Full article reprinted from "The Gray Sheet" - June 9, 2008
The potential market opportunity for an artificial liver keeps players in the game, even though many companies have tried and failed in the past.
Devices designed for patients with liver failure range from blood filters that remove toxins, to more complex biologic systems that use liver cells to replicate the organ's processes outside the body. Beyond the obvious scientific challenges, firms face potential manufacturing and marketing difficulties as well.
Device developers see potential economic benefits if artificial livers can help patients avoid or postpone transplants. Still, developing a device that can take on the hundreds of functions a natural liver performs is a daunting task.
"Everyone else has failed," Vital Therapies CEO Terry Winters acknowledges. "There has been a lot of money lost on this," Winters said, "but there is a big pot of gold to be had."
Vital Therapies Points To Strong Chinese Trial Data
Despite the industry's history, San Diego-based Vital Therapies is optimistic about its chances. The firm hopes to have a biologic artificial liver approved in China by year-end and on the U.S. market by the end of 2010.
Although Vital Therapies is only five years old, the technology on which the firm's ELAD extracorporeal liver assist device is based has been in development for 18 years.
The combination product is an extracorporeal blood pumping system with four human hepatocyte (liver cell) lined cartridges. A patient's plasma is passed through the cartridges, where the cells remove toxins and synthesize proteins and other cellular products, as a normal liver would, before the plasma returns to the body.
Because the liver is unique in its ability to regenerate, Vital Therapies and other firms in this arena hope liver assist devices can support patients until a transplant is available, or until the liver has time to recover.
Eventually, Vital Therapies would like to refine the process until it is as simple as kidney dialysis, Winters told "The Gray Sheet."
According to Vital Therapies, ELAD is the only device in advanced development that uses human, as opposed to pig, liver cells.
Vital Therapies was formed in 2003 to continue development of ELAD after original developer VitaGen/Hepatix went bankrupt (1"The Gray Sheet" Oct. 6, 2003, p. 26).
Roughly 50,000 people suffer from liver failure in the United States each year, but the biggest market by far is China, with about 2 million people in severe liver failure each year, according to Winters.
The Chinese market has helped Vital Therapies thus far avoid being another casualty in the artificial liver effort.
The firm filed for Chinese approval of ELAD in September after conducting a 69-patient randomized trial at two centers in Beijing.
The company is initially focused on treating acute-on-chronic patients, meaning they have underlying chronic disease with some residual liver function, but suffer from acute episodes of liver failure.
Interim results from the first 49 patients showed the 30-day transplant-free survival rate in patients treated with ELAD was 87% compared with 50% in the control group. Winters says subsequent results from the trial are just as promising.
Vital Therapies plans to begin an 18-patient U.S. trial for ELAD by July. The trial will also enroll acute-on-chronic patients with a primary endpoint of 30-day survival. The firm hopes the trial, in conjunction with the Chinese results, will be enough for FDA approval.
Arbios Seeks Funding For Sepet Filter Trial
Also set to begin a pivotal trial for its liver assist device is Arbios Systems. FDA has approved the firm's trial for its Sepet extracorporeal filter system, Arbios announced May 12.
The blood purification device consists of a disposable cartridge designed for use with standard blood dialysis systems in hospital intensive care units. Proprietary permeability characteristics of the fibers in the cartridge cleanse the blood of impurities that otherwise accumulate during liver failure.
While Vital Therapies' ELAD will be regulated as a biologic with help from CDRH, Sepet is regulated as a device only. It does not perform other liver functions besides detoxification.
Other filter-type, extracorporeal liver assist devices include Gambro's MARS Therapy, which uses a protein produced by the liver called albumin to remove toxins. It was 510(k) cleared in 2005 for detoxification after drug overdose or poisoning and became available in China in 2007, but is not FDA cleared for treatment of chronic liver conditions.
Arbios' Sepet trial is designed to enroll up to 173 patients with acute-on-chronic liver failure. In the first phase of the trial, five non-randomized patients will be treated in Germany to validate the trial protocol.
The randomized, controlled phase of the trial will enroll 116 patients at up to 24 sites in the U.S. and Europe. Co-primary endpoints are the percentage of patients with significant (two or more stage) improvement in hepatic encephalopathy grade at the end of one week, and 30-day transplant-free survival in all patients (control and treated) who reach that improvement compared with all patients who do not.
The second primary endpoint, added at FDA's request, aims to show a correlation between the therapy and survival benefit, Arbios said.
A third stage to the trial would allow enrollment to expand by 52 patients upon review by the data safety monitoring board.
Arbios noted that secondary endpoints in the Sepet trial include demonstrating reimbursement advantages compared with standard medical care.
Before the Sepet trial can get off the ground, however, Arbios will need to raise additional capital, according to the company. Arbios expects CE mark approval of the device in Europe by the beginning of 2009, but does not anticipate significant revenue until the pivotal trial is complete and there is more data to support marketing efforts.
Arbios also has a biologic-based artificial liver system in its pipeline called HepatAssist that resembles the ELAD model. HepatAssist differs in its use of pig, rather than human, liver cells.
Arbios was founded in 2000 by the original developers of the HepatAssist technology platform in the early 1990s. The technology was licensed to Circe Biomedical, from which Arbios bought HepatAssist in 2004 after a 171-patient pivotal trial for the system failed to meet its primary endpoint of 30-day survival.
Unlike ELAD and Sepet, which are targeting the acute-on-chronic population, HepatAssist will first be developed for patients with acute liver failure who generally have no liver function and need whole liver support, Arbios says.
Other artificial livers in development include HepaLife Technologies' HepaLife. The system, which also uses cellsderived from pig livers, is in preclinical tests for treatment of acute liver failure (2"The Gray Sheet" Feb. 18, 2008, p. 15).
HepaLife, founded in 1997 as Zeta Corporation, announced May 28 completion of $4.5 million in financing.
Organogenesis also had an artificial liver with pig cells in preclinical development in the 1990s. When the Canton, Mass.-based firm restructured after filing for bankruptcy in 2002, however, it decided not to pursue further development of the liver device in order to focus on its flagship Apligraf regenerative wound care product.
Organogenesis has retained and developed strong intellectual property around the liver assist technology and is now trying to license it to another developer.
Manufacturing, Marketing Challenges Loom
The scientific challenges of supporting an organ as complex as the liver have been the biggest stumbling block for companies in this space, said Vital Therapies' Winters.
The hurdles will not disappear after regulatory clearance, he says. Though Vital Therapies has not set a market price yet for ELAD, he noted that the live cell component of the system is very expensive to manufacture.
The company is on schedule to complete a significant expansion of its manufacturing facility by next month. Its capacity will increase from 200 systems per year to 2,000 systems, and may expand further after the product is approved
Devices without a biological component may not have the same manufacturing demands as other artificial liver devices.
Sepet does not require extra equipment, beyond a standard dialysis system, or large amounts of albumin, Arbios notes. Arbios inked an agreement last fall to have dialysis system maker NxStage be the exclusive manufacturer of the disposable cartridge (3"The Gray Sheet" Oct. 29, 2007, In Brief).
The cost of marketing a new device is also significant. Although the size of the market in China is many times that of the United States, Winters expects to have greater penetration stateside, in part because the United States has a more developed insurance system.
In both markets, there is an opportunity for a new technology to make up for the shortage of available liver transplants, but the Chinese and U.S. markets differ greatly. There is no transplant list in China and the cause of liver disease in almost all cases is hepatitis B, with some hepatitis C, Winters explained.
In the U.S., most patients eligible for liver assist devices are alcoholics or drug addicts. There are some cases of hepatitis C, but almost no cases of hepatitis B.
- Chloe Taft
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