Analyses demonstrate lentiviral vector BB305
unlikely to be the cause of AML in clinical study of LentiGlobin
for SCD
bluebird bio has initiated process with
regulators to resume clinical studies
Company to hold conference call and webcast
today, March 10, 2021, 8:00 AM EST
bluebird bio, Inc. (Nasdaq: BLUE) announced today that
based on the analyses completed to date, it is very unlikely the
Suspected Unexpected Serious Adverse Reaction (SUSAR) of acute
myeloid leukemia (AML) reported in its Phase 1/2 (HGB-206) study of
LentiGlobin gene therapy for sickle cell disease (SCD) (bb1111) was
related to the BB305 lentiviral vector (LVV).
“In addition to our earlier findings of several well-known
genetic mutations and gross chromosomal abnormalities commonly
observed in AML in this patient, our latest analyses identified the
integration site for the vector within a gene called VAMP4. VAMP4
has no known association with the development of AML nor with
processes such as cellular proliferation or genome stability.
Moreover, we see no significant gene misregulation attributable to
the insertion event,” said Philip Gregory, chief scientific
officer, bluebird bio. “In totality, the data from our assessments
provide important evidence demonstrating that it is very unlikely
our BB305 lentiviral vector played a role in this case and we have
shared with the FDA that we believe these results support lifting
the clinical holds on our β-thalassemia and sickle cell disease
programs.”
As reported by bluebird bio on February 25, 2021, laboratory
analyses showed that this patient had significant chromosomal
abnormalities and mutations in genes typically associated with the
development of AML. Specifically, mutations in the RUNX1 and PTPN11
genes have been detected in the leukemic cells of this patient.
Preliminary findings suggested that the BB305 LVV vector was
present in the AML blast cells, but there was not sufficient
information to determine causality.
Since then, and with the advice of several independent leading
academic experts in lentiviral vector gene therapy, bluebird bio
has performed additional scientific assessments to determine where
in the genome the LVV insertion occurred, and if this integration
was responsible for any change in gene regulation or gene
expression nearby.
Multiple independent analyses have confirmed that vector
insertion in the AML cells from this patient took place in the
VAMP4 gene, or vesicle-associated membrane protein 4. VAMP4 itself
has no known role in the development of AML or with any cellular
process related to cancer.
bluebird bio also assessed if there was any disruption to normal
gene regulation or gene expression in and around the site of vector
insertion. Based on completed analyses, the insertion into the
VAMP4 gene has had no impact on gene expression or gene regulation
nor caused any disruption of nearby genes.
Based on the available results to date, bluebird bio believes
that the case of AML is very unlikely related to the BB305 LVV.
Given this, the company has initiated engagement with regulators to
begin the process of resuming clinical studies for sickle cell
disease and β-thalassemia.
A second SUSAR of myelodysplastic syndrome (MDS) in a patient
from Group C of HGB-206 was reported in early February and is
currently being investigated to determine if the clinical findings
meet the criteria to be classified as a case of MDS and, if so, if
LentiGlobin for SCD had any role. The MDS diagnosis was based on
prolonged anemia following LentiGlobin for SCD infusion coupled
with the observation of trisomy 8 in a small percentage of the
patient’s bone marrow cells. However, no blasts or dysplastic cells
were seen in an examination of the patient’s bone marrow, and while
trisomy 8 is associated with myeloid malignancies, this finding is
not sufficient for a diagnosis of MDS in the absence of blasts or
dysplastic cells.
Regulatory Status
The U.S. Food and Drug Administration (FDA) has placed a
clinical hold on the HGB-206 and HGB-210 studies of LentiGlobin for
SCD and the HGB-207 and HGB-212 studies of betibeglogene autotemcel
for β-thalassemia. The company is in dialogue with the FDA in order
to resume all clinical studies currently on clinical hold.
An Article 20 referral procedure was triggered by the European
Commission (EC) and will be conducted by the European Medicines
Agency (EMA). The EMA’s Pharmacovigilance Risk Assessment Committee
(PRAC) will begin the process of reviewing the benefit/risk of
ZYNTEGLO™ (betibeglogene autotemcel) for the treatment of
transfusion-dependent β-thalassemia, during its March 8 – 11
session. The committee will determine whether any additional
pharmacovigilance measures are necessary. The EMA has paused the
renewal procedure for ZYNTEGLO's conditional marketing
authorization (CMA) while the PRAC review is ongoing.
No cases of hematologic malignancy have been reported in any
patient who has received treatment with betibeglogene autotemcel
for transfusion-dependent β-thalassemia, however because it is also
manufactured using the same BB305 LVV used in LentiGlobin for SCD,
the company decided to temporarily suspend marketing of ZYNTEGLO
while the AML case is assessed.
Investor Conference Call Information
bluebird bio will hold a conference call to discuss this update
on Wednesday, March 10 at 8:00 a.m. ET. Investors may listen to the
call by dialing (844) 825-4408 from locations in the United States
or +1 (315) 625-3227 from outside the United States. Please refer
to conference ID number 4148389.
To access the live webcast of bluebird bio’s presentation,
please visit the “Events & Presentations” page within the
Investors & Media section of the bluebird bio website at
http://investor.bluebirdbio.com. A replay of the
webcast will be available on the bluebird bio website for 90 days
following the event.
About HGB-206 and HGB-210
HGB-206 is a Phase 1/2 open-label study designed to evaluate the
efficacy and safety of LentiGlobin gene therapy for sickle cell
disease (SCD) that includes three treatment cohorts: Groups A, B
and C. A refined manufacturing process designed to increase vector
copy number (VCN) and further protocol refinements made to improve
engraftment potential of gene-modified stem cells were used for
Group C. Group C patients also received LentiGlobin for SCD made
from HSCs collected from peripheral blood after mobilization with
plerixafor, rather than via bone marrow harvest, which was used in
Groups A and B of HGB-206.
HGB-210 is a Phase 3 single-arm open-label study designed to
evaluate the efficacy and safety of LentiGlobin gene therapy for
SCD in patients between two years and 50 years of age with sickle
cell disease.
About LentiGlobin for SCD (bb1111)
LentiGlobin gene therapy for sickle cell disease (bb1111) is an
investigational treatment being studied as a potential treatment
for SCD. bluebird bio’s clinical development program for
LentiGlobin for SCD includes the completed Phase 1/2 HGB-205 study,
the Phase 1/2 HGB-206 study, and the Phase 3 HGB-210 study.
The U.S. Food and Drug Administration granted orphan drug
designation, fast track designation, regenerative medicine advanced
therapy (RMAT) designation and rare pediatric disease designation
for LentiGlobin for SCD.
LentiGlobin for SCD received orphan medicinal product
designation from the European Commission for the treatment of SCD,
and Priority Medicines (PRIME) eligibility by the EMA in September
2020.
bluebird bio is conducting a long-term safety and efficacy
follow-up study (LTF-307) for people who have participated in
bluebird bio-sponsored clinical studies of LentiGlobin for SCD. For
more information visit:
https://www.bluebirdbio.com/our-science/clinical-trials or
clinicaltrials.gov and use identifier NCT04628585 for
LTF-307.
LentiGlobin for SCD is investigational and has not been approved
in any geography.
About ZYNTEGLO (betibeglogene autotemcel)
Betibeglogene autotemcel (beti-cel) is a one-time gene therapy
that adds functional copies of a modified form of the β-globin gene
(βA-T87Q-globin gene) into a patient’s own hematopoietic (blood)
stem cells (HSCs). Once a patient has the βA-T87Q-globin gene, they
have the potential to produce HbAT87Q, which is gene
therapy-derived adult Hb, at levels that may eliminate or
significantly reduce the need for transfusions. In studies of
beti-cel, transfusion independence (TI) is defined as no longer
needing red blood cell transfusions for at least 12 months while
maintaining a weighted average Hb of at least 9 g/dL.
The European Commission granted conditional marketing
authorization (CMA) for beti-cel, marketed as ZYNTEGLO™ gene
therapy, for patients 12 years and older with transfusion-dependent
β-thalassemia (TDT) who do not have a β0/β0 genotype, for whom
hematopoietic stem cell (HSC) transplantation is appropriate, but a
human leukocyte antigen (HLA)-matched related HSC donor is not
available.
Non-serious adverse events (AEs) observed during clinical
studies that were attributed to beti-cel included abdominal pain,
thrombocytopenia, leukopenia, neutropenia, hot flush, dyspnea, pain
in extremity, tachycardia and non-cardiac chest pain. One serious
adverse event (SAE) of thrombocytopenia was considered possibly
related to beti-cel.
Additional AEs observed in clinical studies were consistent with
the known side effects of HSC collection and bone marrow ablation
with busulfan, including SAEs of veno-occlusive disease.
For details, please see the Summary of Product Characteristics
(SmPC).
On April 28, 2020, the EMA renewed the CMA for beti-cel. The CMA
for beti-cel is valid in the 27 member states of the EU as well as
the UK, Iceland, Liechtenstein and Norway. In November 2020,
bluebird bio submitted to the EMA an application for renewal of the
CMA; this procedure is currently on hold. The CMA is valid while
the renewal application review is ongoing and while it is on
hold.
The U.S. Food and Drug Administration granted beti-cel Orphan
Drug status and Breakthrough Therapy designation for the treatment
of TDT. Beti-cel is not approved in the U.S. Beti-cel continues to
be evaluated in the ongoing Phase 3 Northstar-2 (HGB-207) and
Northstar-3 (HGB-212) studies.
bluebird bio is conducting a long-term safety and efficacy
follow-up study, LTF-303 for people who have participated in
bluebird bio-sponsored clinical studies of ZYNTEGLO.
About bluebird bio, Inc.
bluebird bio is pioneering gene therapy with purpose. From our
Cambridge, Mass., headquarters, we’re developing gene and cell
therapies for severe genetic diseases and cancer, with the goal
that people facing potentially fatal conditions with limited
treatment options can live their lives fully. Beyond our labs,
we’re working to positively disrupt the healthcare system to create
access, transparency and education so that gene therapy can become
available to all those who can benefit.
bluebird bio is a human company powered by human stories. We’re
putting our care and expertise to work across a spectrum of
disorders: cerebral adrenoleukodystrophy, sickle cell disease,
β-thalassemia and multiple myeloma, using gene and cell therapy
technologies including gene addition, and (megaTAL-enabled) gene
editing.
bluebird bio has additional nests in Seattle, Wash.; Durham,
N.C.; and Zug, Switzerland. For more information, visit
bluebirdbio.com.
Follow bluebird bio on social media: @bluebirdbio,
LinkedIn, Instagram and YouTube.
ZYNTEGLO, betibeglogene autotemcel, beti-cel, and bluebird bio
are trademarks of bluebird bio, Inc.
Forward-Looking
Statements
This release contains “forward-looking statements” within the
meaning of the Private Securities Litigation Reform Act of 1995,
including statements regarding the Company’s timing and
expectations regarding its investigation of the relationship of the
AML and MDS events to the use of lentiviral vector BB305 in
LentiGlobin gene therapy for SCD. Any forward-looking statements
are based on management’s current expectations of future events and
are subject to a number of risks and uncertainties that could cause
actual results to differ materially and adversely from those set
forth in or implied by such forward-looking statements, many of
which are beyond the Company’s control. These risks and
uncertainties include, but are not limited to: the risk that the
Company may not be able to definitively determine whether the
lentiviral vector BB305 used in LentiGlobin gene therapy for SCD
and in betibeglogene autotemcel is related to the safety events in
a timely manner, or at all; the risk that the lentiviral vector
BB305 has caused insertional oncogenic events, including AML; the
risk that insertional oncogenic events associated with lentiviral
vector or additional MDS events associated with myeloablation will
be discovered or reported over time; the risk that regulatory
authorities may impose a clinical hold on additional programs; the
risk that we may not be able to address regulatory authorities’
concerns quickly or at all; the risk that we may not resume patient
treatment with ZYNTEGLO in the commercial context in a timely
manner or at all; the risk that our lentiviral vector platform
across our severe genetic disease programs may be implicated,
affecting the development and potential approval of elivaldogene
autotemcel; the risk that we may not be able to execute on our
business plans, including our commercialization plans, meeting our
expected or planned regulatory milestones, submissions, and
timelines, research and clinical development plans, and in bringing
our product candidates to market; and the risk that with the impact
on the execution and timing of our business plans, we may not
successfully execute our previously announced plans to spin off our
oncology programs into an independent publicly-traded entity. For a
discussion of other risks and uncertainties, and other important
factors, any of which could cause our actual results to differ from
those contained in the forward-looking statements, see the section
entitled “Risk Factors” in our most recent Form 10-K, as well as
discussions of potential risks, uncertainties, and other important
factors in our subsequent filings with the Securities and Exchange
Commission. All information in this press release is as of the date
of the release, and bluebird bio undertakes no duty to update this
information unless required by law.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20210310005286/en/
Media: Jenn Snyder, 617-448-0281
jsnyder@bluebirdbio.com
Catherine Falcetti, 617-583-3411 cfalcetti@bluebirdbio.com
Investors: Elizabeth Pingpank, 860-463-0469
epingpank@bluebirdbio.com
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