DURHAM, N.C.—Interim data on the use of liver cell therapy for the treatment of pediatric patients with urea cycle disorders (UCD) were presented at the recent annual meeting of the Society for Inherited Metabolic Disorders in Pacific Grove, Calif., focused on a liver cell therapy from Cytonet.
UCD is a rare, potentially life-threatening liver metabolism disorder that in its severe form can affect newborns and infants, causing toxic levels of ammonia to accumulate in the body, which can lead to massive and irreversible damage of the nervous system, including the brain. For patients suffering from severe neonatal UCD, liver transplantation remains the only option for long-term stabilization. However, liver transplantation is still very difficult in small infants and success rates clearly increase with age. Therefore, the current goal for Cytonet’s liver cell therapy is to treat severe UCD patients in order to stabilize them until they have reached an age and size that allows liver transplantation to be performed with a high probability of success.
Dr. Thomas Opladen of the University of Heidelberg presented data from a combined interim analysis of two studies performed in Germany, the United States and Canada. Patients less than six months of age with a confirmed diagnosis of UCD (OTCD, CPS1D or ASSD [citrullinemia]) were treated with liver cell therapy and were compared to a historical control group treated with the current standard of care. Advantages for the treated group were seen for parameters such as event-free survival time or incidence of moderate or severe hyperammonemic events. Reduction of such events is the objective of the liver cell therapy in order to avoid irreversible brain damage. The liver cell therapy was well tolerated.
“The markedly prolonged event-free time and the less severe hyperammonemic events after treatment with liver cell therapy are promising and suggest that liver cell therapy may play an important role in managing patients’ ammonia levels,” said Opladen.
Cytonet’s liver cell therapy involves collecting healthy cells from donated livers not suitable for organ transplantation. These cells are infused into the portal vein in six sessions on six consecutive days. “We obtain livers from the United States organ procurement organizations (OPOs). Our OPO partners work with us to identify those livers which are deemed unsuitable to be transplanted and if they are, and they meet Cytonet’s donor criteria in terms of both safety and potential function, then Cytonet would process the liver into functioning hepatocytes,” says Mark Johnson, president and chief operating officer of Cytonet’s U.S. operations. Cytonet freezes the hepatocytes and then proceeds with a stringent three- to four-week week quality control and release regimen to determine if the cells meet safety and functional quality specifications.
The company is currently conducting two ongoing multicenter clinical trials in the United States and Canada (SELICA III) and in Germany (SELICA V). Jörg Schommer, clinical study manager for Cytonet Northern America, notes that the company has partnered with CTI Clinical Trial and Consulting Services, Eurofins and the Medical Genetics Laboratories at Baylor College of Medicine.
In December 2013, Cytonet submitted a Marketing Authorization Application to the European Medicines Agency seeking approval for its liver cell therapy for the treatment of urea cycle disorders in children.
The urea cycle in the liver is the main metabolic pathway for the detoxification of ammonia that originates from the degradation of amino acids from daily food intake. Six sequential steps mediate the conversion of toxic ammonia into non-toxic urea that is excreted in the urine. A severe deficiency of each of the respective enzymes causes a urea cycle disorder. All UCDs are potentially life-threatening diseases, in particular if manifesting during the neonatal period, which usually results from severe enzyme deficiencies (i.e., no or nearly no residual activity). The key feature that is shared by all UCD is hyperammonaemia, which may be excessive. Hyperammonaemia causes acute brain damage with cerebral edema, hemorrhages and irreversible neuronal cell death as well as chronic neurodegeneration if less extensive. The neurotoxic action of ammonia is amplified by accumulation of glutamine, alanine and asparagine in most UCD. The clinical presentation, treatment and prognosis do not substantially vary between the first four enzyme deficiencies (NAGSD, OTCD, CPS1D,ASSD). Patients with UCD can have the first manifestation of the disease at any age.
Cytonet is an international biotechnology company which is located in Weinheim and Heidelberg in Germany as well as in Durham, N.C., in the United States. The company develops and produces cellular products for therapeutic purposes. Cytonet’s goal is to provide alternatives to existing therapies for many diseases with a particular emphasis on liver diseases. For the past several years, Cytonet has worked with internationally-leading metabolism and neonatal centers at Yale University and the University of California, San Diego, to study its liver cell therapy which uses healthy and metabolically functional human liver cells collected from donated livers not suitable for transplant for infusion to treat urea cycle disorders in children.