Safety Study of Ornithine Phenylacetate to Treat Patients With Acute Liver Failure/Severe Acute Liver Injury (STOP-ALF)

General Description

There is strong experimental and clinical rationale for the use of ammonia-lowering therapies in ALF. Ammonia is normally produced in the gut and transformed by the liver into urea. As the liver fails, ammonia increases in the systemic circulation and enters into the brain. The result of a rapid rise in ammonia or related compounds in the cerebral circulation is hepatic encephalopathy (HE), a reversible neuropsychiatric condition that ranges in severity from mild impairment in attention, to delirium, the development of cerebral edema, coma and death. This is a Phase 2a, multi-center, open-label study, conducted in two cohorts in patients diagnosed with acute liver failure/acute liver injury (ALF/ALI) who meet inclusion/exclusion criteria.

This study is designed to provide data on OCR-002 with regards to the effect on circulating ammonia levels in patients with acute liver failure with and without impaired renal function at different doses after single and continuous infusion safety and dose tolerability as well as providing data on the metabolites, glutamine and phenylacetylglutamine in this patient population.

It is anticipated that this early efficacy, safety, tolerability, Pharmacokinetic/Pharmacodynamic (PK/PD) and dose-ranging study will lead to a Phase 3 development program for the use of OCR-002 in the treatment of hyperammonemia due to ALF. No clinical outcome measures will be formally studied because of the small sample size.

Objectives

The primary objective of the study was to evaluate the safety and tolerability of ascending doses of OPA in patients with ALF and severe ALI with and without renal impairment. Secondary objectives included the evaluation of the PK and pharmacodynamic profile of OPA in patients with ALI/ALF. Exploratory objectives included the evaluation of the effects of OPA on serum ammonia.

Outcome

Forty-seven patients with ALI/ALF were enrolled into the study, 36 of whom were predefined as evaluable (OPA infusion 72 hours) for measurement of ammonia-lowering efficacy (Table 1). The normal renal function cohort (serum creatinine level at screening of 1.5 mg/dL [n 5 30]) differed significantly from the impaired renal function cohort (creatinine level >1.5 mg/dL [n 5 17]) by percent female sex (80 versus 41%, respectively), the proportion with acetaminophen overdose as the etiology (83 versus 41%), and by definition, median serum creatinine (0.7 versus 2.5 mg/dL) and percent on continuous renal replacement therapy (CRRT; 3.3 versus 59%, respectively).