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Circe Biomedical’s HepatAssist 2000 System
Graphic courtesy of Circe
The HepatAssist functions as an extracorporeal cell-based bioartificial liver device, relying on an open membrane hollow fiber bioreactor and porcine hepatocytes. The microporous membrane’s pore size is small enough to halt the passage of whole hepatocytes, but large enough to allow the crucial substances in question – soluble and protein-bound toxins, and large molecular weight proteins – to pass through freely. These substances are exchanged between the hepatocytes – housed outside the hollow fibers – and the plasma, which travels on the inside of the fibers. The device has four components: a hollow fiber bioreactor containing primary porcine hepatocytes, two charcoal filters, a membrane oxygenator, and a pump. Additionally, the device must be used in conjunction with a commercially available plasma separation machine, a heater, and temperature and oxygen monitors.
Each treatment generally lasts approximately six hours. The patients’ blood is first separated into plasma and cellular components in a plasmapheresis device. The cellular component remains in the plasmapheresis device, while the plasma goes through processing in the bioreactor. The plasma first goes through two charcoal filters, which filter out of the plasma massive bacteria and particulate matter that the system’s hepatocytes might be unable to handle. After this first detoxificative action, the plasma runs through the hepatocyte-lined hollow fiber column, which is the truly novel therapy that this device offers. The newly cleaned plasma is then reunited with the plasma component, which had been stored in the plasmapheresis device, and the whole blood is reinfused into the patient. During the process, a membrane oxygenator and heater are housed between the charcoal filters and hepatocyte bioreactor, with the purpose of keeping the plasma and the hepatocytes over which they flow at body temperature. The membrane oxygenator provides the porcine hepatocytes with the requisite oxygen for correct function.
Circe completed phase I/II clinical trials in 1997, light years ahead of any of its competitors in the bioartificial liver arena. These trials were found to demonstrate safety and showed encouraging signs in treatment of fulminant hepatic failure (FHF) and primary liver nonfunction (PNF), either as a bridge to transplant or in some cases as a bridge to recovery of normal liver function.
Circe then proceeded on to phase II/III trials, which concluded enrollment in 2001 after a four-year run. The trials treated approximately 180 patients at 20 clinical centers in the US and Europe, with the desired endpoint being the 30-day survival of FHF and PNF acute liver failure patients with or without transplant. Despite results that seemed in large part encouraging, Circe was dealt a huge blow when the FDA deemed the device’s efficacy unproven several months ago, making a full phase III efficacy trial the mandatory next step, rather than approving the device for market.
Circe’s HepatAssist 2000 device was long considered the most promising of the myriad bioartificial liver and liver prosthetic devices currently in development, but has recently run into substantial roadblocks. Circe had been developing and testing the device since 1994, and had poured millions of dollars into the product’s development. The company endured abandonment by its corporate parent, W.R. Grace and Co., in 1999. Circe had been a wholly-owned subsidiary of Grace, but in that year the parent company decided to withdraw its backing as part of a unilateral withdrawal from the biotech industry. Circe’s then-president, Dr. Barry Solomon, managed to raise $16 million dollars in venture capital funding to keep the company alive as an independent entity. In the next two years, Solomon sought and received another substantial round of financing ($28 million), and managed to keep the company floating as the HepatAssist went through phase II/III prospective, randomized, controlled clinical trials. Earlier this year, though, the company took a blow when it was forced to halt its trials for lack of efficacy, and must go back and do full-blown Phase III trials if it wishes to continue the quest to bring the device to market. As of now, the company’s plans are unknown, and it remains unclear as to whether Circe will continue to invest in the HepatAssist product, divest, or keep the project shelved for an extended period.
Also of note are the issues surrounding the use of porcine hepatocytes in the device. The membrane pores are sufficiently large to allow zoonotic diseases to pass through, so adequately miniscule bioburden is a must. Circe uses a comprehensive cell cryopreservation and quarantine system to ensure that cells are disease-free. PERV remains an issue of contention, as throughout the xenotransplantation sphere, although industry players, including those at Circe, continue to consider it a nonviable threat. Of course, none of the patients involved in any of Circe’s trials contracted PERV, as no one ever has.
Presentation by Circe’s Zorina Pitkin:
1999 Bio 108 webpage: http://biomed.brown.edu/Courses/BI108/BI108_1999_Groups/Liver_Team/Liver.html
“Liver Assist Devices: Proof of Life – Executive Briefing.” Startup Online Zine.
http://www.windhover.com/contents/monthly/exex/e_2002900062.htm March 2002
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