Synlogic Reports Positive Interim Phase 1/2a Data Demonstrating Safety, Tolerability and Proof-of-Mechanism in Healthy Volunteers for SYNB1618, in Development for the Management of Phenylketonuria (PKU)
– Data demonstrate statistically significant dose-dependent effects on SYNB1618 activity-associated biomarkers, supporting further development of SYNB1618 –
– SYNB1618 dose established for treatment arm of ongoing Phase 1/2a study in patients with PKU; top-line data expected in mid-2019 –
– Company to hold conference call and webcast today,
"The significant dose-dependent production of SYNB1618-specific
biomarkers in healthy volunteers is an exciting first step towards
delivering a potential therapy for patients with PKU,” said
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, in development for the management of PKU, is designed to function in the gastrointestinal tract (GI) and has been engineered to consume phenylalanine (Phe), an essential amino acid that can accumulate to harmful levels in patients with PKU with severe consequences. SYNB1618 metabolizes Phe to harmless compounds including trans-cinnamic acid (TCA) in the blood which is further metabolized in the liver and excreted as hippurate (HA) in the urine. TCA and HA,therefore, represent specific biomarkers of SYNB1618 activity as demonstrated by Synlogic’s preclinical data that were recently published in Nature Biotechnology.
Phase 1/2a Trial Design
Synlogic’s Phase 1/2a trial is a randomized, double-blind, PBO-controlled study of orally administered SYNB1618, evaluating ascending doses administered on a single day and multiple ascending doses administered over seven days. The primary objective of the study was to assess safety and tolerability of SYNB1618 in HVs and to establish a suitable dose to evaluate in patients with PKU, with secondary objectives to characterize the microbial kinetics of SYNB1618 in feces, as measured by qPCR, and GI tolerability, assessed by GI-related adverse events. Exploratory endpoints were designed to evaluate the pharmacodynamic effects of SYNB1618, including previously identified biomarkers related to SYNB1618 activity, TCA in plasma and HA in urine.
In the SAD portion of this study, six cohorts of four HVs received a single dose of SYNB1618 ranging from 1x1010 to 5x1011 CFU or PBO (3 treated:1 PBO). In the MAD portion of this study, four cohorts of eight HVs received either SYNB1618 at doses of up to 1x1011 CFU TID or PBO (6 treated:2 PBO), for seven days. During the treatment part of the study, subjects were housed in a clinical unit and provided a defined diet. The activity of SYNB1618 was evaluated in fasted subjects in both the SAD and MAD cohorts after administration of a standardized breakfast drink containing a defined amount of protein. At one dose level in the SAD portion of the study, solid food containing an equivalent amount of protein was substituted for the liquid meal. In addition, a labeled Phe tracer (D5-Phe) was orally administered. Blood and urine were collected over a subsequent six-hour period and several metabolites were measured including Phe and SYNB1618-specific biomarkers of Phe metabolism, TCA in blood and HA in urine. This was conducted in the SAD cohorts on the day of dosing and in the MAD cohorts on Day -1 (baseline) and Day 7 (the last day of dosing).
SAD Phase 1 Results:
In the SAD portion of this study, which included a total of 24 subjects, the maximum tolerated dose (MTD) was 2 x 1011 CFU. There were no drug-related significant adverse events (SAEs) reported. All AEs were mild-to-moderate in severity; of the moderately severe AEs, nausea and vomiting were the most common. A statistically significant dose-dependent increase in both plasma TCA and urinary HA was observed in SYNB1618 treated subjects but not in those treated with PBO. Production of metabolites from Phe administered as a free amino acid was similar to Phe administered as whole protein. In addition, production of metabolites was similar whether the protein was administered as a liquid or as a solid meal.
MAD Phase 1 Results:
In the MAD portion of this study, which included a total of 32 subjects, HV were administered PBO or SYNB1618 at doses of up to 1x1011 CFU TID for seven days. No drug-related SAEs were reported. All AEs were mild to moderate and observed in both the SYNB1618-treated and PBO groups. Of the moderately severe AEs, nausea and vomiting were the most common; only one subject in the highest dose cohort discontinued dosing. As observed in the SAD portion of the study, a statistically significant dose-dependent increase in plasma TCA and urinary HA was observed in SYNB1618-treated subjects but not in those treated with PBO. In HVs, who all have normal Phe metabolism, there was no impact on blood Phe levels. All HVs enrolled in the study have cleared SYNB1618 from their GI tracts.
SYNB1618 Clinical Development Plans and Upcoming Milestones
Synlogic’s ongoing Phase 1/2a trial of SYNB1618 will advance in patients
with PKU, who will be administered 7x1010 CFU of SYNB1618.
Conference Call & Webcast Information
About Phenylketonuria (PKU)
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 of PKU involves strict dietary protein restriction with the
consumption of Phe-free protein supplements. 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
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including statements regarding Synlogic’s plans and expectations for the
development of SYNB1618. All statements, other than statements of
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