BIOPHARMA: Biopharmaceutical Products in the U.S. Market
Sample Product Monograph
Antihemophilic factor B
Cross ref: See the entries for recombinant and plasma-derived Factor IX products. See also the Factor VIII Products (#441) entry for information about the mechanism of blood clotting.
Description: Factor IX (FIX; Antihemophilic Factor B) is one of over a dozen factors (proteins) in the blood that help blood form clots and stop bleeding from wounds. Factor IX is a vitamin K-dependent clotting factor synthesized in the liver and required for adequate, normal blood clotting. The molecular weight of human Factor IX protein ranges from 55,000 to 71,000 Daltons (55-71 kDa).
There are two major classes of Factor IX products
1) Factor IX Complex (prothrombin complex concentrate; PCC), a plasma-derived mixture of Factor IX and other clotting factors and proteins; and
2) Coagulation Factor IX, containing more highly purified Factor IX protein (either recombinant or plasma-derived).
Coagulation Factor IX products in the U.S. market include one recombinant and three plasma-derived products:
a) Coagulation Factor IX (Recombinant) or BeneFIX from Genetics Institute/Wyeth (#119);
b) Coagulation Factor IX (Human) Solvent Detergent Treated/Virus Filtered or AlphaNine SD from Alpha Therapeutic Corp. (#460);
c) Coagulation Factor IX (Human) or Mononine from Aventis Behring L.L.C. (#459); and
d) Coagulation Factor IX (Human) or Profilnine SD from Alpha Therapeutic Corp. (#457)
Factor IX Complex products in the U.S. market are:
a) Factor IX Complex or Konyne 80 from Bayer Corp. (#458);
b) Factor IX Complex or Proplex T or from Baxter Hyland Immuno (#462); and
c) Factor IX Complex, Vapor Heated or Bebulin VH Immuno from Baxter Hyland Immuno (#461).
Factor IX Complex (prothrombin complex concentrate or PCC) refers to lyophilized (freeze-dried) products derived from pooled human plasma and containing potentially clinically useful quantities of other vitamin K-dependent clotting Factors II, VII, and X, in addition to Factor IX. Factor IX Complex products also may contain other proteins, including Protein C and Protein S; high molecular weight kininogen; and small quantities of activated clotting factors II, VII, IX, or X. Factor IX Complex may be used for treatment of hemophilia B (Factor IX deficiency) and for even rarer deficiencies of Factors VII and X. It is sometimes useful for treatment of hemophilia A (Factor VIII deficiency) in patients with Factor VIII inhibitors (antibodies). The clotting factors present in the Factor IX Complex are believed to bypass the Factor VIII inhibitors and directly activate Factor X.
Coagulation Factor IX refers to substantially pure Factor IX, either plasma-derived or recombinant, purified of extraneous plasma proteins (e.g., Factors II, VII, and X). Purification may be performed using affinity chromatography and/or immu-no-af-finity chromatography with monoclonal antibodies to Factor IX.
Factor IX Complex is often manufactured from eluate fluid removed after cryoprecipitation (freezing and thawing of plasma) subjected to ion exchange chromatography, e.g., diethyl-amin-oethyl (DEAE) Separose, while Coagulation Factor IX undergoes further purification steps, e.g., immunoaffinity purification. Some of the indications for Factor IX formulations vary among the different products because of differences in composition and whether or not clinical trials for specific indications have been conducted for specific indications.
In patients with hemophilia B, the administration of Coagulation Factor IX or Factor IX Complex products provides an increase in plasma levels of Factor IX and/or Factor VII (with Factor IX Complex), temporarily correcting the coagulation defect of patients with deficiencies in these factors. Plasma levels of Factor II (prothrombin) and Factor X (Stuart-Prower factor) may also be increased by administration of Factor IX Complex products. The in vivo half-life of Factor IX administered to Factor IX deficient patients ranges from 24-36 hours.
One International Unit (IU; unit) of Factor IX is defined by the World Health Organization (WHO) standard as equal to the level of Factor IX found in 1.0 mL of fresh, normal plasma. Generally, one IU of Factor IX activity/kg will increase the plasma level of Factor IX by 0.8%. Formulas for dosage calculations are included in the product insert/labeling. Factor IX has a theoretical maximum specific activity of 250 units/mg of protein.
Nomenclature: Coagulation Factor IX [FDA]; Factor IX Complex [FDA]; Factor IX [SY]; Antihemophilic factor B [SY]; prothrombin complex concentrate [SY]; Christmas factor [SY]; PCC [SY]; FIX [SY]
The term Factor IX (much like Factor VIII) is often used imprecisely or ambiguously to refer to the Factor IX protein (active ingredient) and/or one or both types of marketed Factor IX products Ð Coagulation Factor IX and Factor IX Complex. Other commonly used names for Factor IX protein/products are Christmas factor, plasma thromboplastin component (PTC), and prothrombin complex concentrate (PCC).
Biological: Factor VII (proconvertin) is part of the extrinsic pathway of blood coagulation/clotting. Factor IX is activated by Factor VII/tissue factor complex in the extrinsic coagulation pathway as well as by Factor XIa in the intrinsic coagulation pathway. Activated Factor IX, in combination with activated Factor VIII, activates factor X, which reacts with activated Factor VIII, resulting ultimately in the conversion of prothrombin to thrombin. Thrombin then converts fibrinogen to fibrin (the major structural/fibrous component of blood clots), and a clot can be formed. The administration of the Factor VII present in Factor IX Complex replaces deficiency of this clotting factor, and assists in correcting and preventing bleeding episodes. See the Factor VIII Products entry (#441) for further discussion of blood clotting mechanisms.
History: Manufacture of Factor IX from blood plasma is based on the discovery by Pool, et al., in the 1960s that removal after remova; of cryoprecipitate (Factor VIII and other precipitated clotting factors) after cold-ethanol (e.g. Cohn-Oncley) fractionation, most of the Factor IX remains in the supernatant fluid. The resulting product is crude prothrombin complex concentrate (PCC) containing Factor IX along with other vitamin K-dependent coagulation factors (Factors II, VII and X) and Proteins C and S. Administration of PCC containing these other proteins along with Factor IX is associated with abnormal clotting or thrombogenicity in hemophilia B patients, particularly at high doses, including disseminated intravascular coagulation (DIC) and thromboembolism.
The earliest approved Factor IX Complex product is from Cutter Labs., now Bayer Corp., approved Dec. 31, 1968. The earliest approved Coagulation Factor IX product is from Alpha Therapeutic Corp., approved Dec. 31, 1990. Centeon LLC, now Aventis Behring LLC, formerly manufactured a Factor IX Complex product (approved Feb. 21, 1984; revoked April 1, 1993).
Due to adverse events with PCC, in 1974 the Factor IX Task Force of the International Society on Thrombosis and Hemostasis (ISTH) recommended that 5-10 U of heparin be added to each mL of reconstituted Factor IX Complex/PCC prior to use. However, this did not resolve PCC-associated thrombogenic events. More extensive purification, e.g., additional modern chromatography and/or immunoaffinity purification for manufacture of Coagulation Factor IX, has been adopted to substantially remove extraneous proteins and reduce associated adverse effects.
In patients with hemophilia B (Factor IX deficiency), the administration of Coagulation Factor IX or Factor IX Complex provides an increase in plasma levels of Factor VII (proconvertin) and Factor IX (Antihemophilic factor B), temporarily correcting the coagulation defects in these patients with deficiencies of one or both of these factors. Plasma levels of Factor II (prothrombin) and Factor X (Stuart-Prower factor) are also increased by administration of Factor IX Complex products.
Tech. Transfer: See the Coagulation Factor IX (Recombinant) or BeneFIX entry (#119) for information concerning recombinant Factor IX patents. See the entries below for plasma-derived Factor IX product-related patent information.
Disease: Hemophilia B is a hemorrhagic disorder resulting from a deficiency of functional Factor IX. Hemophilia B is primarily a hereditary (genetic) disease resulting from on or more mutations of the Factor IX gene that reduce the expression and/or functionality of Factor IX protein. The disease-associated mutations are located on the X chromosome and, thus, the disease is sex-linked and occurs almost exclusively in males. Males have only a single X chromosome, and a defect in the Factor IX gene can result in symptoms of hemophilia B. Females may have a defective copy of the Factor IX gene on one of their two X chromosomes and still produce sufficient functional Factor IX to permit normal blood clotting. However, these women are carriers of the defective gene and may pass symptomatic hemophilia B on to their sons and the carrier status on to their daughters.
The disease varies in severity according to the functional Factor IX activity that remains in the patient's blood. Patients with below 1% of normal Factor IX activity are considered to have severe disease, patients with 1%-5% of normal Factor IX activity have moderate disease, and those with Factor IX activity over 5% are considered to have mild disease.
Hemophilia B affects about only about 7,000 people in developed countries (N. America, Europe and Japan), including approximately 3,300 patients in the U.S. Thus, Factor IX and other products for hemophilia B indications easily qualify for orphan status. Hemophilia B occurs in 1 of 25,000-30,000 male births, and accounts for approximately 20% of all patients with hemophilia.
The consequences of hemophilia B, especially in patients with severe disease, can be quite serious. Individuals with severe hemophilia B often have spontaneous internal bleeding, particularly in their muscles and joints (hemarthrosis) that may lead to joint destruction. Frequent hemorrhages can be crippling and life-threatening. Control of bleeding episodes and bleeding that might occur during surgery is critically important for patients with hemophilia B. Factor IX activity-neutralizing antibodies (inhibitors) have been detected in patients receiving Factor IX-containing products, and patients should be monitored for the development of Factor IX inhibitors. Besides reducing the activity of the product (requiring increased dosage), inhibitors may increase the risk of anaphylaxis upon subsequent administration of (challenge with) Factor IX.
Medical: The amount and frequency of required Factor IX infusions vary with each patient and clinical situation. For example, for minor hemorrhages or routine prophylaxis, circulating levels of Factor IX are generally brought up to 15-25% (0.15-0.25 IU/ml) of the normal level. For major trauma or for patients undergoing surgery the circulating level is generally brought up to the 25-50% level, which may require up to 75 units of Factor IX/kg body weight. For minor hemorrhages, the dosage may be repeated in 24 hours. For major trauma or surgery the dosage may be repeated for ten days or longer. The half-life of Factor IX in Factor IX Complex administered to Factor IX deficient patients is 24 to 36 hours. The half-life of Factor VII in Factor IX Complex administered to Factor VII deficient patients is 3 to 6 hours. Severe hemophilia B patients require regular, often high and rather expensive, doses of Factor IX products to maintain hemostasis. If inhibitors (antibodies) to Factor IX are present, additional dosage to overcome the inhibitors is needed.
As a general rule, administration of 1 unit of Factor IX activity per kg body weight can be expected to increase the circulating level of Factor IX by about 1% of normal. For maintenance of an elevated level of the deficient factor, doses are repeated as often as needed. Factor IX is generally infused slowly, e.g., at a rate of approximately 2-3 mL per minute. Clinical studies suggest that relatively high levels of Factor IX may be maintained by daily or twice-daily doses, while lower effective levels may require injections only once every two or three days. A single dose may be sufficient to stop a minor bleeding episode.
The following formula provides a general guide for dose calculations: number of Factor IX I.U. required = body weight (kg) x desired Factor IX increase (% normal) x 1.0 IU/kg. The amount and frequency of Factor IX infusions vary with each patient and clinical situation. Dosage depends on the degree of deficiency and the desired hemostatic level of the deficient factor, along with the condition of patient and his degree of deficiency.
Market: The current market for blood-derived Factor IX clotting products is reported to be approximately $150 million worldwide, with the U.S. representing nearly or about one-half of this. Using this number and presuming all of the estimated 7,000 hemophilia B patients in developed countries worldwide are under treatment, the average cost per treated patient is about $21,400 annually.
Other Factor IX products not included in this pubilcation are available internationally. For example, Nonafact manufactured by the CLB, Products Division (Amsterdam, the Netherlands), a subsidiary of Stichting Sanquin Bloedvorziening (Sanquin), is a plasma-derived lyophilized Factor IX product marketed in the European Union. Manufacture includes purification by anion exchange chromatography and immunoaffinity chromatography using monoclonal antibody CDB-FIX D4 coupled to Sepharose.
Cross ref: See the entry for recombinant Factor IX (BeneFIX) (#119) in the Recombinant DNA Products section.
Coagulation Factor IX (Human) Solvent Detergent Treated/Virus Filtered - AlphaNine SD
Status: approved; marketed
Organizations Involved:
Cross ref: See the Factor IX Products entry (#455).
Description: Coagulation Factor IX (Human) Solvent Detergent Treated/Virus Filtered or AlphaNine SD is a lyophilized (freeze-dried) formulation of purified Factor IX prepared from cold ethanol fractionated Plasma (Human). Manufacturing includes ion exchange chromatography (DEAE cellulose), dual affinity chromatography, virus inactivation using the solvent detergent [tri-n-butyl phosphate (TNBP) and polysorbate 80] and heat (pasteurization) methods, and virus removal by nanofiltration. The final reconstituted product contains a minimum of 150 IU Factor IX per mg of protein (generally 230 IU/mg).
AlphaNine SD is supplied as a sterile lyophilized powder in single use vials along with 10 mL Sterile Water for Injection, USP (10 ml) for reconstitution prior to intravenous injection, along with a double-ended needle and microaggregate filter for use in administration. Each vial of AlphaNine SD is labeled with the number of plasma equivalents of Factor IX/vial, expressed in International Units (IU) referenced to the WHO International Standard. One plasma equivalent is defined as the activity contained in one mL of normal plasma. AlphaNine SD also contains not more than 0.04 unit heparin, 1 mg dextrose, 2.5 µg polysorbate 80 (Tween 80) and 0.25 µg tri(n-butyl)phosphate (TNBP) per IU of Factor IX. AlphaNine SD should be stored at 2-8ûC (refrigerated) and has a shelf life of 12 months. The date of manufacture is defined as the date of the first sterile filtration of the bulk. Levels of Factor VII (proconvertin), Factor II prothrombin) and Factor X (Stuart-Prower Factor) in the product are below the limit of detection (less than 0.04 Factor VII unit, less than 0.05 Factor II unit, and less than 0.05 Factor X unit per IU Factor IX).
First generation AlphaNine manufacturing included a wet heptane/heat treatment step for viral inactivation and ion exchange chromatography, and provided product with a specific activity of 80-120 units/mg of protein. Factor IX has a theoretical maximum specific activity of 250 units/mg of protein. Second generation AlphaNine introduced a further dual affinity chromatography step, resulting in a product with a specific activity of 200 units/mg protein. The current AlphaNine purification process, including dual affinity chromatography and nanofiltration, achieves a specific activity of 230 units/mg of protein.
Solvent detergent viral inactivation eliminates over 12 log of HIV-1; 6 log of HIV-2; over 4.9 log of vesicular stomatitis virus (VSV); and over 5.3 log of Sindbis virus. The ion exchange and dual affinity chromatography steps, respectively, eliminate an additional 1.4 and 4.7 logs of Sindbis virus (a total of 11.4 log). Nanofiltration removes additional viruses, including parvovirus, hepatitis A virus (HAV), some nonenveloped viruses, and particulates larger than 15 nm in diameter.
Nomenclature: Factor IX SD [BIO]; AlphaNine SD [TR]; Coagulation Factor IX (Human) Solvent Detergent Treated/Virus Filtered [FDA]; 9001-28-9 [CAS RN]; Antihemophilic factor B [SY]; Factor IX [SY]; Christmas factor [SY]; Blood coagulation factor IX [SY EINECS]; NDC 49669-3600-2 [NDC]
Manufacture: AlphaNine SD is manufactured from pooled human blood plasma [Plasma (Human)] from which cryoprecipitate (Factor VIII) has been removed. This cryoprecipitate-poor plasma is fractionated (Cohn cold ethanol process), and Factor IX is isolated using diethylaminoethyl (DEAE) cellulose ion-exchange chromatography (probably DEAE Sepharose from Amersham Pharmacia Biotech or similar matrix). The eluate is treated using the solvent detergent process, involving addition of low levels of tri(n-butyl)phosphate (TNBP) and polysorbate 80 (Tween 80), for viral inactivaton. The product is incubated with the solvent detergent mixture for six hours at 27 ± 3ûC. The Factor IX protein is then precipitated with barium citrate and further purified by two sequential affinity chromatography steps utilizing an unspecified polysaccharide as the ligand. This further reduces residual amounts of Factor X and increases purity. The product is filtered (nanofiltered) through a 15 nanometer filtration membrane to remove viruses (both enveloped and nonenveloped viruses, including parvovirus B19 and hepatitis A virus). Vials are filled and the product is lyophilized (freeze-dried), sealed, labeled, and packaged. As a result of adding the nanofiltration step to the dual chromatography and other partitioning steps, the final product has a specific activity averaging 229 (± l23) units of factor IX per mg of protein (based on a theoretical maximum of 250 units/mg).
Studies involving production lots spiked with virus prior to the solvent detergent process have shown that this and subsequent manufacturing steps reduce HIV-1 by at least 12.2 log (i.e., 1012.2); HIV-2 by at least 6.00 log; Sindbis virus (a model for hepatitis C virus) by at least 5.30 log; and vesicular stomatitis virus (VSV) by at least 4.90 log. The ion exchange (DEAE Sepharose) chromatography step has been shown to reduce the concentration of Sindbis virus by 1.41 log; and the two sequential affinity chromatography steps reduce viral concentration by 4.70 log. Altogether, independent of the solvent detergent, heat treatment, and nanofiltration processes, the purification steps used are capable of reducing virus concentrations by about 6 log. Note, viral reduction (inactivation) of AlphaNine (the 1st generation product) was achieved by a wet solvent heating method, involving maintaining the product in n-heptane suspension at 60ûC for 20 hours.
FDA class: Biologic PLA
CBER class: Blood And Blood Derivatives
Approvals: Date = unknown; approval date for Coagulation Factor IX (Human) manufactured by the Abbott Labs. [product no longer in current CBER/FDA listings]
Date = 19780815; Licenses for the Abbott Labs., S. Pasadena, CA, manufacturing facilities and products transferred to a new owner, Alpha Therapeutic
Date = 19841029; PLA supplement 84-069; addition of wet heat treatment/solvent viral inactivation [61ûC, 20 hr. in heptane]
Date = 19901231, PLA; first approval for the solvent detergent inactivated product (AlphaNine SD); orphan designation (granted 07/05/1990; expired 12/31/1997); Note, this is the first approval reported in the CBER/FDA BRMS database and other FDA sources for Coagulation Factor IX (Human) from Alpha Therapeutic Corp.
Date = 19920826; PLA supplement ref. no. 91-0350; Indication = amendment regarding solvent/detergent processing
Indications: [full text of the "INDICATIONS AND USAGE" section of product insert/labeling]:
AlphaNine SD is indicated for the prevention and control of bleeding in patients with Factor IX deficiency due to hemophilia B. AlphaNine SD contains low, non-therapeutic levels of Factors II, VII, and X, and, therefore, is not indicated for the treatment of Factor II, VII or X deficiencies. This product is also not indicated for the reversal of coumarin anticoagulant-induced hemorrhage, nor in the treatment of hemophilia A patients with inhibitors to Factor VIII.
Status: See the Regulatory section of the entry for Factor IX VH (Bebulin VH) (#461) for information about an FDA ruling involving a later, comparable product that was eventually ruled superior to AlphaNine (at the time), granted Orphan designation, and allowed to enter the market.
Tech. transfer: Solvent detergent viral inactivation technology was developed by and nonexclusively licensed from the New York Blood Center. For example, see U.S. patent 4,820,805. See the entry for Pooled Plasma, Solvent Detergent Treated (SD Plasma) (#512) for further information about solvent detergent viral inactivation, used primarily for inactivation of enveloped viruses (e.g., HIV, hepatitis B and C viruses).
Market: Alpha Therapeutic has reported that in clinical trials in patients undergoing surgery, the amount used ranged from 3,295 to 52,200 IU, costing $3,460 to $54,810 (at rate of $1.05/IU). The total units used per subject (mean) was 28,512 IU costing $29,938. For knee surgery, the mean used was 29,983 IU, for hernia repair was 30,720 IU, and for dental surgery was 5,703 IU. The Average Wholesale Price (AWP) was $1.10/IU in 2002, with Medicare reimbursement for inpatient and home care at $1.12/IU and outpatient at $0.51/IU, and Estimated Acquisition Costs (for hospitals, treatment centers) of $0.65/IU (NHF survey).
Alpha reports that over 150 million IU of AlphaNine have been infused without any undesired adverse events.