Long-Term Follow-up Data Show That the 88% of
Patients Treated in the Starbeam Study (ALD-102) Were Free of Major
Functional Disabilities (MFDs) at Two Years, and Continued to
Remain MFD-Free at up to Five Years of Follow-up
bluebird bio, Inc. (Nasdaq: BLUE) today announced updated
results from the clinical development program for its
investigational Lenti-D™ gene therapy in patients with cerebral
adrenoleukodystrophy (CALD) at the 13th European Pediatric
Neurology Society (EPNS) Congress in Athens, Greece.
CALD is a rare genetic and rapidly progressive disease that can
lead to severe loss of neurologic function and death. The Phase 2/3
Starbeam study (ALD-102) is assessing the efficacy and safety of
Lenti-D in boys 17 years of age and under with CALD. Updated data
from the ongoing observational study (ALD-103) of allogeneic
hematopoietic stem cell transplant (allo-HSCT) in boys 17 years of
age and under with CALD were also presented.
“With the longest follow-up from the Phase 2/3 Starbeam study
now up to five years, the data show that all boys with CALD who
were treated with Lenti-D and were free of major functional
disabilities (MFDs) at 24 months continued to be MFD-free.
Importantly, there were no reports of graft failure or
treatment-related mortality, and adverse events were generally
consistent with myeloablative conditioning,” said David Davidson,
M.D., chief medical officer, bluebird bio. “These results support
the potential of Lenti-D as a treatment for CALD, which we hope may
become an option for the boys and their families affected by this
devastating disease.”
Updated Results: Starbeam Study
(ALD-102)
The Phase 2/3 Starbeam study has completed enrollment. All
reported data below are as of April 25, 2019 and reflect a total
population of 32 patients with a median follow-up time of 21.2
months (0.0 – 60.2 months). Of the 32 patients who have received
Lenti-D as of April 25, 2019, 15 have completed ALD-102 and
enrolled in a long-term follow-up study, 14 are currently on-study,
and three are no longer on-study.
The primary efficacy endpoint in the study is the proportion of
patients who are alive and free of MFDs at Month 24. MFDs are six
severe disabilities commonly attributed to CALD and thought to have
the most profound impact on a patient’s ability to function
independently, including loss of ability to communicate, cortical
blindness, need for tube feeding, total incontinence, wheelchair
dependence, and complete loss of voluntary movement.
Of those patients who have or would have reached 24 months of
follow-up and completed the study, 88 percent (N=15/17) continue to
be alive and MFD-free in a long-term follow-up study. The 14
patients currently on study have less than 24 months of follow-up
and have shown no evidence of MFDs. The longest follow-up of the
additional 14 patients was 20.4 months. Three out of the 32 treated
patients did not or will not meet the primary efficacy endpoint;
two patients withdrew from the study at investigator discretion,
and one experienced rapid disease progression early on-study
resulting in MFDs and death.
Secondary and exploratory efficacy outcomes included: changes in
neurologic function score (NFS), a 25-point score used to evaluate
the severity of gross neurologic dysfunction across 15 symptoms in
six categories; resolution of gadolinium enhancement (GdE), an
indicator of active inflammation in the brain; and change in Loes
score, an MRI measurement of white matter changes in CALD. Of the
32 patients treated, 30 had stable NFS following treatment with
Lenti-D, defined as NFS <4, without
a change of >3 from baseline. Loes scores generally stabilized
within 12-24 months and GdE+ enhancement resolved in most patients
following Lenti-D treatment.
The primary safety endpoint is the proportion of patients who
experience acute (≥Grade 2) or chronic graft-versus-host disease
(GvHD) by Month 24. GvHD is a condition that may occur after an
allo-HSCT, where the donated cells view the recipient’s body as
foreign and attack the body. No events of acute or chronic GvHD
have been reported post-Lenti-D treatment and there have been no
reports of graft failure, cases of insertional oncogenesis, or
replication competent lentivirus. The safety profile of Lenti-D is
generally consistent with myeloablative conditioning with busulfan
and cyclophosphamide, the standard preparative regimen completed
prior to HSCT. Three adverse events (AE) have been deemed
potentially related to treatment with Lenti-D and include
BK-mediated viral cystitis (N=1, grade 3) and vomiting (N=2, grade
1); all three resolved using standard measures.
“I see the impact CALD has on my young patients and their
families in my practice and understand the urgent need for
additional treatment options,” said Caroline Sevin, M.D., Pediatric
Neurology Department, Hôpital Bicêtre-Hôpitaux Universitaires Paris
Sud, Le Kremlin Bicêtre, France, and an investigator in the
Starbeam study. “These updated data from the Starbeam study are
encouraging because there continues to be no report of
graft-versus-host disease or graft failure post-Lenti-D treatment,
and Lenti-D utilizes a child’s own cells, eliminating the need for
a donor as well as complications that may be involved with donor
cells.”
Updated Results: ALD-103
Study
Allo-HSCT has been successfully used to treat CALD but comes
with risks, including graft failure, acute and chronic GvHD, and
death, as well as infection as a result of the immune suppression
required post-transplant. The ongoing observational study, ALD-103,
is designed to assess safety and efficacy outcomes of this
treatment option in boys 17 years of age and younger with CALD. The
study measures CALD disease-related outcomes in four patient
cohorts: early disease 1 (N=21; Loes <4 and NFS <1);
early disease 2 (N=9; Loes >4 to 9 and NFS <1); all early disease (N=30; Loes <9 and NFS <1);
and advanced disease (N=10; Loes >9 or NFS >1).
Transplant-related outcomes are assessed by donor stem cell source
and by conditioning regimen.
As of February 11, 2019, 47 patients who had undergone allo-HSCT
were enrolled in the ALD-103 study. Updated results show that early
treatment with allo-HSCT provides improved overall and MFD-free
survival for patients with CALD irrespective of the stage of early
disease. In the all early disease cohort at 24 months
post-allo-HSCT, 77.2 percent of patients achieved MFD-free survival
and 89.1 percent achieved overall survival compared to 35.0 percent
and 52.5 percent, respectively, in the advanced disease cohort at
24 months post-allo-HSCT.
The risk associated with allo-HSCT varied by donor source. While
there were no substantial differences observed between the groups
in ALD-103, more patients who were treated with umbilical cord stem
cells from an unrelated donor (38.9 percent [7/18]) experienced
engraftment failure by Month 24 compared to patients who received
bone marrow or umbilical cord cells from a matched sibling donor or
bone marrow cells from an unrelated donor (zero percent in both
groups).
Analyses done by conditioning regimen showed higher rates of
acute (42.9 percent [6/14]) and chronic (54.5 percent [6/11]) GvHD
in patients who received myeloablative conditioning with busulfan
and cyclophosphamide compared to those who were myeloablated with
busulfan and fludarabine (6.3 percent [1/16] and 13.3 percent
[2/15], respectively). Analyses also showed higher rates of
engraftment failure in patients who received myeloablative
conditioning with busulfan and fludarabine, 28.6 percent (6/21)
experienced engraftment failure by 24 months compared to zero
percent in the busulfan and cyclophosphamide group.
In total, 23.5 percent (8/34) and 27.6 percent (8/29) of
patients enrolled in the study experienced acute and chronic GvHD,
respectively. The overall rates of 100-day and one-year
transplant-related mortality were zero percent (0/38) and 12.1
percent (4/33), respectively. The overall rate of engraftment
failure by Month 24 was 21.6 percent occurring in eight of 37
evaluable patients.
These data suggest that, while allo-HSCT appears to halt disease
progression, it can be associated with serious safety risks and
most transplant-related risks vary by donor source and conditioning
regimen.
Oral Presentations at
EPNS
Phase 2/3 Trial to Address the Safety and Efficacy of Lenti-D
Hematopoietic Stem Cell Gene Therapy for Cerebral
Adrenoleukodystrophy
Presenter: Dr. Caroline Sevin, Hôpital
Universitaire Bicêtre-Paris Sud, Paris, France Date & Time
(Parallel Session 2D: Neurometabolic Disorders I): Wednesday,
September 18, 2019, 4:30 – 6:15 p.m. GMT+3 (9:30 – 11:15 a.m.
EDT)
An observational study of outcomes of Allogeneic
Hematopoietic Stem Cell Transplant in patients with Cerebral
Adrenoleukodystrophy (CALD)
Presenter: Dr. Florian Eichler, Center for Rare
Neurological Diseases, Associate Professor of Neurology,
Massachusetts General Hospital, Harvard Medical School, Boston, USA
Date & Time (Parallel Session 2D: Neurometabolic Disorders
I): Wednesday, September 18, 2019, 4:30 – 6:15 p.m. GMT+3 (9:30
– 11:15 a.m. EDT)
Additional Information About the Clinical Development Program
for Lenti-D
bluebird bio is currently enrolling patients for a Phase 3 study
(ALD-104) designed to assess the efficacy and safety of Lenti-D
after myeloablative conditioning using busulfan and fludarabine in
patients with CALD. Contact clinicaltrials@bluebirdbio.com for more
information and a list of study sites.
Additionally, bluebird bio is conducting a long-term safety and
efficacy follow-up study (LTF-304) for patients who have
participated in bluebird bio-sponsored studies of Lenti-D for
CALD.
For more information about the Phase 2/3 Starbeam study visit:
www.bluebirdbio.com/our-science/clinical-trials or
www.starbeamstudy.com.
The European Medicines Agency (EMA) accepted Lenti-D gene
therapy for the treatment of CALD into its Priorities Medicines
scheme (PRIME) in July 2018, and previously granted Orphan
Medicinal Product designation to Lenti-D.
The U.S. Food and Drug Administration (FDA) granted Lenti-D
Orphan Drug status, Rare Pediatric Disease designation, and
Breakthrough Therapy designation for the treatment of CALD.
About Cerebral Adrenoleukodystrophy
Adrenoleukodystrophy (ALD) is a rare, X-linked metabolic
disorder that is estimated to affect one in 21,000 male newborns
worldwide. ALD is caused by mutations in the ABCD1 gene that affect
the production of adrenoleukodystrophy protein (ALDP) and
subsequently cause toxic accumulation of very long-chain fatty
acids (VLCFAs) primarily in the adrenal cortex and white matter of
the brain and spinal cord.
Approximately 35-40 percent of boys with ALD will develop CALD,
the most severe form of ALD. CALD is a progressive neurogenerative
disease that involves breakdown of myelin, the protective sheath of
the nerve cells in the brain that are responsible for thinking and
muscle control. Symptoms of CALD usually occur in early childhood
and progress rapidly, if untreated, leading to severe loss of
neurologic function, and eventual death, in most patients.
Currently, the only therapeutic option for patients with CALD is
allo-HSCT. Beneficial effects have been reported if allo-HSCT is
performed early in the course of cerebral disease. Potential
complications of allo-HSCT, which can be fatal, include graft
failure and rejection, GvHD, and opportunistic infections,
particularly in patients who do not have an HLA-matched sibling
donor for transplant.
Early diagnosis of CALD is important, as the outcome of
treatment varies with the clinical stage of the disease at the time
of transplant. Newborn screening for ALD is a critical enabler of
early diagnosis and successful treatment of ALD. In the U.S.,
newborn screening for ALD was added to the Recommended Universal
Screening Panel in February 2016 but is currently active in only a
limited number of states. Outside the U.S., the Minister of Health
in the Netherlands has approved the addition of
adrenoleukodystrophy to the newborn screening program, and a pilot
started in 2019.
About bluebird bio, Inc.
bluebird bio is pioneering gene therapy with purpose. From our
Cambridge, Mass., headquarters, we’re developing gene 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 by researching cerebral adrenoleukodystrophy, sickle cell
disease, transfusion-dependent 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.
Lenti-D 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 clinical development and
commercial potential of the Company’s Lenti-D product candidate to
treat cerebral adrenoleukodystrophy. 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. These risks
and uncertainties include, but are not limited to, risks that the
efficacy and safety results for our Lenti-D product candidate from
the Starbeam Study seen to date will not continue or persist, the
risk of cessation or delay of any of the ongoing clinical studies
and/or our development of Lenti-D, the risks regarding future
potential regulatory approvals of Lenti-D, including the risk that
the Starbeam Study will be insufficient to support regulatory
submissions or marketing approval in the U.S. and EU, and the risk
that any one or more of our product candidates will not be
successfully developed, approved or commercialized. 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-Q, 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.
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version on businesswire.com: https://www.businesswire.com/news/home/20190918005480/en/
bluebird bio Investors: Elizabeth Pingpank, 617-914-8736
epingpank@bluebirdbio.com or Media: Victoria von Rinteln,
617-914-8774 vvonrinteln@bluebirdbio.com
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