CAMBRIDGE, Mass.—In January, Synlogic Inc. announced the publication in Science Translational Medicine of clinical data from its Phase 1 clinical study in healthy volunteers and supporting preclinical data from its investigational candidate, SYNB1020, a proprietary “synthetic biotic.” The data support the continued development of SYNB1020, which is currently being evaluated in a Phase 1b/2a clinical trial in patients with cirrhosis and elevated blood ammonia.
“These data demonstrate that we can engineer bacteria to carry out a specific function, deliver them to humans and that they perform as designed,” said Dr. Paul Miller, Synlogic’s chief scientific officer. “Ongoing manufacturing and formulation development work at Synlogic gives us confidence we will be able to scale and formulate our Synthetic Biotic medicines to meet multiple needs in the marketplace for living medicines. The compelling data in this publication encouraged us to advance SYNB1020 into additional clinical studies, and we look forward to presenting data from our trial, designed to evaluate the potential of SYNB1020 to lower ammonia in patients with cirrhosis, in mid-2019.”
The publication, entitled “An Engineered E. coli Nissle Improves Hyperammonemia and Survival in Mice and Shows Dose-dependent Exposure in Healthy Humans,” describes the engineering and characterization of SYNB1020, preclinical studies of SYNB1020 in mouse models of hyperammonemia (OTC spfash and the TAA model) and its safety in healthy mice and non-human primates (NHPs), as well as clinical data from Synlogic’s Phase 1 study of SYNB1020 in healthy volunteers.
“E. coli [strain] Nissle already has a metabolic pathway that makes arginine from ammonia. However, it has limited activity, and when the unengineered bacterium has made the arginine it needs to function, it turns the pathway off. We have used the tools of synthetic biology to create SYNB1020, engineering the bacterium’s genes so that the pathway is programmed to turn on in the low-oxygen environment of the colon, where most of the ammonia is generated, and to remain on and convert ammonia into arginine while there is ammonia present,” says Aoife M. Brennan, president, CEO and chief medical officer at Synlogic.
“Longstanding evidence supports the importance of the gastrointestinal (GI) tract as the major source of ammonia that makes its way into the systemic circulation, so the gut is a good place to address the problem of excess ammonia. In healthy people, the liver is able to take ammonia from the blood and break it down via the urea cycle,” continues Brennan. “In conditions that result in hyperammonemia—such as urea cycle disorders (UCDs), which are genetic mutations in enzymes of the urea cycle, or in cirrhosis where the liver is damaged—the urea cycle is impaired, and so ammonia builds up in the blood. Our approach is designed to reduce the amount of ammonia in the gut so that there is less ammonia available to move into the blood.”
The current standard of care for conditions that result in hyperammonemia, including hepatic encephalopathy stemming from liver damage and UCDs, employs orally administered approaches such as antibiotics, laxatives and ammonia scavengers. However, each of these agents has limitations.
Synlogic’s Synthetic Biotic platform uses synthetic biology to engineer a strain of non-pathogenic bacteria (E. coli Nissle strain) to perform or deliver specific functions lost or damaged due to disease. Orally administered SYNB1020 has been designed to respond to the low-oxygen environment of the large intestine to convert ammonia into arginine, an amino acid. In addition, Synthetic Biotic medicines are engineered to limit their replication after manufacturing so that they don’t grow or colonize the GI tract.
The preclinical data demonstrate that orally administered SYNB1020 is well tolerated in mice and NHPs, clears rapidly from the GI tract following completion of dosing and is not found in tissues outside the GI tract. When OTC spfash mice, a model of a UCD, were fed a high-protein diet to increase their blood ammonia levels, those that were orally dosed with SYNB1020 demonstrated lower blood ammonia and increased survival compared to mice that received heat-killed, inactive SYNB1020. Similar data were obtained in a mouse model of liver damage (TAA model).
The clinical data from Synlogic’s Phase 1 clinical study demonstrate that in healthy volunteers, orally administered SYNB1020 was safe and well tolerated at daily doses up to 1.5 x 1012 colony forming units, and cleared from the gastrointestinal tract within two weeks. In addition, dose-dependent elevation in plasma and urine of nitrate, a biomarker of SYNB1020 activity, was observed in healthy volunteers treated with SYNB1020 but not in those treated with placebo, demonstrating proof of mechanism.
“The data published in Science Translational Medicine demonstrated in preclinical animal models and humans that SYNB1020 is safe, doesn’t colonize the gut, as we intended, and is functioning as designed. These data support the development of SYNB1020 as a potential treatment for hyperammonemia,” Brennan points out. “The question that we are now trying to answer is: will SYNB1020 be able to consume enough ammonia to provide a therapeutic benefit to patients?”
“We are at an exciting convergence between biology and engineering that is enabling us to design and engineer a new class of therapeutics: living medicines based on microbes,” she says. “SYNB1020 was the first demonstration that we could engineer these bacteria and demonstrate that they were carrying out their designed function in both animal models and humans. We believe that there is tremendous potential in this platform and these data give us the confidence to continue its development.”
Synlogic is currently evaluating SYNB1020 in a Phase 1b/2a clinical trial in patients with cirrhosis and elevated blood ammonia for the management of systemic ammonia levels.
“We expect to have data from this study mid-2019. With ammonia-lowering data, we will determine the best clinical development path forward for SYNB1020,” Brennan adds.