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

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

SYNB1934-CP-003 was designed as a 3-part, adaptive study consisting of a dose-escalating, open-label period (DEP; Part 1) of up to 15 weeks, 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

Study Overview

• Status: Terminated
• Conditions: Phenylketonuria
• Intervention / Treatment: Drug: SYNB1934v1; Drug: Placebo

Detailed Description

In the DEP, all enrolled participants maintained a stable diet reflecting their baseline phenylalanine (Phe) intake and received escalating doses of SYNB1934v1 from approximately 3 to 15 weeks to determine an individually titrated dose (iTD), which was defined as the highest dose the participant was able to tolerate. A participant was defined as having reached an iTD if they tolerated 3 weeks at a dose, regardless of whether other doses were tolerated.

Blood Phe level was measured at each dose level after 3 weeks at that level. A responder was defined as a participant who achieved a ≥ 20% reduction in blood Phe level compared to DEP baseline on SYNB1934v1.

Participants who completed at least 3 weeks at their iTD during the DEP entered a 4-week RWP in which they were randomized 1:1 to receive SYNB1934v1 at their iTD determined in the DEP or placebo TID. Randomization was stratified on screening Phe level. Participants remained on their assigned dose (iTD of SYNB1934v1 or matching placebo) for the duration of the RWP, unless they developed intolerance or met other discontinuation criteria, and remained on the same diet they consumed during the DEP. Blood Phe level was measured at Weeks 1, 3, and 4 of the RWP.

Participants who completed the 4-week RWP may have entered the OLE and received SYNB1934v1 for up to 36 months. During the OLE, participants completed a dose ramp to their iTD over time guided by tolerability. The iTD in the OLE may have been different from the iTD in the DEP. The investigator may have escalated the SYNB1934v1 dose up to 1 × 10^12 live cells based on tolerability. Participants were allowed to modify their standard diet, with guidance from the investigator, if their blood Phe level was < 240 µmol/L.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2E 7Z4
      • MAGIC clinic
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • Hamilton Health Sciences Corporation
    • Ottawa, Ontario, Canada, K1H 8L1
      • Children's Hospital of Eastern Ontario
    • Toronto, Ontario, Canada, M5T 3L9
      • University Health Network
• Georgia
  • Tbilisi, Georgia, 0159
    • Medical Genetics and Laboratory Diagnostics Center
• Turkey
  • Ankara
    • Yenimahalle, Ankara, Turkey, 06560
      • Gazi Universitesi Hastanesi
  • Izmir
    • Balçova, Izmir, Turkey, 35340
      • Dokuz Eylül Üniversitesi Araştırma ve Uygulama Hastanesi
• United States
  • California
    • Culver City, California, United States, 90230
      • Science 37
    • Orange, California, United States, 92868
      • Children's Hospital Orange County
    • Palo Alto, California, United States, 94304
      • Stanford University, Department of Pediatrics
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Children's Hospital
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida - Gainesville
  • Illinois
    • Chicago, Illinois, United States, 60611-2991
      • Ann & Robert H. Lurie Children's Hospital of Chicago, Pediatrics
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital, Department of Pediatrics
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University Department of Molecular and Medical Genetics
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • University of Pittsburgh Medical Center - Children's Hospital of Pittsburgh
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina, Pediatrics
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Division of Medical Genetics-Pediatrics, Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • McGovern Medical School/Memorial Hermann Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Male and female participants were enrolled.

Inclusion Criteria:

1. Age ≥ 18 years.
2. Able and willing to voluntarily complete the informed consent process.
3. Diagnosis of phenylketonuria (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 have been obtained more than 7 days apart, as determined by central or local laboratory.
4. Females of childbearing potential must have had a negative pregnancy test at screening and at the end of the DEP (in order to enter the RWP) and RWP (in order to enter the OLE) and been willing to have additional pregnancy tests during the study.
5. Sexually active female participants of childbearing potential must have been willing to use an acceptable method of contraception while participating in the study and for 2 weeks after the last dose.
6. Stable diet including stable medical formula regimen (if used) for at least 1 month prior to screening.
7. If using sapropterin or sepiapterin, must have been on a stable dose for at least 3 months.
8. 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:

1. Currently taking Palynziq® (pegvaliase-pqpz) (within 1 month of screening).
2. Acute or chronic medical, surgical, psychiatric, or social condition or laboratory abnormality that may have increased participant risk associated with study participation, compromised adherence to study procedures and requirements, and, in the judgment of the investigator, would have made the participant inappropriate for enrollment.
3. A known or suspected diagnosis of DNAJC12 deficiency, biopterin synthesis deficiency, or irritable bowel syndrome.
4. Intolerance to or allergic reaction to Escherichia coli Nissle or any of the ingredients in SYNB1934v1 formulation, or an allergy to cinnamon. Known intolerance to proton pump inhibitors and H2 blockers, since one or the other must have been used.
5. 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 the RWP, including planned surgery, hospitalizations, dental procedures, or interventional studies that were expected to require antibiotics. Exception: topical antibiotics were allowed.
6. Pregnant, planning to become pregnant, or breastfeeding.
7. Current participation in any other investigational drug study or use of any investigational agent within 30 days or 5 half-lives (whichever was longer) prior to screening.
8. Ever received gene therapy for treatment of PKU.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DEP (Part 1, SYNB1934v1); Participants received SYNB1934v1 orally immediately after meals on the following dose-ramp regimen: Dose level 1 (Days 1-9): 3 × 10^11 live cells partial dose up to 3 times daily (TID); Dose level 2 (Weeks 4-6): 6 × 10^11 live cells up to TID; Dose level 3 (Weeks 7-9): 1 × 10^12 live cells up to TID.	Drug: SYNB1934v1; SYNB1934v1 consisted of powder for oral suspension packaged in sachets. During dose preparation, the powder was resuspended in water or apple juice prior to administration.
Experimental: RWP (Part 2, SYNB1934v1); Participants who completed the DEP were randomized 1:1 to receive SYNB1934v1 at their iTD established in the DEP orally immediately after meals. Participants remained on this dose of SYNB1934v1 for the duration of the RWP; doses of SYNB1934v1 were not permitted to be modified during the RWP.	Drug: SYNB1934v1; SYNB1934v1 consisted of powder for oral suspension packaged in sachets. During dose preparation, the powder was resuspended in water or apple juice prior to administration.
Placebo Comparator: RWP (Part 2, Placebo); Participants who completed the DEP were randomized 1:1 to receive placebo orally immediately after meals. Participants remained on the same dose of placebo for the duration of the RWP; doses of placebo were not permitted to be modified during the RWP.	Drug: Placebo; Placebo was manufactured using an inactive powder that was color matched to the SYNB1934v1 drug product. In order to maintain study blinding during the RWP, placebo was packaged, labeled, stored, and administered in an identical manner to SYNB1934v1.
Experimental: OLE (Part 3, SYNB1934v1); Participants completed a dose ramp to their iTD guided by tolerability, as described for the DEP, including the full dose-ramp schedule. The iTD in the OLE may have been different from the iTD in the DEP or RWP. The investigator may have escalated the dose of SYNB1934v1 up to 1 × 10^12 live cells based on tolerability; multiple attempts to escalate to a higher dose level were permitted per investigator discretion.	Drug: SYNB1934v1; SYNB1934v1 consisted of powder for oral suspension packaged in sachets. During dose preparation, the powder was resuspended in water or apple juice prior to administration.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Percent Change From DEP Baseline in Blood Phenylalanine (Phe) Level at Week 3 of iTD During the DEP	Baseline for blood Phe level in the DEP was defined as the mean of the duplicate blood Phe level measurements obtained immediately prior to administration of the first dose in the DEP. If only 1 blood Phe level measurement was available, then that measure was used as baseline. The last measurement was the participant's last Week 3 blood Phe level at the iTD of SYNB1934v1.	Up to 15 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change From DEP Baseline in Blood Phe Level at Week 3 of iTD During the DEP	Baseline for blood Phe level in the DEP was defined as the mean of the duplicate blood Phe level measurements obtained immediately prior to administration of the first dose in the DEP. If only 1 blood Phe level measurement was available, then that measure was used as baseline. The last measurement was the participant's last Week 3 blood Phe level at the iTD of SYNB1934v1.	Up to 15 weeks
Number of Participants With a ≥ 20% Reduction From Baseline in Blood Phe Level at Any Time in the DEP	Baseline for blood Phe level in the DEP was defined as the mean of the duplicate blood Phe level measurements obtained immediately prior to administration of the first dose in the DEP. If only 1 blood Phe level measurement was available, then that measure was used as baseline. Blood Phe level was measured at each dose level after 3 weeks at that level.	Up to 15 weeks

Collaborators and Investigators

• Sponsor: Synlogic

Study record dates

Study Major Dates

• Study Start (Actual): July 5, 2023
• Primary Completion (Actual): March 15, 2024
• Study Completion (Actual): March 15, 2024

Study Registration Dates

• First Submitted: February 15, 2023
• First Submitted That Met QC Criteria: March 1, 2023
• First Posted (Actual): March 10, 2023

Study Record Updates

• Last Update Posted (Actual): June 20, 2024
• Last Update Submitted That Met QC Criteria: May 24, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Metabolic; PKU; Inborn error of metabolism; Synpheny; Synlogic; Phe
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Phenylketonurias
• Other Study ID Numbers: SYNB1934-CP-003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No