Treatment of Hyperammonemia and Hepatic Encephalopathy in Liver Failure with L-Ornithine Phenylacetate

Up to 50% of patients with liver cirrhosis have impairment in their mental state, which can manifest as mild disturbances but produce major effect on their quality of life, ability to drive and in daily functioning. On the other hand, this mental impairment may lead to severe confusion, coma, brain herniation culminating in death. For over a hundred years it has been recognised that a toxic gas ?Ammonia? accumulates in the blood and brain of patients with cirrhosis because the diseased liver cannot detoxify this gas. Ammonia produces deleterious effects on the metabolic functioning of the brain. Therefore, ammonia reduction is an important target for the treatment of the brain dysfunction of liver disease. At present there is no proven effective treatment for this life-threatening complication of cirrhosis. It is remarkable that when faced with the situation of liver dysfunction, the muscle becomes an accessory site of ammonia detoxification and the machinery that regulates this process is up-regulated. It has been shown that the provision of the substrate ?glutamate? detoxifies ammonia to a temporary ?safe? molecule ?glutamine?. We and others have shown that this temporary detoxification product, ?glutamine? has the potential to regenerate ammonia in the gut. Our invention provides a potential new approach to controlling ammonia by focussing on the knowledge derived from these concepts. Preliminary studies using our novel compound ?L-Ornithine Phenylacetate? suggests that ?Ornithine? is converted to glutamate in the muscle which provides the substrate for the formation of glutamine. This glutamine incorporates a molecule of ammonia which is excreted in combination with ?Phenylacetate? in the urine, as the compound ?Phenylacetylglutamine?. The administration of ornithine plus phenylacetate to animal models confirms that this treatment reduces ammonia concentration markedly and normalises the severity of brain swelling. Our research proposal will test this novel compound in patients with severe liver disease and focus on its effects on clinically relevant end-points. The studies will be performed by expert hepatologists and intensive care doctors in 2 leading institutions in the UK. All the techniques we describe in the proposal are available to the principle investigator and co-applicants. At present, the novel compound is undergoing strict toxicity testing which will be completed before ethical approval and start of this study. The translation of the results of this study to use for benefit of patients with brain dysfunction of liver disease can occur within 5-7 years.

Hepatic encephalopathy (HE) is a major cause of morbidity and mortality in patients with liver disease and its prevalence in patients with cirrhosis is about 50%. In patients with acute liver failure, HE defines the illness and, cerebral edema and the consequent brain herniation is the cause of death in 30% patients. Ammonia is thought to be central in its pathogenesis and is the major therapeutic target. Treatment of HE is an unmet clinical need. Several studies support the view that in liver failure, the major organ removing ammonia is the muscle, converting ammonia to glutamine, a reaction in which glutamate is utilised. In liver failure, the enzyme responsible for this reaction, glutamine synthase is induced and the provision of glutamate would increase ammonia detoxification. L-Ornithine, a precursor of glutamate, detoxifies ammonia by transformation to glutamine. However, our preliminary studies have shown that this glutamine recirculates and regenerates ammonia in the gut. Phenylacetate has been used to treat urea cycle enzyme disorders, conditions in which increased glutamine drives ammonia production. In this situation, Phenylacetate, reduces ammonia concentration by binding to glutamine and reducing its concentration. Our invention provides a novel method of not only detoxifying ammonia into glutamine but also eliminating the excess glutamine that is generated in combination with Phenylacetate. Detailed pre-clinical studies confirm safety in animals and the effectiveness of this approach in reducing ammonia and reducing brain edema and intracranial pressure. Our proposed ?first in man? studies will determine whether L-Ornithine Phenylacetate, a novel compound that we have developed, reduces ammonia levels in patients with severe liver failure and improves HE and by what metabolic pathways. In the proposed study, we will perform placebo-controlled randomised clinical trials of L-Ornithine Phenylacetate in patients with cirrhosis and acute liver failure and assess clinically relevant end-points.
Impact on clinical practice: HE is manifest in the minimal stage in about 50% of patients with cirrhosis which is associated with poor performance in daily life and a poor quality of life. Severe HE is associated with a high mortality rate. Treatment of HE is an unmet clinical need. It is likely that L-Ornithine Phenylacetate if fully developed and shown to be effective, will have the potential to treat this dreadful complication of liver failure. This ?first in man? study will provide the data that will allow UCL Business to secure a suitable license agreement allowing the compound to be developed to market.