Pre-clinical Data Supports Synlogic's Synthetic Biotic as a Potential Treatment for Phenylketonuria

August 13, 2018



Synlogic, Inc., (Nasdaq: SYBX) announced on 8/13/18 the publication of data from preclinical studies of SYNB1618, the Company’s Synthetic Biotic development program targeting PKU, in Nature Biotechnology.The data demonstrate that oral administration of SYNB1618 significantly reduced blood phenylalanine (Phe) levels, the key metabolite associated with PKU, in mouse models of PKU and resulted in dose-dependent pharmacodynamics in healthy non-human primates (NHPs).

The paper titled “Development of a synthetic live bacterial therapeutic for the human metabolic disease phenylketonuria” appears as an Advance Online Publication on Nature Biotechnology’s website.

“These preclinical studies highlight the potential of our engineered Synthetic Biotic medicines to act with potency within the gut to normalize systemic levels of a toxic metabolite. In addition, in two species, we demonstrate dose-dependent production of biomarkers of activity for SYNB1618, which will be very useful in evaluating its efficacy in our ongoing clinical study in healthy volunteers and patients with PKU,” said Paul Miller, Ph.D., Synlogic’s chief scientific officer. “These data provide compelling evidence to support the continued development of our orally administered Synthetic Biotic medicine, SYNB1618, for the potential treatment of PKU.”

Synlogic’s Synthetic Biotic platform leverages the tools and principles of synthetic biology to engineer a strain of probiotic bacteria (E. coli Nissle) to perform or deliver specific functions lost or damaged due to disease. SYNB1618 is designed to metabolize Phe and was engineered by inserting specific genetic circuits including a bacterial gene that encodes phenylalanine ammonia lyase (PAL). PAL is an enzyme that breaks down Phe to generate trans-cinnamic acid (TCA), which is converted to hippuric acid (HA) in the liver and excreted in urine. Thus, plasma TCA and urinary HA levels can serve as biomarkers of PAL and, therefore, of SYNB1618 activity in vivo.
The publication describes the engineering and characterization of SYNB1618, as well as preclinical studies of SYNB1618 in both a mouse model of PKU (Pah enu2/enu2) and healthy NHPs that have a metabolism and gastrointestinal (GI) physiology more similar to humans. Synlogic scientists confirmed previously reported observations in rodents that Phe is abundant in the small intestine and derived from two sources, the diet and the blood. In both species, Phe re-enters the GI tract in the form of enzymes and secretions via a process known as enterorecirculation, supporting the feasibility of a GI-based approach for Phe consumption.

Synlogic is currently evaluating SYNB1618 in a Phase 1/2a clinical trial for the management of PKU and expects to report interim data from healthy volunteers in 2018 and full data, including cohorts of patients with PKU, in 2019.

PKU is caused by a defect in the gene encoding phenylalanine hydroxylase (PAH), a liver enzyme that metabolizes Phe. Phe is an essential amino acid that enters the body as a component of dietary protein and can be toxic if it accumulates in the blood and brain. Current disease management and approved therapies of PKU involve strict dietary protein restriction with the consumption of Phe-free protein supplements, representing a significant need for additional treatments. Life-long Phe control is challenging due to the highly restrictive nature of the diet, and patients typically experience worsening neurological function depending on the severity of their genetic mutation and their treatment compliance. PKU is diagnosed at birth, and the National PKU Alliance estimates that there are currently 16,500 people living with the disorder in the U.S.

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