Status: approved; marketed

Organizations involved:

Cypress Bioscience, Inc. – R&D; Tech.; USA mark.

Fresenius HemoCare, Inc. – Manuf.

Fresenius Hemotechnology, Inc. - World mark.

Fresenius AG – Parent; Former

Medexus, Inc. – Canada mark.

IMRE Corp. – Former

Baxter Healthcare Corp. – Former

Description: The Prosorba Column is a single-use cylindrical polycarbonate (plastic) extracorporeal plasma filtration column containing an affinity chromatography matrix of nonrecombinant Staphylococcus aureus (S. aureus) Protein A obtained from culture of S. aureus bacteria covalently bound to inert silica granules. The Prosorba Column is used in conjunction with a plasmapheresis (blood filtration) device for the selective removal of antibodies, particuarly clusters of circulating immune complexes (CICs; antibody-antigen clusters) that contribute to immune dys-regulation from a patient’s blood plasma, with CICS removal resulting in stimulation of the patient’s immune responses. After passing a patient’sblood through the extracorporeal (external) plasmapheresis device, which separates plasma (the fluid component of whole blood), and then the Prosorba Column, plasma and cellular components not removed by the column are returned to the patient. This process involves removal of up to about 750-1,500 mg of the circulating IgG-complexes, usually about 1,000 mg (1 gram), from the patient’s plasma.

Protein A is a cell surface component of certain strains of Staphylococcus bacteria with specific binding affinity for the Fc region of immunoglobulin G (IgG; antibodies) and IgG bound to antigens, i.e., circulating immune complexes (CICs). CICs are normally removed from plasma by the phagocytic mechanisms of the immune system. Matrix-bound Protein A affinity chromatography is often used for purification of monoclonal antibodies (as described in various monoclonal antibody product entries). Protein A is a multi-domained protein and can simultaneously bind several immunoglobulins and/or several sites on a immunoglobulin molecule. Protein A is believed to be one of the mechanisms by which Staphylococcal bacteria evade removal/destruction by the immune system.

The Prosorba Column contains approximately 200 mg of Protein A covalently bound to an inert silica-based matrix (using carbodiimide reagent) held within a 300 ml polycarbonate housing containing 123 ± 2 grams of Protein A-silica matrix. Prosorba Columns are packaged in cases containing six sterile columns, with an expiration date of 18 months. The solid-phase matrix, Chromosorb (from Johns Manville Corp.), is diatomite silica (diatomaceous earth) composed of primarily of particulate quartz (silicon dioxide) aggregate material calcined to remove any organic material and harden the surface of the aggregates, in order to lessen breakage and degradation of the covalently bound immunoadsorbent (Protein A) during use. The diatomite material consists primarily (> 80%) of silica with lesser amounts of other minerals, including aluminum oxide, calcium oxide, magnesium oxide, ferric oxide, and the like. Prosorba has an expiration date of 18 months from manufacture.

The Immunosorba System, approved only for humanitarian exemption use, consists of two Immunosorba Protein A columns (similar to Prosorba columns), and a microprocessor controlled monitor, called the Fresenius Citem 10 Monitor, with monitoring including the pH of plasma that is returned to the patient. Unlike single-use Prosorba, the two Protein A columns can be used repeatedly for the same patient up to 12 months from the date of manufacture. After a few treatments, the cost per liter of treated plasma is lower than with plasma exchange. While one column is adsorbing IgG, the other rinsed with a pH 2.2 eluant solution to remove adsorbed IgG and then restored to pH of 7.0 with a buffer solution. The treated plasma leaving the column is re-mixed with blood and returned to the patient. The process is performed on-line and continuous until the desired amount of plasma is processed.

[Recombinant E. coli-expressed Protein A and immunoaffinity chromatography matrices with bound recombinant Protein A are manufactured by RepliGen Corp. These are widely used for monoclonal antibody purification].

Nomenclature: Protein A/Prosorba [BIO]; Prosorba Column [TR; formerly reg. to Cypress, now to Fresenius]; Immunosorba Protein A Column [TR; reg. to Fresenius for hemophilia use]; Protein A blood filtration column [SY]; Protein A plasma affinity chromatography [SY]

Biological.: The mechanism(s) of action of the Prosorba Column and its immune stimulating effects have not been fully determined. Protein A filtration of blood results in partial removal of certain circulating immune complexes (CICs) and antibodies. CICs are thought to have a role in the pathogenesis of rheumatoid arthritis, idiopathic thrombogenic purpura (ITP), other autoimmune diseases, and certain cancers. Removal of CICs in patients with these diseases appears to lessen the severity of symptoms and increase immune functions. The column may have other immune modulatory effects, perhaps due to trace amounts of Protein A entering the blood, recon-figuration of proteins/antibodies as they attach/detach to Protein A, and/or other activities. Because the column becomes saturated after removal of only about 1 gm of IgG, its efficacy is not based on quantitative immunoglobulin depletion.

Prosorba Column treatment appears to reduce the population of small molecular weight CICs, which may interfere with antigen presentation to T-helper cells and blocking the formation of antibodies involved in immune clearance. CICs may also inhibit the formation of anti-idiotypic antibodies, which down-regulate autoantibody responses.

Companies.: Prosorba Column was originally developed and manufactured (including Protein A) IMRE Corp., now by Cypress Bioscience, Inc. The product was originally marketed by Baxter Biotech, Baxter Healthcare Corp., from Feb. 1994 to March 1997. It was then marketed by Cypress in the U.S. for several years. Fresenius HemoCare, Inc., a U.S. subsidiary of Fresenius AG, manufactures Prosorba, including Protein A (in former Cypress facilities in Redmond, WA). Medexus, Inc. markets Prosorba in Canada under license from Fresenius.

In Jan. 1999, Cypress granted Fresenius Hemotechnology, Inc., a U.S. subsidiary of Fresenius AG, exclusive marketing rights in U.S. (shared with Cypress), Europe, parts of Asia, and Latin America (and subject to certain conditions, Japan). Cypress accepted an $8 million payment to cover expected sales of Prosorba for an initial 7-year period, with the company receiving royalties on sales after Jan. 2006. After this date, Cypress and Fresenius would share profits 50/50 from international sales, and profits from U.S. sales would be shared 50/50 until revenue reaches a predetermined threshold, after which Cypress would receive 60% and Fresenius 40%. Fresenius HemoCare handles worldwide clinical development.

In Jan. 2001, after unexpected low sales, the 1999 agreement was renegotiated. Fresenius AG and its U.S. subsidiary, Fresenius HemoCare Inc., received exclusive worldwide distribution rights for rheumatoid arthritis. It was agreed that the $8.0 million upfront fee would still cover all sales in the initial seven-year period. Rather than receiving royalties on sales after Jan. 2006, Cypress will receive $1 million if sales during the first seven years exceed 35,000 units, $2 million if they exceed 50,000 units, and none if the sales are less than 35,000 units, with this one-time payment due Jan. 30, 2008.

Fresenius has a nationwide network of plasmapheresis centers and is a leading supplier of apheresis equipment and disposables. Fresenius provides equipment and performs Prosorba Column plasma filtration at its centers, along with associated nursing, management, and billing support.

Manufacture: Fresenius notes that their are some differences in the manufacture of the Prosorba Column (approved for ITP and RA) and the Immunosorba Protein A Column (humanitarian exemption use for hemophilia A and B). Prosorba Column manufacture includes sterilization, while Immunosorba is manufactured under aseptic conditions in a sterile environment.

FDA class: Medical device PMA

Approvals: Date = 19871200; PMA; first approval; Indication = for immune thrombocytopenic purpura (ITP)

Date = 19970417; Indication = consolidation of manufacturing at Cypress Bioscience, Redmond, WA

Date = 19990315; PMA supplement; Indication = use in the therapeutic reduction of the signs and symptoms of moderate to severe rheumatoid arthritis in adult patients with long standing disease who have failed or are intolerant of disease-modifying anti-rheumatic drugs (DMARDs).

Date = 19991217; PMA supplement; Indication = approval of Phase IV post-approval study protocols

Date 20010828; PMA supplement; Indication = elimination of a shaking step from the manufacturing process

Date = 20011226; PMA supplement; Indication = revised labeling with new post-market safety information regarding episodes of vasculitis in rheumatoid arthritis patients

Date = 20020515; PMA supplement; Indication = reduction in the time of the Protein A-silica reaction step in the manufacturing process and decrease in the amount of carbodiimide used in the process

Date = 20000401; Humanitarian Device Exemption (HDE); Indication = removal of inhibitors (antibodies) from patients with hemophilia A or B.

Date = 20030204; PMA supplement; Indication = extension of the expiration date from 12 months to 18 months.

Indications: [full text of “INTENDED USE/indications:” section of product insert/labeling, 4/2005]:

The PROSORBA Column is indicated for use in the therapeutic removal of immunoglobulin G (IgG) and IgG-containing circulating immune complexes from plasma in patients with idiopathic thrombocytopenic purpura (ITP) having platelet counts less than 100,000 mm3.

The PROSORBA Column is indicated for use in the therapeutic reduction of the signs and symptoms of moderate to severe rheumatoid arthritis in adult patients with long standing disease who have failed or are intolerant to disease-modifying anti-rheumatic drugs (DMARDS). (See Section 2)

Status: The Prosorba Column is regulated by FDA as a Class III medical device.

The Immunosorba Column has received Humanitarian Device Exemption (HDE) from the FDA for use in the treatment of patients with hemophilia A and B with Factor VIII or Factor IX inhibitor (antibody), respectively, titers ≥10 Bethesda units/ml (BU/ml). See the Factor VIII Products and Factor IX Products entries in the Blood Products, Human section for further information about Factor VIII inhibitors/antibodies, which can cause serious complications and/or interfere with Factor VIII used for treatment of hemophilia A, requiring use of increased amounts of Factor VIII to overcome antibody neutralization or use of even more expensive alternative plasma-derived or recombinant therapeutics. An HDE is an FDA medical device application similar in content to a premarket approval (PMA) application. The FDA reviews the preclinical and clinical data and determines the benefits of using the product outweigh the associated risks (when no alternatives are available). HDE applications are exempt from the effectiveness requirements of a PMA. HDE approval allows full commercial marketing of a Humanitarian Use Device (HUD), a device is intended to benefit patients with diseases or conditions that affect fewer than 4,000 individuals in the U.S. per year (essentially orphan indications:). There can be no comparable device already approved for a similar indication, and approval may be revoked when an equivalent device receives approval. Use of a HUD must be approved by the hospital’s Institutional Review Board (IRB) before it can be used in patients for its designated indication(s). However, the IRB need not review and approve individual cases.

No centralized EU approval has been granted.

Tech. transfer: U.S. patent 5,782,792, Jones, F.R., Snyder, H.W., and Balint, J.P., July 21, 1998, assigned to Cypress Bio-science, Inc., describes the preparation of Protein A immuno-adsorbent (Prosorba Column) and extracorporeal removal of IgG and IgG-containing circulating immune complexes from patients’ blood for treatment of rheumatoid arthritis. U.S. patent 5,733,254, “Method for treating patients suffering from immune thrombocytopenic purpura,” assigned to Cypress Bioscience, similarly describes Prosorba Column preparation and use for treatment of immune thrombo-cytopenic purpura (ITP).

U.S. patent 4,681,870, “Protein A-Silica Immuno-adsor-bent and Process for Its Production,” Balint, J.P. and Har-greaves, R.E., issued July 21, 1987, is assigned to IMRE Corp. (now Cypress Bioscience). The abstract states, “An immuno-adsorbent material for removing IgG and IgG-complexes from biological fluids is prepared by covalently binding protein A to a solid-phase silica matrix. It has been found that particularly stable, high-capacity immu-noadsorbents are obtained by derivatizing the silica with amino and/or carboxyl groups, and reacting the protein A with a carbodiimide at a pH in the range from 3.5 to 4.5. Binding through free hydroxyl groups may be achieved with cyanogen halides at a pH in the range from 11.0 to 11.5. After acid washing (pH 2.0-2.5) to remove non-cova-lently bound Protein A, the immuno-adsorbent may be employed in a column for therapeutic treatment of various cancers and autoimmune disorders where IgG-complexes are implicated as suppressing factors in inhibiting a normal immune response.”

Cypress Bioscience in July 1997 nonexclusively licensed patent properties from Dr. M. Strahilevitz concerning extracor-poreal blood filtration. Patents held by Dr. Strahi-levitz include U.S. 6,039,946, “Extracorporeal affinity adsorption devices;” U.S. 5,753,227, “Extracorporeal affinity adsorption methods for the treatment of atherosclerosis, cancer, degenerative and autoimmune diseases;” and U.S. 4,813,924, “Immunological methods for removing species from the blood circulatory system.” These concern blood filtration, but none of these or his other U.S. patents explicitly describe the Protein A-based CIC-removal system of the Prosorba Column. Dr. Strahilevitz received a license fee and receives undisclosed royalties through the life of his relevant patents.

Trials: The pivotal double-blinded sham-apheresis controlled Phase III trial supporting approval of the Prosorba column for rheumatoid arthritis (RA) enrolled 109 patients who were considered the most severely affected of the RA population, having suffered from the disease for an average of 15.5 years (range 1.7-50.6 years for the Prosorba patients), and having failed an average of 5 different disease-modifying anti-rheumatic drug (DMARD) regimens. Nearly half of the patients who completed all 12 Prosorba treatments showed significant clinical improvement by stringent American College of Rheumatology (ACR) criteria. The response was often durable, lasting up to 84 weeks in some patients. There was a statistically significant reduction in swollen and tender joint counts, as well as other improvements, and response was maintained in the absence of any other DMARD therapy during and after treatment.

For idiopathic thrombocytopenic purpura (ITP), retrospective case analyses suggest an overall response rate of 46% and further suggest that among responders, 80% had a durable response of one year.

Note, Repligen Corp. holds key patents and is the primary manufacturer of recombinant Protein A (which is not used in Prosorba).     

Medical: The Prosorba Column is used in conjunction with a plasmapheresis machine in a closed loop. There are four main steps in the use of the device: a) priming the column, b) separating the plasma, c) passing the plasma through the column, and, d) reinfusing the treated plasma back into the patient. Blood is drawn from a vein in the patient’s arm, passed through a plasmapheresis machine which separates the blood cells from plasma (liquid portion of blood), and the plasma is diverted and filtered through the Pro-sor-ba Column a rate of 10-20 mL/min. After passing through the column, the plasma is mixed with the removed blood cells and infused back into the patient through a vein in the other arm. The procedure takes about 2-2.5 hours. A variable amount of plasma may be processed, depending upon the clinical indication.

As little as 250 mL processed per apheresis treatment has been reported to be efficacious for refractory ITP, while most studies reporting the efficacy of for rheumatoid arthritis processed ~1,250 ± 250 mL of plasma per apheresis.

A course of treatment for rheumatoid arthritis (RA) involves a 2-hour procedure once a week for 12 weeks. The Prosorba column is used in conjunction with an apheresis machine, which separates the blood cells from the plasma (liquid portion of the blood). Most patients completing a full 12-week course generally do not require retreatment with Prosorba Column, unlike tumor necrosis factor antibody products which require chronic injections.

Adverse effects experienced by patients during column treatment vary somewhat with the underlying disease and the medications the patient is receiving. Most common adverse events reported in conjunction with treatment of ITP include hypertension, nausea/emesis, chills and/or fever, rash, arthralgias, diarrhea, and abdominal pain. The most common side effects reported in conjunction with RA treatment include joint pain (flare) involving the target joints, fatigue, hypertension, nausea, abdominal pain, flushing, and headache.

Disease: An estimated 250,000 patients in the U.S. with rheumatoid arthritis (RA) have failed treatment of disease-modifying anti-rheumatic drugs (DMARDs), and may be candidates for Prosorba treatment. A survey of Prosorba-treated patients has confirmed the efficacy of the Prosorba column in RA patients who have failed multiple drugs, including newer tumor necrosis factor (TNF) blockers, e.g., Enbrel, Remicade and Humira. The Prosorba Column is particularly suited for the most severe patients, e.g., those with disease for over 10 years and having failed all combinations of DMARDs. This includes perhaps 25% or more of the 2-3 million patients in the U.S. with severe RA.

Market: The Average Wholesale Price (AWP) is not available (product not in 2007, 2005 or 2004 Red Book). The Average Wholesale Price (AWP) in 2002 was $1,090.00/column direct from Fresenius.

The cost has been commonly reported as ~$1,500-$1,800/Prosorba Column. Cypress had planned price reductions after approval for rheumatoid arthritis, expecting greatly improved economies of scale (but significant sales increases did not happen).

Sales of Prosorba were much less than planned by IMRE/Cypress, and probably have remained relatively low (particularly in comparison with other RA therapeutics) since Fresenius assumed the product. Sales related to rheumatoid arthritis have increased, while sales for the ITP indication have declined. For example, sales were $3.0 million in 3rd quarter 2000, $2.3 million in the 2nd quarter, and $1.3 million in the 1st quarter. Of the $3.0 million Prosorba column sales in the third quarter, ~$2.9 million (~97%) were purchased for RA.

In June 2000, Fresenius launched a program that enables rheumatologists to offer the Prosorba Column in their office. However, most sales and use of Prosorba occur within hospital or community blood banks or apheresis centers, particularly those owned by Fresenius.