Vital Therapies, Inc. ELAD Extracorporeal Liver Assist Device


	ELAD^® First human cell-based liver support therapy.

technology

The key to the performance of ELAD^® System is the proprietary C3A human hepatocyte cell line, licensed from the Wistar Institute in Philadelphia and further developed by Baylor College of Medicine. This is an immortal cell line that is grown in ELAD^® cartridges, then stored and shipped worldwide from VTI’s San Diego production facility. The cartridges are then incorporated into an extracorporeal blood pumping system at the patient’s bedside. The cells perform most of the metabolic functions of normal liver cells.

ELAD^® therapy is designed to provide liver support continuously for up to ten days or more to a patient with compromised liver function, allowing time for the patient’s native liver to regenerate to a healthy state, or to stabilize the patient until a suitable donor organ can be found for transplantation.

The ELAD^® System, depicted in the Figure, continuously separates plasma from cellular components by using an "ultrafiltrate" generator. While the cellular components are returned to the patient via the venous access, the ultrafiltrate is circulated through a set of four ELAD^® cartridges containing the C3A cells. The fibers, made of a semi-permeable membrane, permit passage, from the C3A cells to the patient’s ultrafiltrate, of such macromolecules and other cellular products as albumin, Factor V, transferrin, antithrombin III, C3 complement, a-1-antitrypsin, a-fetoprotein, and others, while simultaneously permitting passage of toxins and such nutrients as glucose and oxygen from the ultrafiltrate to the C3A cells. After circulation and multiple passes through the cartridges, the ultrafiltrate then flows through three filters prior to recombining with the cellular components of the patient’s blood and returning to the patient. This circulation is maintained continuously for the duration of ELAD^® therapy.

A number of in vitro and in vivo assays have been utilized to establish the biologic activity of the C3A cell line. The in vitro assays have demonstrated liver-function activity, while the in vivo experiments evaluated the safety of the entire ELAD^® System, as well as liver function. The synthesis of serum proteins is a hallmark of the liver-specific phenotype and C3A cells synthesize a wide variety of liver serum proteins, such as albumin. The production of albumin by the C3A cell line is an indicator of hepatocyte function and it is a convenient marker of cell viability and function. Indeed, one of the key parameters directing the selection of the C3A cell line was its ability to produce high levels of albumin. While growing C3A cells in hollow fiber bioreactors, the albumin and transferrin concentrations in the tissue culture medium passing through the lumen of the hollow fibers are assayed frequently.

A pre-IND feasibility and safety study was completed in 1998 with three healthy sheep. The clinically configured ELAD^® System was connected to the vascular system of each animal. The ELAD^® System was then operated for an initial period of two hours with only inactive (no cells) cartridges. Then the inactive cartridges were replaced with active, C3A cell-filled cartridges, and the ELAD^® System operated for an additional four hours. The animals remained hemodynamically stable throughout the course of the study, whether inactive (cell-free) or active ELAD^® cartridges were connected to the ELAD^® System. At completion of the study, the animals appeared healthy, fully active, and otherwise completely normal. Samples from the animal’s central (arterial) blood line were removed at predetermined intervals throughout the study, as well as from the ELAD^® System ultrafiltrate recirculation loop. The concentrations of human albumin and transferrin began to increase when active cartridges were connected, clearly showing that human liver proteins from the ELAD^® System were being delivered to the animal.