Clinical trial NCT05764239: Efficacy and Safety of SYNB1934 in Patients With PKU (SYNPHENY-3)
Official title: A Phase 3, Double-blind, Placebo-controlled, Randomized Withdrawal Study to Evaluate the Efficacy and Safety of SYNB1934 in Patients With PKU (SYNPHENY-3)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Phenylketonuria
Keywords: PKU
Inborn error of metabolism
Synpheny
Synlogic
Phe
Metabolic
Lead sponsor: Synlogic
Sponsor class: INDUSTRY
First posted: 2023-03-10
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: This was a Phase 2b/3 adaptive study design.
Primary purpose: TREATMENT

Brief summary: 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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Mean Percent Change From DEP Baseline in Blood Phenylalanine (Phe) Level at Week 3 of iTD During the DEP
timeFrame: Up to 15 weeks
Secondary outcomes:
measure: Absolute Change From DEP Baseline in Blood Phe Level at Week 3 of iTD During the DEP
timeFrame: Up to 15 weeks
measure: Number of Participants With a ≥ 20% Reduction From Baseline in Blood Phe Level at Any Time in the DEP
timeFrame: Up to 15 weeks
Other outcomes:
Locations:
city: Culver City
country: United States
facility: Science 37
state: California
city: Orange
country: United States
facility: Children's Hospital Orange County
state: California
city: Palo Alto
country: United States
facility: Stanford University, Department of Pediatrics
state: California
city: Aurora
country: United States
facility: University of Colorado Children's Hospital
state: Colorado
city: Gainesville
country: United States
facility: University of Florida - Gainesville
state: Florida
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago, Pediatrics
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital, Department of Pediatrics
state: Massachusetts
city: Portland
country: United States
facility: Oregon Health and Science University Department of Molecular and Medical Genetics
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center - Children's Hospital of Pittsburgh
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina, Pediatrics
state: South Carolina
city: Nashville
country: United States
facility: Division of Medical Genetics-Pediatrics, Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: McGovern Medical School/Memorial Hermann Hospital
state: Texas
city: Calgary
country: Canada
facility: MAGIC Clinic
state: Alberta
city: Hamilton
country: Canada
facility: Hamilton Health Sciences Corporation
state: Ontario
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario
state: Ontario
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Tbilisi
country: Georgia
facility: Medical Genetics and Laboratory Diagnostics Center
city: Yenimahalle
country: Turkey
facility: Gazi Üniversitesi Hastanesi
state: Ankara
city: Balçova
country: Turkey
facility: Dokuz Eylül Üniversitesi Araştırma ve Uygulama Hastanesi
state: Izmir
Study officials:
References: