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Escherichia Coli, Strain Nissle 1917, Expressing High Affinity Phenylalanine Transporter, Modified Phenylalanine Ammonia Lyase (S92G, H133M, I167K, L432I, V470A) And L-Amino Acid Deaminase

This article discusses a Phase 3 clinical trial investigating the effectiveness and safety of SYNB1934, a novel treatment for Phenylketonuria (PKU). The study, named SYNPHENY-3, aims to assess how well SYNB1934 can reduce blood phenylalanine levels in adults with PKU who have not achieved recommended levels with existing treatments. The trial consists of three parts: a dose escalation period, a randomized withdrawal period, and an open-label extension, providing comprehensive data on the drug’s potential benefits and safety profile.

Table of Contents

What is SYNB1934?

SYNB1934 is an innovative medication being developed to treat Phenylketonuria (PKU), a rare genetic disorder that affects the body’s ability to process an amino acid called phenylalanine[1]. The full name of this treatment is quite complex: “ESCHERICHIA COLI, STRAIN NISSLE 1917, EXPRESSING HIGH AFFINITY PHENYLALANINE TRANSPORTER, MODIFIED PHENYLALANINE AMMONIA LYASE (S92G, H133M, I167K, L432I, V470A) AND L-AMINO ACID DEAMINASE.” For simplicity, it’s referred to as SYNB1934 or SYNB1934v1 in clinical trials.

How Does SYNB1934 Work?

SYNB1934 is a genetically engineered strain of Escherichia coli Nissle 1917, a type of beneficial bacteria. It has been modified to express specific enzymes and transporters that can help break down phenylalanine in the gut[1]. This approach aims to reduce the levels of phenylalanine in the blood of people with PKU, potentially allowing them to have a less restricted diet and better manage their condition.

Clinical Trial Overview

A Phase 3 clinical trial, called SYNPHENY-3, is currently underway to evaluate the effectiveness and safety of SYNB1934 in adults with PKU[1]. This trial is designed to:

  • Assess how SYNB1934 affects blood phenylalanine levels
  • Determine the optimal dose for each participant
  • Evaluate the safety and tolerability of the treatment
  • Investigate how SYNB1934 might impact dietary protein intake

Who Can Participate in the Trial?

The trial is primarily focused on adults (18 years and older) with PKU who have difficulty maintaining recommended blood phenylalanine levels with current treatments. Some key eligibility criteria include[1]:

  • Diagnosis of PKU with uncontrolled blood phenylalanine levels (>360 μmol/L) despite current therapy
  • Stable diet for at least 1 month prior to screening
  • If using certain medications (sapropterin or sepiapterin), must be on a stable dose for at least 3 months
  • Not currently taking Palynziq® (pegvaliase-pqpz) or having received gene therapy for PKU

Trial Structure

The SYNPHENY-3 trial is divided into three main parts[1]:

  1. Dose Escalating, Open-Label Period (DEP): Participants receive increasing doses of SYNB1934 to determine their individually tolerated dose (iTD).
  2. Randomized Withdrawal Period (RWP): Participants are randomly assigned to continue SYNB1934 at their iTD or receive a placebo for 4 weeks.
  3. Open-Label Extension (OLE): Participants can receive SYNB1934 for up to 36 months, with potential adjustments to dosing and diet.

Potential Benefits of SYNB1934

If successful, SYNB1934 could offer several benefits for people with PKU[1]:

  • Reduction in blood phenylalanine levels
  • Potential for less restrictive diets
  • Improved management of PKU symptoms
  • An alternative treatment option for those who don’t respond well to existing therapies

Safety Considerations

As with any clinical trial, safety is a top priority. The study is closely monitoring[1]:

  • Adverse events and their severity
  • Changes in clinical laboratory parameters
  • Changes in vital signs
Participants are carefully screened for any conditions that might increase their risk during the trial.

Aspect Details
Study Name SYNPHENY-3
Phase Phase 3
Drug SYNB1934 (genetically engineered E. coli Nissle 1917)
Condition Phenylketonuria (PKU)
Primary Objective Assess change in blood phenylalanine levels
Study Design 3 parts: Dose Escalation, Randomized Withdrawal, Open-Label Extension
Duration Up to 36 months (varies by participant)
Key Inclusion Criteria Adults with PKU, blood Phe > 360 μmol/L despite current treatment
Key Exclusion Criteria Current Palynziq use, certain medical conditions, antibiotic use, pregnancy
Primary Endpoints Percent change in blood Phe, safety and tolerability

FAQ

  • What is SYNB1934 and how does it work? SYNB1934 is a genetically engineered strain of Escherichia coli Nissle 1917 that expresses enzymes to help break down phenylalanine in the gut. It's designed to lower blood phenylalanine levels in people with PKU by reducing the absorption of this amino acid from the diet.
  • Who can participate in this clinical trial? The trial is primarily for adults (18 years and older) with PKU who have blood phenylalanine levels above 360 μmol/L despite current treatments. Participants must have a stable diet and, if using certain medications, be on a stable dose for at least 3 months.
  • How long does the clinical trial last? The trial has three parts: a dose escalation period lasting 3-15 weeks, a 4-week randomized withdrawal period, and an open-label extension that can last up to 36 months. The total duration varies depending on how long a participant remains in the study.
  • What are the main goals of this clinical trial? The main objectives are to assess the change in blood phenylalanine levels, determine the optimal dose of SYNB1934, evaluate its efficacy compared to placebo, and assess its long-term safety and tolerability in people with PKU.
  • Are there any specific exclusion criteria for the trial? Yes, some key exclusions include: currently taking Palynziq, having certain medical conditions like DNAJC12 deficiency or irritable bowel syndrome, allergies to E. coli Nissle or cinnamon, recent or planned antibiotic use, pregnancy or breastfeeding, and previous gene therapy for PKU.

Ongoing Clinical Trials on Escherichia Coli, Strain Nissle 1917, Expressing High Affinity Phenylalanine Transporter, Modified Phenylalanine Ammonia Lyase (S92G, H133M, I167K, L432I, V470A) And L-Amino Acid Deaminase

  • Study on the Effectiveness and Safety of SYNB1934 for Adults with Phenylketonuria (PKU)

    Not recruiting

    1 1 1
    Investigated drugs:
    Denmark

Glossary

  • Phenylketonuria (PKU): A rare genetic disorder that causes an inability to properly break down the amino acid phenylalanine, leading to its buildup in the body. This can cause serious health problems if left untreated.
  • Phenylalanine (Phe): An essential amino acid found in many foods, particularly those high in protein. People with PKU have difficulty metabolizing this amino acid, so their blood levels need to be closely monitored and controlled.
  • SYNB1934: A genetically engineered strain of bacteria (Escherichia coli Nissle 1917) designed to break down phenylalanine in the gut of people with PKU, potentially lowering blood phenylalanine levels.
  • Dose Escalation: A process in clinical trials where the dose of a drug is gradually increased to find the optimal balance between effectiveness and side effects.
  • Randomized Withdrawal: A study design where participants who respond to a treatment are randomly assigned to continue the treatment or switch to a placebo, allowing researchers to evaluate the drug's ongoing effectiveness.
  • Open-Label Extension: A phase of a clinical trial where all participants receive the active treatment, often used to gather long-term safety and efficacy data.
  • Placebo: An inactive substance that looks like the drug being tested but has no therapeutic effect, used as a control in clinical trials to determine the true impact of the active treatment.
  • μmol/L: Micromoles per liter, a unit of measurement used to express the concentration of substances in blood, such as phenylalanine levels in PKU patients.

References

  1. http://clinicaltrials.eu/trial/study-on-the-effectiveness-and-safety-of-synb1934-for-adults-with-phenylketonuria-pku/