Surgery News - February 2008 - (Page 19)

F E B R U A RY 2 0 0 8 • SURGERY NEWS TRANSPLANT Early Data Suggest Merits of Liver Assist Device B Y M I C H E L E G. S U L L I VA N Else vier Global Medical Ne ws bioartificial liver fueled by immortalized human hepatocytes has cleared the last of its research hurdles in China and is poised for a pivotal phase III trial in the United States early in 2008. In a randomized, controlled, phase III trial in China, the Extracorporeal Liver Assist Device (ELAD) significantly increased transplant-free survival in 69 patients with chronic hepatitis B, compared with a standard of care control therapy. As a result, the State Food and Drug Administration of China is considering whether to approve the device. In conjunction with the upcoming U.S. trial, Vital Therapies Inc., the maker of ELAD, also will ask the U.S. Food and Drug Administration for a compassionate use exception, according to Terry E. Winters, Ph.D., the company’s CEO. “We would propose to make it available in two or three sites in the [United States]” during the trial, Dr. Winters said in an interview. The ELAD passes a patient’s plasma through cartridges lined with the living hepatocytes; the cells remove accumulated toxins while providing the metabolites normally produced by a healthy liver. The device has prompted cautious enthusiasm in the U.S. research community, said Dr. Robert Brown, chief of the division of abdominal organ transplantation and chief of clinical hepatology at Columbia University, New York. These are exciting, preliminary data that need to be validated in a larger study group; the data are “not yet ready for prime time,” he said in an interview. “I am convinced that artificial liver devices can provide temporary liver support. The question is, for how long and how are they best used? We haven’t figured that out, and I don’t know if the China trial has gotten us that much closer.” There must be a U.S. trial, Dr. Brown said, but problems are sure to plague it. “These are very expensive, you have to define the right study population, and it’s extremely hard to remove the impact of transplantation. That’s been the challenge for all these studies to date.” The Technology The ELAD’s use of human hepatocytes differentiates it from other liver assist systems that are either available or in clinical trials, according to Dr. Michael Millis, chairman of the clinical advisory board of Vital Therapies and a member of the company’s board of directors. Filter-based systems use either human albumin or a mixture of sorbents, including powdered activated charcoal. These systems can remove albumin-based toxins but cannot resupply hepatocyte-produced metabolites. The ELAD consists of an extracorporeal blood pumping system and four hepatocyte-lined cartridges, each of which contains about 100 g of cells—the total cellular content is equal to about 30% of an adult liver. The hepatocytes come from the CA3 cell line, developed at Baylor College of Medicine, Houston, and the Wistar Insti- Millis. “As it is, transplants are simply not tute in Philadelphia. The cells originated available for most people. And there is no from a hepatoblastoma, which is the key other effective treatment for these patients.” Dr. Millis presented the results of the to their successful extrahepatic reproduction, said Dr. Winters. Once removed phase III Chinese trial during the annual from the liver, normal hepatocytes will live meeting of the American Association for only about 6 hours and won’t reproduce the Study of Liver Disease in November in culture. The tumorigenic cells, while 2007. The study included interim results preserving normal hepatocyte function, from 49 patients, and data from an addiare genetically programmed to reproduce tional 20 who were enrolled in a dose-findquickly and thus can thrive in a culture en- ing/additional safety trial. Most of the patients (83%) had chronic vironment. “We can grow these cells in hepatitis B infections; the remainder had unlimited numbers,” Dr. Winters said. The hepatocytes are grown directly in chronic hepatitis C infections, and all were the cartridges, which are composed of experiencing acute decompensation. Their semipermeable membrane fibers that per- bilirubin levels were at least 10 times normit the transfer of large molecules, but mal (about 24 mg/dL at screening). The prevent the cells from entering the pa- patients, whose mean age was 39 years, all tient’s plasma. Toxins and nutrients pass had an international normalized ratio of through the membrane into the cellular cultures, where they are metabolized. At the same time, the hepatocytes release albumin, Factor V, transferrin, transforming growth factor-α, and other cellular products back into the plasma. The plasma passes through the cartridges several times and then through a series of At Beijing Youan Hospital, China, in 2007, the system passes three filters with a plasma through cartridges with live immortal human liver cells. pore size of 0.45 mcm before being returned to the pa- greater than 1.5, along with severe fatigue, anorexia, or distension. tient’s body. Patients were randomized to either At least 72 hours of continual treatment are necessary to detoxify the blood ELAD or standard therapy. Everyone reand restore liver metabolite levels suffi- ceived an initial plasma exchange. The 32 ciently for the patient to recover, Dr. ELAD patients then received continuous Winters said. “This is a 24-hour-a-day ELAD treatment (for a mean of 68 hours), while the 17 standard care patients retreatment for at least 3 days.” The system tested in China has under- ceived up to four additional plasma exgone some improvements from the one change sessions. After the initial plasma exchange, mean used in earlier trials, Dr. Winters said. Upgraded cartridges cause less thrombocy- bilirubin levels were about 17 mg/dL. topenia, and improved oxygenation and Levels in control patients stayed steady for nutrient systems boost the cells’ metabo- a day, and then began to increase, reachlism and their metabolic output. Com- ing a peak of about 22 mg/dL by day 3. pared with the phase I and II trial car- During that same period, bilirubin began tridges, the phase III trial cartridges have to decline in ELAD patients, reaching a a significantly improved output of Factor nadir of about 12 mg/dL by day 3, a staV, albumin, transferrin, and transforming tistically significant difference. By this time, ELAD patients were off growth factor-α. Despite its complex nature, the machine the device, and their bilirubin levels began is not difficult to run in a clinic setting, Dr. increasing again, reaching the same level Winters said. “It’s a similar level of tech- as control patients by day 14 (about 24 nology to dialysis, except, of course, it’s mg/dL). By day 84, both groups had dropped used over days instead of hours.” their bilirubin levels to about 5 mg/dL. “This shows us the natural history of the The Chinese Trial Funding for a U.S. phase III trial didn’t ma- recovering liver in both groups,” Dr. Milterialize after Vital Therapies acquired the lis said. “The difference is that at this point, technology, but research opportunities in 65% of the ELAD patients were still alive China did open up. With a huge number and recovering, vs. 41% of the controls.” These patients were judged to have reof chronic hepatitis B infections and a very low rate of liver transplant, the coun- covered from their acute-on-chronic liver try has an enormous need for some kind failure, although they still had chronic liver disease caused by their hepatitis infeceffective therapy. “There are 1.5 million people in China tions. Because survival was greater in the who would be on a liver transplant waiting ELAD group, “It appears that we could be list, if the country even had the infrastruc- seeing liver regeneration, although I stress ture in place to have such a list,” said Dr. we don’t have proof of that except in the COURTESY TERRY E. WINTERS, PH.D. clinical condition of the patients after their ELAD treatment,” Dr. Winters said. Although liver transplant is not a common option for hepatitis B patients in China, the study showed that five control patients and one ELAD patient underwent transplant (29% vs. 3%). Nine ELAD patients (28%) and four control patients (24%) died during the study—a nonsignificant difference. However, Dr. Millis pointed out, the deaths in the ELAD group included five patients who were treated outside of protocol. Survival for patients with 24-48 hours on ELAD was about 50%, but increased to almost 90% as ELAD time increased to 72 hours. After 72 hours, survival began to decline slightly. Safety was considered good, Dr. Millis said. Most patients required platelets, which wasn’t a surprise. “Every extracorporeal device uses up platelets, but that is easily managed, at least in the West, with transfusions.” The ELAD was associated with about a 50% decrease in platelets (from about 100,000/mcL to about 50,000/mcL by day 3), after which the level began to recover. By day 28, the mean platelet level was about 80,000/mcL, with almost full recovery by day 84. The only death related to platelet issues was the one that occurred during the national shortage. Plans for More Research Although the FDA is more receptive than it once was to foreign-produced data, it is unlikely that the ELAD would win U.S. approval based on the Chinese trial, Dr. Jeffrey Punch said in an interview. “The China study does not represent an accurate model of chronic liver failure in the [United States] and Europe. There are many more hepatitis B patients in China,” said Dr. Punch, an ACS Fellow and chief of the division of transplantation at the University of Michigan. The corresponding U.S. patient group would probably be those with alcoholic cirrhosis, because they can experience acute decompensation and are rarely transplanted. In fact, those are the patients Dr. Winters hopes to recruit in the upcoming U.S. trial—at least 150 o

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Surgery News - February 2008 Contents IOM Committee Looks Into Safety Of Work Schedules Expertise Can Extend Liver Resectability Report Faults Specialty Hospitals' EDs Meeting Expectations Silver Lining HOD on Health Longer Liver Life?

Surgery News - February 2008

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