Safety and Tolerability of SYNB1618 in Healthy Adult Volunteers and Adult Subjects With Phenylketonuria

NCT03516487 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: SYNB1618-CP-001
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 4

Brief Summary

This Phase 1/2a, first-in-human, oral single and multiple dose-escalation, randomized, double-blinded, placebo-controlled study is evaluating SYNB1618 in healthy volunteers (HV) and subjects diagnosed with phenylketonuria (PKU), a rare inherited metabolic disorder that occurs in people who are missing an enzyme that the body needs to use phenylalanine (Phe). Eligible subjects receive investigational product (IP) in the clinic and undergo safety monitoring, evaluations, and subsequent follow-up after IP administration.

Conditions

Phenylketonuria; Healthy

Keywords

PKU

Outcome Measures

Primary Outcomes (1)

• Number of Subjects With Treatment-Emergent Adverse Events

  Toxicity is graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Adverse events (AEs) are reported based on clinical laboratory tests, vital sign and weight measurements, physical examinations, electrocardiograms, and any other medically indicated assessments, including subject interviews, from the time informed consent is signed through the end of the safety follow-up period. AEs are considered to be treatment emergent (TEAE) if they occur or worsen in severity after the first dose of study treatment. TEAEs are considered treatment-related if relationship to study drug is possibly related, probably related, or definitely related.

  Up to 4 months

Secondary Outcomes (1)

• Clearance of SYNB1618 From Feces

  Up to 4 months

Study Arms (16)

SAD HV: SYNB1618 (1 x 10^10 CFU)

EXPERIMENTAL

HV subjects receive a single oral dose of SYNB1618 (1 x 10\^10 colony-forming units \[CFU\]) in a chilled buffered solution on Day 1 in the SAD study (Part 1).

Drug: SYNB1618

SAD HV: SYNB1618 (5 x 10^10 CFU)

EXPERIMENTAL

HV subjects receive a single oral dose of SYNB1618 (5 x 10\^10 CFU) in a chilled buffered solution on Day 1 in the SAD study (Part 1).

Drug: SYNB1618

SAD HV: SYNB1618 (1 x 10^11 CFU)

EXPERIMENTAL

HV subjects receive a single oral dose of SYNB1618 (1 x 10\^11 CFU) in a chilled buffered solution on Day 1 in the SAD study (Part 1).

Drug: SYNB1618

SAD HV SB: SYNB1618 (1 x 10^11 CFU)

EXPERIMENTAL

HV subjects receive a single oral dose of SYNB1618 (1 x 10\^11 CFU) in a chilled buffered solution on Day 1 in the SAD study (Part 1). On Day 1, subjects in this cohort receive a solid breakfast (SB) that contains approximately the same amount of calories and protein as the meal supplement shake given to subjects in the other SAD cohorts.

Drug: SYNB1618

SAD HV: SYNB1618 (2 x 10^11 CFU)

EXPERIMENTAL

HV subjects receive a single oral dose of SYNB1618 (2 x 10\^11 CFU) in a chilled buffered solution on Day 1 in the SAD study (Part 1).

Drug: SYNB1618

SAD HV: SYNB1618 (5 x 10^11 CFU)

EXPERIMENTAL

HV subjects receive a single oral dose of SYNB1618 (5 x 10\^11 CFU) in a chilled buffered solution on Day 1 in the SAD study (Part 1).

Drug: SYNB1618

SAD HV: Placebo

PLACEBO COMPARATOR

HV subjects receive a single oral dose of placebo in a chilled buffered solution on Day 1 in the SAD study (Part 1).

Drug: Placebo

SAD PKU: SYNB1618 (7 x 10^10 CFU)

EXPERIMENTAL

Subjects with PKU receive a single oral dose of SYNB1618 (7 x 10\^10 CFU) in a chilled buffered solution on Day 1 in the SAD study (Part 1).

Drug: SYNB1618

SAD PKU: Placebo

PLACEBO COMPARATOR

HV subjects receive a single oral dose of placebo in a chilled buffered solution on Day 1 in the SAD study (Part 1).

Drug: Placebo

MAD HV: SYNB1618 (1 x 10^10 CFU)

EXPERIMENTAL

HV subjects receive oral SYNB1618 (1 x 10\^10 CFU) in a chilled buffered solution 3 times per day (TID) for 7 days in the MAD study (Part 2).

Drug: SYNB1618

MAD HV: SYNB1618 (5 x 10^10 CFU)

EXPERIMENTAL

HV subjects receive oral SYNB1618 (5 x 10\^10 CFU) in a chilled buffered solution TID for 7 days in the MAD study (Part 2).

Drug: SYNB1618

MAD HV: SYNB1618 (7 x 10^10 CFU)

EXPERIMENTAL

HV subjects receive oral SYNB1618 (7 x 10\^10 CFU) in a chilled buffered solution TID for 7 days in the MAD study (Part 2).

Drug: SYNB1618

MAD HV: SYNB1618 (1 x 10^11 CFU)

EXPERIMENTAL

HV subjects receive oral SYNB1618 (1 x 10\^11 CFU) in a chilled buffered solution TID for 7 days in the MAD study (Part 2).

Drug: SYNB1618

MAD HV: Placebo

PLACEBO COMPARATOR

HV subjects receive oral placebo in a chilled buffered solution TID for 7 days in the MAD study (Part 2).

Drug: Placebo

MAD PKU: SYNB1618 (7 x 10^10 CFU)

EXPERIMENTAL

Subjects with PKU receive oral SYNB1618 (7 x 10\^10 CFU) in a chilled buffered solution TID for 7 days in the MAD study (Part 2).

Drug: SYNB1618

MAD PKU: Placebo

PLACEBO COMPARATOR

Subjects with PKU receive oral placebo in a chilled buffered solution TID for 7 days in the MAD study (Part 2).

Drug: Placebo

Interventions

SYNB1618 DRUG

SYNB1618 is supplied in a buffered solution in 5 mL polypropylene cryovials with a nominal 5 mL fill volume, administered with 100 mL of masking buffer solution.

MAD HV: SYNB1618 (1 x 10^10 CFU); MAD HV: SYNB1618 (1 x 10^11 CFU); MAD HV: SYNB1618 (5 x 10^10 CFU); MAD HV: SYNB1618 (7 x 10^10 CFU); MAD PKU: SYNB1618 (7 x 10^10 CFU); SAD HV SB: SYNB1618 (1 x 10^11 CFU); SAD HV: SYNB1618 (1 x 10^10 CFU); SAD HV: SYNB1618 (1 x 10^11 CFU); SAD HV: SYNB1618 (2 x 10^11 CFU); SAD HV: SYNB1618 (5 x 10^10 CFU); SAD HV: SYNB1618 (5 x 10^11 CFU); SAD PKU: SYNB1618 (7 x 10^10 CFU)

Placebo DRUG

Subjects receive placebo orally in a chilled buffered solution (100 mL).

MAD HV: Placebo; MAD PKU: Placebo; SAD HV: Placebo; SAD PKU: Placebo

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 (subject or subject's representative).
• Available for and agrees to all study procedures, including feces, urine, and blood collection and adherence to diet control, inpatient monitoring, follow-up visits, and IP ingestion compliance.
• Female subjects that meet one of the following:
• Premenopausal woman with one 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.
• Postmenopausal woman (12 months or more amenorrhea verified by follicle stimulating hormone assessment and over 45 years of age in the absence of other biological or physiological causes).
• Screening laboratory evaluations (e.g., chemistry panel, complete blood count with differential, prothrombin time/activated partial thromboplastin time, urinalysis, C reactive protein, creatinine clearance) and electrocardiogram must be within normal limits or judged to be not clinically significant by the Investigator.
• Stable diet including protein intake for at least 60 days prior to screening assessments.
• Able to produce at least 2 bowel movements per week on average without the assistance of laxatives.
• Diagnosis of classic PKU by either medical history of blood Phe concentration of \>1200 µmol/L at any time OR genetic diagnosis.
• Blood Phe concentration of ≥ 600 µmol/L at Screening.
• Stable diet including stable medical formula regimen (if used) for 60 days prior to screening assessments.

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 confound interpretation of study safety or pharmacodynamic results and, in the judgment of the Investigator, make the subject inappropriate for enrollment.
• Body mass index \< 18.5 or ≥ 30 kg/m\^2 (\> 40 kg/m\^2 for PKU subjects).
• History of or current immunodeficiency disorder including autoimmune disorders and human immunodeficiency virus 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 within 30 days prior to the anticipated first dose of IP.
• History of active or chronic passage of 3 or more loose stools per day.
• Active laxative use within 30 days prior to the anticipated first dose of IP.
• Active inflammatory or irritable bowel disorder of any grade.
• Active or past history of gastrointestinal bleeding within 60 days prior to the Screening Visit as confirmed via hospitalization-related event(s) or medical history of hematemesis or hematochezia.
• Intolerance of or allergic reaction to E. coli Nissle or any of the ingredients in SYNB1618 or placebo formulations.
• Any condition, prescription medication, or over-the-counter product that may possibly affect absorption of medications or nutrients (e.g., celiac disease, gastrectomy, bypass surgery, ileostomy).
• Currently taking or plans to take any type of systemic (e.g., oral or intravenous) antibiotic within 28 days prior to the anticipated first dose of IP through the final outpatient follow-up. 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 3 months prior to the anticipated first dose of IP.
• Planned surgery, hospitalizations, dental, or interventional studies between screening and last anticipated visit that might require antibiotics.

Sponsors & Collaborators

• Synlogic: lead

Study Sites (4)

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, 15224, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

PRA Health Sciences

Salt Lake City, Utah, 84124, United States

Location

Related Publications (2)

• Puurunen MK, Vockley J, Searle SL, Sacharow SJ, Phillips JA 3rd, Denney WS, Goodlett BD, Wagner DA, Blankstein L, Castillo MJ, Charbonneau MR, Isabella VM, Sethuraman VV, Riese RJ, Kurtz CB, Brennan AM. Safety and pharmacodynamics of an engineered E. coli Nissle for the treatment of phenylketonuria: a first-in-human phase 1/2a study. Nat Metab. 2021 Aug;3(8):1125-1132. doi: 10.1038/s42255-021-00430-7. Epub 2021 Jul 22.

  PMID: 34294923 DERIVED

• Charbonneau MR, Denney WS, Horvath NG, Cantarella P, Castillo MJ, Puurunen MK, Brennan AM. Development of a mechanistic model to predict synthetic biotic activity in healthy volunteers and patients with phenylketonuria. Commun Biol. 2021 Jul 22;4(1):898. doi: 10.1038/s42003-021-02183-1.

  PMID: 34294862 DERIVED

MeSH Terms

Conditions

Phenylketonurias

Condition Hierarchy (Ancestors)

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blind
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Dose-escalating, randomized, double-blinded, placebo-controlled

Study Record Dates

• First Submitted: April 11, 2018
• First Posted: May 4, 2018
• Study Start: April 17, 2018
• Primary Completion: June 21, 2019
• Study Completion: June 21, 2019
• Last Updated: May 13, 2021

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)