Synlogic, Inc., (Nasdaq: SYBX) a clinical stage company applying synthetic biology to probiotics to develop novel, living medicines, announced 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 “A translational pathway for the development of a synthetic organism for the treatment of 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.
To monitor SYNB1618 activity in vivo, Synlogic scientists investigated the production of major SYNB1618-derived metabolites, including TCA and HA. Studies demonstrated that orally administered SYNB1618 resulted in a significant decrease in blood Phe levels independent of dietary protein intake in the PKU mouse model, and inhibited increases in serum Phe after an oral Phe challenge in healthy NHPs. In both species, SYNB1618 exhibited dose-responsive pharmacokinetics, as determined by production of urinary HA.
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. More information about Synlogic’s Phase 1/2a clinical trial in healthy adult volunteers and patients with PKU can be found at https://clinicaltrials.govunder the study ID NCT03516487.