Efficacy and Safety of SYNB1934 in Patients With PKU (SYNPHENY-3)

Study Overview
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Brief Summary
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This is a 3-part, adaptive study consisting of a dose-escalating period (DEP) of up to 15 weeks (Part 1), followed by a 4-week, double-blind, placebo-controlled randomized withdrawal period (RWP) (Part 2), and an open-label extension (OLE) (Part 3) of up to 36 months.

Detailed Description
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In the DEP, all enrolled participants will maintain a stable diet reflecting their baseline Phe intake and receive escalating doses of SYNB1934v1 from approximately 3 to 15 weeks to determine an individually titrated dose (iTD), which is defined as the highest dose the patient is able to tolerate. Participants who complete the DEP at their iTD for at least 3 weeks will enter a 4-week RWP. Participants will be randomized 1:1 to receive SYNB1934v1 at their iTD determined in the DEP or placebo 3 times daily (TID). Participants who complete the 4-week RWP may enter the OLE and receive SYNB1934v1 for up to 36 months. The primary determination of efficacy will be based on the comparison of SYNB1934v1 versus placebo in the RWP. Safety will be evaluated by scheduled monitoring of adverse events, vital signs, and clinical laboratory measurements.

Official Title
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A Phase 3, Double-blind, Placebo-controlled, Randomized Withdrawal Study to Evaluate the Efficacy and Safety of SYNB1934 in Patients With PKU (SYNPHENY-3)

Conditions
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Phenylketonuria

Intervention / Treatment
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* Drug: SYNB1934v1
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Able and willing to voluntarily complete the informed consent process. Diagnosis of PKU and failure to maintain recommended blood Phe levels on existing management (sapropterin, sepiapterin and/or Phe-restricted diet), demonstrated by uncontrolled blood Phe level ≥ 360 μmol/L on current therapy any time during screening and uncontrolled blood Phe level ≥ 360 μmol/L on current therapy when taking the average of the 3 most recent Phe levels from the participant's medical history (inclusive of any screening values). All screening values must be obtained more than 7 days apart, as determined by central or local laboratory. Females of childbearing potential must have a negative pregnancy test at screening and the end of DEP (in order to enter Part 2) and RWP (in order to enter Part 3) and be willing to have additional pregnancy tests during the study. Sexually active female participants of childbearing potential must be willing to use an acceptable method of contraception while participating in the study and for 2 weeks after the last dose. Stable diet including stable medical formula regimen (if used) for at least 1 month prior to screening. If using sapropterin or sepiapterin, must be on a stable dose for at least 3 months. Willing and able to continue current diet, sapropterin, sepiapterin and large neutral amino acids unchanged during screening, DEP, and RWP and to engage in all study activities. Exclusion Criteria: Currently taking Palynziq® (pegvaliase-pqpz) (within 1 month of screening). Acute or chronic medical, surgical, psychiatric, or social condition or laboratory abnormality that may increase patient risk associated with study participation, compromise adherence to study procedures and requirements, and, in the judgment of the investigator, would make the patient inappropriate for enrollment. A known or suspected diagnosis of DNAJC12 deficiency, biopterin synthesis deficiency, or irritable bowel syndrome. Intolerance to or allergic reaction to E. coli Nissle or any of the ingredients in SYNB1934v1 formulation, or an allergy to cinnamon. Known intolerance to proton pump inhibitors and H2 blockers. Currently taking or plans to take any type of systemic (e.g., oral or intravenous) antibiotic within 28 days prior to the first dose of SYNB1934v1 through final safety assessment in RWP, including planned surgery, hospitalizations, dental procedures, or interventional studies that are expected to require antibiotics. Exception: topical antibiotics are allowed. Pregnant, planning to become pregnant, or breastfeeding. Current participation in any other investigational drug study or use of any investigational agent within 30 days or 5 half-lives (whichever is longer) prior to screening. Ever received gene therapy for treatment of PKU.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This is a phase 2b/3 adaptive study design.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RWP (Part 2)<br> | Drug: SYNB1934v1<br>* SYNB1934v1 IMP consists of powder for oral suspension packaged in sachets. During dose preparation, the powder will be resuspended in water or apple juice prior to administration.<br>|
| Placebo Comparator: RWP/Part 2<br> | Drug: Placebo<br>* A placebo will be manufactured using an inactive powder that is color matched to the SYNB1934v1 drug product. In order to maintain study blinding during the RWP, placebo will be packaged, labeled, stored, and administered in an identical manner to SYNB1934v1.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the percentage change in blood phenylalanine (Phe) level | Dose Escalating, Open-Label Period (DEP; Part 1) | up to 15 weeks | 
| To evaluate efficacy of SYNB1934v1 versus placebo in the responder population through the change from baseline to Week 4 in blood Phe level. | Randomized Withdrawal Period (RWP; Part 2) | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the absolute change in Phe level | Dose Escalating, Open-Label Period (DEP; Part 1) | up to 15 weeks | 
| To assess proportion of participants with a ≥ 20% reduction in blood Phe level | Dose Escalating, Open-Label Period (DEP; Part 1) | up to 15 weeks | 
| To evaluate the efficacy of SYNB1934v1 versus placebo in the responder population with regard to the proportion of participants with a blood Phe level ≤ 360 μmol/L | Randomized Withdrawal Period (RWP; Part 2) | 4 weeks | 
| To evaluate the efficacy of SYNB1934v1 versus placebo in the responder population with regard to change from DEP baseline in blood Phe level | Randomized Withdrawal Period (RWP; Part 2) | 4 weeks | 
| To evaluate efficacy of SYNB1934v1 versus placebo in the responder population with regard to percent change from DEP baseline in blood Phe level at Week 4 | Randomized Withdrawal Period (RWP; Part 2) | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PKU, Inborn error of Metabolism, Synpheny, Synlogic, Phe, Metabolic