• Related:  The study treatment and the AE were reasonably related in time, and the 
AE was more likely explained by exposure to the study product than by other causes, 
or the study treatment was the most likely cause of the AE. 
For the purpose of safety analyses and safety reporting, all AEs that are classified as possibly 
related or related will be considered treatment-related events. 
6.2.30.4. Procedures for AE and SAE Collection and Reporting 
Each subject must be carefully monitored for the development of any AEs. This information 
should be obtained in the form of non-leading questions (e.g., “How are you feeling?”) and from 
signs and symptoms detected during each examination, laboratory assessments, observations of 
study personnel, and spontaneous reports from subjects. 
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Adverse events for all eligible subjects (i.e., excluding screen failures) will be recorded in the 
CRF. Any clinically significant laboratory abnormality or other clinically significant finding is 
considered an AE and the AE must be recorded on the appropriate pages of the CRF. The 
diagnosis / underlying etiology rather than the signs/symptoms should be reported as the AE, 
when possible. If no diagnosis is available, report only the signs and symptoms that met AE 
criteria as individual AE terms. 
6.2.30.5. Immediate Reporting of SAEs 
All SAEs for all subjects, including screen failures, must be immediately reported on the SAE 
report form to the Sponsor (or designee) within 24 hours of the Investigator (or designee) 
becoming aware of the SAE. All SAEs must be reported whether or not they are considered 
causally related to drug product. For immediate reporting of SAEs, the Investigator must provide 
assessments of relationship and serious criteria at the time of SAE report submission to the 
Sponsor. The SAE report form and completion guidelines can be found in the Study Operations 
Manual (SOM). All follow-up information on SAEs must also be immediately reported to the 
Sponsor (i.e., within 24 hours). 
Copies of all SAE reports and associated documentation submitted to the Sponsor will be kept in 
the Investigator's study site file. 
Please refer to the SAE report form and associated guidelines for information on how to 
immediately submit SAE reports to the Sponsor. 
6.2.30.6. Safety Reporting to Regulatory Authorities, Ethics Committees, and 
Investigators  
If there are suspected, unexpected serious adverse reactions (SUSARs) associated with the use of 
bb1111 or plerixafor, the Sponsor will notify the appropriate regulatory agency(ies) and all 
participating investigators on an expedited basis and in accordance with applicable regulations.  
The Investigator or Sponsor will notify the IRB/EC and other appropriate institutional regulatory 
bodies of any SUSARs or unanticipated problems, in accordance with local requirements. 
Reporting of SUSARs to regulatory agencies will be performed within 7 or 15 days as indicated 
by the event and in accordance with local regulations. Annual reporting of safety information 
will also be performed by the Sponsor, as required by local regulation. 
6.2.31. 
Pregnancy and Contraception 
Pregnancy is neither an AE nor an SAE, unless a complication relating to the pregnancy occurs 
(e.g., spontaneous abortion, which requires reporting as an SAE). However, all pregnancies 
occurring during this study (in subjects or female partners of male subjects) are to be reported in 
the same time frame as SAEs using the Pregnancy Form. Serious adverse events during the 
course of a pregnancy experienced by a subject or female partner of male subject are required to 
be immediately reported (i.e., within 24 hours) on the SAE report form. 
The course of all* pregnancies, including perinatal and neonatal outcome, regardless of whether 
the subject has discontinued participation in the study, will be followed until outcome, including 
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follow-up of the health status of the newborn at 6 weeks of age and annually thereafter for 
2 years.  
*Exceptions include: 
In cases where the MALE was the study subject, pregnancies resulting from sperm banking prior 
to receipt of drug product will not be followed. 
In cases where the FEMALE was the study subject, pregnancies resulting from oocyte banking 
prior to receipt of drug product in which the pregnancy is carried to term by surrogacy will not 
be followed. 
Busulfan has been shown in animal studies to be teratogenic (see package insert for additional 
details). The effects of administration of bb1111 on the pregnant female or the developing fetus 
are unknown.  
Female subjects of child-bearing potential are required to use 1 method of highly effective 
contraception from Screening to at least 6 months after drug product infusion, and male subjects 
of child-bearing potential are required to use 1 method of highly effective contraception from 
Conditioning to at least 6 months after drug product infusion. Beyond 6 months after drug 
product infusion, subjects should discuss with their physician prior to resuming unprotected 
intercourse. 
Acceptable forms of highly effective contraception for female participants of childbearing 
potential or for partners of male participants who are of childbearing potential include: 
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal ligation or bilateral tubal occlusion (performed at least 3 months prior 
to screening) 
• Vasectomized partner (performed at least 3 months prior to screening) 
• Sexual abstinence (no sexual intercourse) 
Acceptable forms of highly effective contraception for male participants include: 
• Sexual abstinence (no sexual intercourse) 
• History of vasectomy (performed at least 3 months prior to screening) 
• Condom with spermicide used together with highly effective female contraceptive 
methods if the female partner(s) is of childbearing potential (see above for list of 
acceptable female contraceptive methods) 
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6.2.32. 
Unscheduled Visits 
Unscheduled visits may be performed at any time during the study whenever necessary to assess 
for or to follow-up on AEs or as deemed necessary by the Investigator. If the Month 18 Visit 
does not include 18 calendar months, a telephone contact assessment for VOEs is to take place 
after 18 calendar months (post-drug product infusion) have elapsed. Other evaluations and 
procedures to be performed at unscheduled visits will be at the Investigator’s discretion in 
consultation with the Sponsor as appropriate and may be based on those listed in the SOE. 
Unscheduled visits, including any unscheduled assessments or procedures performed at the visit, 
should be promptly entered into the CRF. 
6.2.33. 
Long-term Follow-up Protocol 
Subjects will be followed for 24 months after drug product infusion under this protocol. Then, if 
appropriate consent is obtained, subjects will be followed for an additional 13 years under a 
separate long-term follow-up protocol, which will focus on long-term safety, with an emphasis 
on the assessment of factors associated with risk of hematologic malignancies, and long-term 
efficacy. This follow-up includes recording of SAEs, patterns of vector integration (ISA) in 
DNA from whole blood, and potentially testing peripheral blood leukocytes for RCL as clinically 
indicated. 
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7. 
STATISTICAL PROCEDURES 
Details of the statistical analysis will be provided in a separate document (the Statistical Analysis 
Plan [SAP]). This section provides a general overview of these plans. 
7.1. 
Sample Size Estimation 
The sample sizes for Groups A and B were not determined by formal statistical methods. 
Approximately 41 subjects will be enrolled in Group C, approximately 35 of whom must 
meet the severe VOE criteria as set forth in Inclusion Criterion #3.1.  
Assuming 80% of subjects in Group C who have at least 4 VOEs in the 24 months prior to 
Informed Consent will meet the primary efficacy endpoint of VOE-CR, 35 subjects will provide 
more than 99% power to reject the null hypothesis of 40% at 1-sided alpha of 0.025, using the 
Exact Test per EAST® (Version 6). The success criterion is 60% (21 out of 35) of subjects 
meeting the primary efficacy endpoint VOE-CR, if exactly 35 subjects with at least 4 VOEs in 
the 24 months prior to Informed Consent are enrolled and receive drug product in Group C.  
Power calculations were also performed for the key secondary efficacy endpoints of sVOE-CR 
and Globin Response.  
Assuming 85% of subjects in Group C with at least 4 VOEs in the 24 months prior to Informed 
Consent will meet sVOE-CR, 35 subjects will provide more than 99% power to reject the null 
hypothesis of 50% at 1-sided alpha of 0.025, using the Exact Test per EAST® (Version 6). The 
success criterion is 69% (24 out of 35) of subjects meeting sVOE-CR, if exactly 35 subjects with 
at least 4 VOEs in the 24 months prior to Informed Consent are enrolled and receive drug 
product in Group C.  
Assuming 70% of subjects will meet Globin Response, 41 subjects will provide approximately 
96% power to reject the null hypothesis of 40% at 1-sided alpha of 0.025, using the Exact Test 
per EAST® (Version 6). The success criterion is 59% (24 out of 41) of subjects meeting Globin 
Response, if exactly 41 subjects are enrolled and receive drug product in Group C. 
7.2. 
Populations for Analysis 
The following subject populations will be evaluated and used for presentation and analysis of 
the data: 
• Intent-to-Treat (ITT) Population: All subjects who initiate any study procedures, 
beginning with stem cell collection procedures (mobilization/apheresis or bone 
marrow harvest). 
• Transplant Population (TP): All subjects who receive drug product.  
• Transplant Population for VOE (TPVOE): Subset of TP subjects with at least 4 VOEs 
in the 24 months prior to Informed Consent.  
• Successful Engraftment Population (SEP): A subset of TP subjects who, following 
busulfan myeloablation and drug product infusion, successfully engraft with drug 
product, defined as 3 consecutive absolute neutrophil count (ANC) ≥0.5×109/L 
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laboratory values obtained on different days after the initial post-infusion nadir by 
Day 43. 
The ITT is the primary population for the analysis of safety, the TPVOE is the primary 
population for VOE-related endpoints including the primary efficacy endpoint and the key 
secondary endpoint, the TP is the primary population for the key secondary efficacy endpoint of 
Globin Response and the other secondary efficacy endpoints and pharmacodynamic endpoints. 
The SEP will be used to provide supportive data for subjects who engraft. 
7.3. 
Planned Analyses   
7.3.1. 
Interim Analyses 
Interim analyses are planned in support of regulatory submissions. The timing of these analyses 
and the number of subjects included in each analysis will take into account input from regulatory 
agencies and applicable regulatory guidance. The rationale for each analysis will be documented. 
7.3.2. 
Final Analysis 
A final analysis will be performed when all subjects complete the study.  
7.3.3. 
Additional Data Review 
Safety data are reviewed on an ongoing basis for signal detection, DMC meetings and to support 
preparation of regulatory submission documents. Analyses of study data may also be performed 
for the purposes of internal data review, regulatory agency interactions, and updating the 
scientific community. 
7.3.4. 
Impact of the COVID-19 Pandemic 
A review will be performed to determine which assessments are likely to have been affected by 
the COVID-19 pandemic, and if applicable, analyses will be performed to measure the effect of 
disruptions due to the pandemic on these assessments. 
7.4. 
Statistical Methods 
7.4.1. 
General Methods 
Tabulations will be produced for appropriate demographic, baseline, safety, efficacy, and 
PD parameters. For categorical variables, summary tabulations of the number and percentage 
within each category of the parameter will be presented. For continuous variables, the number of 
observations, mean, standard deviation, median, minimum and maximum values will be 
presented. 
Descriptive summary statistics as well as 2-sided, 95% confidence intervals will be presented on 
selected parameters. By-subject listings of data for all completed and discontinued subjects will 
be provided.  
For Hb, baseline will be defined as the average of the 2 most recent Hb assessments made at or 
prior to the Screening evaluation, which meet the following criteria: 
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i. Assessments must be separated by at least 1 month from each other.  
ii. Assessments must have been drawn no earlier than 24 months prior to Informed Consent 
and may include the Hb result from Screening.  
iii. There should be no pRBC transfusion within 3 months prior to each Hb assessment. 
For subjects who are on chronic, recurrent transfusions, and do not have 2 Hb assessments which 
meet the above criteria, the following criteria can be used: 2 Hb values which meet criteria (i) 
and (iii) that are found within 24 months prior to the start of a regular transfusion program. 
All reported VOEs will be adjudicated (see Section 3.3 for details on the event adjudication 
committee). All sVOE- or VOE-related efficacy endpoint analyses will be based on adjudicated 
sVOEs or VOEs. Supplementary analyses will be performed using protocol sVOEs/VOEs and 
investigator VOEs, where applicable. 
For VOE analysis, baseline will be defined as the annualized number of VOEs over the 
24 months before Informed Consent.  
Unless otherwise specified, for other efficacy, pharmacodynamic, and safety parameters, 
including shifts in key laboratory parameters, baseline will be defined as the first assessment 
during screening (which can be identified by the first record on or after date of ICF, but before 
initiation of stem cell collection). Longitudinal data (collected serially over time on study and 
follow-up) will be presented by appropriate time intervals, such as monthly, quarterly and so 
forth, depending on the nature of the data. 
7.4.2. 
Disposition of Subjects 
A tabulation of the disposition of subjects will be presented, including the number harvested, 
infused, and the number with any post-drug product infusion data available for analysis, and the 
extent of data available. Tables and listings will be provided for subjects in each analysis data 
set, including the distribution of subjects according to genotype. Subject data will also be 
displayed by site. The number of subjects completing the study through 2 years after drug 
product infusion and reasons for study discontinuation will be reported. Deviations from protocol 
treatment and assessment specifications will be tabulated and listed.  
7.4.3. 
Demographic and Baseline Characteristics 
The following demographic and baseline characteristic factors will be summarized: age 
(at diagnosis and at Informed Consent), country of birth, race and ethnicity, SCD-specific 
medical history, and the time from diagnosis to initiation of conditioning, number of VOEs, 
baseline Hb, and chronic transfusion status.  
7.4.4. 
Efficacy Analysis 
In the calculation of non-transfused total Hb for some efficacy endpoints, any subject with a 
β+ allele will produce some endogenous HbA which will not be distinguishable from residual 
transfused HbA, and therefore their contribution to the amount of non-transfused total Hb will be 
underestimated. For these subjects only, HbA will be included as “non-transfused Hb” only for 
samples taken ≥ 60 days after last transfusion. For subjects without a β+ allele, non-transfused 
total Hb is the sum of HbS + HbF + HbA2 + HbAT87Q.  
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7.4.4.1. 
Analysis of Primary Efficacy Endpoint  
The primary endpoint of VOE-CR will be tested against the null hypothesis of 40% using a 
1-sided exact binomial test. The number and percentage of subjects reaching the primary 
endpoint will be presented. The associated 2-sided exact 95% confidence interval will 
be provided. The primary endpoint will be analyzed in the TPVOE for Group C subjects. The 
subject must have been or would have been followed for a minimum of 18 calendar months after 
drug product infusion before the subject can be evaluated for the primary endpoint. If the Month 
18 Visit does not include 18 calendar months, a telephone contact assessment for VOEs can take 
place after 18 calendar months (post-drug product infusion) have elapsed. 
The primary estimand examines the proportion of subjects achieving complete resolution of 
VOEs between 6 months and 18 months after drug product infusion among all subjects who 
receive bb1111 and have at least 4 VOEs in the 24 months prior to Informed Consent. 
Supplementary analyses for the primary endpoint will be detailed in the statistical analysis plan 
(SAP). 
7.4.4.2. 
Analysis of Key Secondary Efficacy Endpoints 
7.4.4.2.1. Analysis of sVOE-CR 
The key secondary endpoint of sVOE-CR will be tested against the null hypothesis of 50% using 
a 1-sided exact binomial test. The number and percentage of subjects reaching this key 
secondary endpoint will be presented. The associated 2-sided exact 95% confidence interval will 
be provided. The endpoint will be analyzed in the TPVOE for Group C subjects. The subject 
must have been or would have been followed for a minimum of 18 calendar months after drug 
product infusion before the subject can be evaluated for the endpoint. If the Month 18 Visit does 
not include 18 calendar months, a telephone contact assessment for VOEs can take place after 18 
calendar months (post-drug product infusion) have elapsed. 
The estimand examines the proportion of subjects achieving complete resolution of severe VOEs 
between 6 months and 18 months after drug product infusion among all subjects who receive 
bb1111 and have at least 4 VOEs in the 24 months prior to Informed Consent. 
7.4.4.2.2. Analysis of Globin Response 
This key secondary endpoint of Globin Response will be tested against the null hypothesis of 
40% using a 1-sided exact binomial test. The number and percentage of subjects reaching this 
key secondary endpoint will be presented. The associated 2-sided exact 95% confidence interval 
will be provided. The endpoint will be analyzed in the TP for Group C subjects. 
Globin Response is defined as meeting the following criteria for a continuous period of at least 
6 months after drug product infusion: 
• Weighted average HbAT87Q percentage of non-transfused total Hb ≥ 30%; AND  
• Weighted average non-transfused total Hb increase of ≥ 3 g/dL compared to baseline 
total Hb OR weighted average non-transfused total Hb ≥ 10 g/dL. 
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The estimand examines the proportion of subjects achieving Globin Response for a continuous 
period of at least 6 months after drug product infusion starting ≥ 60 days after the last pRBC 
transfusion among all subjects who receive bb1111.  
Subjects must meet these criteria for a continuous period of ≥ 6 months after drug product 
infusion (starting ≥ 60 days after last pRBC transfusion). 
The weighted average HbAT87Q percentage is defined as:  
[(t1-t0) × ((p0+p1)/2) + (t2-t1) × ((p1+p2)/2) +…+ (tk-tk-1) × ((pk-1+pk)/2)]/(tk-t0), 
where 
• t0 represents the time of the first HbAT87Q assessment where there is no pRBC 
transfusion in the previous 60 days, and t1, t2, … tk represent continuous time points 
for HbAT87Q assessments after t0 where no pRBC transfusion occurs between these 
timepoints.  
• p0, p1, p2, … pk represent the HbAT87Q percentage at each of these time points.  
• tk-t0 must be at least 6 months.  
HbAT87Q is assessed every 3 months starting from Month 3 after drug product infusion. In the 
event that there are 3 consecutive scheduled HbAT87Q assessments that are within visit window 
but are less than 6 months apart, the ≥ 6-month requirement will not be needed. The weighted 
average may be considered as an average AUC calculation for HbAT87Q percentage.  
Note that the weighted total Hb can be calculated in a similar way. 
Sensitivity and/or supplementary analyses for the key secondary endpoints will be detailed in the 
SAP. 
7.4.4.3. 
Analyses of Other Secondary Efficacy Endpoints 
Analyses of the following secondary efficacy endpoints will be descriptively summarized. More 
details can be found in the SAP.  
Clinical and Disease Evaluation Endpoints: 
(Only for subjects with at least 4 VOEs in the 24 months prior to Informed 
Consent): 
• Change in the annualized number of VOEs in the 24 months after drug product 
infusion compared to the 24 months prior to Informed Consent.  
(Only for Group C subjects with at least 4 VOEs in the 24 months prior to Informed 
Consent):  
• Change in the annualized number of severe VOEs in the 24 months after drug product 
infusion compared to the 24 months prior to Informed Consent. 
• VOE-CR24, defined as complete resolution of VOEs between 6 months and 
24 months after drug product infusion 
• sVOE-CR24, defined as complete resolution of severe VOEs between 6 months and 
24 months after drug product infusion 
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• sVOE-75, defined as at least a 75% reduction in annualized severe VOEs in the 
24 months after drug product infusion compared to the 24 months prior to Informed 
Consent  
Note: The analyses regarding severe VOEs will be based on Group C subjects who have at least 
4 VOEs in the 24 months prior to Informed Consent. 
Characterization of Globin Response (only for Group C subjects who have achieved Globin 
Response): 
• Proportion of subjects who meet the definition of Globin Response at Month 24 
• Duration of Globin Response 
Hematologic Endpoints: 
• Weighted average for the following at Month 6, 12, 18, and 24: 
− non-transfused total Hb 
− HbS percentage of non-transfused total Hb 
− HbS percentage of non-transfused total Hb ≤ 70%, ≤ 60%, ≤ 50% 
− HbAT87Q percentage of non-transfused total Hb 
− non-HbS percentage of non-transfused total Hb 
• Assessment of the following over time: 
− non-transfused total Hb  
− HbS percentage of non-transfused total Hb 
− HbAT87Q percentage of non-transfused total Hb 
− non-HbS percentage of non-transfused total Hb 
• Change from baseline in hemolysis markers, including absolute reticulocyte count, 
% reticulocytes/erythrocytes, total bilirubin, haptoglobin, and lactate dehydrogenase 
• Change from baseline in markers of iron stores including ferritin, liver iron content, 
and if assessed at baseline, cardiac iron content 
• Change from baseline in annualized frequency and volume of packed red blood cell 
(pRBC) transfusions between 6 months and 24 months after drug product infusion  
• Change from baseline in markers of stress erythropoiesis, including erythropoietin 
and serum transferrin receptor 
SCD Burden and Chronic Complications Assessment:  
• Change from baseline in renal function as measured by eGFR  
• Change from baseline in cardiac-pulmonary function via echocardiogram 
(tricuspid regurgitant jet velocity [TRJV], LVEF) and pulmonary function tests 
• Change from baseline in meters walked during 6-minute walk test  
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Hospitalizations and Quality of Life 
• Change from baseline in annualized VOE-related hospital admissions and days  
• Change from baseline in patient-reported quality of life, as measured by PROMIS 
7.4.4.4. 
Analyses of Exploratory Efficacy Endpoints 
Analyses of exploratory efficacy endpoints will be descriptively summarized. Details can be 
found in the SAP.  
7.4.4.5. 
Correlation Analyses between Efficacy Endpoints 
The following correlation analyses will be performed:  
• Globin Response vs VOE-CR  
• Globin Response vs sVOE-CR  
• HbAT87Q percentage at Month 6 vs percent change in annualized sVOEs 
Details of the correlation analyses will be provided in the SAP. 
7.4.5. 
Safety Analyses 
The safety analyses will include evaluation of the incidence of AEs by Preferred Term and 
System Organ Class coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Adverse events will be summarized for the ITT population for those events that occur from 
signing of informed consent through the Month 24 visit. All AEs will be listed and summarized 
for the following time periods: 1) from Informed Consent up to the initiation of the stem cell 
harvest procedure (first administration of mobilization agent, or bone marrow harvest); 2) from 
initiation of the stem cell harvest procedure up to start of conditioning; 3) from start of 
conditioning (approximately D-6) through neutrophil engraftment; 4) from neutrophil 
engraftment  through Month 24 Visit; 5) from the day of drug product infusion (Day 1) through 
Month 24 Visit; 6) from Informed Consent through Month 24 Visit. All AEs will be listed in 
by-patient, by-time data listings, including any events that may have occurred after signing 
Informed Consent but prior to stem cell harvest. 
Changes in laboratory parameters over time will be summarized for the ITT population with 
descriptive statistics, including laboratory shifts tables.  
Additional summaries of safety data may be produced, if warranted for further characterizing the 
safety profile of study subjects. 
7.4.6. 
Pharmacodynamic Analyses 
Analyses of PD endpoints and other exploratory endpoints will be described in the SAP.  
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8. 
ADMINISTRATIVE REQUIREMENTS 
8.1. 
Good Clinical Practice 
The study will be conducted in accordance with the International Conference on Harmonisation 
(ICH) Guideline for GCP and the appropriate regulatory requirement(s). The Investigator will be 
thoroughly familiar with the appropriate use of bb1111 as described in the protocol and 
Investigator’s Brochure. Essential clinical documents will be maintained to demonstrate the 
validity of the study and the integrity of the data collected. Master files should be established at 
the beginning of the study, maintained for the duration of the study and retained according to the 
appropriate regulations. 
8.2. 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki. The IRB/IEC and other appropriate institutional regulatory bodies will review all 
appropriate study documentation in order to safeguard the rights, safety, and wellbeing of the 
subjects. The study will only be conducted at sites where IRB/IEC and other appropriate 
institutional regulatory body approval has been obtained. The protocol, Investigator’s Brochure, 
informed consent, advertisements (if applicable), written information given to the subjects, safety 
updates, annual progress reports, and any revisions to these documents will be provided to the 
IRB/IEC and other appropriate institutional regulatory bodies by the Investigator. 
8.3. 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject or their legal representative prior to study participation. The method of obtaining and 
documenting the informed consent and the contents of the consent will comply with ICHGCP 
and all applicable regulatory requirement(s). If a subject is < 18 years of age at signing of 
informed consent/assent and turns 18 while on study, the subject should re-consent to the adult 
ICF at the next scheduled study visit. 
Consent to this study indicates acknowledgement that follow-up is expected to last 15 years, with 
the first 2 years in this Study HGB-206 and 13 additional years in a long-term follow-up study. A 
brief summary of expected study procedures in the long-term follow-up study will be described 
in the Study HGB-206 consent so that the subject and/or their guardian or legal representative 
are aware of expectations in the long-term follow-up study. Consent for participation in the 
long-term follow-up study will be obtained at the time of enrollment in the long-term follow-up 
study. 
If any concerning chromosomal abnormality or genetic mutation is identified prior to 
conditioning, and the subject intends to continue to stay on study (see Section 6.2.11), 
appropriate informed consent must be obtained after the results have been fully discussed.  
8.4. 
Subject Confidentiality 
In order to maintain subject privacy, all CRFs, accountability records, study reports, and 
communications will identify the subject by initials and the assigned subject number. The 
Investigator will grant monitor(s) and auditor(s) from the Sponsor or its designee and regulatory 
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authority(ies) access to the subject’s original medical records for verification of data gathered 
on the CRFs and to audit the data collection process. The subject’s confidentiality will be 
maintained and will not be made publicly available to the extent permitted by the applicable laws 
and regulations. 
8.5. 
Protocol Compliance 
The Investigator will conduct the study in compliance with the protocol, provided by the 
Sponsor, that has been given approval/favorable opinion by the IRB/IEC and other appropriate 
institutional regulatory bodies. Modifications to the protocol should not be made without 
agreement of both the Investigator and the Sponsor. Changes to the protocol will require written 
IRB/IEC and other appropriate institutional regulatory body approval/favorable opinion prior to 
implementation, except when the modification is needed to eliminate an immediate hazard(s) to 
subjects. The IRB/IEC may provide, if applicable regulatory authority(ies) permit, expedited 
review and approval/favorable opinion for minor change(s) in ongoing studies that have the 
approval /favorable opinion of the IRB/IEC and other appropriate institutional regulatory bodies. 
The Sponsor will submit all protocol modifications to the regulatory authority(ies) in accordance 
with the governing regulations.  
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the Investigator will contact the Sponsor, if circumstances permit, to discuss the 
planned course of action. Any departures from the protocol must be fully documented in the CRF 
and source documentation. 
8.6. 
Direct Access to Source Data 
Monitoring and auditing procedures developed by the Sponsor will be followed, in order to 
comply with GCP guidelines. 
The study will be monitored by the Sponsor or its designee. Monitoring will be done by personal 
visits from a representative of the Sponsor (site monitor) and will include onsite review of the 
CRFs for completeness and clarity, crosschecking with source documents, and clarification of 
administrative matters will be performed. The review of medical records will be performed in a 
manner to ensure that subject confidentiality is maintained. 
The site monitor will ensure that the investigation is conducted according to protocol design and 
regulatory requirements by frequent communications (letter, email, telephone, and fax). 
Regulatory authorities, the IRB/IEC and other appropriate institutional regulatory bodies, and/or 
the Sponsor may request access to all source documents, CRFs, and other study documentation 
for onsite audit or inspection. Direct access to these documents must be guaranteed by the 
Investigator, who must provide support at all times for these activities. 
8.7. 
Case Report Form Completion 
CRFs will be completed for each study subject. It is the Principal Investigator’s responsibility to 
ensure the accuracy, completeness, and timeliness of the data reported in the subject’s CRF. 
Source documentation supporting the CRF data should indicate the subject’s participation in the 
study and should document the dates and details of study procedures, AEs, and subject status.  
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The Principal Investigator or designated representative, should complete the CRF screens as 
soon as possible after information is collected, preferably on the same day that a study subject is 
seen for an examination, treatment, or any other study procedure. Any outstanding entries must 
be completed immediately after the final examination. An explanation should be given for all 
missing data. 
The Principal Investigator must sign and date the Investigator’s Statement at the end of the 
CRF to endorse the recorded data.  
8.8. 
Record Retention 
The Investigator will maintain all study records according to ICHGCP and applicable regulatory 
requirement(s). Records will be retained for at least 2 years following marketing application 
approval or 2 years after formal discontinuation of the clinical development of the investigational 
product or according to applicable regulatory requirement(s). If the Investigator withdraws from 
the responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility. The Sponsor must be notified in writing if a custodial change occurs. 
The Sponsor has full rights over any invention, discovery, or innovation, patentable or not, that 
may occur when performing the study. 
8.9. 
Liability and Insurance 
The Sponsor has subscribed to an insurance policy covering, in its terms and provisions, its legal 
liability for injuries caused to participating persons and arising out of this research performed 
strictly in accordance with the scientific protocol as well as with applicable law and professional 
standards. 
8.10. 
Publication and Presentation of Study Findings and Use of 
Information 
All information regarding BB305 LVV and bb1111 supplied by the Sponsor to the Investigator is 
privileged and confidential information. The Investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from the Sponsor. It 
is understood that there is an obligation to provide the Sponsor with complete data obtained 
during the study. The information obtained from the clinical study will be used towards the 
development of BB305 LVV and bb1111 and may be disclosed to regulatory authority(ies), other 
Investigators, corporate partners, or consultants as required. 
It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer reviewed scientific or medical journal. A Publications Committee comprised 
of Investigators participating in the study and representatives from the Sponsor, as appropriate, 
will be formed to oversee the publication and presentation of the study results, which will reflect 
the experience of all participating clinical sites. No publication or disclosure of study results will 
be permitted except under the terms and conditions of a separate written agreement between 
Sponsor and the Investigator and/or the Investigator's institution. 
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Perez-Simon JA, Caballero MD, Corral M, et al (1998) Minimal number of circulating CD34+ 
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10. 
APPENDICES 
10.1. 
Performance Status Assessments 
10.1.1. 
Karnofsky Performance Status Scale 
The following table presents the Karnofsky performance status scale and should be used for 
subjects ≥ 16 years of age. 
Points 
Description 
100 
Normal, no complaints, no evidence of disease 
90 
Able to carry on normal activity 
80 
Normal activity with effort; some signs or symptoms of disease 
70 
Cares for self; unable to carry on normal activity or to do active work 
60 
Required occasional assistance but is able to care for most of his/her needs 
50 
Required considerable assistance and frequent medical care 
40 
Disabled; required special care and assistance 
30 
Severely disabled; hospitalization indicated. Death not imminent 
20 
Very sick; hospitalization necessary; active support treatment necessary 
10 
Moribund; fatal process progressing rapidly 
0 
Dead 
Source: (Mor et al. 1984)  
10.1.2. 
Lansky Performance Status Scale  
The following table presents the Lansky performance status scale and should be used for subjects 
< 16 years of age. 
Points 
Description 
100 
Fully active, normal 
90 
Minor restrictions in physically strenuous activity 
80 
Active, but tires more quickly 
70 
Both greater restriction of, and less time spent in, active play 
60 
Up and around, but minimal active play; keeps busy with quieter activities 
50 
Gets dressed, but lies around much of the day; no active play; able to participate in all 
quiet play and activities 
40 
Mostly in bed; participates in quiet activities 
30 
In bed; needs assistance even for quiet play 
20 
Often sleeping; play entirely limited to very passive activities 
10 
No play; does not get out of bed 
0 
Unresponsive 
Source: (Lansky et al. 1987)  
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10.2. 
Health-Related Quality of Life, Cognitive Function, and Work 
Productivity Assessments 
• Patient Reported Outcomes Measurement Information System (PROMIS)-57 
measures Pain Interference, Pain-Intensity, Physical Function, Sleep Disturbance, 
Satisfaction with Participation in Social Roles, Anxiety, Depression and Fatigue. 
• PROMIS Pediatric Profile/PROMIS Parent Proxy Profile assess the beliefs of a 
pediatric subject/proxy about Physical Function/Mobility, Anxiety, Depressive 
Symptoms, Fatigue, Peer Relationships, Pain Interference, and Pain Intensity.  
• PROMIS Short Form 6a measures perceived cognitive functioning.  
• EuroQol-5D (EQ-5D-3L) or EuroQol-5D Youth version (EQ-5D-Y) provide a 
general measure of overall health status. The EQ-5D-3L Proxy Version 1 or EQ-5D-
Y Proxy Version 1 may also be used as appropriate.   
• Work Productivity and Activity Impairment-General Health (WPAI-GH/Caregiver 
WPAI-GH) measures impairments in work and usual activities. The results can 
provide a quantitative summary of the amount of work time missed, reduced on-the-
job effectiveness and amount of other usual activities missed due to general health 
problems. 
See sample forms below. 
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Protocol Title: 
A Phase 1/2 Study Evaluating Gene Therapy by Transplantation of 
Autologous CD34+ Stem Cells Transduced Ex Vivo with the 
LentiGlobin BB305 Lentiviral Vector in Subjects with Severe Sickle 
Cell Disease 
Protocol Number: 
HGB-206 Version 13.0 (17 January 2023) 
INVESTIGATOR STATEMENT 
I have read, understood, and agree to abide by all the conditions and instructions contained in 
this protocol. 
I understand that all documentation provided to me by bluebird bio or its designated 
representative(s) concerning this study that has not been published previously will be kept in 
the strictest confidence. This documentation includes the study protocol, Investigator’s 
Brochure, case report forms, and other scientific data. 
I agree to personally conduct or supervise the described investigation(s). 
I agree to inform any subjects, or any persons used as controls, that the Drug Product is being 
used for investigational purposes and I will ensure that the requirements relating to obtaining 
informed consent, as per local regulations and under Good Clinical Practice (GCP), are met. 
I agree to report to the Sponsor adverse events that occur in the course of the investigation(s) 
in accordance with this protocol and as required by local regulations and under GCP.  
I have read and understand the information in the Investigator’s Brochure, including the 
potential risks and side effects of the Drug Product. 
I agree to maintain adequate and accurate records and to make those records available for 
inspection in accordance with local regulations and under GCP. 
I will ensure that an ethics committee that complies with all local regulations and GCP 
requirements will be responsible for the initial and continuing review and approval of the 
clinical investigation.  
I also agree to promptly report to the ethics committee all changes in the research activity and 
all unanticipated problems involving risks to human subjects or others.  
I agree that this study will not commence without the prior approval of the appropriate national 
health authorities together with a properly constituted ethics committee. I agree that no 
changes will be made to the study protocol without the prior written approval of bluebird bio 
and the aforementioned regulatory bodies, as applicable in the relevant laws and regulations. 
I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the 
study(ies) are informed about their obligations in meeting the above commitments. 
 
Investigator Name 
 
Investigator Signature 
 
Date 
 
 
Investigational site or name of institution and location (printed) 
 
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