A company trying to offer a bridge to transplant device for patients waiting for a new liver — a list that is more than 17,000 names long — moved a step closer to being the first to bring an artificial liver device to the U.S. market.

Arbios Systems (Waltham, Massachusetts) reported FDA approval of an Investigational Device Exemption to begin the pivotal clinical trial for Sepet, its out of body liver assist device for blood purification of acutely ill patients suffering from chronic liver disease.

Earlier this year the company said it had received conditional approval for an IDE to begin the trial while it responded to FDA's conditions and request for additional information, more specifically, endpoints of the trial (Medical Device Daily, Feb. 26, 2008).

"We are pleased to have received FDA approval to start the Sepet pivotal trial and to have fully satisfied the points addressed in the FDA's previously issued conditional approval," said Shawn Cain, president/CEO of Arbios. "We were pleased with the compelling results from the Sepet feasibility trial, and we are excited to initiate the pivotal clinical phase of Sepet's development. The pivotal trial design includes adaptive measures to optimize our ability to achieve the trial's primary and secondary endpoints."

Cain said Arbios believes that the trial, if successful, should support the company's filing for approval of the liver assist device in the U.S. and marketing efforts in the U.S. and Europe. He also said the design of the trial is expected to enhance physician acceptance of the device as a "much needed tool in sustaining patients through acute life threatening episodes of liver failure, a market which we believe exceeds a billion dollars annually."

Sepet is a sterile, disposable cartridge containing microporous hollow fibers with permeability characteristics. When a patient's blood is passed through these fibers, blood plasma components of specific molecular weights are expressed through the micropores, thereby cleansing the blood of harmful impurities (hepatic failure toxins as well as various mediators of inflammation and inhibitors of liver regeneration).

Those substances would otherwise progressively accumulate in the patient's bloodstream during liver failure, causing hypotension, increasing risk of sepsis development and accelerating damage to the liver, lungs and other organs, including the brain and kidneys, and suppressing the function and regeneration of the liver.

Sepet is designed for use with standard blood dialysis systems available in hospital intensive-care units.

Because the demand for a liver transplant far exceeds the supply of donor livers, companies like Arbios and Vital Therapies (VTI; San Diego) are trying to develop an artificial liver device to serve as a bridge to transplant. Last year VTI reported that pivotal human trials with its ELAD (Extracorporeal Liver Assist Device) in Beijing were getting promising results for acute liver failure (MDD, Sept. 13, 2007).

Both companies hope to be the first to bring an artificial liver device to the U.S. market.

In 2006 Arbios reported data from the first five patients treated with its Sepet device in its feasibility trial. The results, though preliminary, showed potential for keeping patients with chronic liver disease alive long enough to receive a transplant (MDD, Nov. 2, 2006).

Arbios said there are three segments to the pivotal trial design. During the first segment of the trial, five non-randomized patients will be treated with Sepet to allow the company to validate the patient selection criteria, clinical protocol, case report forms, and other trial related documents. During the second segment of the trial, Arbios said it expects to enroll 116 patients in a randomized, controlled phase of the trial. This segment is targeted to achieve the co-primary endpoints, the company said, which are 1) the percentage of patients achieving improvement in hepatic encephalopathy (HE) grade by a minimum of two grades by the end of Day 7 in the Sepet treatment group versus the standard medical care group, using a 1:1 randomization between the two groups; and 2) the 30-day transplant free survival rate in all patients (control and treatment groups) who do reach a two grade HE improvement versus all patients who do not reach a two grade HE improvement. Pending review and approval by the Data Safety Monitoring Board, the third segment would permit the size of the trial to be increased by an additional 52 patients, if the co-primary efficacy endpoints are reached or have not reached statistical significance but have shown a positive trend, Arbios said. If the co-primary endpoints of the trial are reached upon completion of segment two, extension of the trial into segment three may result in the achievement of statistical significance of one or more secondary endpoints of the trial relating to clinical, functional, and reimbursement advantages for Sepet treatment over standard medical care, according to the company.

Arbios said it would enroll patients with chronic liver disease who are experiencing an acute episode that results in hospitalization with an HE grade of between two and four and who is not responding satisfactorily to standard medical care such as fluid replacement, antibiotics and lactulose for 20 to 26 hours prior to randomization. Patients who are ineligible for a liver transplant, including advanced liver cancer patients and drinking alcoholics, are excluded from the trial, the company noted.

"We hope to shortly receive permission from the German regulatory authority to begin segment one of the pivotal trial at one or two clinical sites in Germany," Cain said. "Over the next several months we will also seek IRB approvals for up to 24 clinical sites in the United States and Europe. While we currently have very limited financial resources, we hope that the FDA's approval to initiate the pivotal trial may enable us to raise the capital needed to implement our clinical and regulatory plans for Sepet."

According to Arbios there is no satisfactory therapy available to treat patients with liver failure, other than maintenance and monitoring of vital functions and keeping patients stable through provision of IV fluids and blood products, administration of antibiotics and support of vital functions, such as respiration.

Arbios develops devices and cell-based therapies for liver failure patients. In addition to the Sepet, the company's product candidate portfolio includes the HepatAssist cell-based liver support system, a bio-artificial liver that combines blood detoxification with liver cell therapy to replace whole liver function in patients with the most severe forms of liver failure.