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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Synlogic Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

completed 15 Mar 2024

Decision date (initial)

2024-01-16

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Synlogic Operating Company, Inc.

External identifiers

EU CT number

2022-502932-37-00

WHO UTN

U1111-1293-5531

ClinicalTrials.gov

NCT05764239

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Dose Escalating, Open-Label Period (DEP; Part 1): To assess the percentage change in blood phenylalanine (Phe) level
Randomized Withdrawal Period (RWP; Part 2): To evaluate the efficacy of SYNB1934v1 versus placebo in the responder population
Open-Label Extension (OLE; Part 3): To assess the safety and tolerability of SYNB1934v1

Secondary objectives 12

1. Part 1: To assess the absolute change in Phe level
2. Part 1: To determine the responder population
3. Part 1: To assess proportion of participants achieving blood Phe level ≤ 360 μmol/L
4. Part 1: To assess the safety and tolerability of SYNB1934v1
5. Part 2: To evaluate the efficacy of SYNB1934v1 versus placebo in the responder population with regard to percent change from DEP baseline in blood Phe level
6. Part 2: To evaluate the efficacy of SYNB1934v1 versus placebo in the responder population with regard to change from DEP baseline in blood Phe level
7. Part 2: 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
8. Part 2: To assess the safety and tolerability of SYNB1934v1
9. Part 2: To evaluate the efficacy of SYNB1934v1 versus placebo in the responder population with regard to the proportion of participants with a ≥ 20% reduction from DEP baseline in blood Phe level at Week 4
10. Part 3: To assess absolute and relative change in blood Phe level in the responder and nonresponder populations
11. Part 3: To assess impact of SYNB1934v1 and dietary protein intake on Phe levels
12. Part 3: To assess impact of SYNB1934v1 on dietary Phe intake

Conditions and MedDRA coding

Phenylketonuria

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Age ≥ 18 years. Participants 12 to 17 years of age may be enrolled after the first 20 participants have completed the DEP, with approval of the DMC.
2. Able and willing to voluntarily complete the informed consent process (adults; parents/guardians) or informed assent process (minors).
3. 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.
4. 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.
5. Sexually active female participants of childbearing potential must be willing to use a highly effective 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 be 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 8

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 increase participant risk associated with study participation, compromise adherence to study procedures and requirements, and, in the judgment of the investigator, would make the participant inappropriate for enrollment.
3. A known or suspected diagnosis of DNAJC12 deficiency, biopterin synthesis deficiency, or irritable bowel syndrome.
4. Intolerance of or allergic reaction to E. coli Nissle or any of the ingredients in SYNB1934v1 or placebo formulations, or an allergy to cinnamon. Known intolerance to proton pump inhibitors and H2 blockers, since one or the other must be 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 IMP 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.
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 is longer) prior to screening.
8. Ever received gene therapy for treatment of PKU.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 5

1. Part 1: Percent change from baseline in blood Phe level at last measurement of the individually titrated dose (iTD) of SYNB1934v1
2. Part 2: Change from baseline to Week 4 in blood Phe level
3. Part 3: Incidence and severity of adverse events
4. Part 3: Changes from DEP baseline in clinical laboratory parameters
5. Part 3: Changes from DEP baseline in vital signs measurements

Secondary endpoints 19

1. Part 1: Change from baseline in blood Phe level at last measurement of the iTD of SYNB1934v1
2. Part 1: A ≥ 20% reduction from baseline in blood Phe level at any time in the DEP
3. Part 1: Blood Phe level ≤ 360 μmol/L at any time of the iTD of SYNB1934v1
4. Part 1: Blood Phe level ≤ 360 μmol/L at any time in the DEP
5. Part 1: Incidence and severity of adverse events
6. Part 1: Changes from baseline in clinical laboratory parameters
7. Part 1: Changes from baseline in vital signs measurements
8. Part 2: Percent change from DEP baseline in blood Phe level at Week 4
9. Part 2: Change from DEP baseline to Week 4 in blood Phe level
10. Part 2: Blood Phe level ≤ 360 μmol/L at Week 4
11. Part 2: Incidence and severity of adverse events
12. Part 2: Changes from baseline in clinical laboratory parameters
13. Part 2: Change from baseline in vital signs measurements
14. Part 2: A ≥ 20% reduction from DEP baseline in blood Phe level at Week 4
15. Part 3: Change from DEP baseline in blood Phe levels
16. Part 3: Blood Phe level ≤ 360 μmol/L
17. Part 3: Change from DEP baseline in blood Phe levels over time
18. Part 3: Change from DEP baseline in blood Phe level over time until first protocol-specified increase in dietary protein intake
19. Part 3: Change from DEP baseline in dietary Phe intake.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Placebo 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Synlogic Inc.

Sponsor organisation

Synlogic Inc.

Address

301 Binney Street Suite 402

City

Cambridge

Postcode

02142-1071

Country

United States

Scientific contact point

Organisation

Synlogic Inc.

Contact name

Neal Sondheimer, M.D., Ph.D. V.P. & Head of Clinical

Public contact point

Organisation

Synlogic Inc.

Contact name

Neal Sondheimer, M.D., Ph.D. V.P. & Head of Clinical

Third parties 8

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 2 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications