First Part of Phase 1/2a Trial Evaluating PKU Treatment Meets Primary Objectives

The first part of a recent phase 1/2a trial has met its primary objectives, demonstrating safety and tolerability of Synlogic Inc.’s SYNB1618 in healthy volunteers and identifying a suitable dose to evaluate in patients with PKU.

“Patients were our inspiration as we began this work, and [they] continue to be as we advance our SYNB1618 program,” Aoife Brennan, MB, BCh, BAO, MMSc, interim CEO and CMO, told Rare Disease Report^®. “Before we spoke with the FDA, we hosted a patient advisory board in order to hear what patients with PKU had to say about the unmet need in PKU treatment options and to gain an understanding of the challenges that they face every day as they manage their blood phenylalanine levels.”

For the randomized, double-blind, placebo (PBO)-controlled phase 1/2a clinical trial, investigators evaluated the effectiveness of orally administered SYNB1618 versus placebo (PBO) in single- (SAD) and multiple-ascending dose (MAD) cohorts of HVs.

In both the SAD and MAD cohorts, the activity of SYNB1618 was assessed in fasted individuals following administration of a standardized breakfast drink with a defined amount of protein. Solid food with an equivalent amount of protein was replaced with the liquid meal at 1 dose level in the SAD portion of the study. A labeled Phe tracer (D5-Phe) was also orally administered.

Over a subsequent 6-hour period, blood and urine samples were collected, and several metabolites were measured, such as Phe and SYNB1618-specific biomarkers of Phe metabolism, TCA in blood, and HA in urine. In the SAD cohorts, these methods were conducted on the day of dosing, and in the MAD cohorts, on day 1 (baseline) and day 7 (the last day of dosing).

The 24 individuals in the SAD cohort, which included the maximum tolerated dose (MTD) was 2 x 10¹¹ CFU and a total of 24 individuals, were not found to experience any drug-related significant adverse events (SAEs). Nausea and vomiting were the most common moderately severe AEs, and all reported AEs ranged from mild to moderate in severity.

In both plasma TCA and urinary HA, a statistically significant dose-dependent increase was noted in individuals administered SYNB1618 but not in those administered PBO. “Production of metabolites from Phe administered as a free amino acid was similar to Phe administered as whole protein,” according to a recent news release. Regardless of whether the protein was given as a liquid or as a solid meal, the production of metabolites was observed to be similar.

For the MAD cohort, which included 32 HVs treated with PBO or SYNB1618 at doses of up to 1x10¹¹ CFU TID for 7 days, no drug-related SAEs were observed. Nausea and vomiting were the most common AEs, and all AEs ranged from mild to moderate in severity. In the highest dose cohort, only 1 individual discontinued dosing. In patients administered SYNB1618, a statistically significant dose-dependent increase in plasma TCA and urinary HA was noted but not in those administered PBO.

“The data demonstrate that SYNB1618, our Synthetic Biotic product candidate is active and performing the metabolic functions that we designed it to carry out in humans,” added Brennan. “It is doing what it was designed to do; this represents an exciting first step in our development of SYNB1618 as a potential therapy for patients with PKU.”

Looking forward, Synlogic anticipates administering 7x10¹⁰ CFU of SYNB1618 to PKU patients. In mid-2019, top-line data from the patient treatment arm of this study is expected to be reported and will include data from patients and HVs.

“Our first step was to demonstrate safety and tolerability of SYNB1618 in healthy volunteers and identify a suitable dose to evaluate in patients with PKU,” Breenan explained. “Next, we will test that this dose is also safe and well tolerated in patients with PKU and will carry out a similar set of analyses to those we did in the healthy volunteers to look for evidence the bacterial are consuming Phe in patients with PKU. We expect to have these data by mid-2019.”