Additional Supplementary Material
Commentary from field experts
Dr. Stephen R. Ash of HemoCleanse, Inc.
The following is transcribed from an interview with Stephen R. Ash, MD, FACP, Chairman and Director of R&D, HemoCleanse, Inc. A key member in the development of the first liver therapy device to receive FDA approval for patient use, Dr. Ash provided us with some very comprehensive information regarding the bioartificial liver field and HemoCleanse's involvement in it.
1. What is your educational and professional background?
I am a practicing Nephrologist in Lafayette, Indiana and a Director of dialysis services for two hospitals and three dialysis (artificial kidney centers). However, I also am Medical Director and/or Director of R&D for three companies which I helped to form: Ash Medical Systems (which focuses on catheters and catheter related devices), HemoCleanse (which focuses on sorbent-based Artificial Liver devices) and Renal Solutions (which is developing a sorbent-based nighttime home hemodialysis system). My formal education included a degree in Physics from Northwestern, an MD degree from University of Kansas, and Internal Medicine and Nephrology training at Indiana University. Nephrology is the portion of Internal Medicine that deals with kidney diseases, using medications and dialysis. Essentially it's the specialty that deals with treating blood by machines outside the body. It's not surprising therefore that of three current attempts to treat liver failure using sorbents, all were conceived, built and tested under direction by Nephrologists (Liver Dialysis, my company's device; MARS, by Drs. Stange and Mitzner; FPSA, by Dr. Falkenhagen).
2. What is the size of the market that your company's liver dialysis apparatus targets, and many units are actually put on the market annually?
There are two types of liver failure, first of all, and each has a widely different market and market size. One type is "Acute Liver Failure or ALF" in which a normal liver is severely damaged by a toxin, a drug overdose (like Tylenol), or an acute viral hepatitis, and the patient develops liver failure (with symptoms of coma, respiratory failure, low blood pressure, kidney failure etc) within usually 8 weeks. The other type is "Acute on Chronic Liver Failure or A-on-C" in which a patient with a liver chronically diseased by hepatitis or alcohol has a "stress" develop such as a bleed in the GI system or infection like pneumonia or peritonitis. The patient then rapidly deteriorates in a few days to Liver Failure, with essentially the same symptoms as ALF. In our randomized controlled studies of Liver Dialysis, a positive outcome was twice as likely for patients treated with Liver Dialysis versus control patients, for those patients with A-on-C (70% vs 35%). There was no proven benefit for patients with ALF, though individual clinical experience with patients before and after our randomized studies indicated a remarkable improvement in many ALF patients after a few treatments (especially if the liver was damaged by acetaminophen).
The number of patients in the U.S. with ALF is about 3000 per year. The number of patients with A-on-C and significant deterioration is approximately 400,000 per year. About 75,000 per year are admitted to hospitals with encephalopathy (stages of mental confusion to sedation to coma) due to A-on-C as the principal diagnosis. The reason for so many A-on-C is that hepatitis is so widespread in the U.S., there are approximately 5,000,000 people in the U.S. with hepatitis, a growing number with Hepatitis C which eventually leads to cirrhosis or scarring of the liver in most patients.
HemoCleanse began to market the Liver Dialysis machine in 1997, in the U.S. and in the Pacific Rim. We had a total of about 30 machines in the market when we licensed the product to HemoTherapies, a start-up Venture funded organization in San Diego. They decided to focus on the U.S. market alone and installed about 8 machines in 8 centers. They focused too broadly on the market and had too few people who really knew the disease and technology. As a result they didn't encourage the use of the machine or direct physicians how to use it without problems, and some centers stopped using the machine. The company eventually ran out of funds and is currently being reorganized under Chapter 11. My company has created the business plan for their company, so things will change for the better.
One lesson from HemoTherapies is that it's not easy to market a new machine for a totally new indication, especially when it's a life support machine. Care of patients with liver failure is very complicated even without using a machine for support, so the users have to be highly educated on proper patient choice, proper judgment in anticoagulating the patient, when to start treatments and when to end them and so on.
3. Does your company harbor any plans to move into the bioartifical liver market at any point?
The answer to that question is, "perhaps". We are currently more interested in improving the ability of the Liver Dialysis system to remove toxins that are very large or protein-bound. In Liver Dialysis a suspension of powdered charcoal and cation exchangers surrounds dialysis membranes, separated by sheet membranes from the blood. Toxins up to 5,000 m.w. are removed, but not cytokines or bilirubin, which are strongly bound to proteins that can't pass through the membranes. We have already done Phase I testing of a module that uses the same type of sorbent suspension but has a pheresis membrane that allows passage of all plasma proteins from blood to contact the powdered sorbents then return to the blood. This will be used in patients with liver failure and sepsis (infection in the blood) or the patients with the worst complications of liver disease.
I do think that bioartificial liver devices will find particular advantage also in the patients with the most severe liver failure, ALF, since the hepatocytes do synthesize substances vital to the patient. However, for the current time, infusing plasma to the patient can replace many of the proteins made by normal liver. Importantly, some of the clinical success of bioartificial devices is due to improvement of the patient's own liver function, and this may be through "autocrine" function. Autocrines are substances created by a cell to tell neighboring cells that they should function as an organ. If these substances are created by the bioartificial device, they may "wake up" the damaged liver cells or help them recover function.
HemoCleanse does hold two patents on very unique bioreactors, one from Washington University and one that is a spinoff of the space program. In either reactor, the cells are retained in a column that allows perfusion with blood or plasma, without need for a membrane. We've done preliminary work with the Wash U reactor, even including animal studies. However, we're not actively pursuing this direction now (see below). We have, however, tested inclusion of various hepatic enzyme systems within our sorbent suspension in animal models of liver failure.
4. In your opinion, how viable is the bioartificial liver, either as a bridge to transport or as a more far-sighted option, and when do you think we'll see an approved, effective version on the market?
There are some significant problems with in use of bioreactors to treat liver failure:
1) Cell source: Currently the cell source for hepatocytes is either from pigs or from human C3A cancer cells (which can propogate for many generations). The problem with pig hepatocyes is that proving they have no transmissible disease such as retrovirus is very difficult. The problem with cancer cell lines is that they might transmit some portions of DNA or RNA to promote cancer growths in the patient. These risks are small but not zero.
2) Membranes: In the Circe device, cells are on the opposite side of a pheresis membrane from the blood. The protection for the passage of retroviruses is completely through deemonstrating lack of transmission in previously treated patients. One questionable outcome, and the project's in trouble. In Vitagen, Exten and other devices, order to prevent passage of retroviruses or DNA or RNA, the cells are placed on the other side of membranes with small pore sizes. In fact the Vitagen system has two such membranes. This greatly limits passage of large or protein-bound toxins to the cells, and diminishes clearance of these toxins.
3) In Vivo function: The toxins of liver failure are also toxic to the hepatocytes in a bioreactor. Although every bioreactor has been shown to have chemical function in some ways similar to the liver in vitro (on the benchtop) there's not yet any indication that during treatment of patients the bioreactors actually diminish ammonium, bilirubin, lactate or any other hepatic toxin. Reasons include the systems aren't designed to allow high mass transfer coefficients between blood and cells, there's a relatively small number of cells, the cells are not highly metabolically active (as with C3A cells), and the toxins of hepatic failure inhibit cell function during treatments.
4) Logistics: To provide bioreactor therapy it's necessary to solve the logistical problem of how to store hepatocytes, fill or activate the bioreactor, prove the cells are active and then treat the patient. Freezing the cells in place within the bioreactor hasn't yet been practical, so "some assembly required" still prevails for systems, if the hepatocytes are metabolically active. If the hepatocytes aren't metabolically active, such as C3A cells, then they can be shipped in the reactors on ice. The therapy may still be successful, but it's more difficult to figure out why.
5) Cost: Estimates of cost of implementing treatments with biologic systems range from $10,000 to $30,000 per treatment, whereas sorbent based systems can be provided for between $1000 and $3000 per treatment.
5. What is the extent of the bioartificial liver's potential, in your opinion? Does it stop at a temporary extracorporeal bridge-to-transport?
I don't think that the entire goal is bridge to transplant. The goal should be bridge to recovery of liver function, and if that fails, then proceed to transplant. We've had patients with acetaminophen-induced liver failure who were going to be transplanted but first recovered after treatment with the Liver Dialysis. In the case of A-on-C patients, if the patient can recover liver function and have reasonable health (as before the deterioration) then a planned liver transplant can be done on an elective basis some months later, rather than an emergency, improving the chances for function of the transplanted liver.
Will we ever have a long-term life support system that will maintain reasonable health in patients with little or no liver function, as we have with the artificial kidney? I think so, but not with current technology. For one thing, we'll need to have a system in which the hepatocytes function continually, as they do in the human body. For another thing, we'll need hepatocytes with direct contact to blood or plasma, without membranes limiting passage of proteins to the cells or to the blood. This means we'll need very safe cell types. Also we need to have cells that won't be rejected by the body. Hepatocyte transplantation has had positive effects when cells are injected in the liver or spleen or placed in the peritoneum, but this is for acute liver failure, not chronic.
6. Why haven't we seen an FDA-approved bioartifical liver on the market yet? What has been the major obstacle to achieving an effective product worthy of FDA approval?
When the Liver Dialysis machine was approved for market in the U.S. it was because we had shown in randomized, prospectively controlled trials that it improved the outcome of at least one group of patients with liver failure (A-on-C). This type of benefit may be proven for bioartificial liver devices for ALF, but it isn't clear yet. For the biologic devices, they must also prove a negative, that there's no chance for transfer of disease to the patient. I think that some company will get there, but I don't know when.
7. What is your personal opinion of the FDA approval process for devices like the bioartificial liver? How would you change it to make it more effective and efficient?
I don't think it can be changed easily. Sorbent based artificial livers are devices, and though the process is arduous, the companies can prove benefit and safety from clearly derived parameters. The Medical Device Act of 1990 requires randomized prospective trials of new 510(k) devices to show that they have the same efficacy and function as current devices. I think this is overly-tough, but the trials can be done and the devices approved. I'd change this to say that if the scientific technology is the same as in previous devices, these trials aren't necessary.
In the biologic area there are always extra questions that arise even after efficacy is shown. Looking at the question of retroviruses, some experts have stated that what's at risk is not a single patient's life but the "whole human genome". Faced with this type of criticism, however true, FDA's going to be very conservative. I don't think I could tell FDA how to make the process easier for bioartificial liver devices.
I'm attaching a number of references to published articles on Liver Dialysis and the DTPF (the sorbent-based pheresis system). You should especially review the most recent publications in Therapeutic Apheresis and ARRT (Advances in Renal Replacement Therapy) (late '01 or early '02)
Ash SR. Treatment of acute hepatic failure with encephalopathy a review. Int J Artif Organs 14(4)191-195, 1991.
Ash SR, Blake DE, Carr DJ, Carter C, Howard T, Makowka L. Neurologic improvement of patients with hepatic failure and coma during sorbent suspension dialysis. ASAIO Trans 37(3)M332-M334, 1991.
Ash SR, Blake DE, Carr DJ, Carter C, Howard T and Makowka L. Clinical effects of a sorbent suspension dialysis system in treatment of hepatic coma (the BioLogic-DT). Int J Artif Organs 15(3)151-161, 1992.
Ash SR, Carr DJ, Blake DE, Rainier JB, Demetriou AA, Rozga J. Effect of sorbent-based dialytic therapy with the Biologic-DT on an experimental model of hepatic failure. ASAIO J 39(3)M675-M680, 1993.
Ash SR, Hemodiabsorption in treatment of acute hepatic failure and chronic cirrhosis with ascites. Artif Organs 18(5)355-362,1994.
Ash SR, Hemodiabsorption in the treatment of acute hepatic failure. ASAIO J 40(1)80-82, 1994.
Wilkinson AH, Ash SR, Nissenson AR. Hemodiabsorption in treatment of hepatic failure. Journal of Transplant Coordination 843-50, 1998.
Ash SR. Letter to the Editor. Artif Organs 22(6)518-519, 1998.
Ash SR. Overview of the treatment of fulminant hepatic failure. 2000 UpToDate, Burton Rose Editor.
Ash SR, Blake DE, Carr DJ, Harker KD. Push-pull sorbent-based pheresis for treatment of acute hepatic failure The BioLogic-detoxifier/plasma filter System. ASAIO J 44(3)129-139, 1998.
Ash SR, Knab WR, Blake DE, Carr DJ, Steczko J, Harker KD, Levy H. Push-pull sorbent-based pheresis and hemodiabsorption in treatment of hepatic failure preliminary results of a clinical trial with the BioLogic-DTPF System. Therapeutic Apheresis 4218-228, 2000.
Steczko J, Bax KC, Ash SR. Effect of hemodiabsorption and sorbent-based pheresis on amino acid levels in hepatic failure. Int J Artificial Organs 6375-388 2000.
Ash SR. Powdered Sorbent liver dialysis and pheresis in treatment of hepatic failure. Therapeutic Apheresis 5(5)404-416, 2001.
Ash SR. Extracorporeal blood detoxification by sorbents in treatment of hepatic encephalopathy. Advances in Renal Replacement Therapy 93-18, 200.
Dr. Robert C. Johnson of VitaGen, Inc.
The following is transcribed from a brief interview with Robert C. Johnson, Chief Operating Officer of VitaGen, Inc. Dr. Johnson was kind enough to give us some information about the progress of VitaGen in developing a bioartificial liver product, and his experience in the field.
What is your educational and professional background?
RCJ: Ph.D. in Biochemistry, from Princeton University.
What are your company's projections of the monetary size of the market that your product, if successful, will target?
RCJ: The market is approximately $500 million in the U.S.
What distinguishes, in your mind, Vitagen's bioartificial liver product from other such extracorporeal bioartificial liver products currently being tested?
RCJ: Vitagen's product uses a human cell line. Also, the therapy is administered continuously, 24 hours per day, for up to 10 days.
Is the end goal of your company to market the ELAD system as a bridge to transplant, or to eventually develop the technology into something that can be more broadly applied, possibly a long-term fix for liver failure patients? If the latter, how do you see the technology developing from the current ELAD system?
RCJ: Our target is for the product to be a bridge to transplant or recovery first. After this, we hope to ultimately use the system on chronic liver failure patients.
What is your personal opinion of the FDA approval process? How would you change it to make it more effective and efficient?
RCJ: We have had good experiences with the FDA. The only problem has been
that they need more reviewers to be able to respond more quickly.
What is your company's contingency plan in the situation that your product is denied FDA approval?
[Question could not be answered for confidentiality reasons.]
Glossary of Medical Terms Used in This Website
a symptom or characteristic that makes a particular therapy unacceptable or out of the realm of possibility.
acute cellular rejection:
an adverse, sudden reaction to outside invasion that causes cell death, usually due to incompatible antibodies.
acute liver failure:
a clinical condition that results from severe and extensive damage to liver cells,leading to failure of the liver to function normally and inducing symptoms including jaundice and varying degrees of mental confusion.
acute-on-chronic liver failure:
a sudden, acute deterioration of liver function in one suffering from chronic liver failure.
physiological proteins that rise in varying levels in response to activation by cytokines, themselves produced in response to physiological challenge such as inflammation, infection, trauma, or drug response.
Water soluble proteins found in blood which bind many water-insoluble substances and contribute keeping pressure within the circulatory system.
alcoholic liver disease:
disease of the liver arising from chronic alcohol abuse; symptoms can be cirrhosis, hepatisis, and steatosis (fatty liver)
a protein released by the liver, whose functionality is to protect the lungs so that they can function normally.
α- antitrypsin deficiency:
an inherited disorder that prevents α- antitrypsin production; it can cause lung damange.
organic molecules composed of a hydrocarbon skeleton and including both carboxylic acid and amino acid functional groups used to form proteins.
part of the hormonal pathway that produces the potent vasoconstrictor angiotensin II and promotes salt and water retention.
an immunoglobulin protein produced by a specific activated B-lymphocyte in response to a particular antigen, or foreign substance (i.e. bacteria or toxins), in the body; binds with antigen and promotes its destruction.
the presence of excess fluid in the peritoneal cavity. A common clinical finding with a wide range of causes, but develops most frequently as a part of the decompensation of previously asymptomatic chronic liver disease
a disease characterized by the erroneous production of antibodies against the body’s own tissues.
a bitter, aqueous, alkaline fluid produced and secreted by the liver, stored in the gallbladder, and discharged into the small intestine to aid in the digestion and absorption of fats.
the congenital absence or closure of the ducts that drain bile from the liver.
Bilirubin results from the breakdown of the hemoglobin in the worn out red blood cells digested by macrophages in the liver and is excreted into bile by hepatocytes.
extensive examination of cells or tissues removed from a living organism for diagnostic purposes.
a disease characterized by clotting of the hepatic vein, the major vein that leaves the liver. Most patients with Budd-Chiari syndrome have an underlying condition that predisposes to blood clotting.
the ability, possessed by an agent, to fight cell division and proliferation; most often used in the context of battling cancer.
malignant tumors of the biliary duct system; can occur intra-hepatically or extra-hepatically.
a white substance synthesized by the liver and used to make cell membranes and steroid hormones.
Chronic Active Hepatitis:
inflammation of the liver that has been continuous for more than 6 months.
a chronic disease of the liver characterized by the replacement of healthy tissue with scar tissue resulting in a loss of function.
the process by which blood clots.
a group of disorders of the blood clotting (coagulation) system in which bleeding is prolonged and excessive.
existing at the time of birth.
the separation of smaller molecules from larger molecules or of dissolved substances from particles in solution by selective diffusion though a semi-permeable membrane.
Various diseases of the brain leading to inflammation
stages of encephalopathy:
0 – subclinical, impaired psychomotor function
1 – varied manifestations including apathy, lack of awareness, anxiety, restlessness,
2 – lethargy, drowsiness, disorientation, incontinence
3 – deep somnolence, incoherent speech
4 – coma
4a – responds to pain stimuli
4b – no response to pain stimuli
a membrane network within the cytoplasm of cells involved in the synthesis, modification, and transportation of cellular materials.
swelling of the endothelium: a layer of flat cells lining the closed internal spaces of the body such as the inside of blood vessels and lymphatic vessels (that convey the lymph, a milky fluid) and the heart.
end stage liver disease:
label given to liver disease when complete liver failure is eminant.
female hormones that are produced by the body and are necessary for the normal sexual development of the female and for the regulation of the menstrual cycle during the childbearing years.
Situated or occurring outside the body.
cancer occurring outside of the liver and biliary system.
molecules that are long chains of lipid-carboxylic acid found in fats and oils and in cell membranes as a component of phospholipids and glycolipids.
the protein from which fibrin is formed/generated in normal blood clotting.
the formation of excessive fibrous tissue, usually due to repair of damaged tissue.
Having or resembling fibers, tough.
Fulminant Hepatic Failure (FHF):
sudden, rapid failure of the liver
a small sac located under the right lobe of the liver into which bile is secreted by the liver and held until needed for digestion.
a small, hard formation in the gallbladder or bile ducts made primarily of cholesterol, calcium salts, and bile pigments.
any of a class of proteins found in blood, milk, and muscles.
the storage form of glucose. Stored in the liver for future energy needs.
a birth irregularity where a localized tissue mass grows rich in small blood vessels.
a procedure for removing metabolic waste products or toxic substances from the bloodstream by dialysis.
the iron containing pigment in red blood cells that aids in the transportation of oxygen throughout the body.
excessive discharge of blood from the blood vessels; profuse bleeding.
maintenance by the highly coordinated, regulated actions of the body systems of relatively stable chemical and physical conditions within the body.
an organic acid found mainly in the lung and liver that prevents clotting of blood.
a benign tumor of the liver.
inflammation of the liver caused by infectious or toxic agents.
a malignant tumor of the liver.
cancer of the hepatocytes (liver cells) within the liver.
a liver cell. Can perform the wide variety of metabolic and secretory tasks undertaken by the liver.
concentration of oxygen in arterial blood that is less than normal.
suppression of the immune response either by drugs or radiation in order to prevent the rejection of grafts or transplants or to control autoimmune diseases.
inadequate blood supply (circulation) to a local area due to blockage of the blood vessels to the area.
the yellowish discoloration of the eyes and skin due to the liver’s failure to remove bilirubin from the blood because of gallstones, liver disease, or the excessive breakdown of red blood cells.
the clear, yellowish fluid portion of blood in which cells are suspended.
a process that separates blood into plasma and its cellular components.
relating to pigs, swine.
Porcine Endogenous Retrovirus (PERV):
a benign virus that has infiltrated the porcine genome. Some worry that therapies that bring humans or human cells in contact with porcine cells might allow transmission of the virus into humans, where it could mutate and become pathogenic.
This is the phenomena that occurs in which the liver is inserted into the recipient, and does not work. It is usually due to ischemia, improper perfusion, or lack of recipient blood flow through graft. Clinical signs of primary non-function include jaundice, problems with blood clotting, and lack of bile flow.
Company Video Links:
The MELS device: http://cito.charite.net/PressRoom/movies/index.shtml
The Liver Dialysis Unit: http://www.hemotherapies.com/html/hu_video.asp
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