- First three patients experienced prompt hematopoietic
reconstitution, and no clonal hematopoiesis
- Early first-in-human data provide insights into relationship
between product specific characteristics, including cell dose,
editing efficiency, and fetal hemoglobin induction
- Additional study results expected in late 2020 once enrollment
is complete and all six patients have longer follow-up
Sangamo Therapeutics, Inc. (Nasdaq: SGMO), a genomic medicine
company, today announced preliminary results from the first three
patients treated in the Phase 1/2 THALES study evaluating
investigational ST-400 ex vivo gene-edited cell therapy in
transfusion-dependent beta thalassemia (TDT). The data are featured
in a poster presentation on December 9, 2019 at the 61st Annual
Meeting of the American Society of Hematology (ASH) in Orlando, FL.
The ST-400 ASH poster will be available on Sangamo’s website in the
Investors and Media section under Events and Presentations at the
beginning of the poster session at 10am Eastern Time.
“The prompt hematopoietic reconstitution and on-target indels in
circulating white blood cells observed in the three patients
treated with ST-400 indicate successful editing with zinc finger
nuclease technology,” said Angela Smith, MD, Associate Professor in
the Division of Pediatric Blood and Marrow Transplantation at the
University of Minnesota, and a Principal Investigator of the THALES
study. “As is the case in other myeloablative conditioning studies
of stem cell transplants for beta thalassemia patients, the full
effects of the treatment may take as long as 12 to 18 months or
more to manifest. Longer-term follow-up, including from additional
patients, will be necessary to understand the safety profile and
potential clinical benefit of ST-400 in beta thalassemia. The
emerging tolerability and safety profile of ST-400, as well as the
induction of fetal hemoglobin and presence of indels, suggest that
further exploration of this novel gene-edited cell therapy is
merited.”
Beta thalassemia is a rare blood disorder caused by a mutation
in the beta-globin gene that results in impaired production of red
blood cells. ST-400 is an autologous cell therapy candidate that
uses gene editing to modify a patient’s own hematopoietic stem
cells (HSCs) to produce functional progeny red blood cells by
increasing fetal hemoglobin.
In the THALES study, hematopoietic stem and progenitor cells
(HSPCs) are collected from the patient, modified using zinc finger
nuclease (ZFN) gene editing technology to disrupt the erythroid
specific enhancer (ESE) of the BCL11A gene, and cryopreserved prior
to infusion back into the patient following myeloablative
conditioning with busulfan. To date, ST-400 has been manufactured
for five patients, three of whom had been treated at the time of
the ASH data cut. ST-400 is being developed as part of a global
collaboration between Sangamo and Sanofi, and with the support of a
grant from the California Institute for Regenerative Medicine
(CIRM).
The three patients treated with ST-400 experienced prompt
hematopoietic reconstitution, demonstrating neutrophil engraftment
in 14-22 days and platelet engraftment in 22-35 days (Table 1). No
emerging clonal hematopoiesis has to date been observed by
on-target indel pattern monitoring in the three treated patients.
Reported adverse events (AEs) are consistent with the known
toxicities of mobilization, apheresis, and myeloablative busulfan
conditioning. One serious adverse event (SAE) related to ST-400 was
reported. As previously disclosed, Patient 1 experienced
hypersensitivity during ST-400 infusion considered by the
investigator to be likely related to the product cryoprotectant
excipient, DMSO, and which resolved by the end of the infusion.
“The early experiences with the first three patients enrolled in
this first-in-human study of ST-400 are providing useful insights
into the patient characteristics, product characteristics and
outcomes, including the relationship between patient genotype,
phenotype, age, CD34+ cell dose, editing efficiency, and induction
of fetal hemoglobin,” said Adrian Woolfson, BM., B.Ch., Ph.D., Head
of Research and Development at Sangamo. “Our understanding of
ST-400 will continue to evolve as we follow the progress of these
and additional patients in the coming year, and those dosed in
Sanofi’s BIVV003 clinical trial, which is evaluating the same
gene-editing approach in sickle cell disease.”
Patient 1
Patient 1, age 36, has a β0/β0 genotype, the most severe form of
TDT, and had 27 annualized packed red blood cell (PRBC) events
prior to enrollment into the study. The patient underwent a second
cycle of mobilization and apheresis due to the low cell dose and
potency achieved in the first cycle. In both ST-400 lots, editing
efficiency was approximately 25%, which was lower than the other
patients enrolled in the study and 12 trial-run lots manufactured
at clinical scale (71% median editing efficiency).
On-target indels in the infused ST-400 product were 23%, and the
CD34+ cell dose was 5.4 x 106 cells/kg. Indels have persisted in
peripheral leukocytes through Month 9. Following ST-400 infusion,
fetal hemoglobin levels increased to approximately 2.7 g/dL at Day
56 and remained elevated compared to baseline at 0.9 g/dL at week
39, the most recent measurement at the time of the ASH data cut.
After an initial transfusion-free duration of 6 weeks, the patient
resumed intermittent PRBC transfusions, with an overall 33%
reduction in annualized PRBC units transfused since
engraftment.
Patient 2
Patient 2, age 30, is homozygous for the severe β+ IVS-I-5
(G>C) mutation and had 18 annualized PRBC events prior to
enrollment into the study. On-target indels in the ST-400 product
were 73%, with a CD34+ cell dose of 3.9 x 106 cells/kg, the lowest
seen across the ST-400 lots manufactured for the 5 enrolled
patients. Indels have persisted in peripheral leukocytes through
Month 6. Following ST-400 infusion, fetal hemoglobin levels
increased as compared with baseline, but have been <1 g/dL
through to 26 weeks, the lowest induction level observed in the
three patients treated to date. The patient is currently receiving
intermittent PRBC transfusions.
Patient 3
Patient 3, age 23, has a β0/β+ genotype that includes the severe
IVS-II-654 (C>T) mutation and had 15 annualized PRBC events
prior to enrollment into the study. On-target indels in the ST-400
product were 54%, with a CD34+ cell dose of 10.3 x 106 cells/kg. At
the time of the ASH data cut indels have persisted in peripheral
leukocytes through Day 56. Following ST-400 infusion, fetal
hemoglobin levels have increased as compared to baseline and were
continuing to rise as of the latest measurement of 2.8 g/dL at Day
90. Following an initial transfusion-free period of 7 weeks, the
patient has received two PRBC transfusions commencing at 62 days
post-infusion.
Patient 4, age 18 with a βWT (αα)/βº (αααα) genotype, and
Patient 5, age 35 with a βº/β+ (severe IVS-I-110 G>A) genotype,
were dosed after the time of the ASH data cut. Sangamo expects to
enroll a sixth and final patient in the study in the coming months.
Results from additional patients and longer-term follow-up data are
expected in the second half of 2020. Sanofi is running a parallel
clinical trial with BIVV003, which uses a similar approach in
sickle cell disease.
“We look forward to longer-term data and data from additional
treated patients next year, where we will be in a better position
to assess safety and the observed clinical effects,” said Karin
Knobe, M.D., Ph.D., Therapeutic Head of Development, Rare Blood
Disorders, Sanofi. “We also look forward to exploring the potential
of BIVV003 as a gene-edited cell therapy for sickle cell disease, a
debilitating disease with significant unmet patient needs. We are
currently enrolling patients.”
About the THALES study
The Phase 1/2 THALES study is a single-arm, multi-site study to
assess the safety, tolerability, and efficacy of ST-400 autologous
hematopoietic stem cell transplant in 6 patients with
transfusion-dependent beta thalassemia (TDT). The age range for the
5 patients enrolled is 18-36 years. ST-400 is manufactured by ex
vivo gene editing of a patient's own (autologous) hematopoietic
stem cells using non-viral delivery of zinc finger nuclease
technology. The THALES study inclusion criteria include all
patients with TDT (β0/β0 or non- β0/β0) who have received at least
8 packed red blood cell transfusions per year for the two years
before enrollment in the study. The FDA recently granted Orphan
Drug status to ST-400.
Table 1: ST-400 Product Characteristics
and Hematopoietic Reconstitution
Patient
Cell Dose (10�/kg)
CD34+ (%)
CFU Dose (10⁵/kg)
On-target Indelsa (%)
Neutrophil Engraftmentb
Day(s)
Platelet Engraftmentc
Day(s)
1d
5.9
91
6.2
23e
14
25
2d
4.5
87
4.0
73
15
22
3f
11.4
90
14.8
54
22
35
4
5.4
86
7.3
80
Pre-Infusion
Pre-Infusion
5
9.5
98
10.5
76
Pre-Infusion
Pre-Infusion
aPercentage of all BCL11A ESE alleles with
an indel; this is not equivalent to the percent of all cells with
at least one edited BCL11A ESE allele.
bNeutrophil engraftment defined as
occurring on the first of 3 consecutive days on which the patient’s
neutrophil count was ≥500 cells/µL.
cPlatelet engraftment defined as occurring
on the first of 3 consecutive measurements spanning a minimum of 3
days (in the absence of platelet transfusion in the preceding 7
days) on which the patient’s platelet count was ≥20,000
cells/µL.
dPatients 1 and 2 received G-CSF from day
+5 through neutrophil engraftment per site’s standard operating
procedure.
ePatient 1 underwent 2 cycles of apheresis
and manufacturing of ST-400; on-target indel percentage for the lot
not shown was 26%. All other patients underwent only one cycle of
apheresis and manufacturing.
fPatient 3 received G-CSF from day +21
through neutrophil engraftment per site’s standard operating
procedure.
About Sangamo Therapeutics
Sangamo Therapeutics is committed to translating ground-breaking
science into genomic medicines with the potential to transform
patients’ lives using gene therapy, ex vivo gene-edited cell
therapy, and in vivo genome editing and gene regulation. For more
information about Sangamo, visit www.sangamo.com.
Sangamo Forward Looking Statements
This press release contains forward-looking statements regarding
Sangamo's current expectations. These forward-looking statements
include, without limitation, statements relating to the
investigational beta thalassemia ex vivo gene-edited cell therapy,
ST-400, including its potential therapeutic benefits; the potential
long-term impacts of ST-400; ST-400 having the potential to be a
predictable and reliable treatment that may bring clinical benefit
to patients with beta thalassemia; plans to advance ST-400 into a
potential registrational study; and other statements that are not
historical fact. These statements are not guarantees of future
performance and are subject to risks and assumptions that are
difficult to predict. Factors that could cause actual results to
differ include, but are not limited to, risks and uncertainties
related to: the research and development process; additional data,
including the risk that the data reported from the THALES study to
date may not be indicative of the final results from the study or
that such final results may not validate and support the safety and
efficacy of ST-400; the completion of the THALES study; the
possibility of unfavorable new clinical data from the THALES study
and further analyses of existing clinical data from the study that
may material change clinical outcomes; the risk that clinical trial
data are subject to differing interpretations and assessments by
regulatory authorities; whether regulatory authorities will be
satisfied with the design of and results from the clincal studies
relating to ST-400, any potential registrational studies or any
other clinical studies of ST-400; Sangamo's reliance on
third-parties to meet their clinical and manufacturing obligations;
Sangamo’s ability to maintain strategic partnerships; and the
potential for technological developments by Sangamo's competitors
that will obviate Sangamo's cell therapy technology. Further, there
can be no assurance that the necessary regulatory approvals will be
obtained for ST-400 or that Sangamo and its partners will be able
to develop commercially viable product candidates. Actual results
may differ from those projected in forward-looking statements due
to risks and uncertainties that exist in Sangamo's operations and
business environments. These risks and uncertainties are described
more fully in Sangamo's Annual Report on Form 10-K for the year
ended December 31, 2018 as filed with the Securities and Exchange
Commission and Sangamo's most recent Quarterly Report on Form 10-Q.
Forward-looking statements contained in this announcement are made
as of this date, and Sangamo undertakes no duty to update such
information except as required under applicable law.
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Investor Relations – Global McDavid
Stilwell 510-970-6000, x219 mstilwell@sangamo.com
Media Inquiries – Global Aron
Feingold 510-970-6000, x421 afeingold@sangamo.com
Investor Relations and Media Inquiries –
European Union & United Kingdom Caroline Courme 33 4 97
21 27 27 ccourme@sangamo.com
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