ELAD is a phase 3 investigational, extracorporeal, human hepatic cell-based liver treatment designed to supplement hepatic function in order to potentially improve survival rates among patients with acute forms of 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 acute forms 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 ELAD treatment, an extracorporeal pumping units draws blood from the subject via a central venous line which passes into the system to generate ultra-filtrated plasma (ultrafiltrate). The subject’s ultrafiltrate is pumped through the hollow fibers of the cartridge, wherein the semipermeable membrane permits a bidirectional flow between the cells (grown between the exterior of the hollow fibers) and the ultrafiltrate (contained in the lumen of the hollow fibers). Toxins, nutrients and dissolved gases pass from the ultrafiltrate to the cells, while the potentially beneficial macromolecules and other substances synthesized by the cells simultaneously pass into the subject’s ultrafiltrate.
After circulation through the ELAD C3A cell cartridges, the ultrafiltrate passes through a 0.2-μm pore size filter, is recombined with the cellular components of the subject’s blood, and is returned to the subject via the central venous line. VTL C3A cells’ metabolic byproducts are thereby returned to the subject to be utilized or to be excreted by the renal or gastrointestinal system. This circulation can be maintained continuously for the duration of the ELAD treatment for up to five days, as determined by the treating physician. The ELAD System monitors and enables adjustment of glucose and oxygen concentrations in the ultrafiltrate, as well as temperature and other parameters, in order to maintain the viability of the C3A cells.
Our Proprietary VTL C3A Cell Bank
The liver is a complex organ comprising several different cell types to perform the majority of its biochemical functions, with hepatocytes being most widely recognized for their roles in synthesis and metabolism. Hepatocyte viability is limited when cultured or expanded outside the body as they very quickly de-diffferentiate or die. Therefore, normal hepatocytes present practical and logistical obstacles for use in a liver-assist product. Cell lines derived from liver cells can alleviate many of these practical and logistical obstacles. The specific cell line that was selected for the allogeneic ELAD System, the VTL C3A cell line, is a sub-clone of a human hepatoblastoma cell line, HepG2. The C3A cell line was developed at Baylor College of Medicine and deposited at the American Type Culture Collection. The specific cells stored in our proprietary cell banks and their progeny are referred to as VTL C3A cells. Under the right conditions, VTL C3A cells rapidly proliferate, allowing growth of the large amount of cells necessary to treat the subject with a liver support system, and with cells that remain metabolically active during treatment. Each ELAD treatment uses approximately one pound of 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, a costly and complex process. As a result, the production and logistics of treatment with our VTL C3A cells does not face some of the challenges commonly associated with autologous cellular therapies.
The VTL C3A cell bank has been subjected to rigorous safety testing for adventitious agents in accordance with regulatory guidance documents. This bank contains enough cells to enable our clinical development and commercialization. We own 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.
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 the cells needed for each patient at our production facility in San Diego, California.
ELAD Mechanism of Action
While the mechanism(s) of action for the ELAD System have not been fully elucidated, several potential mechanisms have been modeled during in vitro studies as outlined below. More recently, ongoing work has related these in vitro results to clinical responses. For example, in 25 subjects (14 treated with ELAD and 11 control) from our VTI-208 study meeting VTL-308 criteria, three proteins produced by the VTL C3A cells (IL-1Ra, VEGF-A, sFas), that showed activity during our in vitro models, have also been shown to increase in VTI-208 subject plasma while on ELAD treatment as compared to control subjects. In contrast, other proteins (procalcitonin and ferritin, markers of inflammation and endothelin-1, a marker of endothelial dysfunction) have been shown to decrease in concentration during ELAD treatment as compared to control subjects, suggestive of a pharmacodynamic response to ELAD treatment consistent with the in vitro findings.
Differentiating Factors of the ELAD System
Unlike other potential therapies developed for acute forms of liver failure in the past, we believe the ELAD System has a unique combination of attributes:
• Biologically active. TThe ELAD System contains biologically active VTL C3A cells and is designed to replicate many liver functions. We believe that an acellular solution to liver failure is unlikely to effectively replace lost liver function. We believe that a cellular approach like ours, capable of replicating key biologic processes, 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.
• Commercially scalable. Our VTL C3A cells used in the ELAD System are immortal and can be expanded in quantities to scale production. Each set of four cartridges used to treat a single patient is grown in a production process that takes up to two months. The process is carefully controlled and is performed under ultra-clean conditions to avoid contamination in our current Good Manufacturing Practices, or 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 shipped under cool conditions. They have been validated to survive for 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 system, flushed with saline and are ready to be used for patient treatment. Our VTL C3A cells usually remain viable for the duration of the patient treatment.