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CAMBRIDGE, Mass.—Synlogic, Inc. has announced positive interim clinical data from the healthy volunteer (HV) arm of its ongoing Phase 1/2a study of SYNB1618 in HVs and patients with phenylketonuria (PKU). The first part of this trial, which evaluated SYNB1618 versus placebo in single- (SAD) and multiple-ascending dose (MAD) cohorts of HVs, successfully met the study’s primary objectives, to demonstrate safety and tolerability of SYNB1618 in HVs and to identify a suitable dose to evaluate in patients with PKU. The Phase 1/2a clinical data demonstrated that oral administration of SYNB1618 resulted in significant dose-dependent production of biomarkers specifically associated with SYNB1618 activity, demonstrating proof-of-mechanism.
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. 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.
Synlogic’s Phase 1/2a trial is a randomized double-blind, placebo-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 placebo (3 treated:1 placebo). In the MAD portion of this study, four cohorts of eight HVs received either SYNB1618 at doses of up to 1x1011 CFU TID or placebo (6 treated:2 placebo), 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).
“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 Aoife Brennan, M.B., B.Ch., Synlogic’s interim president, chief executive officer and chief medical officer. “We have identified a dose for the next phase of our ongoing trial in patients with PKU and we look forward to expanding on these interim results when we report top-line data from the patient treatment arm of this trial in mid-2019. Importantly, the data also demonstrate the potential for our Synthetic Biotic platform to address conditions in which an engineered living medicine can be designed to perform a specific metabolic function within the gastrointestinal tract.”
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 placebo. 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.
In the MAD portion of this study, which included a total of 32 subjects, HV were administered placebo 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 placebo groups. Of the moderately severe AEs, nausea and vomiting were the most common; only one subject in the highest dose cohort discontinued dosing. 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.
Synlogic’s ongoing Phase 1/2a trial of SYNB1618 will advance in patients with PKU, who will be administered 7x1010 CFU of SYNB1618. Synlogic expects to report top-line data from the patient treatment arm of this study in mid-2019, and plans to present final data from this clinical trial, including data from both HVs and patients, at an appropriate medical meeting. Synlogic also plans to optimize the manufacturing process, development and formulation of SYNB1618 in preparation for later stage clinical trials.