ELAD is an investigational extracorporeal, human cell-based liver support system designed with the proposed intent to supplement hepatic function in order to improve survival rates among subjects with liver failure. ELAD incorporates our human liver-derived cells, or VTL C3A cells, contained in four hollow fiber cartridges that are combined with single use customized disposable sets and a reusable ancillary delivery system. Data from ELAD System clinical studies have shown trends that may indicate a potential for ELAD to increase survival rates in patients with liver failure. ELAD has received orphan designation in the United States and Europe for the treatment of patients with acute liver failure.
ELAD System Design and Operation
During treatment with the ELAD System, blood is drawn from the patient via a central venous line and then passes into the ancillary delivery system where plasma ultrafiltrate is isolated by an ultrafiltrate generator. The patient’s plasma ultrafiltrate then passes into the four cartridges where it contacts our VTL C3A cells after passing through fibers which allow appropriate two-way transfer of toxins, metabolites and nutrients, mimicking liver function. The fibers, made of a semi-permeable membrane, permit passage of macromolecules and other substances from our VTL C3A cells to the patient’s plasma ultrafiltrate. At the same time, these fibers permit the passage of toxins such as bilirubin, and nutrients such as glucose, and oxygen from the plasma ultrafiltrate, to our VTL C3A cells. Heparin, a widely-available anti-coagulant drug, is administered during treatment with the ELAD System in some patients to prevent blood-clotting in the ultrafiltrate cartridge.
Treated plasma ultrafiltrate is then filtered, reconstituted with blood cells and returned to the patient via the central venous line. Meanwhile, the ancillary delivery system monitors temperature, pH, and oxygen concentrations in the plasma ultrafiltrate in order to maintain the cells’ viability. Treatment is expected to consist of a single session of continuous treatment lasting between three and ten days, as determined by the treating physician.
Our Proprietary VTL C3A Cell Bank
The key to the performance of the ELAD System is our VTL C3A cell bank. The bank contains human liver-derived cells that can be grown in almost unlimited quantities, stored and shipped worldwide.These properties enable continuous patient treatment for up to ten days usually without changing the cartridges. Moreover, the immortal VTL C3A cells may mimic certain functions of human liver cells, and it has been shown in nonclinical studies that these cells retain many of the specific metabolic processes and pathways of hepatocytes (ELAD® Cellular and System Performance Improvements (Brotherton, et al, AASLD, November 5, 2007)). These functions include an active P450 enzyme system as well as the production of liver specific proteins such as albumin, anti-thrombin III, alpha-fetoprotein, C3 complement, Factor V, transferrin, alpha-1-antitrypsin, growth factors, and immunomodulatory proteins.
The C3A cell line has been studied by independent investigators who have confirmed its hepatocyte properties, such as the presence of a functional cytochrome P450 toxin-processing enzyme system and the production of many liver-specific proteins. However, the C3A cell line does not entirely mimic the behavior of primary hepatocytes. For instance, it has not been shown to process ammonia as effectively as primary hepatocytes do and C3A produces large amounts of alpha-fetoprotein, or AFP. We believe these issues are manageable since excess ammonia can be removed by dialysis if needed, and AFP is a non-toxic fetal analogue of albumin.
In order to better understand the performance of the VTL C3A cell line during the treatment of subjects with acute forms of liver failure, we have initiated a program of research to assess the types of proteins produced by the cells during cell culture, and at different times during treatment. Preliminary results from these studies suggest that the cells express a broad spectrum of cytochrome P450 enzymes not only during culture but also during patient treatment, and that the types and amounts of the enzymes produced can vary presumably in response to the exposure of the cells to the patient’s plasma ultrafiltrate. Furthermore, initial experiments suggest that the production of proteins by the C3A cells can be measured in the plasma ultrafiltrate and are associated with increases in the levels of these proteins in the blood of liver failure patients. The reproducibility of these data need to be confirmed.
We are also evaluating the characteristics of the C3A cells using electron microscopy to see how they change during treatment. Preliminary data suggest that the cells can remain metabolically active throughout the course of treatment and have the ability to organize themselves into structures that have characteristics similar to those found in the normal liver. The functional significance of these structures, if any, is yet to be determined.
We have customized the now-publicly available C3A cell line we originally acquired from Baylor University to create a proprietary VTL C3A cell bank for use in the ELAD System, which we culture and expand through proprietary techniques. This cell bank represents a well-characterized stock of original cells that have been subjected to rigorous testing for viruses, pathogens and other contaminants in order to allow them to be used in humans. This bank contains enough cells to enable our clinical development and commercialization. Vital Therapies owns this VTL C3A cell bank exclusively and on a royalty-free basis. In addition, we have developed proprietary methods for growing, storing and optimizing the function of these cells.
Treatment with the ELAD System is not patient specific and our VTL C3A cells, which are derived from a single source, are used to treat all patients. This process is known as allogeneic cellular therapy. In contrast, autologous cellular therapy uses a patient’s own cells, which are manipulated in individual production batches, and is a costly and complex process. As a result, the production and logistics of treatment with our VTL C3A cells does not face the challenges commonly associated with autologous cellular therapies.
Our proprietary VTL C3A cell bank is stored in three separate locations around the world for security purposes and is used as the basis for growing approximately one pound of cells needed for each patient at our production facility in San Diego, California.
Differentiating Factors of the ELAD System
Unlike other potential therapies developed for acute liver failure in the past, we believe the ELAD System has a unique combination of attributes:
• Biologically active. The ELAD System is a biologically active system that is designed to replicate many liver functions. The functional unit of the liver, the hepatocyte, is thought to be responsible for 500 or more biologic processes necessary for human life. Moreover, many processes of the liver occur at ever-fluctuating rates in response to the liver’s constantly changing biologic environment. As a result, we believe that an acellular solution to liver failure is unlikely to effectively replace lost liver function. We believe that a cellular approach, capable of replicating key biologic processes performed by a human hepatocyte, is best able to provide the requisite flexibility and breadth of function to sufficiently supplement liver function and improve survival in patients with acute liver failure.
• Human cellular therapy. The ELAD System is based on human cells which confer a considerable advantage over non-human, animal-based cell therapies. Given the widespread availability of animal tissues, much work has been done on the use of animal liver cells, often derived from pigs, to treat humans with liver failure. While immunological risk is always present in cellular therapy, the use of non-human animal tissues presents greater immunological risk compared to human cellular therapy. Humans possess naturally occurring antibodies that react with antigens on porcine cell surfaces. These antibodies can mount an immediate attack in the presence of porcine cells, causing these cells to rapidly lose function and die. Moreover, repeated treatments with a porcine cell may cause subsequent immune responses to become increasingly severe. The infusion of porcine enzymes into a patient’s blood stream also poses immunologic risk. We are not aware of any FDA-approved non-human animal-based cellular therapy for use in patients.
• Immortal human liver-derived C3A cells. Our VTL C3A cells used in the ELAD System are derived from a human hepatoblastoma and are immortal. They can be expanded and can survive a session of up to ten days of ELAD System treatment, usually without needing to be replaced during treatment. Hepatocytes are the main cell in the liver and deteriorate rapidly when removed from the body. Hepatocytes cannot be grown outside the body as they de-differentiate and die in a short period of time. The inability to expand makes hepatocytes unsuitable for a liver assist system, which requires large amounts of hepatocytes.
• Commercially scalable. We have developed a process to grow our VTL C3A cell line in our facility in San Diego, California that is designed for scalable production. Each patient set of four cartridges contains a total of about one pound of cells and is grown in a production process that takes about six weeks. The process is carefully controlled and is performed under ultra-clean conditions to avoid contamination in our cGMP compliant production plant. The process is scalable by modular units.
• Minimal manipulation needed by site. Prior to shipment, the ELAD cartridges are put into a dormant state and can survive up to 60 hours before being used for treatment. When the hospital receives the cartridges, they are unpacked by our ELAD System specialists on site, placed on the bedside unit, flushed with saline and are ready to be used for patient treatment. Our VTL C3A cells can remain alive for the duration of anticipated patient treatment, and the ELAD cartridges do not usually need to be replaced, thus enhancing ease-of-use and reducing cost-of goods.