- SYNB1020 Oral Treatment Resulted in a
Significant Dose-Dependent Effect on a Plasma Nitrogen Endpoint
Demonstrating Mechanistic Activity -
- Data Support Initiation of Two Phase 1b/2a
Studies in 2018 -
Synlogic, Inc.,(Nasdaq:SYBX) a clinical-stage drug discovery and
development company applying synthetic biology to probiotics to
develop novel Synthetic Biotic medicines, today announced positive
top-line clinical data from its Phase 1 placebo-controlled single
(SAD) and multiple ascending dose (MAD) clinical trial of SYNB1020
in healthy volunteers. The trial successfully met the primary
objectives demonstrating safety and tolerability in healthy
volunteers and identifying the maximum tolerated dose. Furthermore,
proof of mechanism was demonstrated by a clear signal in a plasma
nitrogen endpoint.
SYNB1020, is a novel, first-in-class, Synthetic Biotic medicine
that is orally delivered and designed to treat elevated blood
ammonia levels, or hyperammonemia, in genetic urea cycle disorders
(UCD) or in chronic liver disease
"The positive data from our Phase 1 study in healthy volunteers,
demonstrates that SYNB1020 was well-tolerated and had a
statistically significant dose-dependent effect on the level of a
nitrogen endpoint, providing evidence to support its mechanism of
action," said Aoife Brennan, M.B., B.Ch., Synlogic’s chief medical
officer. "These data support the hypothesis that SYNB1020 treatment
may provide clinical benefit in patients with UCDs or liver
disease, and will inform dose selection in our planned Phase 1b/2a
study of SYNB1020 in patients, which we expect to begin in the
first half of 2018."
“This first-in-human study represents a significant milestone
for our new class of Synthetic Biotic medicines and demonstrates
that they can operate from the gastrointestinal tract to metabolize
systemic toxins,” said JC Gutiérrez-Ramos, Ph.D., Synlogic’s
president and chief executive officer. “We look forward to
evaluating SYNB1020 in patients, and to moving our second program,
SYNB1618 for the treatment of phenylketonuria into clinical trials
in 2018.
SYNB1020 was safe and well tolerated in subjects in multiple
ascending dose cohorts who received total daily doses of up to
1.5x1012 CFU for 14 days. There have been no serious adverse events
(SAEs), and no cases of infection with the bacteria in this study.
While the study is ongoing, there is no evidence of colonization by
SYNB1020 as all subjects who have completed follow-up have cleared
the bacteria from their systems within the expected timeframe.
In the MAD component of the Phase 1 study, daily dosing of
SYNB1020 over 14 days in healthy volunteers enabled identification
of a dose-response relationship between SYNB1020 oral
administration and changes in a nitrogen endpoint in plasma which
was found to be statistically significant in the highest dose
cohort compared to placebo. In addition, viability and evidence of
mechanistic activity of the Synthetic Biotic was demonstrated in
feces of subjects who received SYNB1020, but not in control
subjects. As expected, SYNB1020 did not lower blood ammonia levels
in these healthy individuals who had normal blood ammonia levels at
baseline. Collectively, the data support the hypothesis that
SYNB1020 treatment may enable metabolism of potentially neurotoxic
blood levels of ammonia in patients with hyperammonemia stemming
from UCDs or liver damage.
About the SYNB1020 Phase 1 Study
The Phase 1 study was a randomized, double-blind,
placebo-controlled trial of orally administered SYNB1020 evaluating
ascending doses each administered on a single day and multiple
ascending doses administered over 14 days. The primary objective of
the studies was to assess safety and tolerability of SYNB1020 in
healthy volunteers. Secondary objectives were to characterize the
microbial kinetics of SYNB1020 in feces as measured by qPCR and
gastrointestinal tolerability assessed by the Gastrointestinal
Symptom Rating Scale. Exploratory endpoints were designed to
evaluate the pharmacodynamic effects of SYNB1020, including
measurements of blood ammonia levels and other related
biomarkers.
The results are from 52 healthy volunteers who were dosed orally
with either SYNB1020 or placebo (ratio three to one), which
includes 28 from 7 cohorts of the SAD study and 24 subjects from 3
cohorts of the MAD study. Complete safety results from the SAD and
MAD Phase 1 study demonstrate that SYNB1020 was well tolerated at
total daily doses up to 1.5x1012 CFU for 14 days. Higher doses were
associated with mild to moderate gastrointestinal symptoms, mainly
nausea and vomiting. The observed dose-dependent changes in a
plasma nitrogen end-point are consistent with SYNB1020’s mechanism
of activity. SYNB1020 is genetically programmed to convert ammonia,
a product of protein degradation, which can be toxic at high
levels, into arginine, a beneficial amino acid.
As expected, based on previous clinical observations with the
un-engineered probiotic and preclinical studies, subjects cleared
SYNB1020 within the expected timeframe. Eight subjects in the MAD
portion of the study continue to be followed for clearance of
SYNB1020.
SAD Phase 1 Results
In the SAD study, seven cohorts treated with total daily doses
of SYNB1020 ranging from 2x109 to 6x1012 CFU were tested against
placebo in a three to one ratio in a total of 28 healthy
volunteers. Subjects received a single dose or three doses on a
single day. The maximum tolerated total daily dose was 1.5 x
1012CFU. There were no SAEs reported, with all AEs being mild to
moderate, the most common being nausea and vomiting at the highest
doses. Three subjects at the highest dose cohorts discontinued
dosing.
MAD Phase 1 Results
All three cohorts reported data from a total 24 healthy
volunteers dosed three times per day with SYNB1020 at total daily
doses of up to 1.5x1012 CFU for 14 days or with placebo (three to
one ratio). No SAEs were reported, all AEs occurred during the
first week of dosing, were mild, and nausea and vomiting were most
common. One subject at the highest dose cohort discontinued dosing.
A dose-responsive nitrogen endpoint was identified in blood which
was found to be statistically significant in the highest dose
cohort compared to placebo. While enrollment and treatment have
been completed, subjects enrolled in the highest dose cohort
continue to be monitored for clearance of SYNB1020.
SYNB1020 Clinical Development Plans and Upcoming
Milestones
Synlogic plans to initiate a Phase 1b/2a study of SYNB1020 in
patients with liver cirrhosis and elevated ammonia in the first
half of 2018 and a second Phase 1b/2a study in patients with UCDs.
Dosing will be determined based on the findings from MAD portion of
this Phase 1 study in healthy volunteers. The company expects to
provide final data from this Phase 1 study at an appropriate
clinical meeting in 2018.
About Synthetic Biotic Medicines and SYNB1020
Synlogic’s innovative new class of Synthetic Biotic medicines
leverages the tools and principles of synthetic biology to
genetically engineer probiotic microbes to perform or deliver
critical functions missing or damaged due to disease. The company’s
two lead programs target a group of rare metabolic diseases –
inborn errors of metabolism (IEM). Patients with these diseases are
born with a faulty gene, inhibiting the body’s ability to break
down commonly occurring by-products of digestion that then
accumulate to toxic levels and cause serious health consequences.
When delivered orally, these medicines can act from the gut to
compensate for the dysfunctional metabolic pathway and have a
systemic effect. Synthetic Biotic medicines are designed to clear
toxic metabolites associated with specific metabolic diseases and
have the potential to significantly improve symptoms of disease for
affected patients. SYNB1020 is genetically programmed to convert
ammonia, a product of protein degradation which can be toxic at
high levels, into arginine, a beneficial amino acid.
About Synlogic
Synlogic is pioneering the development of a novel class of
living Synthetic Biotic medicines, based on its proprietary drug
development platform. Synlogic’s initial pipeline includes
Synthetic Biotic medicines for the treatment of rare genetic
diseases, such as urea cycle disorders (UCD) and phenylketonuria
(PKU). In addition, the company is leveraging the broad potential
of its platform to create Synthetic Biotic medicines for the
treatment of more common diseases, including liver disease,
inflammatory and immune disorders, and cancer. Synlogic is
collaborating with AbbVie to develop Synthetic Biotic-based
treatments for inflammatory bowel disease (IBD). For more
information, please visit www.synlogictx.com.
Forward-Looking Statements
This press release contains “forward-looking statements” that
involve substantial risks and uncertainties for purposes of the
safe harbor provided by the Private Securities Litigation Reform
Act of 1995. All statements, other than statements of historical
facts, included in this press release regarding strategy, future
operations, future financial position, future revenue, projected
expenses, prospects, plans and objectives of management are
forward-looking statements. In addition, when or if used in this
press release, the words “may,” “could,” “should,” “anticipate,”
“believe,” “estimate,” “expect,” “intend,” “plan,” “predict” and
similar expressions and their variants, as they relate to Synlogic
may identify forward-looking statements. Examples of
forward-looking statements, include, but are not limited to,
statements regarding the potential of Synlogic’s platform to
develop therapeutics to address a wide range of diseases including:
inborn errors of metabolism, liver disease, inflammatory and immune
disorders, and cancer; the future clinical development of Synthetic
Biotic medicines; the approach Synlogic is taking to discover and
develop novel therapeutics using synthetic biology; the potential
of Synlogic’s technology to treat hyperammonemia; the expected
timing of initiation of Synlogic’s anticipated clinical trials and
that data from additional studies will demonstrate efficacy of
SYNB1020 for the treatment of hyperammonemia. Actual results could
differ materially from those contained in any forward-looking
statement as a result of various factors, including: the
uncertainties inherent in the preclinical development process; the
ability of Synlogic to protect its intellectual property rights;
and legislative, regulatory, political and economic developments,
as well as those risks identified under the heading “Risk Factors”
in Synlogic’s filings with the SEC. The forward-looking statements
contained in this press release reflect Synlogic’s current views
with respect to future events. Synlogic anticipates that subsequent
events and developments will cause its views to change. However,
while Synlogic may elect to update these forward-looking statements
in the future, Synlogic specifically disclaims any obligation to do
so. These forward-looking statements should not be relied upon as
representing Synlogic’s view as of any date subsequent to the date
hereof.
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version on businesswire.com: http://www.businesswire.com/news/home/20171108005604/en/
SynlogicCourtney Heath,
617-872-2462courtney@scientpr.comorElizabeth Wolffe, Ph.D.,
617-207-5509liz@synlogictx.com
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