Safety, Tolerability and Pharmacodynamics of SYNB1020

This study consists of two parts:

Part 1 (Completed):

A sentinel open-label cohort of subjects with cirrhosis and Model for End-Stage Liver Disease
(MELD) score <12 will be admitted to an inpatient facility for a run in diet, baseline
assessments, IP administration, safety monitoring, and collection of blood, urine, and fecal
samples for evaluation of safety, tolerability, and pharmacokinetics and PD evaluations. Once
the safety and tolerability have been established in Part 1, enrollment will be opened to
subjects in Part 2.

Part 2:

Part 2 of the trial will comprise a randomized, double-blinded, placebo-controlled study in
subjects with cirrhosis and hyperammonemia. Subjects may be pre screened for eligibility
based on medical history and a single fasting spot venous ammonia measurement. Eligible
subjects with elevated fasting spot venous ammonia will then undergo full screening within 7
days of pre screening. Eligible subjects will be admitted to an inpatient facility for a
run-in diet and 24-hour ammonia profile, and those with an elevated 24-hour ammonia AUC will
proceed with randomization, IP administration, safety monitoring, and collection of blood,
urine, and fecal samples for pharmacokinetic and pharmacodynamic (PD) evaluations.

Key Inclusion Criteria:

- Age 18 to 74 years

- Females must be of non childbearing potential

- Able and willing to complete informed consent process

- Available for and agree to all study procedures

- Screening laboratory evaluations within defined acceptable limits or judged to be not
clinically significant by the Investigator

- Diagnosis of chronic, stable, hepatic insufficiency with features of cirrhosis due to
any etiology

- Evidence of elevated portal hypertension by either liver stiffness measurement, the
presence of abdominal or esophageal varices, splenomegaly or ascites (Part 2 only)

- Elevated venous ammonia (Part 2 only)

Key Exclusion Criteria:

- Body mass index < 18.5 or ≥ 40 kg/m2

- Administration or ingestion of an investigational drug within 8 weeks or 5 half-lives,
whichever is longer, prior to screening or current enrollment in an investigational
study

- Allergy to ranitidine or intolerance to any of the excipients (glycerol, CS Health
Easy Fiber.

- Any condition, prescription medication or over-the-counter product that may possibly
affect absorption of medications or nutrients

- Dependence on drugs of abuse

- Apart from chronic liver disease, any acute or chronic medical, surgical, psychiatric,
or social condition including history of cerebrovascular disease (stroke, transient
ischemic attack) or dementia, or laboratory abnormality that may increase the patient
risk associated with study participation, compromise adherence to study procedures and
requirements, confound interpretation of the safety, kinetics, or pharmacodynamics
results, and, in the judgment of the investigator, make the patient inappropriate for
enrollment

- Current of past HE of Grade 2 or higher requiring hospitalization

- Child-Turcotte-Pugh score > 9

- History of liver transplant