Rare Disease Report

Can Probiotic Bacteria Treat PKU? Potential Therapy Enters the Clinic

APRIL 19, 2018
Mathew Shanley
On Wednesday, it was announced that Synlogic had initiated and dosed the first subject in its Phase 1/2a study of SYNB1618 for the treatment of phenylketonuria (PKU).

The drug, being referred to as a “living medicine,” is comprised mostly of a probiotic bacteria called e.coli nissle, and is one of the many ‘synthetic biotics’ in development as part of the company’s development platform.

“Its path is derived from the human microbiome,” said JC Gutiérrez-Ramos, Ph.D., Synlogic’s president and chief executive officer. “People take it for gut health, and what we have done is engineer – in that probiotic bacteria – a number of genes that make the bacteria metabolize and degrade phenylalanine at a high rate. The concept is that you take these engineered probiotics – synthetic biotics – every day, and during the time that it is in your gut and your GI tract, it is performing that function with high potency.”

PKU, a genetic disorder that leads to decreased metabolism and accumulation of the amino acid phenylalanine (Phe), can result in seizures and cognitive impairment if not properly managed. Patients living with PKU currently have very few treatment options and endure a very restrictive diet that is low in protein, the primary source of dietary Phe. With SYNB1618, Synlogic is aiming to accomplish 2 things; degrade Phe from dietary intake, but also interfere with the normal recycling of Phe between the gut and the blood. This process makes it a dual-mechanism.

“What we have seen so far is impressive preclinical results, both in rodents and in non-human primates,” said Gutiérrez-Ramos. “We understand those responses and preclinical safety, and we think that this could be, potentially, both efficacious and safe. That’s what we’re setting out to demonstrate. It could prove to be a positive alternative for PKU patients.”

This Phase 1/2a clinical trial is a single and multiple dose-escalation, randomized, double-blind, placebo-controlled study of orally administered SYNB1618 in up to 56 healthy adult volunteers and 24 adult subjects with PKU. It has been designed to evaluate safety, tolerability, kinetics, and pharmacodynamics as well as exploratory end- points associated with the ability of SYNB1618 to metabolize Phe. Part 1 will evaluate a single-ascending dose in an inpatient setting over 4 days in healthy volunteers, who will be tested in up to 6 dose cohorts (3 treated : 1 placebo) to identify the maximum tolerated dose within the single dose range studied. Part 2 will evaluate a multiple-ascending dose in an inpatient setting over 10 days in healthy volunteers, who will be tested in up to 4 cohorts (6 treated : 2 placebo) and treated at doses that will not exceed the maximum tolerated dose from the single-ascending dose part of the study.

Once the highest maximum tolerated dose cohort and the single-ascension dose PKU cohort have been completed, a multiple-dose cohort of subjects previously diagnosed with PKU over 18 years of age will be evaluated.

“Our goal is really to help [these individuals] have a normal diet, including, certainly, a significant amount of normal proteins – maybe even double the amount of protein [that they’re currently taking],” Gutiérrez-Ramos said.

“PKU is very special,” he concluded. “It is a serious disease that can be managed, but takes a toll on individuals and certainly, the more we interact with PKU patients and their families, the more we understand what they need. We think that this program could lead to a very important drug, and that’s what we’re working toward.”

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