Safety, Tolerability and Pharmacodynamics of SYNB1353 in Healthy Adult Volunteers

NCT05462132 | Completed Phase 1 FDA Drug

• 1 other identifier: SYNB1353-CP-001
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase 1, double-blind (Sponsor-open), placebo-controlled, randomized, dose-escalation, inpatient study using a multiple-ascending dose (MAD) design to assess the safety, tolerability, and PD of SYNB1353 in HVs.

Conditions

Homocystinuria

Keywords

HCU; Amino acid metabolism; Inborn error of metabolism

Outcome Measures

Primary Outcomes (1)

• Number of participants with abnormal laboratory values and/or adverse events

  Lab results outside of the central laboratory normal range parameters will be considered abnormal and reviewed for clinical significance and reported as AEs. AEs will be evaluated using the NCI CTCAE v5.0

  Day -2 through Day 8

Secondary Outcomes (1)

• The rate at which the SYNB1353 strain clears

  Up to 14 weeks following the last dose of IMP

Study Arms (8)

Cohort 1

EXPERIMENTAL

HV subjects receive doses 3 × 10\^11 live cells of SYNB1353 and 30 mg/kg of methionine. Subjects will receive a single dose of SYNB1353 on the first day of dosing (Day 1), on Days 2 and 3 subjects will receive up to 2 doses of IMP (BID), and on Days 4 to 7 subjects will receive up to 3 doses of IMP (TID). A methionine loading study will be performed on Day -1 and Day 7 after an overnight fast. A dose of methionine of 30 mg/kg will be evaluated.

Drug: SYNB1353

Cohort 2

EXPERIMENTAL

HV subjects receive doses 3 × 10\^11 live cells of SYNB1353 and up to 100 mg/kg of methionine. Subjects will receive a single dose of SYNB1353 on the first day of dosing (Day 1), on Days 2 and 3 subjects will receive up to 2 doses of IMP (BID), and on Days 4 to 7 subjects will receive up to 3 doses of IMP (TID). A methionine loading study will be performed on Day -1 and Day 7 after an overnight fast. A dose of methionine of up to 100 mg/kg will be evaluated.

Drug: SYNB1353

Cohort 3

EXPERIMENTAL

HV subjects receive doses 6 × 10\^11 live cells of SYNB1353 and 30 mg/kg of methionine. Subjects will receive a single dose of SYNB1353 on the first day of dosing (Day 1), on Days 2 and 3 subjects will receive up to 2 doses of IMP (BID), and on Days 4 to 7 subjects will receive up to 3 doses of IMP (TID). A methionine loading study will be performed on Day -1 and Day 7 after an overnight fast. A dose of methionine of 30 mg/kg will be evaluated.

Drug: SYNB1353

Cohort 4

EXPERIMENTAL

HV subjects receive doses 6 × 10\^11 live cells of SYNB1353 and up to 100 mg/kg of methionine. Subjects will receive a single dose of SYNB1353 on the first day of dosing (Day 1), on Days 2 and 3 subjects will receive up to 2 doses of IMP (BID), and on Days 4 to 7 subjects will receive up to 3 doses of IMP (TID). A methionine loading study will be performed on Day -1 and Day 7 after an overnight fast. A dose of methionine of up to 100 mg/kg will be evaluated.

Drug: SYNB1353

Cohort 5

EXPERIMENTAL

HV subjects receive doses 1 × 10\^12 live cells of SYNB1353 and 30 mg/kg of methionine. Subjects will receive a single dose of SYNB1353 on the first day of dosing (Day 1), on Days 2 and 3 subjects will receive up to 2 doses of IMP (BID), and on Days 4 to 7 subjects will receive up to 3 doses of IMP (TID). A methionine loading study will be performed on Day -1 and Day 7 after an overnight fast. A dose of methionine of 30 mg/kg will be evaluated.

Drug: SYNB1353

Cohort 6

EXPERIMENTAL

HV subjects receive doses 1 × 10\^12 live cells of SYNB1353 and up to 100 mg/kg of methionine. Subjects will receive a single dose of SYNB1353 on the first day of dosing (Day 1), on Days 2 and 3 subjects will receive up to 2 doses of IMP (BID), and on Days 4 to 7 subjects will receive up to 3 doses of IMP (TID). A methionine loading study will be performed on Day -1 and Day 7 after an overnight fast. A dose of methionine of up to 100 mg/kg will be evaluated.

Drug: SYNB1353

Cohort 7

EXPERIMENTAL

HV subjects receive doses less than or equal to 2 × 10\^12 live cells of SYNB1353 and 30 mg/kg of methionine. Subjects will receive a single dose of SYNB1353 on the first day of dosing (Day 1), on Days 2 and 3 subjects will receive up to 2 doses of IMP (BID), and on Days 4 to 7 subjects will receive up to 3 doses of IMP (TID). A methionine loading study will be performed on Day -1 and Day 7 after an overnight fast. A dose of methionine of 30 mg/kg will be evaluated.

Drug: SYNB1353

Cohort 8

EXPERIMENTAL

HV subjects receive doses less than or equal to 2 × 10\^12 live cells of SYNB1353 and up to 100 mg/kg of methionine. Subjects will receive a single dose of SYNB1353 on the first day of dosing (Day 1), on Days 2 and 3 subjects will receive up to 2 doses of IMP (BID), and on Days 4 to 7 subjects will receive up to 3 doses of IMP (TID). A methionine loading study will be performed on Day -1 and Day 7 after an overnight fast. A dose of methionine of up to 100 mg/kg will be evaluated.

Drug: SYNB1353

Interventions

SYNB1353 DRUG

SYNB1353 IMP is formulated as a nonsterile solution intended for oral administration. SYNB1353 is subsequently lyophilized to form the bulk drug product. The lyophilized product is sieved into powder form and filled into high-density polyethylene (HDPE) bottles. Placebo will be manufactured using an inactive powder that is color matched to the SYNB1353 drug product. L-Methionine will be supplied as dry powder and will be suspended in a diluent prior to use.

Cohort 1; Cohort 2; Cohort 3; Cohort 4; Cohort 5; Cohort 6; Cohort 7; Cohort 8

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age ≥ 18 to ≤ 64 years.
• Able and willing to voluntarily complete the informed consent process.
• Available for and agree to all study procedures, including feces, urine, and blood collection and adherence to diet control, inpatient monitoring, follow-up visits, and compliance with all study procedures.
• Female subjects who meet 1 of the following:
• WOCBP must not be breastfeeding.
• Premenopausal women with at least 1 of the following:
• i. Documented hysterectomy ii. Documented bilateral salpingectomy iii. Documented bilateral oophorectomy iv. Documented tubal ligation/occlusion v. Sexual abstinence is preferred or usual lifestyle of the subject d. Postmenopausal women (12 months or more amenorrhea verified by follicle- stimulating hormone \[FSH\] assessment and over 45 years of age in the absence of other biological or physiological causes).

You may not qualify if:

• Acute or chronic medical, surgical, psychiatric, or social condition or laboratory abnormality that may increase subject risk associated with study participation, compromise adherence to study procedures and requirements, or may confound interpretation of study safety or PD results and, in the judgment of the Investigator, would make the subject inappropriate for enrollment.
• Body mass index \< 18.5 or ≥ 35 kg/m2.
• History of or current immunodeficiency disorder including human immunodeficiency virus (HIV) antibody positivity.
• Hepatitis B surface antigen positivity (subjects with hepatitis B surface antibody positivity and hepatitis B core antibody positivity are not excluded, provided that the hepatitis B surface antigen is negative).
• Hepatitis C antibody positivity, unless a hepatitis C virus ribonucleic acid test is performed, and the result is negative.
• History of febrile illness, confirmed bacteremia, or other active infection deemed clinically significant by the Investigator within 30 days prior to the anticipated first dose of IMP.
• History of (within the past month) passage of 3 or more loose stools per day, where "loose stool" is defined as a Type 6 or Type 7 on the Bristol Stool Chart (see Appendix 1).
• Inflammatory or irritable bowel disorder of any grade experienced within the previous 60 days.
• Active or past history of GI bleeding within 60 days prior to the Screening Visit as confirmed by hospitalization-related event(s) or medical history of hematemesis or hematochezia.
• Underlying cardiovascular disease or uncontrolled gastroesophageal reflux disease
• Intolerance of or allergic reaction to EcN, esomeprazole and all other PPIs, or any of the ingredients in SYNB1353 or placebo formulations.
• Allergy or intolerance to multiple antibiotics which would preclude use of antibiotics for eradication of SYNB1353 in case of colonization.
• Currently taking or plans to take Methotrexate, Azuridine, Nitrous Oxide, Phenytoin, or Carbamazepine.
• Currently taking or plans to take any type of systemic (e.g., oral or intravenous) antibiotic within 28 days prior to the first anticipated dose of IMP through final assessment, including planned surgery, hospitalizations, dental procedures, or interventional studies that are expected to require antibiotics. Exception: topical antibiotics are allowed.
• Major surgery (an operation upon an organ within the cranium, chest, abdomen, or pelvic cavity) or inpatient hospital stay within the past 3 months prior to Screening.

Sponsors & Collaborators

• Synlogic: lead

Study Sites (1)

High Point Clinical Trials Center

High Point, North Carolina, 27265, United States

Location

MeSH Terms

Conditions

Homocystinuria; Metabolism, Inborn Errors

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hyperhomocysteinemia; Amino Acid Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Decisions will be made based on a blinded review of tolerability, clinical observations, safety laboratory assessments, and, optionally, PD.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Dose-escalation decisions will be made once at least 6 subjects in a cohort have received IMP and have had at least 24 hours of post-dose observation. Dose escalation will be up to approximately 3-fold per cohort.

Study Record Dates

• First Submitted: July 7, 2022
• First Posted: July 18, 2022
• Study Start: July 7, 2022
• Primary Completion: November 27, 2022
• Study Completion: November 27, 2022
• Last Updated: March 17, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)