Interim futility analyses identified a lack of SYNB1020 efficacy.

This Phase 1b/2a, randomized, double-blind, placebo-controlled study was designed to evaluate the safety, tolerability, and pharmacodynamics of SYNB1020 in hepatic insufficiency and cirrhosis patients with hyperammonemia, with dosing of the investigational medicinal product (IMP) administered in an inpatient unit and subsequent outpatient follow-up for SYNB1020 clearance in two study parts.

In Part 1, a sentinel open-label cohort of subjects with cirrhosis and Model for End-Stage Liver Disease (MELD) score <12 was admitted to an inpatient facility for a run-in diet, baseline assessments, IMP administration, safety monitoring, and collection of blood, urine, and stool samples for evaluation of safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations. Subjects in Part 1 were enrolled sequentially to receive SYNB1020. Once the safety and tolerability were established in Part 1, enrollment was opened to subjects in Part 2.

Part 2 comprised a randomized, double-blind, placebo-controlled study in subjects with cirrhosis and hyperammonemia. Subjects were permitted to 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 then underwent full screening within 7 days of pre-screening. Eligible subjects were admitted to an inpatient facility for a run-in diet and 24-hour ammonia profile, and those with an elevated 24-hour ammonia area under the curve (AUC) (>1.2 × the upper limit of normal [ULN]) proceeded with computer-generated randomization in a 1:1 ratio to receive either SYNB1020 or matching placebo. Randomization was followed by IMP administration, safety monitoring, and collection of blood, urine, and stool samples for PK and PD evaluations.

Key Inclusion Criteria:

• Age ≥ 18 to < 75 years
• Females must have been of non-childbearing potential
• Able and willing to complete informed consent process
• Available for and agreed 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/m^2
• Administration or ingestion of an investigational drug within 8 weeks or 5 half-lives, whichever was 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 have affected 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 have increased the subject risk associated with study participation, compromised adherence to study procedures and requirements, confounded interpretation of the safety, kinetics, or PD results, and, in the judgment of the Investigator, made the subject inappropriate for enrollment
• Current or past hepatic encephalopathy of Grade 2 or higher requiring hospitalization
• Child-Turcotte-Pugh score > 9
• History of liver transplant

All subjects who received at least 1 dose of study treatment

All AEs occurring from the time a subject signs informed consent through the safety follow-up period (i.e.,up to 70 days) were documented, regardless of the causal relationship to study drug. AEs that occurred or worsened in severity after the first dose of study treatment were considered treatment emergent (i.e., TEAEs).

AE documentation included duration (onset and resolution dates), severity using the NCI CTCAE (version 4.03), assessment of causality, seriousness, and whether specific action or therapy was required. In summaries, preferred terms are counted only once per subject at the maximum reported grade.

Interim futility analyses identified a lack of SYNB1020 efficacy (plasma ammonia AUC) compared with placebo, resulting in study termination.

Part 1 was open-label; Part 2 was double-blinded