Synlogic’s new solid oral formulation of its leading investigational candidate SYNB1618 for treating people with phenylketonuria (PKU) is safe in healthy volunteers, according to data from a bridging study.
This positive result supports further development of the new formulation, and the company plans to initiate a Phase 2 clinical trial evaluating its potential in aHUS patients in the first half of 2020.
“We are pleased with the results of this study, which have allowed us to select a maximum tolerated dose of the solid, oral formulation of SYNB1618 to move into a Phase 2 clinical trial,” Richard Riese, MD, PhD, Synlogic’s chief medical officer, said in a press release.
PKU is a genetic disorder characterized by the toxic build-up of phenylalanine — an amino acid (the building blocks of proteins) obtained through the diet — in the blood and organs, leading to tissue damage, mainly in the brain.
SYNB1618 consists of a genetically modified bacterium (E. coli Nissle) that is considered a probiotic — live friendly microorganisms that improve gut health — to break down phenylalanine at a high rate through a dual mechanism.
The modified bacteria are designed to produce two enzymes involved in the degradation of phenylalanine — phenylalanine ammonia lyase (PAL) and L-amino acid deaminase (LAAD). These enzymes not only break phenylalanine down from dietary intake, but also influence its recycling between the gut and the blood.
This way, phenylalanine is converted into harmless molecules, including phenyl-lactic acid in the urine and trans-cinnamic acid in the blood, which is then broke down into hippuric acid in the liver and eliminated through the urine, providing potentially relevant biomarkers of SYNB1618’s activity.
Preclinical studies showed that administration of a liquid oral form of SYNB1618 effectively broke down phenylalanine in mouse models of PKU and in healthy non-human primates, via assessment of SYNB1618’s activity biomarkers levels. It also led to a 38% reduction in phenylalanine blood levels in PKU mice.
The safety and tolerability of SYNB1618 (in solution form) was further tested in 70 healthy volunteers and PKU patients during a Phase 1/2 clinical study (NCT03516487). Results not only confirmed the safety of SYNB1618, but also identified its most suitable dose and revealed a significant dose-dependent activity by measuring SYNB1618’s activity biomarkers.
In the meantime, Synlogic optimized the manufacturing process and developed a new solid oral formulation of SYNB1618 that maintains bacteria viability and activity. Its improved quality attributes and convenience suggested that this new formulation could be a more suitable therapeutic option.
“Development of a solid oral formulation of a Synthetic Biotic medicine that is stable at room temperature and can be administered at home, is a major achievement for our platform and a meaningful innovation for SYNB1618,” said Aoife Brennan, MB BCh, Synlogic’s president and chief executive officer.
A randomized, double-blind, placebo controlled bridging study evaluated the safety, tolerability, and phenylalanine-degradation activity of SYNB1618’s new formulation in healthy volunteers. The study was also designed to select optimal doses for a future Phase 2 clinical trial of the therapy’s effectiveness in PKU patients.
Results showed that the maximum tolerated dose of SYNB1618 was 2 x 1012 live cells, and that a dose ramp improved the therapy’s tolerability. SYNB1618’s maximum phenylalanine-degradation activity also required the maintenance of pH values.
“We look forward to presenting the full data set from our bridging study at an appropriate scientific meeting, and to providing more detail regarding the Phase 2 clinical trial design at a later date,” Riese added.
Brennan said that the company is “a step closer to providing a new therapeutic option that is suitable for all patients with PKU regardless of age or disease type.”
SYNB1618 was granted fast track designation by the U.S. Food and Drug Administration (FDA) in April 2018. This designation is meant to expedite the therapy’s clinical development, regulatory review, and entry into the market upon approval.
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