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Notification report


Full notification file


General information

Notification Number
B/NL/20/014

Member State to which the notification was sent
Netherlands

Date of acknowledgement from the Member State Competent Authority
19/08/2020

Title of the Project
HGB-210 "A Phase 3 Study Evaluating Gene Therapy by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo with the LentiGlobin BB305 Lentiviral Vector in Subjects with Sickle Cell Disease."

Proposed period of release:
01/09/2020 to 01/09/2021

Name of the Institute(s) or Company(ies)
Leiden University Medical Center, Albinusdreef 2
2333 ZA Leiden
PO Box 9600
2300 RC Leiden
The Netherlands;


3. Is the same GMO release planned elsewhere in the Community?
No

Has the same GMO been notified elsewhere by the same notifier?
No

GMO characterization

GMO is a:
RNA Virus

Identity of the GMO:
The genetically modified organism (GMO) is bb1111 (also known as LentiGlobin Drug
Product for sickle cell disease [SCD] and herein referred to as bb1111).
bb1111 consists of an autologous CD34+ cell-enriched population from patients with SCD that
contains hematopoietic stem cells (HSCs) transduced with the BB305 lentiviral vector (LVV)
that encodes a variant of the normal human hemoglobin (Hb) βA-globin (HBB) gene (i.e.,
HBBT87Q) that results in the production of βA-T87Q-globin, a non-sickling βA-globin molecule
with a single amino acid (aa) substitution of glutamine (Gln; Q) for threonine (Thr; T) at aa
position 87 (T87Q), suspended in a cryopreservation solution.
bb1111 is being evaluated for the treatment of adults and pediatric subjects ≥2 and ≤50 years
of age with SCD (for subjects <18 years of age who have a willing, matched human leukocyte
antigen (HLA)-identical sibling hematopoietic cell donor are excluded). bb1111 will only be
administered to subjects with SCD as a single intravenous (IV) infusion, only under containeduse
conditions within hospitals that have been approved by bluebird bio for administration of
bb1111.
The BB305 LVV production system is a third-generation-like, multi-plasmid, split-packaging
system, of self-inactivating (SIN) design. During LVV production, a hybrid cytomegalovirus
(CMV)/human immunodeficiency virus-1 (HIV-1) long terminal repeat (LTR) with modified
Unique 3’ region (U3) conferring the SIN property controls transcription of vector RNA from
the transfer plasmid. The stably integrated proviral cDNA contains only the HIV-1-derived
U3-R-U5 region, packaging signal (psi), central polypurine tract (cPPT) and Rev-response
element (RRE), and the HBBT87Q transgene under the transcriptional control of the erythroidspecific
human β-globin promoter and enhancer elements. The BB305 LVV and proviral form
do not contain any genes other than the HBBT87Q transgene.
In the context of this document, the “donor DNA” or “insert” is the integrated transgenic
cDNA, consisting of the HIV-1-derived LTR with SIN (U3) LTR, psi (+), cPPT and RRE,
and the HBBT87Q transgene under the transcriptional control of the erythroid-specific human
β-globin promoter and enhancer elements; the “vector” is the BB305 LVV; the “recipient or
parental organism” is the SCD patient’s cells (most importantly CD34+ HSCs); and the GMO
is the transduced SCD CD34+ HSCs (bb1111).
There is no risk of formation of replication-competent lentivirus (RCL) and bb1111 is free of
infectious LVV particles that are capable of being released in the environment. The BB305
proviral DNA encoding the HBBT87Q transgene is stably integrated within the cellular genomic
DNA (gDNA) or chromosomes of the transduced SCD CD34+ HSCs. For bb1111, no risks to
the environment or animal health can be identified. Therefore, the overall risks for human
health are considered negligible.
bb1111 is related to, but a different product than, LentiGlobin Drug Product for transfusiondependent
β-thalassemia (TDT) (INN betibeglogene autotemcel; tradename ZYNTEGLO®),
that was granted a conditional marketing authorization in the EU. ZYNTEGLO is indicated
for patients 12 years and older with TDT who do not have a β0/β0 genotype, for whom HSC
transplantation is appropriate but a human leukocyte antigen (HLA)-matched related HSC
donor is not available. For ZYNTEGLO, the BB305 LVV is also used to transduce TDT
HSCs, but because they contain different mutations in the HBB gene than are present in SCD,
the transgenic βA-T87Q-globin protein corrects a different phenotypic abnormality (absent or
non-functional βA-globin chains result in failure to form Hb tetramers, resulting in
accumulation and aggregation of a-globin chains and RBC loss).


Information relating to the recipient or parental organisms from wich the GMO is derived
Common NameGenusSpeciesSubspeciesStrainPathovar
HumanHomoSapiens---

European Commission administrative information

Consent given by the Member State Competent Authority:
Yes
17/11/2020 00:00:00
Remarks: