With 51 patients enrolled, data from the
long-term follow-up study (LTF-303) show that all patients treated
with beti-cel who achieve transfusion independence (TI) remain free
from transfusions, with the longest follow-up of seven years
Across Phase
3 studies, 89% (32/36) of evaluable patients across ages and
genotypes achieved TI and remain transfusion free, including 91%
(20/22) of evaluable pediatric patients under the age of
18
The absence
of drug product-related adverse events beyond two years
post-infusion supports a favorable long-term safety profile of
beti-cel
Data from bluebird bio’s Phase 1/2 and Phase 3
clinical studies represent more than 220 patient-years of
experience with beti-cel
bluebird bio, Inc. (Nasdaq: BLUE) today presented data
from several studies of betibeglogene autotemcel (beti-cel) gene
therapy (licensed as ZYNTEGLO™ in the EU and UK) in adult,
adolescent and pediatric patients with transfusion-dependent
β-thalassemia (TDT). These data were presented during EHA2021
Virtual, the 26th Annual Congress of the European Hematology
Association, taking place June 9-17, 2021.
“Our maturing clinical data continue to deliver the results we
had hoped for, with patients free from transfusions and maintaining
strong hemoglobin levels over the course of years,” said Richard
Colvin, M.D., Ph.D., VP, interim chief medical officer, bluebird
bio. “TDT is usually diagnosed in the first two years of life, and
patients with this disease will require regular blood transfusions
for the rest of their lives – most as often as every few weeks. It
is truly transformative for these patients and their families that
they no longer need ongoing blood transfusions.”
TDT is a severe genetic disease caused by mutations in the
β-globin gene that result in reduced or significantly reduced
hemoglobin (Hb). In order to survive, people with TDT require
chronic blood transfusions to maintain adequate Hb levels. These
transfusions carry the risk of progressive multi-organ damage due
to unavoidable iron overload.
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
patients have the βA-T87Q-globin gene, they HSCs have the potential
to produce HbAT87Q, which is gene therapy-derived adult Hb, at
levels that can eliminate or significantly reduce the need for
transfusions.
In studies of beti-cel, transfusion independence 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.
“Many of my patients, some of whom are very young, require
transfusions every few weeks in order to survive,” said Evangelia
Yannaki, M.D., Ph.D., Director, Gene and Cell Therapy Center,
Hematology Department, George Papanikolaou Hospital, Thessaloniki,
Greece. “While transfusions provide benefit, dependence on them
carries complications such as iron overload and severely
compromises their quality of life. The long-term beti-cel data
presented at EHA are particularly encouraging, as markers of
healthy red blood cell production and iron burden reduction
improved among patients who achieved transfusion independence.”
As of the data cut-off of March 9, 2021, a total of 63
pediatric, adolescent and adult patients, including 19 patients
with at least five years of follow-up, eight with at least six
years and two with up to seven years across β0/β0 and non-β0/β0
genotypes and ages, have been treated with beti-cel in the Phase
1/2 HGB-204 (Northstar) and HGB-205 studies and the Phase 3 HGB-207
(Northstar-2) and HGB-212 (Northstar-3) studies. Data from bluebird
bio’s Phase 1/2 and Phase 3 clinical studies represent more than
220 patient-years of experience with beti-cel.
Long-term follow-up study LTF-303
After participating in and completing the two years of follow-up
in any of the Phase 1/2 or Phase 3 studies (HGB-207, HGB-212),
patients treated with beti-cel were invited to enroll in a 13-year
long-term follow-up study, LTF-303. As of March 9, 2021, 51 of 63
beti-cel-treated patients across age groups and genotypes spanning
a broad range of TDT severity have completed two years of follow-up
in the parent study and were enrolled in LTF-303 (22 treated in
Phase 1/2 studies, 29 treated in Phase 3 studies) with a median
post-infusion follow-up of 44.2 months (min-max: 22.9 – 86.5).
Of the 51 patients enrolled in LTF-303, 40 patients achieved
transfusion independence (TI): 15/22 (68%) patients treated in
Phase 1/2 and 25/29 (86%) patients treated in Phase 3. All patients
achieved TI in the parent studies and maintained it through last
follow-up in LTF-303.
As of the data cut-off date, all patients who achieved TI
remained free from transfusions through their last follow-up
(n=40). Phase 1/2 patients had a median duration of ongoing TI of
57.1 months (min-max: 15.8 – 84.1) and Phase 3 patients had a
median ongoing TI duration of 26.3 months (min-max: 13.1 –
39.4).
Weighted average hemoglobin (Hb) in patients who achieved TI
reached normal or near-normal levels in the Phase 1/2 studies (10.3
g/dL; min-max: 9.1 – 13.2) and in the Phase 3 studies (11.8 g/dL;
min-max: 9.4 – 13.7).
Liver iron concentration (LIC) after infusion in patients who
achieved TI decreased toward normal levels over time, particularly
in patients with a high iron burden at baseline. Patients with
severe (LIC >15 mg/g, n=5) and significant (LIC ≥7 – 15 mg/g,
n=14) iron burden at baseline had a median reduction of 59% and
37%, respectively, from baseline to Month 48. At 48 months,
assessments were available for 2/5 and 6/14 patients.
Prior to beti-cel infusion, all patients were on iron chelation,
which is needed to reduce excess iron caused by chronic blood
transfusions. Of the 40 patients who achieved TI following
treatment with beti-cel, 73% (29/40) restarted iron chelation after
beti-cel infusion and the majority (59%, 17/29) of patients who
restarted iron chelation after infusion have since stopped; and 28%
(11/40) were able to receive phlebotomy (blood removal), which is a
preferred method for iron reduction. Of the 11 patients who were
able to receive phlebotomy, 10 have not received phlebotomy in more
than seven months and their total unsupported Hb at last study
visit ranged from 10.5 to 14.0 g/dL.
There were no deaths, and no vector-derived
replication-competent lentivirus nor events of insertional
oncogenesis or malignancy have been reported in patients enrolled
in LTF-303.
No drug-related adverse events (AEs) were reported in the
long-term follow-up study. Serious AEs during LTF-303 unrelated to
beti-cel included gonadotropic insufficiency, ectopic pregnancy,
gall bladder wall thickening/polyp, bacteremia, neutropenia,
cholelithiasis, diabetic ketoacidosis, pulmonary embolism, fetal
death (as a result of a miscarriage) and major depression (n=1 for
each).
Phase 3 Northstar-2 and Northstar-3 studies
As of March 9, 2021, 41 patients were treated in the Phase 3
studies HBG-207 (Northstar-2; n=23; median follow-up 24.3 months
[min-max: 13.0 - 27.5]); and HGB-212 (Northstar-3; n=18; median
follow-up 23 months [min-max: 4.1 – 26.8]).
Following treatment with beti-cel, 89% (32/36) of evaluable
patients across ages and genotypes in both Phase 3 studies achieved
transfusion independence (TI). As of the data cut-off date, these
patients continue to be free of transfusions for a median duration
of 25 months (min-max: 12.5 – 38.5), with median weighted average
total hemoglobin levels during TI of 11.6 g/dL (min-max: 9.3 –
13.7).
Median gene therapy-derived hemoglobin (HbAT87Q) was stable
approximately six months post-infusion: 8.8 g/dL at Month 6 (n=33);
9.2 g/dL at Month 9 (n=34); 8.7 g/dL at Month 12 (n=36); 9.3 g/dL
at Month 18 (n=29); and 8.9 g/dL at Month 24 (n=26).
In exploratory analyses, biomarkers of ineffective
erythropoiesis trended toward normal over time in patients who
achieved TI, supporting the disease-modifying potential of beti-cel
in patients with TDT; additionally, biomarkers of hemolysis
normalized in patients who achieved TI.
The treatment regimen, comprising mobilization/apheresis,
conditioning and beti-cel infusion, has a safety profile consistent
with the known effects of mobilization with G-CSF and plerixafor
and myeloablation with single-agent busulfan.
Grade ≥3 veno-occlusive liver disease in three patients was
attributed to busulfan conditioning and resolved with defibrotide
treatment. One patient developed serious, Grade 3 congestive heart
failure unrelated to drug product, which was downgraded to Grade 1
at 5 months and resolved at 12 months.
Adverse events (AEs) considered related or possibly related to
the drug product included thrombocytopenia (n=3), abdominal pain
(n=3), leukopenia (n=1), neutropenia (n=1), pain in extremity
(n=1), tachycardia (n=1) and autoimmune disorder (n=1).
Post-infusion non-hematologic Grade ≥3 AEs in ≥3 patients in
either study unrelated to beti-cel included oropharyngeal
inflammation (n=29), febrile neutropenia (n=20), epistaxis (n=8),
decreased appetite (n=6), pyrexia (n=5), alanine aminotransferase
increase (n=5) and veno-occlusive liver disease (n=3). There were
no deaths, no graft failures or graft-versus-host disease (GVHD),
and no cases of replication-competent lentivirus, insertional
oncogenesis, clonal predominance, or malignancy.
Phase 3 pediatric patients
As of March 9, 2021, 27 pediatric patients (<12 years: n=16;
≥12 to <18 years: n=11) were treated in the Phase 3 HGB-207
(Northstar-2) and HGB-212 (Northstar-3) studies and had a median
follow-up of 25.5 months (min-max: 4.1 – 41.5 months).
Following treatment with beti-cel, 91% (20/22) of evaluable
patients under the age of 18 years (ages 4 to 17), including 10
patients under age 12, achieved transfusion independence (TI).
These patients continue to be free of transfusions through their
last follow-up, with median weighted average Hb levels during TI of
10.0 g/dL in patients under age 12 (n=10) and 11.7 g/dL in patients
age 12-18 (n=10).
The median baseline score for 18 patients who achieved TI was
79.90 (range, 47.83-97.83; n=18) on the PedsQL-4.0; healthy
children reach scores of approximately 84. At 24 months,
improvement in quality of life was approximately three-fold higher
than the minimal clinically significant meaningful difference
(MCMD, a change between 4.30 and 4.83 points) as measured by the
PedsQL-4.0. Improvements were more pronounced in patients with more
severe scores at baseline, showing greater than five-fold higher
improvements over the MCMD.
Adverse events (AEs) in pediatric patients during the HGB-207
and HGB-212 trials that were considered related or possibly related
to beti-cel were non-serious and included tachycardia (Grade 1,
n=1) and abdominal pain (Grade 1, n=2) on the day of infusion, and
Grade 3 thrombocytopenia in one patient post-infusion.
There were no deaths, no graft failures or GVHD, and no cases of
replication-competent lentivirus or insertional oncogenesis. No
clonal predominance has been observed.
Grade 4 veno-occlusive liver disease occurred in two patients
(ages ≥12 to <18 years) and one Grade 2 event occurred in a
patient age <12 years; all events resolved after treatment with
defibrotide.
Post-infusion non-hematologic Grade ≥3 AEs in ≥2 patients <18
years of age (n=27) unrelated to beti-cel included stomatitis
(n=15), febrile neutropenia (n=15), epistaxis (n=6), decreased
appetite (n=5), alanine aminotransferase increase (n=3), hypoxia
(n=3), pyrexia (n=3), pharyngeal inflammation (n=3), mucosal
inflammation (n=3), veno-occlusive disease (n=2) and dyspepsia
(n=2).
The presentations are now available on demand on the EHA2021
conference website:
Oral Presentation [S257]: Betibeglogene autotemcel Gene
Therapy for the Treatment of Transfusion-Dependent β-Thalassemia:
Updated Long-Term Efficacy and Safety Results Presenting
Author: Dr. Evangelia Yannaki, Director, Gene and Cell Therapy
Center, Hematology Department, George Papanikolaou Hospital,
Thessaloniki, Greece Session Title: Cellular Immunotherapy
and Gene Therapy – Clinical Date & Time: Available on
Demand, Friday, June 11; 9:00 a.m. CEST/3:00 a.m. EDT; Live Q&A
Session
Oral Presentation [S266]: Betibeglogene autotemcel in
Patients With Transfusion-Dependent β-Thalassemia: Updated Results
From HGB-207 (Northstar-2) and HGB-212 (Northstar-3) Presenting
Author: Professor Franco Locatelli, Director, Department of
Pediatric Hematology and Oncology, Ospedale Pediatrico Bambino
Gesù, Rome, Italy Session Title: Changing the Scene on
Thalassemias Date & Time: Available on Demand, Friday,
June 11; 9:00 a.m. CEST/3:00 a.m. EDT; Live Q&A Session
ePoster [EP1301]: Interim Results of Betibeglogene autotemcel
Gene Therapy in Pediatric Patients with Transfusion-Dependent
β-thalassemia (TDT) Treated in the Phase 3 Northstar-2 (HGB-207)
and Northstar-3 (HGB-212) Studies Presenting Author: Dr.
Andreas E. Kulozik, Chairman, Department of Pediatric Oncology,
Hematology and Immunology, and Director, Hopp Children's Cancer
Center, University of Heidelberg, Heidelberg, Germany
About betibeglogene autotemcel (beti-cel)
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 hemoglobin (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.
beti-cel is manufactured using the BB305 lentiviral vector
(LVV), a third-generation, self-inactivating LVV. The promoter, a
regulatory element of the LVV that controls the expression of the
transgene, selected for BB305 is a cellular (non-viral) promoter
that drives gene expression only in the erythroid lineage cells
(red blood cells and their precursors).
The European Commission granted conditional marketing
authorization (CMA) for beti-cel, marketed as ZYNTEGLO™ gene
therapy, for patients 12 years and older with 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 the second
renewal of the CMA. This procedure is currently on hold while the
EMA's Pharmacovigilance Risk Assessment Committee (PRAC) reviews
the safety of ZYNTEGLO. The CMA is valid while the renewal
application review is ongoing by the regulatory agency.
The FDA granted beti-cel Orphan Drug status and Breakthrough
Therapy designation for the treatment of TDT.
bluebird bio is on track to complete its rolling Biologics
License Application (BLA) submission to the FDA for beti-cel in
mid-2021. This submission is anticipated to include adults,
adolescents and children with transfusion dependent β-thalassemia
across all genotypes (including non-β0/β0 genotypes and β0/β0
genotypes). 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 beti-cel.
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 including cerebral adrenoleukodystrophy, sickle cell
disease, β-thalassemia and multiple myeloma using three gene
therapy technologies: gene addition, cell therapy 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 and bluebird bio are trademarks of bluebird bio,
Inc.
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Statements
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the risk factors discussion in bluebird bio’s Annual Report on Form
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and Exchange Commission. These risks and uncertainties include, but
are not limited to: the risk that the efficacy and safety results
from our prior and ongoing clinical trials will not continue or be
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will be insufficient to support regulatory submissions or marketing
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Investors: Elizabeth Pingpank, 617-914-8736
epingpank@bluebirdbio.com
Media: Victoria von Rinteln, 617-914-8774
vvonrinteln@bluebirdbio.com
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