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

Exclusion Criteria

• •1. 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.
• •2. Body mass index \< 18.5 or ≥ 30 kg/m\^2 (\> 40 kg/m\^2 for PKU subjects).
• •3. History of or current immunodeficiency disorder including autoimmune disorders and human immunodeficiency virus antibody positivity.
• •4. 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).
• •5. Hepatitis C antibody positivity, unless a hepatitis C virus ribonucleic acid test is performed and the result is negative.
• •6. History of febrile illness, confirmed bacteremia, or other active infection within 30 days prior to the anticipated first dose of IP.
• •7. History of active or chronic passage of 3 or more loose stools per day.
• •8. Active laxative use within 30 days prior to the anticipated first dose of IP.
• •9. Active inflammatory or irritable bowel disorder of any grade.
• •10. 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.
• •11. Intolerance of or allergic reaction to E. coli Nissle or any of the ingredients in SYNB1618 or placebo formulations.
• •12. 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).
• •13. 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.
• •14. 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.
• •15. Planned surgery, hospitalizations, dental, or interventional studies between screening and last anticipated visit that might require antibiotics.
• •16. Taking or planning to take probiotic supplements (enriched foods excluded) within 28 days prior to the anticipated first dose of IP and for the duration of participation and follow-up.
• •17. Dependence on drugs of abuse.
• •18. Regular alcohol consumption in excess of 14 standard drinks/week for men and in excess of 7 standard drinks/week for women and/or any evidence of binge or heavy drinking (according to National Institute on Alcohol Abuse and Alcoholism guidelines). One drink is equivalent to 12 g of alcohol: 12 oz (360 mL) of beer, 5 oz (150 mL) of wine or 1.5 oz (45 mL) of 80 proof distilled spirits.
• •19. Administration or ingestion of an investigational drug within 60 days or 5 half-lives, whichever is longer, prior to the Screening Visit or current enrollment in an investigational study. (PKU subjects who participate in the PKU SAD cohort may be eligible for screening for the PKU MAD cohort ≥ 30 days after the last dose of IP.)
• •20. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular (including stable coronary artery disease/angina or prior cardiac stent), hepatic, neurologic, or allergic disease including drug allergies.
• •21. Screening laboratory parameters within the acceptable range.
• •22. Currently taking (within 1 week prior to screening) sapropterin (KUVAN®).
• •23. Currently taking (within 6 months prior to screening) pegylated recombinant phenylalanine ammonia lyase (PALYNZIQ™).
• •24. History of a severe immune reaction based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) after administration of pegylated recombinant phenylalanine ammonia lyase (PALYNZIQ).