Synlogic Presents Data at the 2018 Liver Meeting, the Annual Meeting of the American Association for the Study of Liver Disease (AASLD)
- Data support ongoing evaluation of Synthetic BioticTM SYNB1020 for the potential treatment of hyperammonemia -
“Hepatic Encephalopathy is a major cause of morbidity and mortality in
patients with chronic liver disease. Elevated blood ammonia is an
important risk factor for HE, however, it is difficult to measure in the
setting of multicenter clinical trials,” said
Two presentations were given at the Liver Meeting, both were selected as posters of distinction. The data are summarized below:
- Blood Ammonia Levels are Labile and Responsive to Protein Intake
in Patients with Compensated Cirrhosis Without Overt Hepatic
Synlogicconducted a study in patients with cirrhosis who have not had an episode of overt hepatic encephalopathy (HE) to determine the level and inter-individual variability of fasting blood ammonia and the impact of a standard protein meal on blood ammonia levels. In addition, blood ammonia reference ranges of healthy volunteers at five clinical sites were compared as well as the intra-sample variability between fresh samples or fresh and frozen samples.
The data demonstrated that:
- Sample handling and processing have a major impact on ammonia levels and are critical for data quality
- Venous ammonia is elevated in a subset of patients with cirrhosis without a history of overt HE and increases significantly after a meal containing 20g of protein for at least two hours
- Normal ranges determined using healthy volunteers and strict sample processing and analysis procedures can differ significantly from the normal range provided by the kit manufacturer
- There is an excellent correlation between paired fresh samples, however, freezing affects ammonia levels
- Age and gender do not appear to influence ammonia levels, however, as expected, higher MELD score is associated with higher baseline ammonia
The study provided key foundational data for the establishment of optimal protocols for blood ammonia measurement in Synlogic’s ongoing Phase 1b/2a clinical trial of its ammonia consuming Synthetic Biotic strain, SYNB1020, in patients with cirrhosis and elevated ammonia.
- Genetically Engineered E.coli Nissle Attenuates Hyperammonemia
in Two Experimental Models of Hepatic Encephalopathy
The study was designed to explore the effect of Synthetic Biotic strains engineered to consume ammonia on plasma ammonia levels and bio-markers of liver damage in two rodent models of liver damage, the mouse thioacetamide (TAA) model and the rat bile duct ligation (BDL) model. The rat BDL model studies were conducted in the laboratory of Synlogic’s collaborator,
Christopher Rose, Ph.D., Professor at the Department of Medicineat the Université de Montréal and a researcher at the Centre de recherche du Centre hospitalier de Université de Montréal (CRCHUM) where he heads the Hepato-Neuro Laboratory.
The study evaluated two engineered strains of E.coli Nissle: SYNARG, designed to consume ammonia and convert it to arginine, and SYNARG+BUT which was engineered to also synthesize the short chain fatty acid butyrate in the gastrointestinal (GI) tract. Butyrate has been reported to reduce inflammation and help maintain gut barrier integrity.
The data demonstrated that:
- In vitro SYNARG and SYNARG+BUT both consume ammonia and produce arginine and SYNARG+BUT also produces butyrate
- Statistically significant reductions in serum ammonia were observed in both the mouse TAA and rat BDL models
- Markers of liver injury were reduced in TAA mice, suggesting additional potential benefits of the engineered strains in liver disease beyond the direct consumption of ammonia in the GI tract
Future studies will also explore the effect of Synthetic Biotic medicines on measures of cognitive function in the rat BDL model. Elevated levels of ammonia in the brain lead to neurological symptoms, including impaired memory, shortened attention span, seizures, lack of muscle coordination and coma. The study provided supportive evidence for the potential beneficial effect of Synthetic Biotic medicines designed to consume ammonia from the GI tract in attenuating chronic liver disease.
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