Synlogic Presents Clinical and Preclinical Data from Synthetic Biotic™ Medicine Programs for Treatment of Inborn Errors of Metabolism at Annual Meeting of The Society for Inherited Metabolic Disorders
– 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 –
“Our first clinical trial was a major milestone for
In its initial programs,
“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
Summary of Data from the Phase 1 Study of SYNB1020 in
Data 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
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 Program
SYNB1020 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 Program
SYNB1618 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.
Hyperammonemia 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 Medicines
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 reduce toxic metabolites associated with specific metabolic diseases and have the potential to significantly improve symptoms of disease for affected patients.
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