Late last week, the synthetic biology company Synlogic announced data from a Phase 1/2a study of their living biologic designed for the treatment of Phenylketonuria (PKU). The findings of the first-in-human study of a frozen liquid formulation of the drug—known as SYNB1618—in healthy volunteers and patients with PKU, showed that the drug was safe and well tolerated. In addition, there was no systemic toxicity and no evidence of colonization—SYNB1618 was cleared within four days of the last dose. These data demonstrate the potential to use engineered bacteria in the treatment of rare metabolic disorders through the consumption of toxic substances in the GI tract.

These data are published in Nature Metabolism, in the paper entitled, “Safety and pharmacodynamics of an engineered E. coli Nissle for the treatment of phenylketonuria: a first-in-human Phase 1/2a study.”

Aoife Brennan
Aoife Brennan

“Our orally administered Synthetic Biotic medicines are intended to address the needs of PKU patients of all ages and disease types through the consumption of phenylalanine (Phe) in the gastrointestinal tract,” said Aoife Brennan, MB, ChB, Synlogic’s president and chief executive officer.

PKU is an inherited metabolic disease that manifests at birth and is marked by an inability to break down Phe, an amino acid that is commonly found in many foods. Left untreated, high levels of Phe become toxic and can lead to serious neurological and neuropsychological problems.

SYNB1618 is an engineered a strain of E. coli Nissle 1917, in which the genes encoding phenylalanine ammonia lyase and L-amino acid deaminase have been inserted into the genome, These genes allow for bacterial consumption of Phe within the gastrointestinal tract.

Dose-responsive increases in strain-specific Phe metabolites in plasma and urine were observed, demonstrating SYNB1618 is able to consume Phe and convert it to non-toxic metabolites in the GI tract of both healthy volunteers and patients with PKU.

The team at Synlogic published a second paper last week, this time in Communications Biology, describing the development of a mechanistic model predicting the potential for Phe-lowering efficacy in PKU patients. The paper, entitled, “Development of a Mechanistic Model to Predict Synthetic Biotic Activity in Healthy Volunteers and Patients with Phenylketonuria,” used findings from the Phase 1/2a study to inform a mechanistic model of strain activity in PKU patients.

It remains unclear, the authors write, to what extent Phe consumption by SYNB1618 in the GI tract lowers plasma Phe levels in PKU patients. The model predicts SYNB1618 function in non-human primates and healthy subjects by combining in vitro simulations and prior knowledge of human physiology.

Mark Charbonneau, PhD, head of quantitative biology at Synlogic, and first-author on the paper, tweeted that activity of orally administered strains, “is affected by gastric emptying, changing intestinal pH, oxygen and nutrient availability, strain viability, and dose.” He continues, “predicting the translational potential of these therapeutic strains necessitates the development of mathematical frameworks for integrating data from in vitro and in vivo model systems to predict the behavior of engineered strains in these dynamic conditions.”

In addition, the authors extend a model of plasma Phe kinetics in PKU patients, informing clinical development of potential treatments for PKU. Phe removal from the GI tract by SYNB1618 is predicted to correlate strongly with reduction of Phe in the blood. The results of this dose-response model suggest Phe-consuming Synthetic Biotic medicines such as SYNB1618 may have potential to achieve clinically meaningful reduction of blood phenylalanine levels in patients with PKU. SYNB1618 continues to advance in a proof-of-concept Phase 2 clinical trial in adults with PKU, SynPheny-1 study (NCT04534842), with data expected in the second half of 2021.