– Expanded clinical data set from Phase 1 study
confirms proof of mechanism and supports continued development of
SYNB1020 for treatment of hyperammonemia –
– A Phase 1b / 2a clinical trial to further
evaluate SYNB1020 is open and screening patients –
Synlogic (Nasdaq:SYBX), a clinical-stage company applying
synthetic biology to probiotic bacteria to develop novel living
medicines, announced the presentation of the expanded clinical data
set from its first-in-human Phase 1 study of SYNB1020, a Synthetic
Biotic medicine being developed for the treatment of hyperammonemia
associated with urea cycle disorders (UCDs) and cirrhosis. In
addition, new preclinical data from this program and from a second
Synthetic Biotic medicine, SYNB1618, being developed for the
treatment of phenylketonuria (PKU), were presented at the 40th
Annual Meeting of the Society for Inherited Metabolic Disorders
(SIMD) which is being held in San Diego from March 11 to 14,
2018.
“Our first clinical trial was a major milestone for Synlogic,
providing proof-of-mechanism of a new modality of cell-based
therapies which uses engineered probiotic bacteria to treat
disease,” said J.C. Gutiérrez-Ramos, Ph.D., Synlogic’s president
and chief executive officer. “In contrast to other cell-based
therapies, we are developing our Synthetic Biotic medicines to have
predictable drug qualities, with engineered potency and
dose-dependent activity. The data presented at SIMD demonstrate we
have established these standards in our lead programs and we look
forward to continuing to evaluate the broad potential of our
Synthetic Biotic platform.”
In its initial programs, Synlogic is developing Synthetic Biotic
medicines for the treatment of inborn errors of metabolism (IEMs)
such as UCDs and PKU. These therapies are designed to function in
the gastrointestinal (GI) tract to convert metabolites such as
ammonia and phenylalanine (Phe) that build up to toxic levels in
the blood of patients with UCD and PKU, respectively, to harmless
metabolites that can be excreted from the body. Synlogic has
initiated a Phase 1b/2a clinical trial of SYNB1020, in patients
with cirrhosis and elevated ammonia, designed to evaluate safety
and tolerability as well as lowering of blood ammonia levels, an
important endpoint in this patient population.
“Clinical data presented at SIMD demonstrate that SYNB1020 is
well-tolerated, rapidly cleared following discontinuation of
dosing, and functions as designed in humans, supporting its
continued development for the treatment of patients with
hyperammonemia,” said Aoife Brennan, M.B., B.Ch., Synlogic’s chief
medical officer. “Additionally, we are pleased to report our Phase
1b / 2a study designed to evaluate safety and tolerability as well
as lowering of blood ammonia in patients with liver cirrhosis, is
now open and screening subjects. In the first half of this year, we
also expect to initiate a clinical trial of SYNB1618 for the
treatment of PKU, based on preclinical data presented at SIMD, and
anticipate we will have data from both clinical studies by the end
of 2018.”
Summary of Data from the Phase 1 Study of SYNB1020 in Healthy
VolunteersData from Synlogic’s Phase 1 study in healthy
volunteers were presented at SMID and demonstrated that SYNB1020, a
probiotic engineered to convert ammonia into an essential amino
acid arginine (Arg), was safe and well tolerated in 52 healthy
volunteers up to a maximum tolerated daily dose of 1.5x1012 CFU for
14 days. There were no serious adverse events (SAEs), AEs observed
at higher doses in the single ascending dose stage of the study
designed to establish the maximum tolerated dose, were mild to
moderate nausea and vomiting which resolved rapidly. As designed,
the bacteria did not colonize and all subjects cleared SYNB1020
from their systems within two weeks of the final dose. Blood
ammonia levels were in the normal range at baseline and, as
expected in healthy individuals who maintain tight control over
ammonia levels, there was no change in this end-point over the
course of the study. In the MAD component of the Phase 1 study, a
tracer study was undertaken using orally administered 15N ammonium
chloride, a substrate for SYNB1020. This revealed a dose-dependent
relationship between administration of SYNB1020 and change in
plasma and urinary nitrate, a terminal product of Arg degradation,
compared to baseline that was statistically significant in the
highest dose cohort compared to placebo. In addition, a dose
dependent relationship was observed in total urinary nitrate. These
mechanistic data demonstrate that the strain was functioning as
designed in humans.
About Synlogic’s Phase 1b / 2a Study of SYNB1020 in Patients
with CirrhosisSynlogic has recently initiated a Phase 1b/2a
clinical study in patients with cirrhosis and elevated blood
ammonia that is designed to evaluate safety and tolerability as
well as ammonia lowering, an end-point that has been closely
related to clinical outcome in prior studies in this patient
population.
The study has two parts: an initial sentinel open-label cohort
of subjects with cirrhosis and a MELD (Model for End-Stage Liver
Disease) score <12 will receive orally administered SYNB1020 (5
x 1011 CFU TID) for six days. Subjects will be admitted to an
inpatient facility for a run-in diet, baseline assessments, safety
monitoring, and collection of blood, urine, and fecal samples for
evaluation of safety, tolerability, and pharmacokinetic and
pharmacodynamic evaluations of treatment. Once safety and
tolerability have been established in these subjects, enrollment
will be opened to subjects in Part 2.
Part 2 of the trial comprises a randomized, double-blind,
placebo-controlled study in patients with cirrhosis and
hyperammonemia. Eligible subjects will be admitted to an inpatient
facility for a run-in diet and 24-hour ammonia profile, and those
with an elevated 24-hour ammonia AUC will proceed with
randomization and receive either placebo or orally administered
SYNB1020 (5 x 1011 CFU TID) for six days. The primary endpoint of
the study is safety and tolerability. In addition, the study will
evaluate the effect of SYNB1020 administration on plasma ammonia
levels as well as other exploratory endpoints. More information on
this study can be found at www.clinicaltrials.gov under the study
ID NCT03447730.
Summary of Preclinical Data Supporting the SYNB1020
ProgramSYNB1020 is an engineered probiotic designed to function
in the GI tract to convert toxic ammonia into arginine, an
essential amino acid. Data presented at SMID demonstrated that in a
mouse model of chronic hyperammonemia a dose-dependent lowering of
plasma ammonia was observed in SYNB1020 treated mice that
corresponded to improved survival in animals that were made
hyperammonemic on a high protein diet.
SYNB1020 activity was also demonstrated using a modified version
of the Synthetic Biotic strain that had been engineered to further
convert L-arginine into D-arginine, a related but distinct form of
the amino acid that cannot be metabolized in mammalian cells and is
excreted in the urine. This allows the duration of strain activity
to be followed in vivo. D-arginine was measured in urine and plasma
in non-human primates (NHPs). The data demonstrated that the
Synthetic Biotic medicine was active over the six-hour sampling
period in both NHPs and mice. As seen in the Phase I human study,
an elevation in urinary nitrate was observed in NHPs dosed with
SYNB1020. Clearance of SYNB1020 was assessed in both mouse and NHP.
SYNB1020 was detectable in feces of both species during dosing and
was rapidly cleared (within 7 days) following cessation of dosing,
consistent with a non-colonizing probiotic strain.
Summary of Preclinical Data Supporting the SYNB1618
ProgramSYNB1618 is an engineered probiotic designed to function
in the GI tract to convert Phe into trans-cinnamic acid (TCA), a
harmless metabolite that can be further metabolized in the liver to
generate hippuric acid (HA) which is excreted in the urine. Levels
of plasma TCA and urinary HA provide useful biomarkers for the
activity of SYNB1618. The data presented at SIMD demonstrate that
in a mouse model of PKU, administration of SYNB1618 resulted in a
decrease in blood Phe concentration compared to mice receiving a
control strain. SYNB1618 was effective at lowering blood Phe from
both the diet and from systemic Phe that is actively recirculated
into the GI tract. Blood Phe lowering correlated with HA production
in the urine of SYNB1618-treated mice. SYNB1618 also inhibited
elevation of blood Phe in healthy NHPs following an oral Phe
dietary challenge and demonstrated drug-like dose response
properties. This work supports the future development of SYNB1618
as a treatment for patients with PKU.
About HyperammonemiaHyperammonemia is a metabolic
condition characterized by an excess of ammonia in the blood, which
can result in severe and life-threatening consequences for
patients. In healthy individuals, ammonia is primarily produced in
the intestine as a byproduct of protein digestion and microbial
degradation of nitrogen-containing compounds. Ammonia is then
converted to urea in the liver and is excreted in urine. However,
if the liver’s ability to convert ammonia to urea is compromised,
either due to a genetic defect such as UCDs, or acquired liver
disease, ammonia accumulates in the blood. Elevated blood ammonia
levels are toxic to the brain and can have severe consequences
including neurologic crises requiring hospitalization, irreversible
cognitive damage and death.
About Phenylketonuria (PKU)PKU is a rare IEM caused by a
genetic defect in phenylalanine hydroxylase (“PAH”), the enzyme
used to break down Phe leading to accumulation of Phe in the blood
and brain, where it is neurotoxic and can lead to neurological
deficits and even death. Despite recommendations supporting
life-long control of Phe levels, compliance is challenging due to
the highly restrictive nature of the diet, putting patients at risk
for cognitive and psychiatric disease and supporting the need for
novel treatment approaches.
About Synthetic Biotic MedicinesSynlogic’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 reduce toxic metabolites associated with
specific metabolic diseases and have the potential to significantly
improve symptoms of disease for affected patients.
About SynlogicSynlogic is pioneering the development of a
novel class of living medicines, Synthetic Biotic medicines, based
on its proprietary drug development platform. Synlogic’s current
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 StatementsThis 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, hyperammonemia
and other liver disorders, cancer, and inflammatory and immune
disorders; 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 urea cycle disorders and
phenylketonuria; and the advancement of our collaborations. 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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For SynlogicMEDIA:Courtney Heath,
617-872-2462courtney@scientpr.comorINVESTORS:Elizabeth
Wolffe, Ph.D., 617-207-5509liz@synlogictx.com
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