RICHMOND, Calif., Sept. 5, 2018 /PRNewswire/ -- Sangamo
Therapeutics, Inc. (NASDAQ: SGMO) today reported 16 week reductions
in urinary glycosaminoglycans (GAGs), a key biomarker of
Mucopolysaccharidosis Type II (MPS II) disease pathophysiology, in
Cohort 2 of the Phase 1/2 CHAMPIONS Study evaluating SB-913.
SB-913 is a zinc finger nuclease (ZFN) in vivo genome
editing product candidate being evaluated for the treatment of MPS
II, also known as Hunter syndrome. In Cohort 2 at 16 weeks
post-dosing, mean reductions were observed in total urinary GAGs,
dermatan sulfate, and heparan sulfate of 51%, 32%, and 61%,
respectively. The data were presented today at the 2018 Annual
Symposium of the Society for the Study of Inborn Errors of
Metabolism (SSIEM) being held in Athens,
Greece.
The CHAMPIONS Study is the first evaluation of an in vivo
genome editing treatment in humans. The clinical trial is
evaluating three separate doses of SB-913 over a planned 36 month
study period. Today's presentation included early safety and
efficacy results for Cohort 1 (low dose) and Cohort 2 (mid dose),
with two patients enrolled in each. Enrollment and dosing of Cohort
3 (high dose, 5x the mid dose) was recently completed.
MPS II is a genetic lysosomal storage disease caused by
deficiency of the iduronate-2-sulfatase (IDS) enzyme which is
needed to break down or recycle glycosaminoglycans (GAGs) dermatan
sulfate and heparan sulfate. Without IDS enzyme, the GAGs
accumulate in nearly all organs and body tissues. Chronic
accumulation of GAGs inside cellular lysosomes results in cellular
engorgement, organomegaly, tissue destruction, and organ system
dysfunction.
"In MPS II patients, we know that when the IDS enzyme is infused
intravenously, it is rapidly taken up by cells and breaks down the
stored GAGs. We have previously hypothesized that even very low
amounts of IDS secreted continuously into the circulation could be
adequate to reduce GAGs and potentially provide the first
indication of efficacy for SB-913," said Dr. Joseph Muenzer, a professor of pediatrics and
genetics at the University of North
Carolina (UNC) School of
Medicine in Chapel Hill and
principal investigator on the study.
Dr. Muenzer continued: "In the CHAMPIONS Study, the observed
reduction across total GAGs, dermatan sulfate and heparan sulfate
in Cohort 2 is encouraging. We hope to understand the clinical
relevance of these changes by conducting a controlled withdrawal of
enzyme replacement therapy (ERT) in patients enrolled in the study
soon. Withdrawal from weekly ERT infusions would be a very
meaningful outcome for patients with MPS II."
SB-913 is designed to treat MPS II by using Sangamo's ZFN genome
editing technology to insert a new copy of the IDS gene into a
precise location in the DNA of liver cells to enable a patient's
liver to produce a continuous and stable supply of the missing
human IDS enzyme. SB-913 is a single intravenous infusion of AAV6
vectors packaging ZFNs and a copy of the IDS gene. The ZFNs are
designed to enter the cells as inactive DNA instructions in a
format designed only for liver cells to unlock. Once "unlocked,"
the ZFNs then identify, bind to and cut the DNA in a specific
location within the albumin gene. Using the cells' natural DNA
repair processes, Sangamo believes liver cells can then insert the
IDS gene at that precise location. Driven by the strong albumin
promoter, the IDS gene would then express IDS enzyme and would be
taken up by tissues and cells where the enzyme breaks down dermatan
sulfate and heparan sulfate GAGs into individual sugars.
"We are encouraged by the safety and tolerability profile
observed to date and by the GAG reductions at week 16 in Cohort 2.
We have recently infused the two Cohort 3 patients at a dose that
is five times higher than the mid-dose of Cohort 2, and we look
forward to seeing those results," said Dr. Edward Conner, MD, Chief Medical Officer of
Sangamo. "If longer-term data from this study continue to be
positive, therapeutic genome editing has the potential to bring
tremendous medical progress for MPS II and other monogenic
diseases."
About the Results Presented at SSIEM
In the CHAMPIONS Study, two patients are enrolled into each of
three dose cohorts:
- Cohort 1 (low dose) — 5e12 vector genomes per kilogram body
weight (vg/kg) of SB-913 (a starting dose level Sangamo determined
through discussions with the United States Food and Drug
Administration as appropriate for the first-ever infusions of an
in vivo genome editing treatment)
- Cohort 2 (mid dose) —1e13 vg/kg of SB-913 (2x the starting
dose)
- Cohort 3 (high dose) — 5e13 vg/kg of SB-913 (5x the mid
dose)
All subjects receive ERT weekly. Biochemical measurements of
urinary GAGs and plasma IDS are obtained at screening and baseline
visits and every four weeks during the initial phase of the
trial.
Safety
Safety data presented today were collected and
analyzed as of July 10, 2018 and
included information on the first five subjects. In all subjects,
administration of SB-913 was generally well-tolerated. There were
no serious adverse events (SAEs) reported as related to
SB-913. The majority of adverse events (AEs) reported were
mild (Grade 1) and resolved without treatment. All AEs reported as
related to SB-913 were mild (Grade 1), resolved without treatment,
and did not show evidence of dose dependence. Two SAEs were
reported and both were determined by the site investigator to be
due to primary MPS II disease and unrelated to SB-913 treatment. No
persistent transaminitis was observed in any subject.
Efficacy
Glycosaminoglycans (GAGs)
|
Total
GAG
% Change
at
16
weeks
Mean
(SD)
|
Dermatan
Sulfate
% Change
at
16
weeks
Mean
(SD)
|
Heparan
Sulfate
% Change
at
16
weeks
Mean
(SD)
|
Cohort 1 (Subject
1)
|
+13.0
|
-14.5
|
-15.6
|
Cohort 1 (Subject
2)
|
+4.8
|
+22.6
|
-31.4
|
Cohort 1 Mean
(SD)
|
+8.9
(5.8)
|
+ 4.1
(26.2)
|
-23.5
(11.2)
|
|
|
|
|
Cohort 2 (Subject
3)
|
-62.5
|
-47.4
|
-69.9
|
Cohort 2 (Subject
4)
|
-39.1
|
-16.3
|
-53.0
|
Cohort 2 Mean
(SD)
|
-50.8
(16.5)
|
-31.8
(22.0)
|
-61.5
(12.0)
|
For Cohort 2 subjects, total GAGs, dermatan sulfate and heparan
sulfate observations were below baseline throughout the sixteen
weeks with the exception of one excursion when a sample was
obtained four days after one subject was hospitalized for an SAE of
atrial fibrillation, unrelated to study drug, and was hypotensive
for several hours. At the next measurement, this patient's GAGs
returned to the previous low range observed since week 4.
Plasma IDS
At baseline and for the first 16 weeks
post-dosing of SB-913, plasma IDS activity (measurements obtained
at trough of weekly ERT dosing) was below the level of
quantification of the current assay.
In addition to UNC, clinical sites
around the United States have been
actively participating in the CHAMPIONS Study including UCSF
Benioff Children's Hospital Oakland, Cincinnati Children's
Hospital, The Children's Hospital of Philadelphia, Lurie Children's Hospital of
Chicago, University of Minnesota, and New York
University.
Next Steps
Two subjects in Cohort 3 (high dose, 5x the
mid dose) have recently been infused, and the study's safety
monitoring committee will review cumulative data from all three
dose cohorts later this year. Sangamo will work with site
investigators to determine when withdrawal of ERT is appropriate
for individual patients. Sangamo plans to present longer-term
safety and efficacy results from the CHAMPIONS Study in February at
the 2019 WORLDSymposium meeting in Orlando, Florida.
About MPS II (Hunter syndrome)
Mucopolysaccharidosis
Type II (MPS II, Hunter syndrome) is an X-linked recessive
lysosomal storage disorder that occurs almost exclusively in males.
MPS II is caused by mutations in the gene encoding iduronate
2-sulfatase (IDS), resulting in a deficiency of IDS, a lysosomal
enzyme required for the degradation of the glycosaminoglycans
(GAGs) heparan and dermatan sulfate. The absence of IDS enzyme
results in lysosomal GAG accumulation, leading to skeletal
abnormalities, cardiac and respiratory obstructions, organomegaly,
and in severe form of the disease, cognitive impairment and
typically death in adolescence. The estimated incidence of MPS II
is 0.6 to 1.3 per 100,000 live male births1.
Current standard of care treatment for MPS II consists of chronic
IV enzyme replacement therapy (ERT). However, IV ERT requires
life-long, weekly infusions because the hIDS is cleared from
circulation in the body within hours of treatment due to its short
half-life and has not been shown to address the neurological
symptoms of the disease.
Conference Call
Sangamo will host a conference call
today, September 5, 2018, at
9:00 a.m. ET, which will be open to
the public. The call will also be webcast live and can be accessed
via a link on the Sangamo Therapeutics website in the Investors and
Media section under Events and Presentations.
The conference call dial-in numbers are (877) 377-7553 for
domestic callers and (678) 894-3968 for international callers. The
conference ID number for the call is 8798741. For those unable to
listen in at the designated time, a conference call replay will be
available for one week following the conference call, from
approximately 11:00 a.m. ET on
September 5, 2018 to 11:59 p.m. ET on September
12, 2018. The conference call replay numbers for domestic
and international callers are (855) 859-2056 and (404) 537-3406,
respectively. The conference ID number for the replay is
8798741.
About Sangamo
Sangamo Therapeutics is focused on
translating ground-breaking science into genomic therapies that
transform patients' lives using the Company's platform technologies
in genome editing, gene therapy, gene regulation and cell therapy.
For more information about Sangamo, visit www.sangamo.com.
Forward-Looking Statements
This press release contains forward-looking statements
regarding Sangamo's current expectations. These forward-looking
statements include, without limitation, statements related to the
potential for SB-913 to treat MPS II, including the potential for
ZFNs to be effectively designed to consistently produce IDS through
genome editing, the potential for significant medical progress for
MPS II and other monogenic diseases given the therapeutic potential
of genome editing, if the data from this trial continue to be
positive, plans to conduct a controlled withdrawal of weekly ERT
infusions in MPS II patients in the CHAMPIONS Study and anticipated
next steps for the CHAMPIONS Study, including safety monitoring
committee review, Sangamo's expectation that it will present
longer-term safety and efficacy results from the CHAMPIONS Study in
February at the 2019 WORLDSymposium meeting, and other statements
that are not historical fact. These statements are not guarantees
of future performance and are subject to certain risks,
uncertainties 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 early data,
including the risk that the early data from the CHAMPIONS Study may
not be representative of final results after all patients are
treated in the study and all data are collected and analyzed;
Sangamo's ability to complete the CHAMPIONS Study; whether the
final results from the CHAMPIONS Study will validate and support
the safety and efficacy of SB-913, including the risk that the
early efficacy data from the second cohort in the CHAMPIONS Study
to date may not be maintained or replicated; Sangamo's reliance on
partners and other third-parties to meet their clinical and
manufacturing obligations, and its ability to maintain strategic
partnerships. Further, there can be no assurance that the necessary
regulatory approvals for SB-913 will be obtained or that Sangamo
and its partners will be able to develop commercially viable
product candidates for the treatment of MPS II and other diseases.
Actual results may differ from those projected in forward-looking
statements due to these and other risks and uncertainties that
exist in Sangamo's operations and business environments. These
risks and uncertainties are described more fully in Sangamo's
Quarterly Report on Form 10-Q for the quarter ended June 30, 2018, as filed with the Securities and
Exchange Commission. 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.
1Burton, B.K., Jego, V., Mikl, J. et al. J Inherit
Metab Dis (2017) 40: 867-74
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